EPA-540-R-070-002 

OSWER 9285.7-82 

January 2009 

Risk Assessment Guidance for Superfund 

Volume I: Human Health Evaluation Manual 

(Part F, Supplemental Guidance for Inhalation Risk Assessment)

Final 

Office of Superfund Remediation and Technology Innovation

Environmental Protection Agency 

Washington, D.C. 
TABLE OF CONTENTS

1. INTRODUCTION......................................................................................................................1 

1.1 Background....................................................................................................................1 

1.2 Purpose and Scope .........................................................................................................2

1.3 Effects on Other Office of Superfund Remediation and Technology 

Innovation Guidance................................................................................................3 

2. BACKGROUND ON DERIVATION OF INHALATION TOXICITY VALUES ..............4 

2.1 Application of Inhalation Dosimetry .............................................................................4 

2.1.1 Default Approach - Extrapolation from Experimental Animal Data..............5 

2.1.2 Default Approach - Extrapolation from Human Occupational Data ..............9 

2.2 Derivation of the Inhalation Unit Risk.........................................................................10 

2.3 Derivation of the Reference Concentration .................................................................10 

3. CHARACTERIZING EXPOSURE .......................................................................................13 

3.1 Introduction..................................................................................................................13 

3.2 Estimating Exposure Concentrations for Assessing Cancer Risks..............................13 

3.3 Estimating Exposure Concentrations for Calculating Hazard Quotients.....................14 

3.3.1 Step 1: Assess Duration ................................................................................14 

3.3.2 Step 2: Assess Exposure Pattern...................................................................15 

3.3.3 Step 3: Estimate Exposure Concentration.....................................................17 

3.4 Estimating Exposure Concentrations in Multiple Microenvironments .......................18 

3.4.1 Using Microenvironments to Estimate an Average Exposure 

Concentration for a Specific Exposure Period.......................................................18 

3.4.2 Estimating an Average Exposure Concentration Across Multiple 

 Exposure Periods ...................................................................................................19 

4. SELECTING APPROPRIATE TOXICITY VALUES........................................................20 

4.1 Sources for Inhalation Toxicity Data...........................................................................20 

4.2 Recommended Procedure for Assessing Risk in the Absence of 

 Inhalation Toxicity Values...........................................................................................21 

5. ESTIMATING RISKS ............................................................................................................22

5.1 Cancer Risks Characterized by an Inhalation Unit Risk..............................................22 

5.2 Hazard Quotients .........................................................................................................24 

6. EXAMPLE EXPOSURE SCENARIOS ................................................................................24

6.1 Residential Receptor ....................................................................................................24

6.2 Commercial-Industrial/Occupational Receptor ...........................................................25 

6.3 Construction Worker....................................................................................................25 

6.4 Trespasser/Recreational Receptor................................................................................25 

i 
7. TARGET CONCENTRATIONS FOR SCREENING 

 ANALYSIS OF INHALATION PATHWAYS......................................................................26

7.1 Target Contaminant Concentrations in Air..................................................................26 

7.2 Screening Levels for Other Media...............................................................................26 

7.2.1 Soil Screening Levels ...................................................................................27 

7.2.2 Tap Water Screening Levels.........................................................................28 

7.2.3 Soil Gas or Ground Water Screening Values for Vapor Intrusion ...............28 

8. DEVELOPING AGGREGATE AND CUMULATIVE RISK ESTIMATES ....................28 

8.1 Estimating Cumulative Risk and Hazards Across Multiple Chemicals.......................28 

8.1.1 Cancer Risks .................................................................................................29 

8.1.2 Hazard Quotients ..........................................................................................29 

8.2 Aggregating Risk and Hazard Quotients Across Exposure Routes.............................29 

9. RISK CHARACTERIZATION..............................................................................................30

9.1 Highly Exposed or Susceptible Populations and Life Stages ......................................30 

9.1.1 Children.........................................................................................................30 

9.1.2 Workers.........................................................................................................31 

9.2 Uncertainties in Inhalation Risk Assessment...............................................................31 

9.2.1 Development of Exposure Concentrations ..................................................32 

9.2.2 Toxicity Assessment .....................................................................................32 

9.2.3 Estimating Cancer Risks...............................................................................33 

9.2.4 Estimating Risk and Hazard from Multiple Chemicals and 

Exposure Pathways .......................................................................................33 

10. REFERENCES.......................................................................................................................34 

APPENDIX A ............................................................................................................................ A-1

APPENDIX B .............................................................................................................................B-1 

APPENDIX C ............................................................................................................................C-1 

ii 
LIST OF TABLES 

Table 1: RAGS Part A Equation Describing the Estimation of Inhalation Exposure .....................2 

Table 2: Contaminant Properties and Dosimetric Adjustment Factors ...........................................7 

Table 3: The Use of Uncertainty Factors in Deriving an Inhalation Reference 

Concentration...................................................................................................................12 

Table 4: Recommended Procedure for Calculating Risk-Based Screening Concentrations for 

Contaminants in Air........................................................................................................27 

LIST OF FIGURES 

Figure 1: Human Respiratory Tract .................................................................................................8 

Figure 2: Recommended Procedure for Deriving Exposure Concentrations and Hazard Quotients 

for Inhalation Exposure Scenarios.....................................................................................16 

Figure 3: Guidance on Assessing Risk from Early-Life Exposures for Chemicals 

Acting by a Mutagenic Mode of Action for Carcinogenicity........................................23 

LIST OF EQUATIONS 

Equation 1: NOAEL[ADJ] .................................................................................................................5 

Equation 2: NOAEL[HEC] from Animal Data ..................................................................................6 

Equation 3: NOAEL[HEC] from Human Data .................................................................................10 

Equation 4: Inhalation Unit Risk ...................................................................................................10 

Equation 5: Reference Concentration ............................................................................................11 

Equation 6: Exposure Concentration for Assessing Cancer Risks ................................................14 

Equation 7: Exposure Concentration for Acute Exposure Scenarios ............................................17 

Equation 8: Exposure Concentration Chronic for Subchronic Exposure Scenarios......................18 

Equation 9: Exposure Concentration for a Specific Exposure Period, 

Microenvironments........................................................................................................................19 

iii 
LIST OF EQUATIONS (CONT.) 

Equation 10: Exposure Concentration Across Multiple Exposure Periods, 

Microenvironments........................................................................................................................19 

Equation 11: Cancer Risk ..............................................................................................................22 

Equation 12: Hazard Quotient .......................................................................................................24 

iv 
ACKNOWLEDGEMENTS 

This guidance was developed by the Inhalation Risk Workgroup, which included regional and 

headquarters staff in EPA’s Office of Superfund Remediation and Technology Innovation (OSRTI), 

the Office of Research and Development (ORD), the Office of Children’s Health Protection 

(OCHP), The Office of Air and Radiation (OAR), and the Office of Solid Waste and Emergency 

Response (OSWER). Dave Crawford of OSRTI headquarters and Michael Sivak of EPA Region 2 

provided project management and technical coordination of its development. 

