DRAFT EPA/100/ J

- 11/001

DO NOT CITE OR QUOTE External Review Draft

Ma y 2011



## Guidance for Applying Quantitative Data

t o Develop Data

- Der iv ed Extrapolation Factors for

Inter species and Intra s pecies Extrapolation

NOTICE

THIS DOCUMENT IS A N EXTERNAL REVIEW DRAFT. It has not been formally released
by the U.S. Environmental Protection Agency and should not at this stage be construed to
represent Agency policy. It is being circulated for comment on its technical accuracy and policy
impl ications.

Office of the Science Advisor

Risk Assessment F orum U.S. Environmental Protection Agency
Washington, DC 20460This document is a draft for review purposes only and does not constitute Agency policy.

5/11/11 DRAFT: DO NOT CITE OR QUOTE ii DISCLAIMER

This document is distributed solely for the purpose of predissemination peer review under

applicable information quali ty guidelines. It has not been formally disseminated by EPA. It

does not represent and should not be construed to represent any Agency determination or policy.

Mention of trade names or commercial products does not constitute endorsement or

recommendati on for use.

ABSTRACT

This document describes the U.S. EPA’s approach for developing quantitative factors for

extrapolating effect levels from animals to humans and to address human variability. These

extrapolations have been covered by the uncertainty factors UF A and UF H , respectively. In the

absence of quantitatively

- valuable data, default values for these uncertainty factor values may be

applied. However, informative data that describe variability in chemical distribution

(toxicokinetics, TK) and d ose

- response (toxicodynamics, TD) should be first considered. This

document describes the separation of UF A and UF H into TK and TD components and describes

the process for identifying pertinent data useful for quantifying inter

- and intraspecies differenc es

to serve as the basis for nondefault, data

- derived extrapolation factors (DDEF s ). Key

considerations include identifying a tissue concentration associated with a given response level,

and identifying and measuring a biological response associated with the corresponding toxicity.

Interspecies TK variability is quantified on the basis of doses or concentrations that produce the

same tissue concentration in animals and humans; intraspecies TK variability is defined as

differences in tissue concentration a ttained from the same human exposure; TD variability is

defined on the basis of doses or concentrations that produce the same response. This approach is

consistent with the approach for deriving reference concentration (RfC) values; it represents a

point in the continuum of approaches that includes default approaches, categorical default values

(e.g., body

- weight scaling), and integrated biologically based dose

- response models.This document is a draft for review purposes only and does not constitute Agency policy.

5/11/11 DRAFT: DO NOT CITE OR QUOTE iii CONTENTS

LIST OF TA BLES

................................ ................................ ................................ .......................... v

LIST OF FIGURES

................................ ................................ ................................ ........................ v

LIST OF ABBREVIATIONS

................................ ................................ ................................ ........ vi

PREFACE

................................ ................................ ................................ ................................ .... viii

AUTHORS, CONTRIBUTORS AND REVIEWERS

................................ ................................ .. ix

1. INTRODUCTION

................................ ................................ ................................ ..................... 1

1.1. BACKGROUND

................................ ................................ ................................ ............... 1

1.2. PURPOSE AND SCOPE

................................ ................................ ................................ ... 2

2. TECHNICAL CONCEPTS AND PRINCIPLES FOR DDEF

................................ .................. 5

2.1. B ACKGROUND

................................ ................................ ................................ ............... 5

2.2. EXTRAPOLATION WITH DDEFs

................................ ................................ .................. 7

2.2.1. Approaches to Deriving DDEFs

................................ ................................ ............. 7

2.2.1.1. TK and TD Models

................................ ................................ .................. 8

2.2.1.2. Use of Ratios to Calculate DDEF

................................ .......................... 10

2.2.2. Qualitative Considerations

................................ ................................ .................... 13

2.2.3. Information Quality

................................ ................................ .............................. 13

2.2.4. Additional Considerations

................................ ................................ .................... 14

2.2.4.1. Mode of Action

................................ ................................ ...................... 14

2.2.4.2. Use of In Vitro Data

................................ ................................ .............. 15

2.2.4.3. Uncertainty and Variability

................................ ................................ ... 16

2.2.4.4. Multiple Critical Effects

................................ ................................ ........ 17

2.2.4.5. Screening Level vs. Refined Risk Assessments

................................ .... 17

3. DDEFs BASED ON TOXICOKINETICS ( TK)

................................ ................................ ..... 18

3.1. GENERAL CONSIDERATIONS

................................ ................................ ................... 18

3.1.1. Dose Metric

................................ ................................ ................................ ........... 19

3.1.2. Dose S election

................................ ................................ ................................ ...... 22

3.1.3. In Vitro Data

................................ ................................ ................................ ......... 22

3.2. INTERSPECIES TOXICOKINETIC EXTRAPOLATION (EF AK )

............................... 23

3.2.1. Considerations for EF AK

................................ ................................ ....................... 23

3.2.2. Computation

................................ ................................ ................................ .......... 25

3.2.2.1. Use of TK Models

................................ ................................ ................. 25

3.2.2.2. Use of Ratios

................................ ................................ ......................... 25

3.2.3. Relationship to Other EPA Guidance

................................ ................................ ... 27

3.2.4. Conclusions for EF AK

................................ ................................ ........................... 28

3.3. INTRASPECIES TOXICOKINETIC EXTRAPOLATION (EF HK )

............................... 29

3.3.1. Considerations for EF HK

................................ ................................ ....................... 29

3.3.1.1. Susceptible Groups or Individuals

................................ ......................... 29

3.3.1.2. Target Tissues

................................ ................................ ........................ 31

3.3.1.3. Dose Response

................................ ................................ ....................... 31This document is a draft for review purposes only and does not constitute Agency policy.

5/11/11 DRAFT: DO NOT CITE OR QUOTE iv CONTENTS (continued)

3.3.2. Computation

................................ ................................ ................................ .......... 3 2

3.3.2.1. Use of TK Models

................................ ................................ ................. 32

3.3.2.2. Use of Ra tios

................................ ................................ ......................... 32

3.3.3. Conclusions for EF HK

................................ ................................ ........................... 33

4. DDEFs BASED ON TOXICODYNAMICS (TD)

................................ ................................ .. 34

4.1. GENERAL CONSIDERATIONS

................................ ................................ ................... 34

4.1.1. Mode of Action

................................ ................................ ................................ ..... 35

4.1.2. Relating Response to Dose or Concentration

................................ ....................... 35

4.1.3. Range of Doses or Concentrations

................................ ................................ ........ 36

4.2. INTERSPECIES TOXICODYNAMIC EXTRAPOLATION (EF AD )

............................ 36

4.2.1. Considerations for EF AD

................................ ................................ ....................... 37

4.2.1.1. Mode of Action

................................ ................................ ...................... 37

4.2.1.2. Target Tissues

................................ ................................ ........................ 37

4.2.1.3. Dose Response

................................ ................................ ....................... 38

4.2.1.4. In Vitro Data

................................ ................................ .......................... 38

4.2.2. Computation

................................ ................................ ................................ .......... 39

4.2.2.1. Use of TD Models

................................ ................................ ................. 39

4.2.2.2. Use of Ratios

................................ ................................ ......................... 39

4.2.3. Conclusions for EF AD

................................ ................................ ........................... 40

4.3. INTRASPECIES TOXICODYNAMIC EXTRAPOLATION (EF HD )

............................ 40

4.3.1. Considerations for EF HD

................................ ................................ ....................... 41

4.3.1. 1. Susceptible Groups or Individuals

................................ ......................... 41

4.3.1.2. Target Tissues

................................ ................................ ........................ 41

4.3.1.3. In Vitro Data

................................ ................................ .......................... 41

4.3.2. Computation

................................ ................................ ................................ .......... 42

4.3.2.1. Use of TD Models

................................ ................................ ................. 42

4.3.2.2. Use of Ratios

................................ ................................ ......................... 42

4.3.3. Conclusions for EF HD

................................ ................................ ........................... 44

5. FINAL STEPS

................................ ................................ ................................ ......................... 46

6. REFERENCES

................................ ................................ ................................ ........................ 47

APPENDIX: CASE STUDIES TO ACCOMPANY DATA

- DERIVED

EXTRAP O LATION FACTOR DOCUMENT

................................ .................... A

- 1This document is a draft for review purposes only and does not constitute Agency policy.

5/11/11 DRAFT: DO NOT CITE OR QUOTE v LIST OF TABLES

Table 1. Example equations used to derive DDEFs

................................ ................................ .... 11

LIST OF FIGURES

Figure 1. Derivation of RfDs/RfCs using uncertainty factors.

................................ ...................... 6

Figure 2. Decision process for DDEFs

................................ ................................ .......................... 9

Figure 3. Interspecies toxicokinetics

................................ ................................ ............................ 24

Figure 4. Interspecies extrapolation based on AUC

................................ ................................ .... 27

Figure 5. Intraspecie s toxicokinetics

................................ ................................ ............................ 30

Figure 6. Interspecies toxicodynamics

................................ ................................ ......................... 37

Figure 7. Intraspecies toxicodynamics

................................ ................................ ......................... 43This document is a draft for review purposes only and does not constitute Agency policy.

5/11/11 DRAFT: DO NOT CITE OR QUOTE vi LIST OF ABBREVIATION S

ADME absorption, distribution, metabolism, elimination ; toxicokinetics

AUC are a under the curve

AUC

sens area under the curve at a percentile of interest in the sensitive human population

AUC A are a under the curve in the animal

A UC gen are a under the curve at a measure of central tendency in the general human

population

AWQCD Ambient Water Quality Criterion document

BBDR biologically based dose response

BMD benchmark dose

BMD 10 benchmark dose corresponding to a 10% increase in response

BMDL lower 95% confidence limit of the benchmark dose

BMDL 05 benchmark dose corresponding to a 5% increase in response

Cl clearance

Cl int intrinsic clearance

C

max maximum c oncentration

CSAF s chemical

- specific adjustment factors

CYP cytochrom e P450

DDEF s data

- derived extrapolation factors

ED 10 effective dose producing a 10% response rate

EGBE ethylene glycol monobutyl ether

HED human equivalent dose

ILSI International Life Sciences Institute

IPCS International Programme on Chemical Safety

IRIS Integrated Risk Information System

K

m Michaelis constant , substrate concentration at rate of 1/2 V

max LOAEL lowest

- observed

- adverse

- effect level

MOA mode of action

NOAEL no

- observed

- adverse

- effect level

NRC National Research Council

PBPK physiol ogicall y

- based pharmacokinetic

POD point of departure

RfC referenc e concentration

RfD reference dose

TD toxicodynamics

TK toxicokinetics

U.S. EPA U.S. Environmental Protection Agency

UF uncertainty f actor

UF A interspecies uncertainty factor

EF AD to xicodynamic c omponent of interspecies extrapolation factor

EF AK toxicokinetic c omponent of interspecies extrapolation factor

UF H intraspecies uncertainty factorThis document is a draft for review purposes only and does not constitute Agency policy.

5/11/11 DRAFT: DO NOT CITE OR QUOTE vii LIST OF ABBREVIATIONS (continued)

EF HD toxicodynamic component of intraspecies extrapolati on factor

EF HK toxicokinetic component of intraspecies extrapolation factor

V

max theoretical maximal initial velocity

WHO World Health OrganizationThis document is a draft for review purposes only and does not constitute Agency policy.

5/11/11 DRAFT: DO NOT CITE OR QUOTE viii PREFACE

This guidance document is intended to help U.S. Environmental Protection Agency

(EPA) risk ass essors take a data

- based approach to nonlinear low

- dose extrapolation. It

describes data recommendations and methods or procedures to calculate data

- derived

extrapolation factors (DDEF s ) for chemicals for inter

- and intraspecies extrapolation. While

serv ing the same purpose as uncertainty factors, these extrapolation factors are based on data

directly pertinient to the chemical of interst, rather than having their basis on default assumptions

about inter

- and intra

- species variability. EPA’s 2005 Guideli nes for Carcinogen Risk

Assessment (or ― Cancer Guidelines ‖) (U.S. EPA, 2005) describes the EPA’s current practice of

examining all relevant and available data first when performing a risk assessment. When

chemical

— and/or

— site

- specific data are unavailable or insufficient, the EPA uses default

assumptions or processes in order to continue with the risk assessment. Under this practice

, EPA

guidance suggests invoking defaults only after the data are determined not to be usable at a

particular point in the as sessment. Both the Cancer Guidelines and the EPA document, An

Examination of EPA Risk Assessment Principles and Practices: a Staff Paper (U.S. EPA, 2004),

note that this is a shift in paradigm from the older practice of assuming that default values or

pro cesses will be used unless there are sufficient data to warrant a departure from the default.

Neither document describes specific approaches to using data rather than default uncertainty

factors in low

- dose extrapolation. This document, Guidance for Appl ying Quantitative Data to

Develop Data

- Derived Extrapolation Factors for Interspecies and Intraspecies Extrapolation

,
describes those approaches and processes

.

The members of the Risk Assessment Forum Technical Panel on Data

- Derived

Extrapolation Factors emphasize that the information offered here is neither a checklist nor a set

of requirements that must be met in order to perform inter

- and intraspecies dose extrapolation.

It presents guidance and codi f ies many of the best practices available when evalu ating data for

the purpose of inter

- and intraspecies extrapolation factor development. This will contribute to

consistency in the EPA processes and decisions.This document is a draft for review purposes only and does not constitute Agency policy.

5/11/11 DRAFT: DO NOT CITE OR QUOTE ix AUTHORS, CONTRIBUTOR S

, AND REVIEWERS

AUTHORS
John Lipscomb, Co

- Lead, U.S. Environmental Protec tion Agency, Office of Research and
Development , Cincinnati, OH 45268

Anna Lowit, Co

- Lead, U.S. Environmental Protection Agency, Office of Pesticide Programs

, Arlington, VA 22202

Brenda Foos, U.S. Environmental Protection Agency, Office of Children ’ s Healt h Protection

, Washington, DC 20460
Audrey Galizia, U.S. Environmental Protection Agency, Office of Research and Development

, Edison, NJ 08837
Elaina Kenyon, U.S. Environmental Protection Agency, Office of Research and Development

, RTP, NC 27709
Ginger Mose r, U.S. Environmental Protection Agency, Office of Research and Development

, RTP, NC 27709
Rita Schoeny, U.S. Environmental Protection Agency, Office of Water , Washington, DC 20460

CONTRIBUTORS
Rory Conolly, U.S. Environmental Protection Agency, Office o f Research and Development

, RTP, NC 27709
Deirdre Murphy, U.S. Environmental Protection Agency, Office of Air and Radiation , RTP, NC

27709

Bruce Rodan, U.S. Environmental Protection Agency, Office of Research and Development

, Washington, DC 20460

Risk As sessment Forum Staff

Michael Broder, Science Coordinator/DDEF Project Staff Lead, U.S. Environmental Protection
Agency, Office of the Science Advisor, Washington, DC 20460
Gary Bangs, Acting Executive Director

, 2009, U.S. Environmental Protection Agency, O ffice of
the Science Advisor, Washington, DC 20460
Kathryn Gallagher, Executive Director, 2010, U.S. Environmental Protection Agency,
Washington, DC 20460

Elizabeth Lee Hofmann, Executive Director , 2007

- 2008, U.S. Environmental Protection Agency,
Washingto n, DC 20460

Resha Putzrath, former Health Science Coordinator , U.S. Environmental Protection Agency,

Office of the Science Advisor, Washington, DC 20460

ACKNOWLEDGMENTS

The technical assistance of Ms

. Bette Zwayer is gratefully acknowledged.This document is a draft for review purposes only and does not constitute Agency policy.

5/11/11 Page 1 o f 49 DRAFT: DO NOT CITE OR QUOTE 1. INTRODUCTI ON 1

1.1. BACKGROUND 2

Risk assessment is the U.S. Environmental Protection Agency (EPA or Agency )’s key 3

process for deriving scientific information for making sound decisions on managing risks to 4

human health and the environment (U.S. EPA, 2004). No risk assessme nt can reflect true risk 5

with absolute certainty, so it is important that uncertainties be handled in a predictable, 6

scientifically defensible way that is both consistent with the EPA’s mission and responsive to the 7

needs of decision makers (U.S. EPA, 2004 ). This involves decreasing uncertainty in estimates 8

wherever possible, defining uncertainty and variability in estimates

, and quantifying the 9

uncertainty when feasible. Historically, the Agency has used default uncertainty factors to 10

compensate for a la ck of information. As science has advanced, however, there has been a 11

growing effort to increase reliance on the available data to modify the values for these 12

uncertainty factors (IPCS, 2005); this guidance describes an approach for using such information 13

for developing Data

- Derived Extrapolation Factors (DDEF s ). 14

An Examination of EPA Risk Assessment Principles and Practices: a Staff Paper 15

(U.S. EPA, 2004) notes that the EPA has published a number of documents that provide 16

direction in describing uncertain ty in risk estimates including the following : 17

18

19

Risk Characterization Handbook (U.S. EPA, 2000) 20

Guiding Principles for Monte Carlo Analysis (U.S. EPA, 1997) 21

May 1997 Policy for Probabilistic Analysis (U.S. EPA, 1997a, b) 22

Risk Assessment Guidance for Super fund: Volume III

— Part A, Process for Conducting 23

Probabilistic Risk Assessment (U.S. EPA, 2001a) 24

25

26
Given that risk assessors never have a complete data set, it is accepted practice to use 27

default values and processes in order to allow a risk assessment to p roceed in the absence of data. 28

The EPA uses the definition of default assumption articulated by the National Research Council 29

(NRC): ―the option chosen on the basis of risk assessment policy that appears to be the best 30

choice in the absence of data to the contrary‖ (NRC, 1983). The NRC, in its report Science and 31This document is a draft for review purposes only and does not constitute Agency policy.

5/11/11 Page 2 o f 49 DRAFT: DO NOT CITE OR QUOTE Judgment in Risk Assessment (NRC, 1994), supported EPA’s use of defaults as a reasonable way 1

to deal with uncertainty. That report stated that the EPA should have principles for choosing 2

default options and for judging when and how to depart from them. 3

Since then, the EPA now initiates the process of choosing a method for developing 4

uncertainty factors by evaluating the available data

— guidance suggests invoking default values 5

only when data are un available or insufficient. This contrasts with the previous position of using 6

the strength of the data as the basis for moving away from default values for uncertainty factors. 7

Specifically, the 2005 Guidelines for Carcinogen Risk Assessment (or ― Cancer Guidelines ‖) 8

(U.S. EPA, 2005) state “these cancer guidelines view a critical analysis of all of the available 9

information...as the starting point from which a default option may be invoked if needed to 10

address uncertainty or the absence of critical informati on.” Thus, while risk assessors have 11

generally tried to make maximum use of available data, the shift away from standard default 12

assumptions was codified as EPA science policy with the publication of the 2005 Cancer 13

Guidelines. Evaluating the available d ata will improve the scientific basis of risk assessments 14

when data are sufficient for refining uncertainty factors (UFs). In cases where data are not 15

sufficient, hazard and risk characterizations will be improved

, and data needs can be noted and 16

potentia lly filled in the future (Murray and Andersen, 2001; Meek, 2001; Meek et al., 2001; 17

Bogdanffy et al., 2001). 18

19

1.2. PURPOSE AND SCOPE 20

U.S. and international efforts have improved the scientific basis for human health risk 21

assessments by increasing the use of mec hanistic and kinetic data. For example, the EPA’s 2005 22

Cancer Guidelines (U.S. EPA, 2005) emphasize the use of mode

- of

- action (MOA) information 23

in characterizing potential health effects of exposure to environmental agents. International 24

efforts

, includi ng those by the International Life Science Institute (ILSI) and the World Health 25

Organization (WHO)’s International Programme on Chemical Safety (IPCS), have developed 26

frameworks for evaluating animal data to determine the human relevance of described MOAs 27

( Boobis et al., 2008 ; Seed et al., 2005; Sonnich

- Mullin et al., 2001). These documents guide the 28

qualitative and quantitative evaluation of the relevance of a particular animal model of action in 29

humans and discuss the use of in vivo and in vitro data wh en considering animal

- to

- human 30This document is a draft for review purposes only and does not constitute Agency policy.

5/11/11 Page 3 o f 49 DRAFT: DO NOT CITE OR QUOTE extrapolation. The 2005 Cancer Guidelines (U.S. EPA, 2005), and other documents like IPCS’s 1

chemical

- specific adjustment factors (CSAF s ) guidance (IPCS, 2005), the Methods for 2

Derivation of Inhalation Reference Concentratio ns and Application of Inhalation Dosimetry 3

(U.S. EPA, 1994), and An Examination of EPA Risk Assessment Principles and Practices:Staff 4

Paper Prepared for the U.S. EPA by Members of the Risk Assessment Task Force (U.S. EPA, 5

2004) also encourage the use of so phisticated models like physiologically based pharmacokinetic 6

(PBPK) and biologically based dose

- response (BBDR) models in interspecies extrapolation. 7

This document deals specifically with the development and use of data

- derived factors in 8

the calculation of nonlinear low

- dose estimates, or safety assessments. The goal of DDEFs is to 9

maximize the use of available data and improve the scientific support for a risk assessment. The 10

processes described herein have benefited from the continuing discussion in t he scientific 11

community on ways to replace the 10

- fold u ncertainty f actors (10× UFs) that have historically 12

been used in deriving safety assessments such as reference doses (RfD s ), minimal risk levels

, 13

and acceptable daily intakes. WHO’s IPCS guidance for deriving CSAFs was finalized in 2005. 14

This CSAF guidance describes approaches for use of kinetic and mechanistic data to refine inter

15

a nd intraspecies extrapolation factors. The IPCS guidance is largely based on analyses by 16

Renwick (1993) and Renwick a nd Lazarus (1998), which describe the use of toxicokinetic and 17

toxicodynamic data as a means of replacing the traditional 10× UFs for human sensitivity and 18

experimental animal

- to

- human extrapolation. This data

- derived approach assigns values for 19

toxicokin etic and toxicodynamic differences as replacements for each traditional 10× UF. 20

Important distinctions between IPCS (2005) and the present EPA guidance are that IPCS restricts 21

toxicokinetic evaluations to the central compartment, disallowing local tissue metabolism to be 22

quantified as part of the toxicokinetic processes; division of the animal to human extrapolation 23

unevenly, attributing a greater fraction of default uncertainty to TK than to TD; and a general 24

level of depth. 25

The current document describes the EPA’s approach to calculating extrapolation values 26

based on data; these are called data

- derived extrapolation factors ( DDEF s )

. DDEFs are similar 27

in concept to IPCS/WHO’s CSAFs in that the standard extrapolation factors are separated into 28

toxicokineti c (TK) and toxicodynamic (TD) components, and kinetic and mechanistic data are 29

used to derive refined interspecies or intraspecies extrapolation factor(s). Conceptually, DDEFs 30This document is a draft for review purposes only and does not constitute Agency policy.

5/11/11 Page 4 o f 49 DRAFT: DO NOT CITE OR QUOTE (and CSAFs) may not be limited to a specific chemical but may also apply to che micals with 1

common structural characteristics, common MOA

, or common toxicokinetic characteristics or 2

determinants. An appendix to this document contains case study examples taken from the 3

Integrated Risk I nformation System (IRIS) and from p rogram o ffice records. These case studies 4

present the application of principles contained in this document to data and modeling studies for 5

actual chemicals and should serve as instructional aides. 6

Topics most relevant to the derivation and use of DDEFs are the focus o f this document. 7

Thus, there are concepts beyond the scope of this guidance that are not discussed in detail here: 8

approaches for selecting critical effects; establishing key events in an MOA analysis; 1 deriving 9

points of departure; performing benchmark d ose analysis; and developing and evaluating PBPK 10

and BBDR models. In addition, this document deals only with DDEF for the areas of inter

- and 11

intraspecies extrapolation; there is no discussion of factors that have been used for other areas of 12

uncertainty or variability (e.g., duration, database deficiencies

, or lack of a 13

no

- observed

- adverse

- effect

- level [NOAEL]). 2 14

15

1 Mode of action (MOA) refers to a series of key, determinant

, and necessary interactions between the toxicant an d
its molecular target(s) that lead to the toxic response. Refer to Section 2.2.4.1 for further information.

2 Note:The Food Quality Protection Act (FQPA) mandates the use of a presumptive 10

- fold factor for the protection

of infants and children in addit ion to inter

- and intraspecies factors. This factor can only be modified based upon

reliable data. The FQPA factor is not discussed in this document.This document is a draft for review purposes only and does not constitute Agency policy.