OSRTI would like to acknowledge the efforts of all the Inhalation Risk Workgroup members who 

supported the development of the guidance by providing technical input regarding its content and 

scope: 

Marcia Bailey, Region 10 Deirdre Murphy, OAR/OAQPS 

Bob Benson, Region 8 Henry Schuver, OSWER/OSW

Dave Crawford, OSWER/OSRTI Michael Sivak, Region 2 

Arunas Draugelis, Region 5 John Stanek, ORD/NCEA 

Brenda Foos, OCHP Daniel Stralka, Region 9 

Gary Foureman, ORD/NCEA Timothy Taylor, OSWER/OSW

Susan Griffin, Region 8 John Whalan, ORD/NCEA 

Ofia Hodoh, Region 4 Erik Winchester, ORD/OSP 

Jennifer Hubbard, Region 3 

Ann Johnson, OA/OPEI Former Members: 

Jeremy Johnson, Region 7 Cheryl Overstreet, Region 6 

Kevin Koporec, Region 4 Neil Stiber, ORD/OSP 

Sarah Levinson, Region 1 

OSRTI would also like to acknowledge the efforts of the external peer review panel members 

who provided input on the draft version of the document: 

Sandra Baird, Massachusetts Department of Environmental Protection 

Selene Chou, Agency for Toxic Substances and Disease Registry 

Lynne Haber, Toxicology Excellence for Risk Assessment 

Anita Meyer, US Army Corps of Engineers 

Peter Valberg, Gradient Corporation 

Henry Roman, Eric Ruder, and Tyra Walsh of Industrial Economics, Incorporated in Cambridge, 

MA provided technical assistance to EPA in the development of this guidance under Contract 

Number 68-W-01-05. 

v 
LIST OF ACRONYMS 

μg Microgram 

μm Micrometer 

ADAF Age Dependent Adjustment Factor 

AT Averaging Time 

ATSDR Agency for Toxic Substances and Disease Registry 

BMCL Benchmark Concentration, Lower confidence limit 

BMD Benchmark Dose 

BW Body Weight 

CA Contaminant Concentration in Air 

CERCLA Comprehensive Environmental Response, Compensation, and Liability Act 

CSF Cancer Slope Factor 

DAF Dosimetric Adjustment Factor 

ED Exposure Duration 

EC Exposure Concentration 

EF Exposure Frequency 

EPA Environmental Protection Agency 

ER Extra-respiratory 

ET Exposure Time 

ETh Extrathoracic 

Fr Fractional Deposition in region r 

Ftotal Total particle deposition in respiratory tract 

Hb/g-animal Animal Blood:Gas Partition Coefficient 

Hb/g-human Human Blood:Gas Partition Coefficient 

HEAST Health Effects Assessment Summary Table 

HEC Human Equivalent Concentration 

HI Hazard Index 

HQ Hazard Quotient 

ICRP International Commission for Radiological Protection 

IR Inhalation Rate 

IRIS Integrated Risk Information System 

IUR Inhalation Unit Risk 

kg Kilogram 

LEC10 Lower limit on Effective Concentration, using a 10 percent response level 

LOAEL Lowest Observable Adverse Effect Level 

ME Microenvironment 

MF Modifying Factor 

mg Milligram 

MOA Mode of Action 

MRL Minimal Risk Level 

MW Molecular Weight 

NCEA National Center for Environmental Assessment 

NOAEL No Observable Adverse Effect Level 

ORD Office of Research and Development 

OSRTI Office of Superfund Remediation and Technology Innovation 

vi 
LIST OF ACRONYMS (CONT.) 

OSWER Office of Solid Waste and Emergency Response 

PBPK Physiologically Based Pharmacokinetic 

POD Point of Departure 

ppm Parts Per Million 

PPRTV Provisional Peer Reviewed Toxicity Value 

PRG Preliminary Remediation Goal 

PU Pulmonary 

Q-alv Alveolar ventilation rate 

QSAR Quantitative Structure-Activity Relationship 

RAGS Risk Assessment Guidance for Superfund 

RBC Risk-Based Concentration 

RfC Reference Concentration 

RfD Reference Dose 

RGDR Regional Gas Dose Ratio 

RDDR Regional Deposited Dose Ratio 

RME Reasonable Maximum Exposure 

SA Surface Area 

SSL Soil Screening Level 

STSC Superfund Health Risk Technical Support Center 

TB Tracheobronchial 

TOT Total Respiratory System 

UF Uncertainty Factor 

Ve Minute Volume 

vii 
1. INTRODUCTION 

The Environmental Protection Agency’s (EPA’s) Superfund Program has updated its approach for 

determining risk from inhaled chemicals to be consistent with the inhalation dosimetry methodology 

described in Methods for Derivation of Inhalation Reference Concentrations and Application of 

Inhalation Dosimetry (USEPA, 1994; hereafter, the Inhalation Dosimetry Methodology).1

 This 

document provides Superfund site risk assessors with guidance that should help more consistently 

address the Inhalation Dosimetry Methodology. 

This document outlines recommended processes consisting of a series of steps as well as 

recommended equations for EPA Regions to consider when estimating inhalation exposure and risk 

at Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) sites. 

This guidance is intended to provide a recommended methodology for consistently addressing the 

inhalation pathway in risk assessments for Superfund sites. 

Some of the statutory provisions described in this document contain legally binding requirements. 

However, this document does not substitute for those provisions or regulations, nor is it a regulation 

itself. Thus, it cannot impose legally binding requirements on EPA, States, or the regulated 

community, and may not apply to a particular situation based upon the circumstances. Any 

decisions regarding a particular remedy selection decision will be made based on the statute and 

regulations, and EPA decisionmakers retain the discretion to adopt approaches on a case-by-case 

basis that differ from this guidance where appropriate. EPA may change this guidance in the future. 

1.1 Background 

EPA’s Risk Assessment Guidance for Superfund (RAGS), Part A (USEPA, 1989; hereafter, RAGS, 

Part A) outlined a previously recommended approach for conducting site-specific baseline risk 

assessments for inhaled contaminants.2

 According to the original RAGS approach, the inhalation 

exposure estimate was typically derived in terms of a chronic, daily “air intake” (mg/kg-day) using 

the following general approach. The intake of the chemical was estimated as a function of the 

concentration of the chemical in air (CA), inhalation rate (IR), body weight (BW), and the exposure 

scenario. Age-specific values for BW and IR were used when evaluating childhood exposures. 

Table 1 presents the RAGS, Part A equation for calculating intake for inhalation exposure. 

Inhalation toxicity values were “converted” into similar units for the risk quantification step. Cancer 

risk was estimated by multiplying the chronic daily intake of the chemical from the air by the 

“inhalation cancer slope factor” (CSFi); the Hazard Quotient (HQ) for non-cancer effects was 

estimated by dividing the intake of the chemical by an “inhalation reference dose” (RfDi).3 

The approach outlined in RAGS, Part A was developed before EPA issued the Inhalation Dosimetry 

Methodology, which describes the Agency’s refined recommended approach for interpreting 

1

 The Inhalation Dosimetry Methodology can be found at the following web address: 

http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=71993. 

2

 See sections 6.6.3, 7.2.3, 7.3.3, and 8.2 of RAGS, Part A. 

3

 EPA defines an HQ in RAGS, Part A as: “The ratio of a single substance exposure level over a specified time period 

(e.g., subchronic) to a reference dose (RfD) for that substance derived from a similar exposure period” (USEPA, 1989). 

1
2

inhalation toxicity studies in laboratory animals or studies of occupational exposures of humans to 

airborne chemicals. Under the Inhalation Dosimetry Methodology, the experimental exposures are 

typically extrapolated to a Human Equivalent Concentration (HEC), and a reference concentration 

(RfC) is typically calculated by dividing the HEC by uncertainty factors (UFs). As described in the 

Agency’s Guidelines for Cancer Risk Assessment (USEPA, 2005a), the HEC developed in 

accordance with the Inhalation Dosimetry Methodology typically is also used in developing an 

inhalation unit risk (IUR) for cancer risk assessment (which may also be called an inhalation cancer 

slope factor).4 The procedure that was used to calculate the published RfC or IUR is described in 

the Integrated Risk Information System (IRIS) profile or other toxicological reference document for 

a chemical. 

TABLE 1 

RAGS, PART A EQUATION DESCRIBING THE ESTIMATION OF INHALATION EXPOSURE 

Equation Location in RAGS, Part A 

Intake (mg/kg-d) = CA x (IR/BW) x (ET x EF x ED)/AT Exhibit 6-16, Page 6-44 

Key: CA (mg/m3

) = contaminant concentration in air; IR (m3/hr) = inhalation rate; BW (kg) = body weight; ET 

(hours/day) = exposure time; EF (days/year) = exposure frequency; ED (years) = exposure duration; and AT (days) = 

averaging time (period over which exposure is averaged). 