5/11/11 Page 5 o f 49 DRAFT: DO NOT CITE OR QUOTE

2. TECHNICAL CONCEPTS A ND PRINCIPLES FOR DD EF 1

2.1. BACKGROUND 2

The methodologies of the EPA derivation of reference concentrations (RfC s ) and RfDs 3

(the predominant EPA nonlinear approaches) recognize steps for inter

- and intraspecies 4

extrapolation, both of which may include the application of uncertainty factors to an 5

experimental result to account for recognized uncertainties in, and variability inherent in, the 6

extrapolations from the experimental data conditions to estimates appropriate to the assumed 7

human scenario (U.S. EPA, 2011 , 2002 b

, 1994

, 1993 ). This document describes an approach to 8

performing inter

- and intraspecies extrapolations based on the use of the best available science 9

and data. DDEFs are factors estimated from quantitative data on interspecies differences or 10

human variability (illustrated in Figure 1). DDEFs may consider both toxicokinetic and 11

toxicodynamic properties. These factors can be derived for a single agent or chemical, for a 12

class of chemicals with shared chemical or toxicological properties

, and for a group of chemicals 13

that share a mode or mechanism of action or toxicokinetic characteristics. As described below, 14

DDEFs ca n be calculated using sophisticated toxicodynamic or toxicokinetic models or can be 15

calculated as ratios using key kinetic or dynamic data. With regard to interspecies extrapolation, 16

the EPA currently recognizes a hierarchy of approaches ranging from the preferred approach 17

using PBPK modeling (U.S. EPA, 2006

, 1994 ) down to default approaches for situations for 18

which data do not support an alternate approach, with DDEFs falling intermediate in this 19

hierarchy. 20

The default approach for the inhalation exposure route involves a combination of 21

application of a categorical dosimetric adjustment factor and a residual uncertainty factor 22

(U.S. EPA, 1994). The dosimetric adjustments are based on the following: 23

24

Anatomic and physiologic differences between species 25

Phy sical differences between particles and gases 26

Whether the toxic effect(s) are portal of entry or systemic in nature 27

28This document is a draft for review purposes only and does not constitute Agency policy

3/ 11 /1 1

6 of 49 DRAFT

— DO NOT CITE OR QUOTE Figure 1

. Derivation of RfDs/RfCs using uncertainty factors.This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 7 o f 49 DRAFT: DO NOT CITE OR QUOTE For the oral exposure route, the default appro ach for interspecies extrapolation involves 1

scaling the applied dosing, according to body weight, to the 3⁄4 power

, and a residual uncertainty 2

factor (U.S

. EPA, 2011 ). Apportioning the default values for both inter

- and intraspecies 3

extrapolation is based o n data for various chemicals. It is generally recognized that toxicokinetic 4

data are more widely available than toxicodynamic data. The magnitude of variation in the 5

available TK data suggest s that the interspecies uncertainty factor might be evenly divi ded 6

be t ween TK and TD components. These values are 1⁄2 order of magnitude in value and can be 7

seen in various documents as values of 3, 3.0, 3.16

, or 3.2. Regardless of their values, the 8

mathematical combination of two factors of 1⁄2 order of magnitude each results in a value of 9

10 (i.e., 3 × 3 = 10). After quantifying TK differences between species, the residual uncertainty 10

factor associated with either route (oral or inhalation) has a default value of 3, which may be 11

modified based on available data (U.S

. EPA, 2011 , 1994 ). In accordance with the hierarchy of 12

approaches, when available agent

- specific data are supportive of DDEF derivation, a 13

data

- de r ived approach is preferred over using the RfC approach or 3⁄4 body

- weight scaling. 14

15

2.2. EXTRAPOLATION WITH DDEF s 16

Th e foundation of DDEFs is the concept that the toxicity of a particular agent is due to a 17

combination of both toxicokinetic and toxicodynamic factors and that those factors can be 18

quantified in animals and humans. For purposes of this guidance, toxicokinet ics (TK) is defined 19

as the determination and quantification of the time course and dose dependency of absorption, 20

distribution, metabolism

, and excretion of chemicals (sometimes referred to as pharmacokinetics 21

or ADME). Toxicodynamics (TD) is defined as t he determination and quantification of the 22

sequence of events at the cellular and molecular levels leading to a toxic response. There is no 23

clear separation between TK and TD because the processes leading to biological responses 24

include aspects of both

— in cluding interactions between TK and TD processes. 25

26

2.2.1. Approaches to Deriving DDEFs 27

The focus of this guidance is on extrapolation from animals to humans, and within the 28

human population. Extrapolation can be accomplished by one of several approaches ranging 29

from the use of highly sophisticated BBDR models to the calculation of relatively simple ratios 30

using TK or TD data describing critical factors in inter

- or intraspecies extrapolation. The 31This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 8 o f 49 DRAFT: DO NOT CITE OR QUOTE following text describes these approaches. In the absenc e of data for perform ing sophisticated 1

modeling or for deriv ing DDEF values, default approaches are used. Figure 2 is a flowchart 2

depicting the decision process used in deriving and applying extrapolation factors

. 3

4

2.2.1.1. TK and TD Models 5

TK and TD models represent the p referred approach to intra

- and/or interspecies 6

extrapolation. They vary in level of complexity from classical compartmental and simple 7

statistical response models to physiologically realistic models of TK and TD processes, up to and 8

including BBDR models . These models provide a quantitative description of the biological 9

processes involved in the toxicokinetics and/or MOA of chemical(s). In these TK and TD 10

models, some measure of the internal dose is related to the external dose and mode of action, 11

respe ctively. 12

TK modeling is the process of developing a mathematical description of ADME in a 13

living organism. Two common types of model s are (1 ) data

- based classical noncompartmental 14

or compartmental models and (2 ) PBPK models. Data

- based models, also kn own as classical 15

models, mathematically describe the temporal change in chemical concentration in blood, tissue

, 16

or excreta of the species in which the data were generated. The classical models treat the body 17

as a single homogenous or multicompartment sys tem with elimination occurring in a specific 18

compartment; the characteristics of the compartments (number, volume, etc

. ) are hypothetical in 19

that they are chosen for the purpose of describing the data rather than a priori based on the 20

physiological charact eristics of the organism. Due to these characteristics, classical models are 21

used for interpolation, i.e., within the range of doses, dose route

, and species in which the data 22

were generated (Renwick, 1994). 23

PBPK models differ from classical compartmental models in that they are com posed of 24

compartments with realistic tissue volumes that are linked by blood flow. Other parameters used 25

in these models account for chemical

- specific characteristics that can be independently measured 26

in both humans and labora tory animals (usually using in vitro techniques); these 27

chemical

- specific parameters include tissue solubility (i.e., partition coefficients), binding

, and 28

metabolism. These models are used to simulate the relationship between applied dose and 29

internal do se. They are more data intensive to develop compared to classical compartmental 30This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 9 o f 49 DRAFT: DO NOT CITE OR QUOTE 1

Figure 2

. Decision p rocess for DDEFs. The availability of an adequate

pharmacokinetic (PK) or pharmacodynamic (PD) model is first considered foll owed by
analysis of the availability of adequate data to describe the toxicokinetics (TK) and/or the
toxicodynamics (TD) of the chemical. With the availability of an adequate model or

data, data

- derived extrapolation factors for intraspecies ( EF AK , EF AD ) and interspecies
extrapolation ( EF HK , EF HD ) are developed. Such data

- derived factors are preferred over default factors. In the absence of an adequate model or d ata, default factors are used.

2
*For interspecies extrapolation, the default procedure is 3⁄4 b ody

- weight scaling for oral 3

(U.S

. EPA, 2006) and the RfC method (U.S

. EPA, 1994) for inhalation to account for 4
potential TK differences with a 3 × factor for potential TD differences. The composite 5

factor (CF) accounts for inter

- and intraspecies extrapola tion and can comprise default or 6

DDEF values for the four extrapolation factor components. 7

8This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 10 o f 49 DRAFT: DO NOT CITE OR QUOTE models, but they are advantageous because they can be used for extrapolation (i.e., across dose 1

range, among animal species, between routes of exposure

, and across exposure scenarios) 2

(Krishnan and Andersen, 1994; U.S. EPA, 2006 ). 3

TD models can be developed when there are sufficient data to both ascertain the MOA 4

and to quantitatively support model parameters that represent rates and other quantities 5

associated with key precursor events in the MOA. A BBDR model describes biological 6

processes at the cellular and molecular level s in such a way as to link target tissue dose with 7

adverse effect; in practice

, BBDR models are often described as a combined TK/TD model. 8

The se models may be used for extrapolation. However, with adequate understanding of the 9

nature of the response, empirical data describing the dose

- response function in relevant species 10

or population groups are sufficient to serve as the basis for DDEF deriva tion; in these cases

, a 11

fully developed TD model may not be required. 12

DDEF values are extrapolation factors, as opposed to uncertainty factors, per se. DDEF 13

values are quantitatively derived based on TK and / or TD data for t he chemical under evaluation. 14

D DEF values are not the same as the default uncertainty factor values, but the values for the 15

DDEF components may sometimes be similar to default values for uncertainty factors. 16

Developing a DDEF value reduces uncertainty and carries with it a change in no menclature. 17

18

2.2.1.2. Use of Ratios to Calculate DDEF 19

In the absence of sufficient data to develop a robust TK or TD model, the risk assessor 20

need not necessarily use default 10× UFs. DDEFs can be calculated as ratios using data from 21

key studies evaluating TK or T D profiles or properties of a particular chemical. Example 22

equations for calculating DDEFs are provided in Table 1 and are described in more detail in 23

Sections 3 (TK) and 4 (TD). 24

In general, interspecies extrapolation involves calculating a ratio of human data for a 25

kinetic or dynamic parameter to animal data for a kinetic or dynamic parameter. Similarly

, for 26

intraspecies extrapolation, a ratio is calculated using data from the sensitive population and that 27

for the general, or average, population. Data t o derive the TK factors may come from in vivo or 28

in vitro studies. For TD, in general, interspecies extrapolation may come from in vivo studies 29

but will often be accomplished with in vitro data in a relevant tissue. When data on toxic effects 30This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 11 o f 49 DRAFT: DO NOT CITE OR QUOTE 1

Table 1

. Example equations used to derive DDEFs

Extrapolation Toxicokinetic s (see Section 3) Toxicodynamic s (see Section 4)

Animal to human

(i nterspecies)

Within h uman ( i ntraspecie s)

2

EF AK = extrapolation factor for interspecies extrapolation covering toxicokinetics

. 3

Dose A = administered or external dose to the animal

. 4

Dose H = administered or external dose to the human

. 5

EF AD = e xtrapolation factor for interspecies extrapolation covering toxicodynamics

. 6

Concentration A = concentration of the agent at the tissue in the animal

. 7

Concentration H = concentration of the agent at the tissue in the human

. 8

EF HK = extrapolation factor for int raspecies extrapolation covering toxicokinetics

. 9

AUC gen = area under the curve at a measure of central tendency in the general human population

. 10

AUC

sens = area under the curve at a percentile of interest in the human population

. 11

EF HD = extrapolation facto r for intraspecies extrapolation covering toxicodynamics

. 12

Concentration gen = concentration at a measure of central tendency in the general human population

. 13

Concentration

se ns = concentration at a percentile of interest in the human population

. 14

15

16

are availa ble in humans, these data may be used directly for the point of departure (POD) 17

development

, eliminating the need for the interspecies extrapolation. Likewise

, they can be used 18

to inform an interspecies factor when the POD is derived from animals. 19

For DD EFs involving interspecies extrapolation, it is preferred that the ratio be based on 20

data at or near the POD. When sufficient data are available, DDEF values should be calculated 21

for a range of doses near the POD because the shape of the dose

- response cur ve can vary among 22

species. Metabolism and kinetic properties can vary across doses, particularly in the higher dose 23

ranges; thus

, using estimates at or near the POD helps avoid introducing significant uncertainty 24

in the DDEF estimate caused by nonlinearit y in kinetic properties. Evaluating a range of PODs 25

takes into account the variability of the DDEFs based on the POD selected. The interspecies 26

DDEF should be derived using an estimate of central tendency, such as the mean, median

, or 27

mode, depending on the characteristics of the data. It is, however, important to evaluate 28This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 12 o f 49 DRAFT: DO NOT CITE OR QUOTE variability in the DDEF. Thus, it is recommended that, to the extent possible, the hazard and risk 1

characterizations reflect the upper and lower confidence bounds on the DDEF. 2

By con trast with interspecies extrapolation, when calculating intraspecies DDEFs, the 3

ratio involves consideration of a measure of central tendency of the general population and lower 4

percentiles of interest (e.g., 1 st , 2.5 th

, or 5 th ) to represent the sensitive populations. As the needs 5

of risk managers and decision makers vary, it is recommended that a range of percentiles be 6

evaluated and reported in the hazard and risk characterizations. 7

Toxicokinetic ratios (for either interspecies or intraspecies extrapolat ion) are based upon 8

the relevant dose metric, such as area under the curve (AUC) and the maximum concentration 9

(C

max ). 3 Other metrics (e.g., AUC above a threshold) may be used if supported by the data or if 10

relevant for a particular chemical or MOA. For toxicants that bind covalently or cause 11

irreversible damage, especially as a consequence of subchronic or chronic exposure, an 12

integrated measure of dose over time such as AUC is generally used (O’Flaherty, 1989). In the 13

case of effects occurring as a con sequence of acute exposure, C

max may be more appropriate 14

(Boyes et al., 2005; Barton, 2005). When data on chemical

- specific AUC, C

max , or clearance 15

(Cl) are not available, a chemical

- related physiological parameter (e.g., renal glomerular 16

filtration rate) that is critical to the onset of toxicity or to the MOA may be used. 17

As Table 1 indicates

, there are generally four DDEFs that can be calculated, given 18

sufficient information. Two are for extrapolation from animal data to humans: EF AK is 19

calculated to ac count for TK variability, while EF AD deals with TD variability. Likewise

, there 20

are two factors dealing with variability within the human population: EF HK for TK and EF HD for 21

TD. Table 1 provides example equations for calculating these DDEFs. Section 3 describes 22

specifics for TK factors for interspecies ( see Section 3.2) and intraspecies ( see Section 3.3) 23

extrapolation. Section 4 describes TD factors for both animal to human ( see Section 4.2) and 24

within human ( see Section 4.3) extrapolation. Section 5 describes how to combine the EF AK , 25

EF AD , EF HK , and EF HD into the composite UF. 26

The overall goal of DDEFs is to maximize the use of available data and improve the 27

overall scientific support for a risk assessment. Figure 2 provides a flowchart of the decisi on 28

process for extrapolation used in deriving DDEFs. As shown in the figure, inter

- and 29

3 Clearance can be used to calculate this ratio when it can be assumed or demonstrated that the relevant dose metric
is AUC or concentration at steady state.This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 13 o f 49 DRAFT: DO NOT CITE OR QUOTE intraspecies extrapolation can be accomplished using a combination of TK or TD models, 1

DDEFs derived from ratios, and/or use of defaults. As described in more detail in Sections 3 and 2

4, it is important for the hazard and/or risk characterizations to include thorough and transparent 3

discussions of methods and data used to support extrapolation approaches. 4

5

2.2.2. Qualitative Considerations 6

Although in some cases there may not be sufficient data for a quantitative estimate of a 7

DDEF, there may still be information to support a UF different from the default. For example, 8

there may be qualitative evidence that a MOA identified in animals is not relevant to humans. A 9

framework d eveloped by ILSI for evaluating the relevance of an animal MOA can be found in 10

Seed et al. (2005), Meek et al. (2003)

, and Boobis et al. (2008). The human relevance 11

framework provides a transparent and logical thought process by which animal and human MOA 12

data can be evaluated on both a qualitative and quantitative basis. In these cases

, where only 13

qualitative data are available, a thorough weight

- of

- evidence analysis should be considered with 14

the hazard and/or risk characterization to discuss the derivat ion of the DDEF along with 15

associated uncertainties in the available database. 16

17

2.2.3. Information Quality 18

Critical evaluation of all data used to support the development of DDEFs is necessary. 19

This includes data used to provide qualitative support for the MOA a nd choice of dose metric, as 20

well as data used in the quantitative derivation of the DDEF itself. Supporting studies can be 21

evaluated using criteria set forth in various EPA guidance documents, including the recently 22

published 2005 Cancer Guidelines , as w ell as earlier guidelines specific to neurotoxic, 23

reproductive

, and developmental endpoints (U.S. EPA, 1998, 1996, 1991). In addition, the 24

general principles outlined in the EPA information quality guidelines are applicable in the 25

critical evaluation of d ata used to support DDEF development (U.S. EPA, 2002a). The 26

remainder of this section highlights some areas of special emphasis that are particularly relevant 27

to the DDEF derivation process including MOA, uncertainty and variability

, and dealing with 28

mult iple responding organs or tissues. 29

Use of secondary data sources is one particular area of concern. Examples of secondary 30

data sources include compilations of pharmacokinetic parameters (e.g., Brown et al., 1997) and 31This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 14 o f 49 DRAFT: DO NOT CITE OR QUOTE studies cited and summarized in toxici ty profiles and review articles. In general, for princip al 1

and supporting studies used directly in DDEF derivation, review of the original literature is 2

necessary. In the case of critical assumptions and data, contradictory results from different 3

studies are best resolved by review of the original publications. 4

Quantitative TK and TD data used in the DDEF

- derivation process requires particular 5

attention to the appropriateness of the study design, the analytical methodology used

, and the 6

statistical analys is of the data. Consideration of appropriate study design extends beyond simply 7

verifying that the methods used were adequate for the goals of the study; it also encompasses 8

consideration of the relevancy of the animal species or in vitro test system to e valuate MOA. 9

Relevance can be assessed in both qualitative and quantitative terms. For example, if there is a 10

lack of species concordance (i.e., a particular TK or TD process does not occur in humans) or 11

effects occur only under physiologically unrealist ic conditions or not in the tissue evaluated, then 12

its relevancy is questionable and uncertain. Criteria used in arriving at such a determination have 13

been published for both the more general case (Seed et al., 2005) and particular endpoints 14

including var ious forms of rodent cancer (Proctor et al., 2007; Maronpot et al., 2004). Particular 15

considerations relevant to the use of in vitro data are discussed below. Another important factor 16

in terms of relevancy is consideration of whether the TK or TD respons e represents a uniquely 17

susceptible tissue, process

, or population. This is a critical determinant in evaluating the use of 18

data to describe intraspecies variability. 19

20

2.2.4. Additional Considerations 21

2.2.4.1. Mode of Action 22

Information on MOA can greatly enhance DDEF de rivation, even when a complete 23

explication of mechanism is not available. In the 2005 Cancer Guidelines , the EPA describes 24

MOA evaluation as the critical information that defines the conditions under which a toxicant 25

causes its effect, the relevance of an imal data for hazard identification

, and the most appropriate 26

approach to low

- dose extrapolation. The 2005 Cancer Guidelines also present a framework for 27

evaluating data in support of MOA determination. Major components of this framework include 28

a descri ption of the hypothesized MOA and a discussion of the experimental support for the 29

hypothesized MOA based on modified Hill criteria (U.S. EPA, 2005) for demonstrating 30

associations in human studies. 31This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 15 o f 49 DRAFT: DO NOT CITE OR QUOTE MOA is defined as a sequence of key events and processes, starting with the interaction 1

of an agent with a cell, proceeding through operational and anatomical changes, and resulting in 2

toxicity. A key event is an empirically observable precursor step that is itself a necessary 3

element of the MOA or is a biologic ally based marker for such an element. MOA is contrasted 4

with ―mechanism of action,‖ which implies a more detailed understanding and description of 5

events, often at the molecular level, than is meant by MOA (U.S. EPA, 2005). 6

DDEFs for both TK and TD are e ndpoint driven

— that is, considered in the context of the 7

toxic endpoints most relevant for purposes of the risk assessment. Understanding MOA for the 8

agent(s) of interest helps to ensure that the TK or TD parameter used to derive the DDEF will be 9

robust s cientifically. The key events in MOA are likely to identify important metabolite(s) and 10

potential species differences. Moreover, data on key events may be used directly to estimate the 11

EF AK or the EF AD

. 12

13

2.2.4.2. Use of In Vitro Data 14

In vitro assays play an impor tant role in defining DDEFs; however, care must be taken to 15

avoid taking isolated findings out of context. Consideration of interspecies differences in ADME 16

is essential because the dose to target tissue in any given exposure scenario is a balance among 17

m ultiple and competing ADME processes. Thus, in vitro data should not be used for quantitative 18

purposes unless interpreted in the context of the intact system. Among the questions to be 19

considered when applying in vitro data to DDEFs are the following : 20

21

22

Was the toxicologically active form of the agent studied? 23

How directly was the measured response linked to the toxic effect? 24

Are the biological samples used in the assays derived from equivalent organs, tissues, cell 25
types, age, stage of development, and s ex of the animals/humans in which the target 26
organ toxicity was identified? 27

What is the range of variability (e.g., diverse human populations and lifestages) that the 28
biological materials cover? 4 29

4 Quality (purity, viability, source) of the samples is of particular concern

, with biological materials derived from
human organ donors.This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 16 o f 49 DRAFT: DO NOT CITE OR QUOTE If the effect occurs or can be measured in several tissues, is the studied tissue or tissue 1
preparation an appropriate surrogate? Or, i n situations where the effect is not localized, 2

is the effect consistent across tissues? 3

Does the design of the study allow for statistically valid comparisons based on such 4

factor s as replication and sample size? 5

Was chemical uptake considered when the chemical was applied to the samples so as to 6
give comparable intracellular concentrations across tissues, and similar tissues across 7
species? 8

Do the concentrations in the in vitro st udies allow for comparison with in vivo 9

conditions? 10

11

12
All of these issues affect the utility of applying in vitro data for risk assessment: a clear 13

discussion of these points helps to clarify the appropriateness of the information used for 14

deriving DDEFs. 15

16

2.2.4.3. Uncertainty and Variability 17

The application of the inter

- and 18

intraspecies UFs attempts to account for both 19

the variability (true heterogeneity) and 20

uncertainty (lack of knowledge) the in the data 21

available (see Textbox 1, U.S. EPA, 2002 b ). 22

The DDEFs de scribed in this document 23

evaluate variability within the data. Evaluation 24

of the sources and magnitude of uncertainty is 25

appropriate (U

. S

. EPA, 2 005 , 2001, 1997a, b ). 26

Quantitative uncertainty analyses may be 27

undertaken but are not presented in this docum ent. When quantitative approaches are not 28

feasible, qualitative uncertainty analyses may be developed. As is consistent with the 2005 29

Cancer Guidelines : ― a default option may be invoked if needed to address uncertainty or the 30

absence of critical informat ion.” 31

32 Textbox 1

Variability refers to true heterogeneity or diversity.
This may be due to differences in exposure as well as
differences in response. Those inherent differences are

re ferred to as variability. Differences among
individuals in a population are referred to as
interindividual variability, while differences for

one i ndividual over time are referred to as
intraindividual variability.

Uncertainty occurs because of lack of knowledge. It is
not the same as variability. Uncertainty can often be
reduced by collecting more and better data, while
variability is an inherent property of the population
being evaluated. Variability can be better character ized

with more data but cannot be eliminated. Efforts to
clearly distinguish between variability and uncertainty
are important for both risk assessment and risk

characterization.

Source: U.S. EPA (2002 b ).This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 17 o f 49 DRAFT: DO NOT CITE OR QUOTE 2.2.4.4. Multiple Critical Effects 1

For some toxicants

, multiple critical effects may be identified during hazard 2

identification. In some cases, these effects may be the result of a single MOA. However, for 3

others, the critical effects may have different or unknown MOAs. It is possible that the 4

uncertainty and/or variability associated with the TK and/or TD of each effect may differ, 5

resulting in different DDEFs. The results generated for the multiple responding tissues/organs, 6

particularly if multiple MOA s are operational or MOA is unknown, should be presented for 7

comparison (for example, in a table that is accompanied by a discussion of the methods used). 8

Unless there is scientific support for doing so, it is important not to mix DDEFs derived for one 9

ti ssue or one MOA with DDEFs derived from a different tissue. For example, DDEF values for 10

kidney effects may not apply to liver effects. 11

12

2.2.4.5. Screening

- Level vs. Refined Risk Assessments 13

Extrapolation is most scientifically robust when data are first evaluated prior to the use of 14

defaults. However, with a multitude of types of data, analyses

, and risk assessments, as well as 15

the diversity of needs of decision makers, it is neither possible nor desirable to specify 16

step

- by

- step criteria for decisions to invoke a default option. Some risk assessments may be 17

limited by time or resource constraints. Other risk assessments may provide only screening level 18

evaluations. In these cases, the risk assessment may be more likely to resort to one or more 19

default assumpti on s . On the other hand, risk assessments used to support significant risk 20

management decisions will often benefit from a more comprehensive assessment. 21

22This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 18 o f 49 DRAFT: DO NOT CITE OR QUOTE

3. DDEF s BASED ON TOXICOKINET ICS (TK) 1

3.1. GENERAL CONSIDERATIONS 2

Toxicokinetics is concerned with delivery of the biologically active chemical species to 3

the target tissue of interest. Data on tissue concentrations of toxicants or clearance rates of 4

toxicant removal serve as the basis for deriving extrapolation factors foor toxicokinetic 5

components. This sectio n provides a discussion of factors common to derivation of both inter

6

and intraspecies uncertainty factors to account for TK variability. Data on the quantitative 7

differences in the TK between animals and humans are used for interspecies extrapolation 8

( E F AK ); differences in susceptibility within the human population are used for the intraspecies 9

extrapolation ( EF HK ). Thus

, the factor EF AK accounts for extrapolation from laboratory animals 10

to the general human population. The EF HK factor accounts for the variation in the 11

dose/exposure

- response relationship between the general human and potentially susceptible 12

human individuals or groups. Note, the term susceptible is also used to describe sensitive 13

individuals or groups, as these two terms are often used interchangeably

, and no convention for 14

their use is widely accepted (U.S. EPA, 2004). Developing a DDEF for TK requires knowledge 15

about the relationship between external dose and internal (target tissue) concentrations. This 16

information can come from st udies in which tissue concentrations are observed

, both types of 17

data are recorded, or can come from adequate TK models, which expand the range of confidence 18

from that of the empirical observations. TK models, especially PBPK models, represent an 19

importan t tool through which in vitro observations can be interpreted in the context of the intact 20

system. As such, they represent an advantageous means to evaluate the impact of studies 21