The Superfund Program has updated its inhalation risk paradigm to be compatible with the 

Inhalation Dosimetry Methodology, which represents the Agency's current methodology for 

inhalation dosimetry and derivation of inhalation toxicity values.5 This document recommends that 

when estimating risk via inhalation, risk assessors should use the concentration of the chemical in air 

as the exposure metric (e.g., mg/m3

), rather than inhalation intake of a contaminant in air based on 

IR and BW (e.g., mg/kg-day). 

1.2 Purpose and Scope 

The intake equation described above (RAGS, Part A, Exhibit 6-16) is not consistent with the 

principles of EPA’s Inhalation Dosimetry Methodology because the amount of the chemical that 

reaches the target site is not a simple function of IR and BW. Instead, the interaction of the inhaled 

contaminant with the respiratory tract is affected by factors such as species-specific relationships of 

exposure concentrations (ECs) to deposited/delivered doses and physiochemical characteristics of 

the inhaled contaminant. The Inhalation Dosimetry Methodology also considers the target site where 

the toxic effect occurs (e.g., the respiratory tract or a location in the body remote from the portal-ofentry) when applying dosimetric adjustments to experimental concentrations (USEPA, 1994). 

Therefore, this RAGS, Part A equation is not recommended for estimating exposures to inhaled 

contaminants. 

4

 The phrase “inhalation cancer slope factor,” as used in this guidance, refers generally to the risk per a measure of 

inhalation exposure. Inhalation exposure in cancer bioassays or occupational studies from which slope factors may be 

derived is most commonly expressed as an exposure concentration (e.g., μg agent/m3

 air). Please note that this differs 

from past use of the phrase “inhalation cancer slope factor” or “CSFi” by the Superfund program to refer to a cancer 

slope expressed as an “inhalation intake” (e.g., RAGS, Part A (USEPA, 1989)). 

5 For additional information about the Superfund program’s adoption of the Inhalation Dosimetry Methodology, please 

refer to the summary of a 2003 Superfund workshop on inhalation risk assessment: 

http://www.epa.gov/oswer/riskassessment/pdf/finalinhalationriskworkshop.pdf. 
The purpose of this document is to provide a recommended approach for developing the information 

necessary to assist risk assessment and risk management decision-making at waste sites involving 

potential risks from inhalation exposures.6, 7 This includes providing equations that may be used in 

conducting baseline risk assessments and in calculating risk-based concentrations (RBCs). It is 

intended that RAGS, Part F will replace those portions of RAGS, Part A, which addressed inhalation 

risk. 

1.3 Effects on Other Office of Superfund Remediation and Technology Innovation Guidance 

EPA recommends that the intake equation presented in RAGS, Part A (USEPA, 1989, Exhibit 6-16) 

should no longer be used when evaluating risk from the inhalation pathway. Implementation of a 

risk assessment approach consistent with the Inhalation Dosimetry Methodology will also affect the 

following guidance documents: RAGS, Part B, Section 3.3: Volatilization and Particulate Emission 

Factors (USEPA, 1991); and the Office of Solid Waste and Emergency Response’s (OSWER’s) 

Draft Guidance for Evaluating the Vapor Intrusion to Indoor Air Pathway from Groundwater and 

Soils (USEPA, 2002a; hereafter the Vapor Intrusion Guidance). EPA no longer recommends using 

the equations in Section 3.3 of RAGS, Part B nor the inhalation toxicity values generated using 

simple route-to-route extrapolation, such as those presented in the 2002 draft Vapor Intrusion 

Guidance and related documents.8 

This guidance does not affect the equations pertaining to risk from inhaled chemicals in the Soil 

Screening Guidance (USEPA, 1996), Section 2.4, or the Supplemental Guidance for Developing Soil 

Screening Levels for Superfund Sites (USEPA, 2002b), Sections 4.2.3, 5.3.2 and Appendix B, other 

than to clarify that the IURs and RfCs used in the equations are based on continuous exposure (24 

hours per day). If the exposure scenario of interest is less than 24 hours per day, the scenariospecific exposure time (ET) in hours per day should be used in the equations and the averaging time 

should be in units of hours (see Equations 6 and 8 in this document). RAGS, Part D (USEPA, 2001) 

is also not affected by RAGS, Part F, as it includes sufficient flexibility to accommodate the 

revisions described in this guidance. In addition, the screening values presented on the “Regional 

Screening Levels for Chemical Contaminants at Superfund Sites” screening level/preliminary 

remediation goal table are consistent with RAGS, Part F (USEPA, 2008a).9 Readers can contact 

EPA headquarters with questions about the compatibility of specific Superfund documents with 

RAGS, Part F. 

6

 Note that the assessment of risk from inhaled nanoparticles is outside the scope of this document. 

7

 If a site contains asbestos contamination, risk assessors should contact EPA’s Technical Review Workgroup for Metals 

and Asbestos for assistance. 

8 Related documents include the Johnson and Ettinger (1991) Model for Subsurface Vapor Intrusion into Buildings 

spreadsheet models (http://www.epa.gov/oswer/riskassessment/airmodel/johnson_ettinger.htm) and the accompanying 

User’s Guide for Evaluating Subsurface Vapor Intrusion into Buildings (USEPA, 2004a). 

 This table can be found on EPA Regions 3, 6, and 9 websites (http://www.epa.gov/reg3hwmd/risk/human/rbconcentration_table/index.htm; http://www.epa.gov/earth1r6/6pd/rcra_c/pd-n/screen.htm; and http://www.epa.gov/ 

region09/waste/sfund/prg/index.html). 

3

9
2. BACKGROUND ON DERIVATION OF INHALATION TOXICITY VALUES 

For all exposure routes, there are generally two approaches for deriving toxicity values. One 

involves the derivation of a reference value (e.g., RfC or RfD), while the other involves derivation of 

a predictive cancer risk estimate (e.g., an oral or inhalation CSF, such as an IUR). For the inhalation 

route, both approaches rely on EPA’s Inhalation Dosimetry Methodology for the extrapolation of 

experimental concentrations to HECs. This extrapolation is described in Section 2.1 and its 

subsections. The approaches for deriving a toxicity value from the HEC are described in Sections 

2.2 and 2.3 and differ depending on the type of toxicity value (e.g., RfC, IUR). This information is 

provided for background purposes only. The procedures outlined in Section 2 are typically 

performed by IRIS chemical managers or by inhalation toxicologists at the National Center for 

Environmental Assessment’s (NCEA’s) Superfund Health Risk Technical Support Center 

(STSC) rather than as part of a baseline risk assessment. 

2.1 Application of Inhalation Dosimetry 

The Inhalation Dosimetry Methodology recognizes a hierarchy of approaches that can be used for 

determining the HEC that is used to derive the RfC or IUR. Generally, the preferred approach is to 

use physiologically-based pharmacokinetic (PBPK) models.10 With sufficient data, a PBPK model 

is capable of calculating the amount of the chemical that reaches the target organ in an animal from 

any exposure scenario and then estimating what human exposure would result in this same amount 

of chemical reaching the target organ (i.e., the HEC). PBPK models can also be used to derive 

continuous ECs from human and animal studies with less-than-continuous exposures. Because 

constructing a valid PBPK model is an information-intensive process that typically requires 

substantial chemical-specific data, this approach has rarely been used (USEPA, 2004b); an example 

can be found in the IRIS file for vinyl chloride (USEPA, 2000a). In cases where a complete PBPK 

model is not available, an intermediate model relying on certain chemical-specific data may be used 

(USEPA, 1994).11 

If the database to support the preferred approach is inadequate, an alternative approach, called the 

Default Chemical Category-Specific Method can be used. This method incorporates the use of 

limited or categorical chemical-specific and physiological information. The default method is 

discussed below, followed by the procedures outlined in the Inhalation Dosimetry Methodology for 

deriving the RfC and IUR as they apply to the interpretation of animal and human data. 