(especially those using human tissues) conducted in vitro. 22

The TK portion of each factor ( EF AK , EF HK ) is combined with the corresponding TD 23

factor s to assemble the composite extrapolation factor ( see Section 5) . Where the data are not 24

sufficient to derive a DDEF for TK, other approaches can be considered for EF AK or EF HK

. For 25

example

, t he RfC approach (U

. S

. EPA, 1994) when evaluating inhalation data or 3⁄4 body

- weight 26

scaling

, or a default as described in Figure 2

. 27

I mportant questions to address for TK are given below : 28

29

What is /are the critical effect (s) and POD being used for t his assessment? 30This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 19 o f 49 DRAFT: DO NOT CITE OR QUOTE What is the MOA or mechanism for that toxicity? Have the key events been identified 1
and quantified? Do these key events identify important metabolic steps? 2

Are the process of absorption, distribution, metabolism

, and elimination of the c hemical 3
well characterized? Do animals and humans metabolize the chemical(s) in a similar way 4
(qualitatively and quantitatively)? 5

Are there data in human populations describing variation in important kinetic 6
parameter(s) for this chemical(s)? Do these da ta identify a susceptible population(s) or 7
lifestage(s)? Can the degree of this susceptibility be estimated? 8

9

10
TK data may be developed empirically or through compartmental or physiologically 11

based TK models. Section 2.2.2 describes how d ata

, models , and approaches are evaluated for 12

their appropriateness. For each critical effect identified for a particular agent, separate DDEF 13

analyses are conducted for EF AK and EF HK . As such, da ta for multiple susceptible 14

tissues/endpoints can be evaluated

, concentrat ing on those tissues that demonstrate adverse 15

responses near the POD for the critical effect

. 16

17

3.1.1. Dose Metric 18

Dose metric is a term used to identify a measure of the internal dose that is associated 19

with the health outcome of interest. It describes target ti ssue exposure in terms of the toxic 20

chemical moiety (parent or metabolite) and is expressed in appropriate time

- normalized terms. 21

For example, acute effects are often most related to peak concentrations, whereas effects 22

occurring following a prolonged exp osure are often best correlated with time

- normalized (e.g., 23

area under the concentration

- time curve) measures of exposure. The choice of the dose metric is 24

an important component in TK extrapolations . This choice depends on whether toxicity is best 25

ascri bed to a momentary or transient tissue exposure or a cumulative dose to target tissue. For a 26

given chemical, the appropriate dose metric will also be determined by

, and can vary with

, both 27

the duration of exposure and the adverse effect of concern (U.S. E PA, 2006 ). Selection of an 28

appropriate dose metric based upon specific endpoints involves several elements including those 29

described in more detail below : 30

31

Duration of exposure and effect; 32

Identification of the active chemical moiety; 33This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 20 o f 49 DRAFT: DO NOT CITE OR QUOTE Selection of the org an or tissue group in which some measure of internal dose is desired; 1

and 2

Selection of the measure of exposure that best correlates with toxicity. 3

4

5
Whether an adverse effect is a consequence of acute

- or chronic

- duration exposure 6

impacts the choice of do se metric. For acute, reversible effects (e.g.

, sensory irritation, narcosis), 7

a measure of instantaneous or peak tissue exposure such as C

max may be the most appropriate 8

dose metric (Alarie, 1973; Boyes et al., 2005). For chronic effects, in the absence of MOA 9

information to the contrary, it is generally assumed that some integrated cumulative measure of 10

tissue exposure to active toxicant is the most appropriate dose metric, e.g.

, area under the curve 11

(AUC). Alternative choices such as amount of chemica l or rate of metabolite production can be 12

used as appropriate for a particular agent or MOA (U.S. EPA, 2006 ). For example, there may be 13

a case where a temporally large influx of active chemical to a target site in a relatively short 14

period of time (peak e xposure) is observed, in which case

, a less commonly used metric such as 15

time above a critical concentration (TACC) may be most appropriate. In such an instance, the 16

d ata and rationale in support of a particular dose metric need to be presented. 17

Clearance , while not typically considered a dose metric, can be useful in DDEF 18

derivation. Clearance is mathematically inversely related to AUC (e.g., AUC = dose/clearance) ; 19

thus

, differences in clearance values can be used in calculation of ratios. When metaboli sm 20

represents the primary or sole clearance mechanism, either of two clearance models may be 21

applicable. Intrinsic clearance (Cl int ) has been used for interspecies scaling of administered 22

doses in drug development (Houston and Carlile, 1997). Cl int is ca lculated as V

max /K

m , and is in 23

units of volume cleared of the substrate per unit time. V

max is the theoretical maximal initial 24

velocity of the reaction

, and K

m is the substrate concentration driving the reaction rate at one

- half 25

V

max . Cl int can be extrap olated to the whole body with knowledge of protein binding and the 26

recovery of the protein or cellular or subcellular fraction used in the in vitro investigations 27

(Carlile et al., 1997). Hepatic clearance (Cl hep ) is also based on V

max / K

m measurements but 28

includes a substrate deliver y term, whose value is governed by hepatic blood flow. These 29

measures of clearance differ in that Cl int is not bounded by hepatic blood flow, but Cl hep cannot 30

exceed hepatic blood flow. While metabolic rate constants ( V

max and K

m ) derived from in vitro 31This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 21 o f 49 DRAFT: DO NOT CITE OR QUOTE data can also be scaled up and incorporated into PBPK models, the use of these clearance models 1

is a simpler approach

, useful when an appropriate PBPK model is unavailable. Classical, 2

compartmental TK analyses and measures of cl earance are best suited for conditions where 3

metabolism represents a detoxication process, when substrate concentration is less than the K

m 4

value

, and when metabolism represents the major clearance mechanism. 5

Whether toxicity is attributable to a parent ch emical, a metabolite

, or some combination 6

of metabolites is a critical consideration. The active chemical moiety can be identified through 7

studies in which the toxicities induced by the parent chemical and metabolite(s) are compared or 8

from the results of studies using enzyme inhibitors and/or inducers. In vitro studies can also be 9

quite useful in this regard under appropriate conditions (see S ection s 2.2.3.2 and 3.1.3). 10

Quantifying differences in dosimetry can be difficult when metabolic pathways become complex 11

(e.g., where competition among pathways may be concentration dependent). If the metabolic 12

pathway bifurcates and the identity of the bioactive metabolite(s) are unknown or unquantifiable, 13

determination of the appropriate dose metric can be highly uncertain. 14

The organ or tissue group where the toxic effects occur is ideally the site from which 15

estimates of internal dose (tissue concentration) are generated. In practice

, this information may 16

be unavailable in the absence of an appropriate PBPK mode l. It may be necessary to use 17

absorbed dose of the parent chemical as a surrogate measure of internal dose. Another surrogate 18

dose metric is measurement of parent chemical or active metabolite in circulating blood if the 19

relationship between target tissu e dose and blood is known or can be reliably inferred from 20

experimental data. Some data have demonstrated that blood:air partition

- coefficient values may 21

vary app reciably between species but that tissue:air (e.g., liver:air) partition coefficients are 22

sim ilar among mammalian species (Thomas, 1975). It seems reasonable to use the cross

- species 23

similarity in the primary determinant of diffusion from blood into tissues as a justification to rely 24

on concentrations of the toxicant in blood as a surrogate for t issue concentrations. However, 25

when local tissue bioactivation may be a determinant of the toxic response, this should be given 26

careful consideration. Those issues notwithstanding, measures of internal dose in circulating 27

blood (see IPCS, 2005) may be us ed as the basis for DDEF derivation under either of these 28

conditions: 29

30

31This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 22 o f 49 DRAFT: DO NOT CITE OR QUOTE When evaluating interspecies differences, the distribution from blood to sensitive 1

(critical) tissues is shown to be or can be assumed to be the sa me between animals and 2

humans

. 3

When e valuating intraspecies differences, the distribution from blood to sensitive 4

(critical) tissues is shown to be or can be assumed to be the same between members of 5
the general human and potenti ally sensitive human groups

. 6

7

8

Because few data are available fo r concentrations of toxicants in human solid 9

tissues

― such as liver, kidney, etc.

— compared with data describing toxicant concentrations in 10

human blood, model predictions for solid tissue compartments are less certain than predictions of 11

toxicant concentrations in blood. Partitioning of the active chemical f rom blood into systemic 12

target tissues may be governed more by physicochemical than by biological processes. This may 13

be considered another basis for relying on data describing the concentration and variability of the 14

biologically active metabolite in the central compartment

. 5 For example, the ratio of blood lipid 15

to tissue lipid concentrations may be a key determinant in the diffusion of lipophilic compounds 16

out of blood; however, differences in tissue lipid composition between species may be fairly 17

smal l compared to differences in blood flow and metabolic activity. 18

19

3.1.2. Dose Selection 20

Because variability in internal dosimetry may be a function of dose, the selection of the 21

external exposure (inhaled concentration or orally ingested dose) is important. In ca ses where 22

toxicokinetics is nonlinear, the dose selected for the DDEF derivation will impact the magnitude 23

of EF AK or EF HK

. U sing a dose at or near the POD alleviates some concerns regarding 24

nonlinearities in metabolism. Alternatively, d ata that show a l inear relationship between external 25

dose and internal dose metrics can indicate generalizability of the EF AK or EF HK to doses that 26

may be higher or lower than those used in its calculation. 27

28

3.1.3. In Vitro Data 29

In vitro techniques are important tools in evaluati on of toxicokinetics as information can 30

be gathered that are impractical or unethical to collect in the intact animal or humans

. However, 31

5 The central compartment is defined as blood, plasma

, or serum in the systemic circulation. All tissues except those
representing the portal of entry are defined as peripheral compartments

.This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 23 o f 49 DRAFT: DO NOT CITE OR QUOTE it is important when deriving EF AK and EF HK to consider interspecies differences in ADME

. In 1

vitro data should used for quantitative purposes only when interpreted in the context of the intact 2

system , as discussed in S ection 2.2. 4. 2. Care must be taken to avoid taking isolated findings out 3

of context

. 4

5

3.2. INTERSPECIES TOXICOKINETIC EXTRAPOLATION ( EF AK ) 6

This section provi des a discussion of the quantitative differences in the TK between 7

animals and humans that are used for interspecies extrapolation ( EF AK ). In this process

, 8

t oxicokinetic d ifferences between species are characterized as the ratio of applied doses in the 9

te st species of interest and humans that result in the same level of the internal dose metric ( see 10

Figure 3)

. T hese values for the dose metric may be calculated from the external doses actually 11

used in the dose

- response evaluations, or by normalizing the do se metric to account for 12

administered dose (e.g., correcting AUC for each species by dividing the AUC by the external 13

dose) when the relationship between the values for the dose metric value and the applied dose are 14

linear in the range of extrapolation. I llustrative case studies are included in the appendix. 15

16

3.2.1. Considerations for EF AK 17

Extrapolation of TK data obtained in animal models to humans ( EF AK ) is evaluated for 18

each potential critical effect of interest. Data for multiple susceptible tissues/endpoint s are 19

evaluated, concentrating on those tissues that demonstrate adverse responses near the POD for 20

the critical effect. This analysis includes consideration of MOA, identification of the active 21

chemical agent for this particular effect

, and determination of the appropriate dose metric. This 22

is evaluated as a weight

- of

- evidence approach emphasizing both qualitative and quantitative 23

evidence. An important part of this process is evaluating concordance of metabolic processes 24

between the animal model and hu mans. An additional consideration is whether the kinetic data 25

are from a ―typical‖ or average adult animal as opposed to an animal model system that may be 26

unusually sensitive for a particular effect (e.g., metabolic knockout). 27

28This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 24 o f 49 DRAFT: DO NOT CITE OR QUOTE 1
Figure 3

. Interspecies t oxicokinetics. In keeping with guidance set for inhaled

substances (U.S. EPA, 1994), interspecies differences in toxicokinetics are defined as
differences in the external dose producing the same level of the dose metric in the ta rget tissue of interest in test animals and in humans representative of the general population.

Because it is the default assumption of the Agency that humans are considered more

sensitive than animals, EF AK is the ratio of animal dose:human dose suitable for
developing a value consistent with its placement in the denominator (i.e., reference value

= POD/UF). For clarity in presentation, EF AK is applied to the external dose in animals.