10 EPA defines PBPK models in the IRIS glossary as a model that estimates the dose to a target tissue or organ by taking 

into account the rate of absorption into the body, distribution among target organs and tissues, metabolism, and excretion 

(USEPA, 2008b). For further information about PBPK modeling, please refer to Approaches for the Application of 

Physiologically Based Pharmacokinetic Models and Supporting Data in Risk Assessment (USEPA, 2006a). 

11 The Inhalation Dosimetry Methodology recognizes the existence of alternate approaches in addition to the two 

presented in this guidance. The PBPK approach is generally preferred. In the absence of such a model, alternate models 

may be more optimal than the default approach when default assumptions or parameters can be replaced by more 

detailed, biologically-motivated descriptions or actual data, respectively. For instance, a model may be considered more 

optimal if it incorporates chemical or species-specific information or if it accounts for mechanistic determinants. See 

Table 3-6 in the Inhalation Dosimetry Methodology for more details on the hierarchy of approaches (EPA, 1994, page 3­

40). 

4
2.1.1 Default Approach - Extrapolation from Experimental Animal Data 

The default method involves a two-step procedure that uses limited or categorical chemical-specific 

and physiological information to calculate the HEC. First, the chosen point of departure (POD) from 

the experimental data for a chemical is adjusted to derive a concentration intended to represent an 

equivalent dose under conditions of continuous exposure (7 days a week, 24 hours a day).12 In the 

second step, this concentration is then multiplied by a Dosimetric Adjustment Factor (DAF) to 

generate the HEC. Further details on each step are outlined below. 

2.1.1.1 Duration Adjustment to Continuous Exposure 

Most of the inhalation studies of laboratory animals used to derive RfCs and IURs involve an 

exposure regimen of four to six hours per day, five to seven days per week, for 13 weeks or more 

(equivalent to 10 percent or more of the lifetime of the animal). The POD concentration from an 

animal study is mathematically adjusted to reflect an equivalent dose under conditions of continuous 

exposure.13 Adjustment of duration to a continuous exposure scenario is regularly applied as a 

default procedure to studies with repeated exposures but not to single-exposure inhalation toxicity 

studies in animals (USEPA, 1994). Operationally, this is accomplished by applying a c x t product 

(where “c” is concentration, and “t” is duration of exposure) for both the number of hours in a daily 

exposure period and the number of days per week that the exposure is experienced. For example, if 

exposure in a particular study was 6 hours per day, 5 days per week, the experimental exposure is 

multiplied by 6/24 x 5/7 to calculate an equivalent continuous exposure. The general equation 

provided in the Inhalation Dosimetry Methodology (USEPA, 1994, Equation 4-2) for calculating 

duration-adjusted exposure levels in mg/m3 for experimental animals is presented below. 

NOAEL[ADJ] = E x D x W (Equation 1) 

Where: NOAEL[ADJ] (mg/m3

) = the NOAEL or analogous exposure level 

obtained with an alternate approach (e.g., LOAEL, LEC10), adjusted 

for duration of experimental regimen; 

E (mg/m3

) = the NOAEL or analogous exposure level observed in 

the experimental study; 

D (h/h) = number of hours exposed/24 hours; and 

 W (days/days) = number of days of exposure/7days. 

Using the example above, the assumption is that the product of c x t, not concentration alone, is 

associated with the toxicity observed. This is roughly equivalent to implying that if an effect occurs 

from a chemical at an exposure of 6 hours per day at 40 parts per million (ppm), that same effect will 

12 Examples of PODs include the no-observed-adverse-effect level (NOAEL); the lowest-observed-adverse-effect level 

(LOAEL); Benchmark Concentration, Lower confidence limit (BMCL); and the Lower limit on an Effective 

Concentration using a 10 percent response level (LEC10). For definitions of the various PODs, please refer to the IRIS 

glossary (http://www.epa.gov/ncea/iris/help_gloss.htm). 

13 Continuous exposure refers to 24 hours per day, 7 days per week. 

5
occur at an exposure of 24 hours per day at 10 ppm.14 Note that this adjustment always produces a 

lower concentration value than that administered to experimental animals. Thus, as stated in A 

Review of the Reference Dose and Reference Concentration Processes (hereafter, the RfD/RfC 

Review), application of this procedure results in an automatic margin of protectiveness for chemicals 

for which concentration alone may be the more appropriate dose metric, and it reflects the maximum 

dose for chemicals for which total or cumulative dose is the appropriate measure (USEPA, 2002c). 

If a different procedure is used to calculate the continuous exposure, it should be fully discussed in 

the relevant technical support document for the chemical (e.g., IRIS profile, Provisional Peer 

Reviewed Toxicity Values (PPRTVs) Assessment). For additional discussion, including the 

uncertainties associated with this approach, see Section 4.3.2 of the Inhalation Dosimetry 

Methodology and Section 4.4.2.1 of the RfD/RfC Review (USEPA, 2002c). 

2.1.1.2 Dosimetric Adjustment to Human Equivalent Concentration 

Typically, the adjusted POD concentration from the animal study is next converted to an HEC using 

the following equation (USEPA, 1994, Equation 4-3): 

NOAEL[HEC] = NOAEL[ADJ] x DAF (Equation 2) 

Where: NOAEL[HEC] (mg/m3

) = the NOAEL or analogous exposure level 

obtained with an alternate approach, dosimetrically adjusted to 

an HEC; 

NOAEL[ADJ] (mg/m3

) = the NOAEL or analogous exposure level 

obtained with an alternate approach, adjusted for duration of 

experimental regimen; and 

DAF = Dosimetric Adjustment Factor for the specific site of

 effects (e.g., respiratory tract region or extra-respiratory). 

The DAF is typically based on ratios of animal and human physiologic parameters. The specific 

DAF used depends on the nature of the contaminant (e.g., particle or gas) and the target site where 

the toxic effect occurs (e.g., respiratory tract or a location in the body remote from the portal-ofentry). For example, the DAF can be based on either the Regional Gas Dose Ratio (RGDR), for 

gases with respiratory effects, or the Regional Deposited Dose Ratio (RDDR) for particles. 

Table 2 provides information on the site of effects for the different chemical types. It also lists the 

physiologic parameters considered when calculating the DAF for specific regions of the body.15 In 

addition, the table provides references to the equations from the Inhalation Dosimetry Methodology 

used in deriving the DAFs. Figure 1 provides a schematic of the human respiratory tract, illustrating 

each of the different regions. 

14 This assumption is based on Haber=s Law, which states that Athe incidence and/or severity of an adverse health effect 

depends on the total exposure to a potentially toxic substance. Total exposure (K) is the concentration of the substance 

(c) times the duration time of exposure (t), (i.e., c x t=K)@ (Gaylor, 2000). 

15 The three main regions of the respiratory tract include the following: 1) Extrathoracic (includes nose, mouth, 

nasopharynx, oropharynx, laryngopharynx, and larynx); 2) Tracheobronchial (includes trachea, bronchi, and 

bronchioles); and 3) Pulmonary (includes respiratory bronchioles, alveolar ducts, alveolar sacs and the alveoli). 