2

3
Furthermore, it is important to assess the relationship of externall y applied dose to 4

internal dose metric over the entire range of dose levels used in the critical study. There should 5

be careful attention paid both to measures of central tendency and to variability, particularly in 6This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 25 o f 49 DRAFT: DO NOT CITE OR QUOTE the range of concentrations or doses cl ose to the point of inflection (where the shape or slope of 1

the dose response curve changes) because of potential nonlinearities in metabolism. 2

3

3.2.2. Computation 4

For TK extrapolation, the goal is to determine differences in dosimetry between animals 5

and humans

. For interspecies extrapolation, toxicokinetically equivalent exposures (doses) are 6

determined by fixing the internal dose (level of the dose metric at or near the POD) and 7

determining the ratio of external (applied ) dose that result s in the same level of the dose metric in 8

animals and humans. This approach is consistent with that in the RfC guidance for inhalation 9

toxicants (U

. S

. EPA, 1994). 10

11

3.2.2.1. Use of TK Models 12

A PBPK or other TK model provides the most biologically appropriate approach for 13

evaluating inte rspecies TK extrapolation. The model is subject to evaluation as previously 14

described (U.S. EPA, 2006 ) . The model can be used in different ways, depending on the model 15

and the circumstances. In some cases, the TK model may be used directly to perform 16

in terspecies extrapolation (i.e., to derive a Human Equivalent Concentration or Dose that 17

includes TK considerations ) , thus alleviating the need for EF AK . In other cases, the TK model 18

may be used to derive EF AK

. 19

20

3.2.2.2. Use of Ratios 21

When AUC or concentration at s teady state is the relevant dose metric, and if advanced 22

TK models are not available, EF AK can be derived using a ratio of doses producing the same 23

AUC value. This is ac complished by identifying external doses associated with the AUC value 24

produced in ani mals at the point of departure (AUC A ), demonstrated below ( see Equation 1 and 25

Figure 4 ). The human dose that produces the same AUC value as observed in animals (AUC A ) is 26

the TK equivalent dose. In these cases, differences between the animal and the human dose 27

producing the same AUC value in each species are captured as the DDEF. See below: 28

29

30

31

32This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 26 o f 49 DRAFT: DO NOT CITE OR QUOTE AUC = Do se/Clearance ( 1 ) 1

2

AUC A = D A / Cl A = D H / Cl H 3

4

5
Using these data, EF AK is calculated according to E quation 2

. 6

7

(2) 8

9

10
Using AUC as an example, the value for the dose metric would be AUC A , that is the 11

AUC value determined in animals at the POD. Thus

, in this example, Equation 2 can be 12

conceptualized as 13

14

EF AK = D A producing AUC A / D H producing AUC A (3) 15

16

where 17

AUC A = area under t he curve in the animal 18

D A = the animal external dose 19

D H = the human external dose

. 20

21

22
This is graphically presented in Figure 4. 23

24This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 27 o f 49 DRAFT: DO NOT CITE OR QUOTE 1

2
Figure 4

. Interspecies extrapolation based on AUC. In this example, AUC is the

appropriate do se metric, and the relationship between dose and AUC is determined in
animals and in humans. This method can be used to develop a Human Equivalent Dose

or Concentration , or in the calculation of E F AK

. Calculation of E F AK requires knowledge
of applied dos es in animals (D A ) and in humans (D H ) that produce the AUC value
determined in animals at the point of departure (AUC A ).

3

4

Because clearance values are the mathematical reciprocal of internal dose (AUC), they 5

may also be used to calculate a DDEF value. As humans are assumed to be more sensitive than 6

experimental animals (in this instance, they clear toxicants more slowly), the human clearance 7

value remains in the denominator. Calculations using C

max are developed in a manner similar to 8

that for AUC. 9

10

3.2.3. Rela tionship to Other EPA Guidance 11

The development and use of advanced information on tissue dosimetry to serve as the 12

basis for quantitative, nondefault uncertainty factors is consistent with existing EPA guidance 13

and philosophy (U.S. EPA, 2006

, 2002 ). The E PA’s Inhalation Reference Concentration 14

Methodology presents a continuum of approaches from complete lack of knowledge to 15This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 28 o f 49 DRAFT: DO NOT CITE OR QUOTE biologically based dose

- response models (U.S. EPA, 1994). T here are two approaches that each 1

cover the interval between lack of knowl edge and knowledge of target tissue and target tissue 2

concentrations in test species and humans. The first is for reactive (Category 1 ) gases and 3

inhaled particles that damage portal of entry (respiratory tract) tissues, and the second is for 4

gases that a re absorbed and produce their toxicity in tissues bathed by circulating blood 5

(Category 3 gases). For C ategory 1 gases, toxicity information identifies the affected region of 6

the respiratory tract and species differences in regional respiratory tract surf ace area and airflow 7

(respiratory rate) serve as the basis to quantify species differences in dosimetry. For C ategory 3 8

gases, species differences in the solubility of the compound in blood (the blood:air partition 9

coefficient) serve as the basis upon whi ch to quantify species differences in dosimetry. More 10

recent guidance (U.S. EPA, 2011 ) on orally encountered toxicants instructs the application of 11

dose scaling by the ratio of species body weights raised to the 3⁄4 power (human BW:animal 12

BW) 3/4 . Each of t hese guidance documents indicates that their approaches are intermediates, to 13

be superceded when more detailed information on tissue dosimetry can be developed. The 14

subject of the present guidance is the development and interpretation of quantitative 15

toxi cokinetic data for the purpose of developing nondefault values for inter

- and intraspecies 16

uncertainty/extrapolation. 17

18

3.2.4. Conclusions for EF AK 19

Mathematically, EF AK may be the ratio of the external doses in animals at or near the 20

POD to the value at a central tendency measure of external doses in the general human 21

population that each result in the same level of the dose metric (this represents developing the 22

Human Equivalent Concentration or the Human Equivalent Dose )

. EF AK values may be 23

calculated for multip le organs/effects . T he same PODs should be used for test animals and 24

humans for a given organ/effect. Quantitatively, DDEF values for UF A components might be 25

less than 1 if humans are less sensitive

. 26

Confidence in EF AK is increased when decisions and cal culations are well documented 27

and made transparent. This includes description of t oxicity data identifying the target tissue, 28

chemical species, MOA

, and species concordance of effects. Data describing the TK

, the 29

metabolism of the compound

, and the relat ionship between administered dose and internal dose 30This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 29 o f 49 DRAFT: DO NOT CITE OR QUOTE are also summarized. Data that show a linear relationship between external dose and internal 1

dose metrics can be specifically reiterated in this description; this will indicate generalizability of 2

the EF AK to doses that may be higher or lower than those used in its calculation. Because 3

animal

- to

- human differences in target tissue concentrations may not be consistent for all 4

responding tissues or organs, a comparison of POD and DDEF values from multiple a ffected 5

organs will increase confidence in health

- protectiveness of the developed DDEF value for the 6

critical organ. R esults can be presented in tabular form for ease of comparison across endpoints. 7

8

3.3. INTRASPECIES TOXICOKINETIC EXTRAPOLATION ( EF HK ) 9

This se ction provides a discussion of the quantitative differences in the TK among 10

humans for intraspecies extrapolation ( EF HK ). From a toxicokinetic standpoint, among humans 11

experiencing the same external dose, susceptibility is due to higher target tissue conc entrations of 12

the toxicant in some individuals or group s relative to the majority of the human population . TK 13

differences for intraspecies extrapolation are characterized as the ratio of an internal dose metric 14

attained in the general human population to the dose metric from susceptible humans exposed to 15

the same e xternal dose or concentration. Illustrative examples are included in the appendix. 16

17

3.3.1. Considerations for EF HK 18

3.3.1.1. Susceptible Group s or Individuals 19

Potentially susceptible group s /lifestages ( e.g., chi ldren , elderly

, or age

- related 20

susceptibility

, or those with a disease making them susceptible to a toxicant) can be identified. 21

In some instances, individuals may have a condition or difference in some physiologic or 22

biochemical process that may be a det erministic factor in dosimetry that serves as the basis for 23

assumed sensitivity (e.g., polymorphism of a given metabolizing enzyme). In these cases, the 24

distribution of the dose metric among the population will not have a unimodal distribution ( see 25

Figur e 5 , left panel ). In other cases, sensitivity may be distributed throughout the general 26

population, and sensitive individuals may be those in the tail of the distribution (i

. e., unimodal; 27

see Figure 5 , right panel ) . Documenting this information and/or the se assumptions serves as the 28

basis for selecting a unimodal or a bimodal distribution of sensitivity. The selection of a bimodal 29

or unimodal

- base d analysis will be a function of the available data and must be made on a 30This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 30 o f 49 DRAFT: DO NOT CITE OR QUOTE Figure 5

. Intraspecies t oxicokinetics. From a toxicokinetic standpoint, susceptibility is
based on attaining higher target tissue concentrations of the toxicant. For this evaluation,
a fixed exposure is studied

, and human interindividual variability is measured as differences in the value of the dose metric between sensitive and generally representative
population groups. When a group of the population can be identified as potentially
susceptible, toxicokinetic data from that group can be compared to the genera l population
(left panel). EF HK should be determined as the ratio of the level of the dose metric at
some point in the upper 50% of the distribution (i.e., 95 th , 97.5 th , 99 th percentile) for those

deemed sensitive to the level of the dose metric at a cent ral tendency measure of the
general population. However, when a separate distribution of values for the susceptible
population is not available, then a slightly different analysis is conducted (right panel). In

this case, EF HK should be determined as the ratio of the level of the dose metric at a
percentile of the population considered sensitive (i.e., 95 th , 97.5 th , 99 th percentile) to the
level of the dose metric at a central tendency measure of the general population.

1

2

chemical

- by

- chemical basis. The decision to quantify differences via a unimodal or bimodal 3

analysis should be undertaken on a chemical

- by

- chemical basis and be based on the strength of 4

the available data for the chemical and for the susceptible population group. One of the 5

challenges in conducting a bimodal analysis will be the availability of data describing chemical 6

disposition and/or physiological and biochemical parameters for the susceptible population 7

group. 8

9This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 31 o f 49 DRAFT: DO NOT CITE OR QUOTE 3.3.1.2. Target Tissues 1

When responses are observed in several organs at or near t he same dose level, a 2

comparison of EF HK values developed for those tissues will be informative. However, the 3

selection of a target organ for calculating human variability other than the one serving as the 4

basis for animal

- to

- human extrapolation needs to be accompanied with a justification. This also 5

extends to instances in which human studies identify effects in an organ or tissue and variability 6

is assessed in another organ or tissue. The extrapolation approach will be perceived as most 7

consistent when the same tissue or organ is used for each phase of the extrapolation procedure. 8

9

3.3.1.3. Dose Response 10

Because variability in internal dosimetry may be a function of dose, the selection of the 11

external exposure (e.g., inhaled concentration or orally ingested dose ) is important. 12

Conceptually

, the animal POD is first extrapolated to produce a toxicokinetically equivalent 13

human dose or concentration. The DDEF for interspecies differences in TD should be applied to 14

the tissue concentration defining the Human Equival ent Exposure to complete interspecies 15

adjustment. It is this species

- adjusted concentration that is most appropriate for application in 16

the evaluation of human interindividual variability. 17

The basis for comparison of human variability is at the level of t he internal, rather than 18

the external dose. Thus, it is important that the relationship between internal and external doses 19

be well characterized. Comparisons of the external doses that produce the same level of the 20

internal dose (between susceptible and nonsusceptible groups) can be substantially complicated 21

when there are nonlinearities in the relationship between external dose and internal 22

concentration. This is particularly difficult when nonlinearity of dose is for one group and not 23

for the other. This complication can be avoided when the comparison is made because 24

difference s in internal doses developed from the same external exposure. 25

Specific differences among humans, particularly those demonstrated in vitro (i.e., 26

intrinsic clearance), are most reliable when they are translated into differences in dosimetry

. 27

This may include evaluations of multiple different doses. 28

29This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 32 o f 49 DRAFT: DO NOT CITE OR QUOTE 3.3.2. Computation 1

For intraspecies TK extrapolation, differences in dosimetry are characterized for human 2

groups or lifestages by compa rison to the general population. Thus

, the comparisons are among 3

differences in internal dosimetry (or target site dose) resulting from the same external exposure. 4

To address human variability, some attention must be devoted to identifying a susceptible 5

population group or a fraction of the general population considered to be sensitive. TK data are 6

then analyzed to determine values for the dose metric in the general and sensitive groups. 7

8

3.3.2.1. Use of TK Models 9

A PBPK or other TK model provides the most robust approach for evaluating 10

intraspecies TK extrapolation. The model is subject to evaluation as previously described 11

(U.S. EPA, 2006 ). When an appropriate model is available, it can be used in different ways 12

depending on the model. In some cases, the TK m odel may directly account for within human 13

variation and/or include data from the sensitive group

, thus e liminating the need for EF HK . In 14

other cases, the T K model may be used to derive dose metric values for calculat ing the value of 15