6
7

TABLE 2 

CONTAMINANT PROPERTIES AND DOSIMETRIC ADJUSTMENT FACTORSa 

Chemical Type 

Site of 

Effects 

Parameters Considered in Derivation 

of DAF for Regions of the Bodyb 

DAF Equation Numbers 

in Inhalation Dosimetry 

Methodologyc 

Category 1 Gases 

(e.g., acrolein, 

hydrogen fluoride, 

chlorine) 

Respiratory -Minute volume (ETh, TB) 

-Surface area (ETh, TB, PU) 

-Mass transport coefficient (TB, PU) 

-Fraction of inhaled chemical penetrating 

the respiratory region (PU) 

-Alveolar ventilation rate (PU) 

4-18 (ETh), 4-21 & 4-22 

(TB), 4-28 (PU) 

Category 2 Gases 

(e.g., acetonitrile, 

xylene, propanol, 

isoamyl alcohol) 

Respiratory 

and Remote 

-Mass transport coefficients (ETh, TB) 

-Blood:gas partition coefficient (ET, TB, 

ER) 

-Cardiac output (ETh, TB, ER) 

-Alveolar ventilation rate (PU) 

-Surface Area (PU) 

-Minute volume (ER) 

4-18 (ETh), 4-21 & 4-22 

(TB), 4-28 (PU), 4-48 

(ER)d,e 

Category 3 Gases 

(e.g., benzene, 

styrene) 

Remote Blood:gas partition coefficient (ER) 4-48d 

Particles Respiratory 

and Remote 

-Minute volume (TOT, ER) 

-Surface area (TOT) 

-Fractional deposition of particle (TOT, 

ER) 

-Body weight (ER) 

-Inhaled concentration (ER) 

4-14 (TOT), 4-15 (ER) 

a

 Due to the complexities inherent in evaluating the health effects associated with exposure to gases, no definitive 

or comprehensive list of Category 1, 2, or 3 gases is available. Risk assessors should consult with an inhalation

toxicologist in order to classify a specific gas as Category 1, 2, or 3, since there is overlap between the sites of 

effects and the parameters considered in deriving the DAF for different regions of the respiratory tract. 

b Additional discussion of the terms used in this table can be found in the Inhalation Dosimetry Methodology. c

 The Inhalation Dosimetry Methodology provides equations for deriving DAFs for the different contaminant 

categories. The equations listed in this table are the default equations for each specific region in the body. 

d

 This refers to Equation 4-48 that is found on page 4-60 of the Inhalation Dosimetry Methodology. e The equations presented for Category 2 gases in the Inhalation Dosimetry Methodology contain errors. Therefore, 

this table refers to the equations for Category 1 and 3 gases, which are expected to cover respiratory and remote

effects from Category 2 gases. 

Acronyms: ETh = Extrathoracic; TB = Tracheobronchial; PU = Pulmonary; ER = Extra-respiratory; TOT = Total

respiratory system. 
8

FIGURE 1 

HUMAN RESPIRATORY TRACT 

Source: EPA (1994), Figure 3-1, Page 3-5. 

Category 1 gases are highly water-soluble and/or are rapidly irreversibly reactive in the respiratory 

tract (e.g., acrolein, hydrogen fluoride, chlorine). They do not significantly accumulate in the blood, 

and therefore their effects are usually exclusively respiratory (USEPA, 1994). The DAF for 

Category 1 gases consists of an RGDR and is based on the animal to human ratio of the minute 

volume (Ve) divided by the surface area (SA) of the region of the respiratory tract where the effect 

occurs.16 See Appendix A, Sections 1, 2, and 3 of this guidance for examples of specific Category 1 

DAF equations. 

 

16 For the purposes of this document, the Ve is defined as the total ventilation per minute and equals the product of the 

tidal volume (the air volume entering or leaving the lungs with a single breath) and the respiratory frequency. 
Category 3 gases are relatively water-insoluble and are unreactive in the respiratory tract (e.g., 

benzene, styrene). Their toxicity is generally at sites remote to the respiratory tract (USEPA, 1994). 

The DAF for Category 3 gases is based on the ratio of the animal blood:gas partition coefficient 

(Hb/g-animal) and the human blood:gas partition coefficient (Hb/g-human). See Appendix A, Section 4 of 

this guidance for an example of a Category 3 DAF equation. 

Category 2 gases are moderately water-soluble and may be rapidly reversibly reactive or moderately 

to slowly irreversibly reactive in respiratory tract tissue (e.g., acetonitrile, xylene, propanol, isoamyl 

alcohol). These gases have potential for significant accumulation in the blood, so they can exhibit 

both respiratory and remote toxicity (USEPA, 1994). The DAF for respiratory effects of Category 2 

gases consists of an RGDR and is based on the animal to human ratio of the Ve and the SA of the 

region of the respiratory tract where the effect occurs, as for Category 1 gases. The DAF for extrarespiratory (ER) effects of a Category 2 gas is based on the ratio of the Hb/g-animal and the Hb/g-human, as 

for Category 3 gases. 

Particles also vary by solubility and reactivity. However, the default equations used to estimate the 

predicted regional deposition fractions for particles are based on non-soluble, non-hygroscopic 

particles (USEPA, 1994, Section 4.3.5.3). The DAF for a particle causing an effect in the respiratory 

tract is the RDDRr. The RDDRr is based on the animal to human ratio of the Ve and the fractional 

deposition of the particle in that region (Fr), divided by the SAr of the region where the effect occurs. 

This derivation, from the Inhalation Dosimetry Methodology, conservatively assumes that 100 

percent of the deposited dose remains in the respiratory tract; clearance mechanisms are not 

considered. The DAF for a particle causing an ER effect, the RDDRER, is based on the animal to 

human ratio of the Ve and the total deposition of the particle in the entire respiratory tract (Ftotal), 

divided by BW (USEPA, 1994). The RDDRER assumes that 100 percent of the deposited dose in the 

entire respiratory tract is available for uptake into the systemic circulation. See Appendix A, Section 

5 for examples of specific particle DAF equations. 

2.1.2 Default Approach - Extrapolation from Human Occupational Data 

When human data are available to derive an RfC, duration adjustments are often required to account 

for differences in exposure scenarios (e.g., extrapolation from an 8 hour/day occupational exposure 

to a continuous chronic exposure). The default approach recommended by the Inhalation Dosimetry 

Methodology for adjusting the POD concentration (e.g., the no observable adverse effect level 

(NOAEL)) obtained from human study data is provided below in Equation 3 (USEPA, 1994, 

Equation 4-49).17,18 

17 If sufficient data are available, a PBPK model or intermediate approach using chemical-specific information may be 

employed in preference to the default method for extrapolating human occupational data to an HEC. 

18 EPA’s IRIS glossary defines an adverse effect as the following: “A biochemical change, functional impairment, or 

pathologic lesion that affects the performance of the whole organism, or reduces an organism's ability to respond to 

an additional environmental challenge” (USEPA, 2008b). 

9
NOAEL[HEC] = NOAEL x (VEho/VEh) x 5 days/7 days (Equation 3) 

Where: NOAEL[HEC] (mg/m3

) = the NOAEL or analogous exposure level obtained with 

an alternate approach, dosimetrically adjusted to an ambient HEC; 

NOAEL (mg/m3

) = occupational exposure level (time-weighted average over 

an 8-hour exposure period); 

VEho = human occupational default minute volume over 8 hours (10 m3

); and

 VEh = human ambient default minute volume over 24 hours (20 m3

). 

2.2 Derivation of the Inhalation Unit Risk 

The default approach for determining predictive cancer risk recommended by EPA’s Guidelines for 

Carcinogen Risk Assessment (USEPA, 2005a; hereafter, Cancer Guidelines) is a linear extrapolation 

from exposures observed in the animal or human occupational study.19 This approach involves 

drawing a straight line from the POD to the origin. The default linear extrapolation approach is 

generally considered to be conservatively protective of public health, including sensitive subpopulations (USEPA, 2005a). The slope of this line is commonly called the slope factor, and when 

the units are risk per μg/m3

, it is also called the IUR. EPA defines an IUR in the IRIS glossary as 

“the upper-bound excess lifetime cancer risk estimated to result from continuous exposure to an 

agent at a concentration of 1 μg/m3 in air” (USEPA, 2008b). Equation 4 below presents a linear 

extrapolation from a POD of 10 percent response (LEC10).20 

IUR = 0.1/LEC10[HEC] (Equation 4) 

Where: IUR (μg/m3

)

-1 = Inhalation Unit Risk; and 

LEC10[HEC] (μg/m3

) = the lowest effective concentration using a 10 

 percent response level, dosimetrically adjusted to an HEC. 