EF HK

. 16

17

3.3.2.2. Use of Ratio s 18

Where TK models are not available

, EF HK can be derived using a ratio ( see Equation 4 ). 19

T he value for the dose metric employed for the general population ( e.g., AUC gen ) would be that 20

level of the dose metric identified from initial studies with animals o r humans and further 21

extrapolated to account for interspecies differences in toxicodynamics. The value for the dose 22

metri c in sensitive individuals (e.g., AUC

sens ) s hould be determined from empirical data or 23

pharmacokinetic modeling. 24

25

26

( 4 ) 27

28This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 33 o f 49 DRAFT: DO NOT CITE OR QUOTE w here 1

EF HK = factor for intraspecies extrapolation covering toxicokinetics 2

AUC gen = a rea under the curve at a measure of central tendency in the general human 3
population 4

AUC

sens = a rea under the curve at a percentile of interest in the sens itive human population 5

Cl gen = c learance at a measure of central tendency in the general human population 6

Cl

sens = c learance at a percentile of interest in the sensitive human population

. 7

8

9
Because clearance values are the mathematical reciprocal of int ernal dose (AUC), they 10

may also be used to calculate a DDEF value. Because susceptible humans may be assumed to be 11

more sensitive than general humans ( e.g., they clear toxicants more slowly), the sensitive human 12

clearance value remains in the denominator. 13

14

3.3.3. Conclusions for EF HK 15

The EF HK is essentially a comparison of internal doses resulting from the same external 16

exposure to both the general population and sensitive individuals. When using an empirical 17

ratio , the EF HK is the ratio of the dose metric value at a percentile of the distribution intended to 18

represent sensitive individuals to the dose metric value at a central tendency measure of the 19

general population. Quantitatively, DDEF values for human interindividual variability can not be 20

less than one

. 21

T he dose selected for quantifying human interindividual variance may have an impact on 22

the magnitude of variability. The dose adjusted from the animal POD is the preferred dose for 23

quantitation of human variability

. While DDEF values may be calculated for multiple 24

organs/effects (or even doses), the same external dose needs to be used as the starting point when 25

calculating dose metric values f or the sensitive and the general populations. 26

Documentation should descri be the mathematical method to be employed

, the type of 27

distribution and percentile ( s ) of interest ; the dose metrics (e.g., AUC of parent compound in 28

kidney)

, and the target tissues for which EF HK are developed. Confidence in the extrapolation is 29

improved when distribution types are justified or e xplained. 30

31This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 34 o f 49 DRAFT: DO NOT CITE OR QUOTE

4. DDEF s BASED ON TOXICODYNAM ICS (TD) 1

4.1. GENERAL CONSIDERATIONS 2

Toxicodynamics describes the critical interaction of the active chemical moiety with the 3

target site and the ensuing sequence of events leading to toxicity

. Data that describe the dose

4

r esponse relationship serve as the basis for deriving extrapolation factors for toxicodynamic 5

components. This section provides a discussion of factors common to inter

- and intraspecies 6

extrapolation for TD. In contrast to TK, which focuses on differences in internal dosimetry , TD 7

differences are quantified as differences in concent ration 6 producing the same level of response 8

between animals and humans

, as well as among humans. TD evaluation s may include multiple 9

response leve ls, critical effects

, key eve nts

, or analytical methods

. Developing a DDEF for TD 10

requires knowledge about the relationship between an event measured in vitro or in vivo (e.g., 11

receptor binding) and the end result (the adverse health condition). Doses or concentrations 12

producing the measured event can be obtained in vitro or in vivo, but they must be obtained in 13

the tissue of interest or a suitable surrogate. TD models, the most complex of which may be 14

represented by BBDR models, represent an important tool through which predictions may be 15

confidently made to extend the range of empirical observations. Comparisons between animals 16

and humans or to quantify human interindividual differences are made on the basis of doses or 17

concentrations that produce the same level of the same measur ed respons e. 18

Quanti t ative differences b etween animals and humans are used for interspecies 19

extrapolation ( EF AD ), whereas differences in susceptibility within the human population are used 20

for the intraspecies extrapolation ( EF HD ). Thus, the EF AD is used t o extrapolate findings in 21

laboratory animals to the general human population , and the EF HD is used to extrapolate to 22

sensitive human group s and life stages . The TD portion of each ( EF AD , EF HD ) is combined with 23

the corresponding TK factor to form the compo site extrapolation factor

. 24

Although a complete MOA understanding is not required, derivation of a DDEF for TD 25

relies heavily on understanding a MOA for the critical effect(s) i dentified for risk assessment

. 26

I mportant questions to address include the follo wing: 27

6 When using a biologically based dose

- response model, differences may be quantified as the ratio of dose metrics in
respective species or population groups producing the same level of the response. However, DDEF values for TD
may also be quantified as the ratio of in vitro concentrations producing the same level of the response.This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 35 o f 49 DRAFT: DO NOT CITE OR QUOTE What is /are the critical effect(s) and POD(s) being used for this assessment? ( E ach of 1

these should be considered in this process

. ) 2

What is the MOA or mechanism(s) for that toxicity? Have the key events been 3
identified? Can they be measured? 4

Is th e MOA or mechanism(s) in the animal model relevant to humans (qualitatively 5
and/or quantitatively)? 6

Are the data on the key events amenable to modeling such that a uniform measure in 7
animals and humans can be derived? If not, do the available data points include a 8
response level that is sufficiently similar in animals and humans? 9

Are there data in human populations that describe population variation? Do these data 10
identify a sensitive group (s) or lifestages ? Can the degree of this sensitivity be 11

estimate d? 12

13

14

4.1.1. Mode of Action 15

TD extrapolation should be endpoint driven ( considered in the context of the toxic 16

endpoints most relevant for purposes of risk assessment ) . The choice of critical effect should be 17

justified, when possible, based on findings of respon se in exposed humans. Understanding MOA 18

for the agent(s) of interest helps to ensure that the TD responses used to derive the DDEF will be 19

robust scientificall y. Th ese response s could include receptor affinity, enzyme inhibition

, and 20

molecular change s

, a mong others. R epair of DNA or tissue damage, biological thresholds, 21

residual function

, and other processes that could contribute to nonlinearity in effect are 22

considered and discussed. Experimental systems and measured responses should be the same or 23

com parable. 24

25

4.1.2. Relating Response to Dose or Concentration 26

TD data may be developed from the results of in vivo or in vitro studies. In some cases, 27

in vivo data may be used, but care should be taken to control for the influence of toxicokinetic s. 28

If there are existing human data measuring the response, then these data can be used to derive the 29

POD, thereby removing the need for the UF A

. Likewise, if there are data from the mo st sensitive 30

human group , those data c ould be used for the risk assessment , and an UF H may not be needed. 31

Care should be taken to ensure that kinetic factors do not confound the interpretation of 32

response data. Comparisons based on internal dose metric are preferred over applied dose ; that 33This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 36 o f 49 DRAFT: DO NOT CITE OR QUOTE is

, the concentration producing the level of resp onse (rather than applied dose or concentration) 1

is preferred so that TD response may be distinguished from TK differences . Tissue

- specific 2

metabolism could also influence the actual target concentrations and must be considered. Blood 3

levels are an accep table measure of internal dose when it can be shown that they are proportional 4

to concentrations of toxicant in target tissue or biological preparation. 5

When using in vitro systems, the response measured should be representative of the 6

toxicity ; that is, t he measured endpoint should be the same as

— or highly related to

— the critical 7

effect or key event . In cases where the measured response differs, it is important to describe the 8

potential impact of these differences on the final DDEF . When using in vitro d ata, the 9

comparability of chemical uptake between animal and human tissues should be demonstrated. In 10

vitro results should include data describing the test chemical metabolism by the system used to 11

generate response data. 12

13

4.1.3. Range of Doses or Concentrations 14

The relationship between the doses, tissue concentrations

, and/or in vitro concentrations 15

used to derive the DDEF

, and those attained in the toxicity studies characterizing the POD

, 16

should be characterized . Optimally, the concentrations used in studies characterizing response 17

include the concentration at the POD. This is important because the variability in the response 18

may change with increasing or decreasing dose or concentration. Doses and/or tissue 19

concentrations may also be compared to those expec ted from environmental exposure; this is 20

part of the consideration of overall relevance of the test system

. 21

22

4.2. INTERSPECIES TOXICODYNAMIC EXTRAPOLATION ( EF AD ) 23

This section provides information on calculating TD differences between species . These 24

are charact erized as the ratio of the concentrations (concentrations used in vitro or the level of 25

the dose metric) in animals and humans producing the same level of response. Note that the 26

level of comparison is the response, and it is not a comparison of responses produced by the 27

same concentration ( see Figure 6 )

. Illustrative examples are included in the appendix. 28This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 37 o f 49 DRAFT: DO NOT CITE OR QUOTE Figure 6

. Interspecies t oxicodynamics. The TD difference between test animals and

humans is calculated from dose or conc entration

- response relationships most often
determined in test systems or animals generally representative of the respective species.
The comparison is made for doses or concentrations producing the same level of

response

, and comparisons are made using v alues representing the central tendency.

1

2

4.2.1. Considerations for EF AD 3

4.2.1.1. Mode of Action 4

Endpoint(s) must be chosen from which to derive the EF AD , and it is preferred for the 5

endpoint(s) to be the actual critical effect or a key event in the TD pathway. For each endpoint 6

evaluated, it must be determined whether the data are from an animal typical of the responding 7

species/strain/sex/lifestage opposed to an animal model system that may be unusually sensitive 8

for a particular effect. This might be important in tra nsgenic animals and in animal models used 9

to study specific human diseases (e.g., spontaneously hypertensive rats). Animal models and 10

MOA(s) based on them are evaluated for human relevance. 11

12

4.2.1.2. Target Tissues 13

Where there are data from the molecular targets i n both species, but the data are not from 14

the critical target organ, the data can be used only if there is sufficient information that one tissue 15

is an appropriate surrogate for another. For example, a target enzyme may be present in several 16This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 38 o f 49 DRAFT: DO NOT CITE OR QUOTE tissues, incl uding blood; however, blood is easily obtained from humans

, but tissue from the 1

target organ is not. Studies may show that the chemical effect on this target enzyme in blood 2

correlates very well and is entirely predictive of the effect in the target organ , and indeed the 3

enzyme structure, function

, and chemical affinity is the same regardless of tissue. Such 4

information would be necessary to allow using comparisons of chemical effects in the blood 5

enzyme in both humans and laboratory animals

. 6

7

4.2.1.3. Dose Respo nse 8

The choice of response level to use for comparison depends on many factors: 9

10

Completeness of dose response 11

L in earity of the dose response 12

U nderstanding of the effect along the toxic p athway at that response level 13

14

15
The magnitude of EF AD may be a funct ion of the response level chosen for extrapolation. 16

Confidence is increased when the response level employed for EF AD calculation approximates 17

the response level at the POD and when the ratio of doses producing the same response level in 18

animals and human s is similar over a range of doses

. When data are available to describe the full 19

dose

- response curve, e valuating the shape of the dose curves for animals and humans can 20

provide important information. I f the shapes of the curves are different, then the ma gnitude of 21

EF AD will depend on the response level selected. Note that concentrations causing greater 22

magnitude s of effect may also produce nonspecific cellular changes that could confound the 23

comparisons. 24

25

4.2.1.4. In Vitro Data 26

When using data from in vitro syst ems, the activity of the parent chemical and/or 27

metabolites , as well as the extent of metabolism of the compound by the in vitro system , should 28

be known . The in vitro assay should measure a response that can be linked to the toxic outcome, 29

and the assays should employ the same (responding) tissues from the in vivo test animal 30

species/strain/sex/lifestage and from humans. Experimental systems should be as closely 31This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 39 o f 49 DRAFT: DO NOT CITE OR QUOTE matched between species as possible, and the concentrations of toxicant in vitro should be 1

com pared to tissue concentrations (the dose metric) at the POD

. S ee S ection 2.2.3.2 for other 2

general considerations. 3

4

4.2.2. Computation 5

4.2.2.1. Use of TD Models 6

A biologically based dose response or other TD model provides the most robust approach 7

for evaluating interspe cies TD extrapolation. The model is subject to evaluation as described 8

previously (U.S. EPA, 2006 ) . When available, the model can be used to inform several 9

decisions, depending on the model. In some cases, the TD model may be used directly to 10

perform in terspecies extrapolation and to derive a Human Equivalent Concentration or Dose that 11

includes TD considerations, thus alleviating the need for EF AD . In other cases, the TD may be 12

used to derive the EF AD used. 13

14

4.2.2.2. Use of Ratios 15

When PD models are not availabl e, EF AD would be calculated as a ratio describing the 16

relationship between the tissue concentrations producing a set response in human compared to 17

animal tissues, preferably at, or near, the response level at the POD. For example, ―x response 18

level‖ may b e a 10% response if ED 10 or BMD 10 is used. The EF AD would be calculated as 19

follows: 20

21

( 5 ) 22

23

where 24

EF AD = f actor for interspecies extrapolation covering 25
toxicodynamics 26

Concentration A

- - x response level = c oncentration of the ag ent at the tissue in the animal 27
resulting in a x % response 28