2.3 Derivation of the Reference Concentration 

EPA defines an RfC in the IRIS glossary as “an estimate (with uncertainty spanning perhaps an 

order of magnitude) of a continuous inhalation exposure to the human population (including 

sensitive subgroups) that is likely to be without appreciable risk of deleterious effects during a 

lifetime” (USEPA, 2008b). The RfC is derived after a review of the health effects database for a 

chemical and identification of the most sensitive and relevant endpoint along with the principal study 

or studies demonstrating that endpoint. EPA Chemical Managers use UFs to account for recognized 

 According to the Cancer Guidelines, “[a] nonlinear approach should be selected when there are sufficient data to 

ascertain the mode of action [MOA] and conclude that it is not linear at low doses and the agent does not demonstrate 

mutagenic or other activity consistent with linearity at low doses” (USEPA, 2005a, page 3-22). In addition, [l]inear 

extrapolation should be used when there are MOA data to indicate that the dose-response curve is expected to have a 

linear component below the POD” (USEPA, 2005a, page 3-21). This information will appear on the IRIS profile or 

other toxicological information source for a chemical. Chemicals with a mutagenic MOA are thought to pose a higher 

risk during early life. Procedures for assessing cancer risk from these chemicals are outlined in Section 5.1. 

20 The POD used in Equation 4 is an LEC10, which is the lower 95 percent confidence limit on the concentration 

corresponding to a 10 percent response rate (i.e., the EC10). Other PODs may be substituted for this value, which could 

be associated with alternative response levels (e.g., 1 percent, 5 percent). 

10

19
uncertainties in the extrapolations from the experimental data conditions to an estimate appropriate 

to the assumed human scenario (USEPA, 1994). See Table 3 for a description of the standard UFs. 

The formula used for deriving the RfC from the HEC is provided below. 

RfC = NOAEL[HEC]/(UF)1 (Equation 5) 

Where: RfC (mg/m3

) = Reference Concentration 

NOAEL[HEC] (mg/m3

) = The NOAEL or analogous exposure level 

obtained with an alternate approach, dosimetrically adjusted to an 

HEC; and 

UF = Uncertainty factor(s) applied to account for the extrapolations required 

from the characteristics of the experimental regimen. 

1

 Some toxicological information sources for RfCs will incorporate an additional factor to account for deficiencies 

in the available data set, called a modifying factor (MF). In 2002, however, EPA published the RfD/RfC Review, 

which recommended that the use of MFs be discontinued because their purpose is “sufficiently subsumed in the 

general database UF” (USEPA, 2002c, page xviii). Therefore, RfCs published subsequent to this document will 

not include MFs. 

11
TABLE 3 

THE USE OF UNCERTAINTY FACTORS IN DERIVING AN INHALATION REFERENCE 

CONCENTRATION 

Standard UFs Processes Considered in the UF Purview 

H = Human to sensitive human: Extrapolation of valid 

experimental results from studies using prolonged exposure 

to average healthy humans. Intended to account for the 

variation in sensitivity among the members of the human 

population. 

-Pharmacokinetics/Pharmacodynamics 

-Sensitivity2 

-Differences in body weight (age, obesity) 

-Concomitant exposures 

-Activity pattern 

-Does not account for idiosyncrasies 

A = Animal to human: Extrapolation from valid results of 

long-term studies on laboratory animals when results of 

studies of human exposure are not available or are 

inadequate. Intended to account for the uncertainty in 

extrapolating laboratory animal data to the case of average 

healthy humans. 

-Pharmacokinetics/Pharmacodynamics 

-Relevance of laboratory animal model 

-Species sensitivity 

S = Subchronic to chronic: Extrapolation from less-thanchronic exposure results on laboratory animals or humans 

when there are no useful long-term human data. Intended 

to account for the uncertainty in extrapolating from less 

than chronic NOAELs to chronic NOAELs. 

-Accumulation/Cumulative damage 

-Pharmacokinetics/ Pharmacodynamics 

-Severity of effect 

-Recovery 

-Duration of study 

-Consistency of effect with duration 

L = LOAEL to NOAEL: Derivation from a LOAEL 

instead of a NOAEL. Intended to account for the 

uncertainty in extrapolating from LOAELs to NOAELs. 

-Severity 

-Pharmacokinetics/Pharmacodynamics 

-Slope of dose-response curve 

-Trend, consistency of effect 

-Relationship of endpoints 

-Functional vs. histopathological evidence 

-Exposure uncertainties 

D = Incomplete to complete data: Extrapolation from 

valid results in laboratory animals when the data are 

“incomplete.” Intended to account for the inability of any 

single laboratory animal study to adequately address all 

possible adverse outcomes in humans.1 

-Quality of critical study 

-Data gaps 

-Power of critical study/supporting studies 

-Exposure uncertainties 

1 The RfD/RfC Review indicates that this UF accounts for the potential for deriving an underprotective RfD/RfC as a result of an 

incomplete characterization of the chemical’s toxicity or if the existing data suggest that a lower reference value might result if 

additional data were available (considering both the lacking and available data for particular organ systems as well as life stage) 

(USEPA, 2002c).

2 The RfD/RfC Review also stresses that susceptible populations and life stages are accounted for with this UF (USEPA, 2002c). 

Source: USEPA, 1994, Table 4-9, page 4-77. 

12
3. CHARACTERIZING EXPOSURE 

3.1 Introduction 

This section describes an approach for characterizing exposure in a baseline risk assessment that is 

consistent with the Inhalation Dosimetry Methodology. The approach involves the estimation of 

exposure concentrations (ECs) for each receptor exposed to contaminants via inhalation in the risk 

assessment. ECs are time-weighted average concentrations derived from measured or modeled 

contaminant concentrations in air at a site, adjusted based on the characteristics of the exposure 

scenario being evaluated.21,22 

Equations for estimating ECs are provided below. This document does not provide default input 

values for the exposure parameters referenced in these equations. EPA recommends the use of sitespecific exposure values consistent with the exposure pathways and receptors at a site wherever 

practicable and appropriate. If a risk assessor opts to rely on default exposure input values, current 

Superfund-supported values may be found at the exposure assessment portion of the Superfund 

website: (http://www.epa.gov/oswer/riskassessment/superfund_hh_exposure.htm). 

3.2 Estimating Exposure Concentrations for Assessing Cancer Risks 

The estimation of an EC when assessing cancer risks characterized by an IUR involves the CA 

measured at an exposure point at a site as well as scenario-specific parameters, such as the exposure 

duration and frequency.23 The EC typically takes the form of a CA that is time-weighted over the 

duration of exposure and incorporates information on activity patterns for the specific site or the use 

of professional judgment. The equation for estimating an EC for use with an IUR is presented 

below. 

21 The default method for deriving inhalation toxicity values also involves calculating time-weighted ECs, as discussed in 

Sections 2.1.1.1 and 2.1.2. 

22 The ECs in this document are in units of μg/m3

. Inhalation toxicity values presented on IRIS are typically expressed in 

units of μg/m3

 or mg/m3, which are mass units. Some regulatory contexts require the use of volumetric units such as 

ppm. The conversion from mass units to volumetric units depends on the molecular weight (MW) of the material as well 

as the ambient temperature and atmospheric pressure. To convert from ppm to mg/m3

, the following equation can be 

used: ppm × MW = mg / m3 ; where MW is the molecular weight of the gas and V is the volume of 1 gram molecular 

V 

weight of the airborne contaminant. This is derived by the formula V = RT/P; where R is the ideal gas constant, T is the 

temperature in Kelvin (K = 273.16 + T°C) and P is the pressure in mm Hg. The value of R is 62.4 when T is in Kelvin, 

(K = 273.16 + T°C), the pressure is expressed in units of mm Hg and the volume is in liters. The value of R differs if the 

temperature is expressed degrees Fahrenheit (°F) or if other units of pressure are used (e.g., atmospheres, kilopascals). 

23 ECs are typically based on either estimated (i.e., modeled) or measured contaminant concentrations in air. 

13
EC = (CA x ET x EF x ED)/AT (Equation 6) 

Where: EC (μg/m3

) = exposure concentration; 

CA (μg/m3

) = contaminant concentration in air; 

ET (hours/day) = exposure time; 

EF (days/year) = exposure frequency; 

ED (years) = exposure duration; and 

 AT (lifetime in years x 365 days/year x 24 hours/day) = averaging time 

3.3 Estimating Exposure Concentrations for Calculating Hazard Quotients 

When estimating ECs for non-cancer or cancer hazards characterized by an HQ, risk assessors 

should match each exposure scenario at a site to the appropriate EC equation, based on the scenario 

duration and frequency of exposure.24 Figure 2 presents a flowchart to assist risk assessors with this 

process and provides recommended equations that can be used to estimate the EC for each type of 

scenario.25 As shown in Figure 2, the recommended process for estimating ECs to be used in 

calculating an HQ involves the following three steps: 1) assess the duration of the exposure scenario; 

2) assess the exposure pattern of the exposure scenario; and 3) estimate the scenario-specific EC. 

3.3.1 Step 1: Assess Duration 

The first step in the recommended process of estimating an EC for use in calculating an HQ involves 

assessing the duration of the exposure scenario at a site. Step 1 in Figure 2 indicates that the risk 

assessor first should decide whether the duration of the exposure scenario is generally acute, 

subchronic, or chronic. Toxicologists have long been aware that effects from a single or short-term 

exposure can differ markedly from effects resulting from repeated exposures. The response by the 

exposed person depends upon factors such as whether the chemical accumulates in the body, 

whether it overwhelms the body’s mechanisms of detoxification or elimination, or whether it 

produces irreversible effects (Eaton & Klaassen, 2001). Therefore, ideally, the chemical-specific 

elements of metabolism and kinetics, reversibility of effects, and recovery time should be considered 

as part of this recommended process when defining the duration of a site-specific exposure scenario. 

24 Traditionally, the HQ approach was limited to non-cancer hazard assessment. However, the HQ approach may also be 

appropriate for carcinogens with a non-linear mode of action. The 2005 Cancer Guidelines state the following on this 

subject: "For cases where the tumors arise through a nonlinear mode of action, an oral reference dose or an inhalation 

reference concentration, or both, should be developed in accordance with EPA’s established practice for developing such 

values ... this approach expands the past focus of such reference values (previously reserved for effects other than 

cancer) to include carcinogenic effects determined to have a nonlinear mode of action" (USEPA, 2005a; page 3-24). 

25 Figure 2 was developed for the evaluation of inhalation exposures. While the concepts presented in this flowchart may 

be useful for assessing other exposure routes (e.g., oral or dermal), these other routes are beyond the scope of this 

document, and therefore, are not explicitly considered. Caution should be used when using Figure 2 to evaluate other 

exposure routes, as considerations beyond those outlined in the flowchart may apply (e.g., time to reach steady state for 

dermal exposures). 

14
To the extent possible, exposure durations (EDs) evaluated in a site-specific risk assessment should 

be consistent with the ED represented by the toxicity value. However, frequencies or durations of 

human exposures often are not as clearly defined as those in animal studies with controlled 

exposures, particularly for intermittent exposures. For example, the emission of some volatile 

chemicals into the ambient air may vary with temperature and season, providing fluctuating 

exposures for humans living near the source. Therefore, risk assessors should use best professional 

judgment to determine if the ED in a given scenario is reasonably similar to the duration associated 

with the toxicity value. Risk assessors should describe the uncertainties associated with their choice 

of toxicity value in the risk characterization section of the risk assessment (see Section 9.2.2 of this 

document). For situations where duration-appropriate toxicity values are not available, please follow 

the procedures outlined in Section 4.2 and Appendix C of this document. 

The specific definition for each exposure duration category may vary depending on the source of the 

toxicity value being used. For Tier 1 toxicity values obtained from EPA’s IRIS database, acute 

exposures are defined as lasting 24 hours or less; subchronic exposures are defined as repeated 

exposures by the oral, dermal, or inhalation route for more than 30 days, up to approximately 10 

percent of the human lifespan; and chronic exposures are defined as repeated exposures for more 

than approximately 10 percent of the human lifespan (USEPA, 2008b).26, 27 

After deciding which duration the exposure scenario most closely matches, risk assessors should 

then proceed to Step 2, following the path of the selected duration. Note that if an acute duration is 

selected, risk assessors should proceed directly to Step 3 to estimate an acute EC for each acute 

exposure period. 

3.3.2 Step 2: Assess Exposure Pattern 

Step 2 of the recommended process for estimating an EC for use in a hazard quotient involves 

assessing the exposure pattern for each exposure scenario at a site. This entails comparing the 

exposure time and frequency at a site to that of a typical subchronic or chronic toxicity test.28 

26 Note that other sources of toxicity values may define exposures differently. For example, the Agency for Toxic 

Substances and Disease Registry (ATSDR) (which publishes Minimal Risk Levels (MRLs)) defines acute exposures as 

occurring from one to 14 days, intermediate exposures as greater than 14 to 364 days, and chronic exposures as 365 days 

or longer. However, the toxicity values are based on the same underlying toxicological concepts described in this 

section. 

27 Exposures with a duration lasting between 24 hours and 30 days should be treated as subchronic for the purposes of 

this document. 

28 Exposure regimens vary from study to study. Risk assessors should use best professional judgment to determine if the 

exposure pattern in a given scenario is reasonably similar to a typical regimen for a subchronic or chronic study. 

15
FIGURE 2

RECOMMENDED PR MMENDED PROCEDURE F OCEDURE FOR DERIVING EXPOSURE CONCENTRATIONS AND HAZARD 

INHALATION EXPOSURE SCENARIOS

S s ss es

n oIs the 

Aatiduration of the exposure duration of the exposure : 1r uAcute scenarios generally acute, scenarios generally acute, 

p eSt D(e.g., minutes/ subchronic, or subchronic, or (e

(e

Shours to days)* chronic? chronic? 

Subchronic Subchronic

e

r

n

(e.g., weeks to years)* (e.g., weeks to years)*

2: 

A

s

s

e

ss 

E

x

p

o

s

u

re 

P

a

t

t

2

:

A

s

s

e

s

s

E

x

p

o

s

u

r

e

P

a

t

t

No 

Is the 

Are there Are there EF genera

EF genera

1 or more periods 1 or more periods at least as freque

at least as freque

of exposure, each of which is of exposure, each of which is No chronic chronic toxicity te

generally at least as generally at least as frequent frequent occupational s

occupational s

as a subchronic subchronic toxicity test toxicity test (e.g., 6-8 hrs/

(e.g., 6-8 hrs/

(e.g., 6-8 hrs/day, (e.g., 6-8 hrs/day, 5 days/wk

5 days/wk

5 days/wk)?H50 wks/yr)

a e t

EC 

e

C

S

e

t p

Calculate Calculate acuteEC & HQs for EC & HQs for

Yes Yes 

Calculate subchronic subchronic EC & HQs for EC & HQs for Calculate chronic chronic EC 

EC 

t

m

i

each acute exposure period each acute exposure period each subchronic exposure period each subchronic exposure period Equation 8

Equation 7 Equation 7 Equation 8Equation 8 Equation 12

E

s

Equation 12 Equation 12 Equation 12 [Repeat for each chem

e

t p 

3: 

p

: [Repeat for each chemical] [Repeat for each chemical]

* The specific definition for each duration category may vary depending on the source of the toxicity value being used. Fo r Tier 1 toxicity values obtaine

acute exposures are defined as those lasting 24 hours or less;subchronic exposures are defined as repeated exposures for more than 30 days, up to approximately 10 percent of the life span in humans; 

chronic exposures are defined as repeated exposures for more than approximately 10 percent of the life span in humans (EPA, 2008b).

For the purposes of this document, short-term exposures, defined by the IRIS glossary as repeated exposures for more than 24 hours, up to 30 days, s

H Exposure regimens vary from study to study. Risk assessors should use best professional judgment to determine if the exposure pattern in a given sc

typical regimen for a chronic or subchronic study.