Concentration H

-- x response level = c oncentration of the agent at the tissue in the human 29
resulting in a x % response , where x is the same response 30

value

. 31This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 40 o f 49 DRAFT: DO NOT CITE OR QUOTE To evaluate the extent to which the shape of the dose

- response curve varies between 1

animals and humans and

, thus

, impacts the magnitude of the EF AD , a range of response levels 2

should be evaluated . The rationale and implications for choosing the point for extrapolation 3

should also be presented. 4

5

4.2.3. C onclusions for EF AD 6

Mathematically, the EF AD will be the relationship between the concentrations or dose 7

metric values resulting in the same level of response in both the test species and the generally 8

re presentative human (often the 70

- kg adult male)

. DD EF values may be calculated for multiple 9

PODs and organs/effects, but the same response levels in animals and humans should be used for 10

quantitation when possible. Confidence in the value (knowing whether the DDEF value may 11

vary depending on the response level) is improved when EF AD values developed from multiple 12

points on the concentration

- response curve are compared; the shape/slope of the curves may also 13

influence these values. Quantitatively, EF AD can be less than one if the data show humans are 14

inher ently less sensitive than animals. 15

A summary of all conclusions and their scientific support should be provided . Data 16

describing the dose response of the compound in animals and humans can be specifically 17

reiterated in this description; this will indicate the extent to which the EF AD value can be 18

generalized to doses that may be higher or lower than those used in its calculation. 19

20

4.3. INTRASPECIES TOXICODYNAMIC EXTRAPOLATION ( EF HD ) 21

This section describes derivation of the EF HD

. TD variability within the human 22

population is calculated as the relationship between concentrations or dose metric values 23

producing the same level of the response in the general population and in susceptible groups or 24

individuals

. From a toxicodynamic standpoint, susceptibility is base d on attaining a given level 25

of response at a lower concentration of toxicant. For this evaluation, multiple response levels, 26

critical effects (or key events), analytical methods

, or susceptible groups or individuals may be 27

considered. No data sets were identified upon which a conclusive case study example could be 28

developed for intraspecies toxicodynamic extrapolation. 29

30This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 41 o f 49 DRAFT: DO NOT CITE OR QUOTE 4.3.1. Considerations for EF HD 1

4.3.1.1. Susceptibl

e Group s or Individuals 2

Susceptibility in the human population may be due to lifestage, health status or disease 3

state, genetic disposition

, or other factors. Considering susceptibility to more than one critical 4

effect may require consideration of more than one life

- stage; critical windows of development, 5

and

, therefore, windows of susceptibility, occur a t different times for various tissues, organs

, and 6

systems. Currently, sufficient data to address susceptibility are rarely available; however, 7

r esearch in this area is rapidly expanding . For example, population variation, such as genetic 8

polymorphisms, is an expanding area of study. It is anticipated that the increased availability 9

and experience applying ―omics‖ technologies will benefit the derivation of DDEF s

, in general

, 10

and EF HD

, in particular. A data

- derived EF HD is feasible

, given human data are of sufficient 11

quality; the data address aspects of the critical effect consistent with that identified from 12

applicable human or animal studies; and the stud ies have been conducted in the segment(s) of 13

individuals or the population deemed sensitive. 14

Ideall y, data will be robust enough to enable more than point estimates in the general and 15

susceptible groups. As discussed in more detail below, distributional analysis of response data 16

should be conducted to identify points for use in quantitation. The relat ionship between the 17

measured response and the toxicity endpoint of concern (e.g., critical effect or key event) should 18

be described , whether determined in vivo or in vitro

. 19

20

4.3.1.2. Target Tissues 21

For calculation of EF HD , d ata for multiple responding tissues can b e evaluated

, and 22

multiple DDEF s can be derived. It is particularly important to evaluate those tissues that 23

demonstrate response at doses or concentrations near those for the critical effect. 24

25

4.3.1.3. In Vitro Data 26

Given the constraints on generation of human r esponse data in vivo

, in vitro studies offer 27

an appealing alternative. Samples selected for in vitro investigation should represent the general 28

human population as well as those groups or individuals thought or demonstrated to be 29

susceptible. See S ection 2.2.3.2 for other general considerations

. 30

31This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 42 o f 49 DRAFT: DO NOT CITE OR QUOTE 4.3.2. Computation 1

For TD extrapolation, the goal is to determine the difference between humans on the 2

basis of concentration producing the same response level. For quantitation, data on the critical 3

response(s) are de rived from a population that includes susceptible groups or individuals. 4

Because the data available to define potentially susceptible groups or individuals could be 5

viewed in different ways, a statistical analysis may be helpful to determine distribution type ( see 6

Figure 7 ): 7

8

A unimodal distribution where the potentially susceptible group(s) represent the tail of 9
the distribution because they cannot be separated from the general population

. 10

A bimodal (or multimodal) distribution where the group(s) can be r eadily identified

. 11

12

13
Documenting critical response data, assumptions made

, and the distribution selected will 14

serve as the basis for quantitation. 15

16

4.3.2.1. Use of TD Models 17

A biologically based dose response or other TD model provides the most robust approach 18

for evaluating intraspecies TD extrapolation. When sufficient data are available, these TD 19

models can be structured and exercised to include differences in mode

- of

- action components that 20

may be lifestage

- dependent or influenced by other potentially susceptib ility

- inducing conditions 21

such as genetic polymorphisms. Specific to EF HD , it is critical that the model parameter 22

reflecting the underlying cause of susceptibility in a group be well documented. When an 23

appropriate model is available, it can be used in different ways depending on the model. In some 24

cases, the TD model may directly account for within human variation and/or include data from 25

the sensitive group

, thus el iminating the need for EF HD

. In other cases, the TD may be used to 26

derive EF HD

. 27

28

4.3.2.2. Use o

f Ratios 29

When TD models are not available and there are groups or individuals that can be 30

identified as sensitive, then the EF HD may be defined as the ratio between the concentrations 31

32This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 43 o f 49 DRAFT: DO NOT CITE OR QUOTE Figure 7

. Intraspecies t oxicodynamics. D DEF values for TD are defined by ratios of
concentrations producing the same level of response in the general population and some
defined percentile (e.g., 1 st , 2.5 th , 5 th , etc.) for the distribution representing sensitive
individuals. When a specific gro up of the population can be identified as potentially
susceptible, TD data from that group can be compared to the general population ( P anels A1
and A2). Panel A1 presents a dose

- response curve (cumulative distribution plot) for both
populations that demon strates the central tendency (solid line) and confidence bounds, or
bounds of variability (dashed lines)

, for data obtained from the general population and from
an identifiable sensitive group. In this example, the level of response (Y

- axis) has been

sele cted (e.g., 10%

- response level), and the concentrations producing this level of response in
the general and sensitive populations/groups are obtained from the X

- axis. Panel A2 is

derived from the same data used for P anel A1, but it presents the distributi on of
concentrations producing the defined level of response only; no other dose

- response data are

carried over into P anel A2. Alternately, when potentially susceptible individuals represent a
small percentage of the general population ( P anels B1 and B2), a slightly different analysis is

conducted. In this case, EF HD should be determined as the ratio of the concentrations
producing the same level of response (1) at a measure of the central tendency in the
population to (2) the concentration producing the response level at a percentile of the general
population considered sensitive (e.g., 1 st , 2.5 th , 5 th percentile). Panel B1 demonstrates this
comparison using the concept of confidence bounds on the dose

- response relationship

, and

P anel B2 demonstrates the distribution of concentrations producing the response, only at the
response level chosen for comparison (e.g., the 10%

- response level).This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 44 o f 49 DRAFT: DO NOT CITE OR QUOTE producing the same level of response in the general population and a lower percentile in the 1

sensitive group (see Figur e 7) using Equation 6 : 2

3

( 6 ) 4

5

where 6

EF HD = factor for intraspecies extrapolation covering toxicodynamics 7

Concentration gen = c oncentration producing the in response the general human 8
population 9

Concentration

sens = c oncentrat ion producing the response at a percentile of interest for 10
the sensitive group

. 11

12

13
When sensitivity among the population exhibits a unimodal distribution, the EF HD is the 14

ratio of the concentration that elicits a level of response at the central tendency of the distribution 15

to the concentration that elicits the same level of response in sensitive individuals (e.g., 5 th , 2.5 th

, 16

and 1 st percentiles of the distribution; sensitive individuals will respond at lower concentrations)

. 17

It is important to define and justify the point(s) in the distribution representing sensitive groups 18

or individuals. 19

When sensitivity among the population exhibits a bimodal (or multimodal) distribution, 20

the DDEF is determined in a similar manner, using the concentration s (e.g., 5 th , 2 .5 th

, and 1 st 21

percentiles of the concentration distribution) that elicit the specific level of response in the 22

sensitive individuals for the most susceptible group (s) . The values selected to describe the 23

potentially sensitive group(s) or individuals are d efined and presented at varying levels . T he 24

selection of the response level and the percentile of the distribution used to describe the 25

potentially sensitive group(s) or individual(s) is a n important issue s

. This is a situation where the 26

communication be tween risk assessment and risk management is essential. 27

28

4.3.3. Conclusions for EF HD 29

A biologically based dose response or other TD model provides the most robust approach 30

for evaluating intraspecies TD extrapolation. When using empirical ratios , the EF HD will b e the 31This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 45 o f 49 DRAFT: DO NOT CITE OR QUOTE ratio of the concentration producing the specified level of response in the general human 1

population to the concentration producing the same level of response in susceptible groups or 2

individuals. Increased confidence in the EF HD is developed when t he concentration used for the 3

comparison of responses is compared to doses or concentrations at the POD. Quantitatively, 4

EF HD can not be less than one

. 5

The risk assessor describes all choices and their rationales, including the use of m ultiple 6

response lev els, critical effects (or key events), analytical methods

, or data from susceptible 7

groups or individuals

. The conclusions include a clearly worded description of the mathematical 8

method (s) employed and a presentation of the relationship between the measu red response and 9

toxicity ( i.e., critical effects or key events ). This description should clearly identify and provide 10

the justification for available data and points in the distribution(s) representing sensitive 11

individua ls. Attention should be paid to c haracterizing the distribution type employed for 12

analysis; uncertainty in the choice of distribution type can be reduced by presenting DDEF 13

values resulting from multiple distribution types. 14

15This document is a draft for review purposes only and does not constitute Agency polic y.

5/11/11 Page 46 o f 49 DRAFT: DO NOT CITE OR QUOTE 5. FINAL STEPS 1

The composite DDEF is calculated after the appropri ate DDEF values for inter

- and 2

intraspecies differences in TK and TD have been derived. The composite factor is calculated by 3

multiplying the specific factors (default and/or DDEF s), as shown in Equation 7 . This is entirely 4

analogous to calculating compo site UF s when using the 10 × defaults for UF A and UF H

. The 5

composite DDEF may be less or greater than 100. 6

7

8

CF = EF AK × EF AD × EF HK × EF HD ( 7 ) 9

10

where 11

CF = composite uncertainty factor 12

EF AK = factor for interspecies extrapolation covering toxicokinetics 13

EF AD = factor for interspecies extrapolation covering toxicodynamics 14

EF HK = factor for intraspecies extrapolation covering toxicokinetics 15

EF HD = factor for intraspecies extrapolation covering toxicodynamics 16

17

18
In practice, data may only be available to develop a DDEF for one component of 19

extrapolation or another (e.g., data for EF AK but not EF AD ). In these cases

, the remaining 20

extrapolation is done by an appropriate default procedure

. As such, DDEF s and defaults (i.e., 21

UFs) are used in combination. O ften this default will be a 3 × UF

— as described in the existing 22

RfC methodology and the 3⁄4 body

- weight procedure ( U

. S

. EPA, 2011

, 1994 ) . When data are not 23

available to develop DDEF s for ei ther component of interspecies or intraspecies extrapolation, 24

the 10 × default value for the uncertainty factor is applied. 25

F i nally, the composite factor provides the total magnitude of the factor

. The values 26

derived for each of the components and the resulting extrapolations should be clearly reported 27

and characterized. T he relationship of each of these doses or concentrations to both the POD and 28

to doses or concentrations likely attained from environmental exposures should be presented. 29

30This document is a draft for review purposes only and does not constitute Agency polic y.

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U.S. EPA (U.S. Environmental Protection Agency) (2011) Recommended Use of Body Weight3 ⁄ 4 as the Default 19

Method in Derivation of the Oral Reference Dose . Risk Assessment Forum, Washington, DC; EPA100/R

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