[Repeat for each chemical]

16
For exposure scenarios with a subchronic duration, risk assessors should follow the center path on 

the flowchart. Step 2 in this path asks whether there are one or more periods of exposure, each of 

which is generally as frequent as a subchronic toxicity test (e.g., 6-8 hours per day, 5 days per week). 

If the exposure scenario matches this description, risk assessors should proceed to Step 3 and 

estimate a subchronic EC for each subchronic exposure period. However, if the exposure pattern 

contains periods that are significantly shorter and/or involve significantly less frequent exposures 

than indicated in the flow chart, risk assessors should derive acute ECs for each of these exposure 

periods. If it is difficult to determine whether a specific exposure scenario is best modeled as a 

subchronic exposure or as a series of independent acute exposures, due to uncertainty in the time 

required to return to baseline following exposure, risk assessors may want to derive ECs using both 

approaches. 

If the exposure scenario has a chronic duration, risk assessors should follow the right hand path on 

the flowchart. Step 2 in this path asks whether the exposure frequency (EF) is generally as frequent 

as a chronic animal toxicity test or a human occupational study (e.g., 6-8 hours per day, 5 days per 

week, for 50 weeks per year). If the exposure scenario matches this description, risk assessors 

should proceed to Step 3 and estimate a single chronic EC. However, if the scenario differs 

significantly from this pattern, risk assessors should proceed to the second question under the 

subchronic duration path and proceed as outlined above. 

3.3.3 Step 3: Estimate Exposure Concentration 

Step 3 of the recommended process involves estimating the EC for the specific exposure scenario based on 

the decisions made in Steps 1 and 2. For acute exposures, the EC is equal to the CA. Risk assessors can 

estimate an acute EC for each acute exposure period at a site using Equation 7. For longer-term exposures, 

risk assessors should take into consideration the exposure time, frequency, and duration for each receptor 

being evaluated as well as the period over which the exposure is averaged (i.e., the averaging time (AT)) to 

arrive at a time-weighted EC. If there are one or more exposure periods that are generally as frequent as a 

subchronic toxicity test, risk assessors should use Equation 8 to estimate a subchronic EC for each of these 

exposure periods. (Exposure periods with significantly less frequency should be treated as acute 

exposures.) If the exposure pattern is generally as frequent as a chronic toxicity test of an occupational 

study, risk assessors should use Equation 8 to estimate a single chronic EC for the duration of the exposure. 

Acute Exposures 

EC = CA (Equation 7) 

Where: EC (μg/m3) = exposure concentration; 

CA (μg/m3

) = contaminant concentration in air; 

17
Chronic or Subchronic Exposures 

EC = (CA x ET x EF x ED)/AT (Equation 8) 

Where: EC (μg/m3

) = exposure concentration; 

CA (μg/m3

) = contaminant concentration in air; 

ET (hours/day) = exposure time; 

EF (days/year) = exposure frequency; 

ED (years) = exposure duration; and 

AT (ED in years x 365 days/year x 24 hours/day) = averaging time 

Note: If the duration of the exposure period is less than one year, the units in the above equation 

can be changed to the following: EF (days/week); ED (weeks/exposure period); and AT 

(hours/exposure period). 

It is important to use the EC equation that most closely matches the exposure pattern and duration at 

a site. For instance, if the exposure pattern at a site consists of a series of short (e.g., 4-hour) periods 

of high exposure separated by several days of no exposure, the approach outlined above recommends 

estimating an acute EC for each acute exposure period. If the chronic EC equation (Equation 8) 

were to be used instead, the result would be an average EC value that may lead to an underestimate 

of risk since the inhaled concentrations could be higher than acute toxicity values during periods of 

exposure. 

3.4 Estimating Exposure Concentrations in Multiple Microenvironments 

When detailed information on the activity patterns of a receptor at a site is available, risk assessors 

can use these data to estimate the EC for either non-carcinogenic or carcinogenic effects. The 

activity pattern data describe how much time a receptor spends, on average, in different 

microenvironments (MEs), each of which may have a different contaminant concentration level.29 

By combining data on the contaminant concentration level in each ME and the activity pattern data, 

the risk assessor can calculate a time-weighted average EC for a receptor. Because activity patterns 

(and hence, MEs) can vary over a receptor’s lifetime, EPA recommends that risk assessors pursuing 

the ME approach first calculate a time-weighted average EC for each exposure period characterized 

by a specific activity pattern (e.g., separate ECs for a school-aged child resident and a working adult 

resident). These exposure period-specific ECs can then be combined into a longer term or lifetime 

average EC by weighting the EC by the duration of each exposure period. The following sections 

further explain these two steps. 

3.4.1 Using Microenvironments to Estimate an Average Exposure Concentration for a Specific 

Exposure Period 

The ME approach can be used to estimate an average EC for a particular exposure period during 

which a receptor has a specified activity pattern. As a simplified example, a residential receptor may 

29 EPA defines a microenvironment in Air Quality Criteria for Particulate Matter: Volume II as a defined space that can 

be treated as a well-characterized, relatively homogeneous location with respect to pollutant concentration for a specified 

time period (e.g., rooms in homes, restaurants, schools, offices, inside vehicles, or outdoors) (USEPA, 2004b). 

18
be exposed to a higher concentration of a contaminant in air in the bathroom for 30 minutes per day 

while showering, and exposed to a lower concentration in the rest of the house for the remaining 

23.5 hours per day. In this case, risk assessors can use the CA value experienced in each ME 

weighted by the amount of time spent in each ME to estimate an average EC for the period of 

residency in that house using Equation 9.30 This approach may also be used to address exposures to 

contaminants in outdoor and indoor environments at sites where both indoor and outdoor samples 

have been collected or where the vapor intrusion pathway has been characterized. 

n 

EC j = ∑(CAix ETix EFi ) x EDj/ATj (Equation 9) 

i =1 

Where: ECj (μg/m3) = average exposure concentration for exposure 

period j; 

CAi (μg/m3

) = contaminant concentration in air in ME i; 

ETi (hours/day) = exposure time spent in ME i; 

EFi (days/year) = exposure frequency for ME i; 

EDj (years) = exposure duration for exposure period j; and 

ATj (hours) = averaging time = EDj x 24 hours/day x 365 days/year. 

3.4.2 Estimating an Average Exposure Concentration Across Multiple Exposure Periods 

To derive an average EC for a receptor over multiple exposure periods, the average EC from each 

period (as calculated above in Equation 9) can be weighted by the fraction of the total exposure time 

that each period represents, using Equation 10. For example, when estimating cancer risks, the risk 

assessor may calculate a lifetime average EC where the weights of the individual exposure periods 

are the duration of the period, EDj, divided by the total lifetime of the receptor. Alternatively, when 

estimating an HQ, risk assessors can use Equation 10 to calculate less-than-lifetime average ECs 

across multiple exposure periods. In that case, the AT will equal the sum of the individual EDs for 

all of the exposure periods. 

n 

ECLT = ∑(ECjx EDj ) /AT (Equation 10) 

i =1 

Where: ECLT (μg/m3) = long-term average exposure concentration; 

ECj (μg/m3

) = average exposure concentration of a contaminant in air for 

exposure period j; 

EDj (years) = duration of exposure period j; and 

AT (years)1

 = averaging time. 

1 When evaluating cancer risk, the AT is equal to lifetime in years. When evaluating non-cancer hazard, the AT is equal 

to the sum of the EDs for each exposure period. 

30 If one or more MEs involve acute exposures, risk assessors should conduct a supplemental analysis comparing the CA 

for each of those MEs to a corresponding acute toxicity value to ensure that receptors are protected from potential acute 

health effects. 

19 
4. SELECTING APPROPRIATE TOXICITY VALUES 

After characterizing the exposure scenarios and estimating ECs for each receptor at a site, the risk 

assessor should select appropriate inhalation toxicity values for each inhaled contaminant. For 

estimating cancer risks, this typically involves identifying and evaluating available published cancer 

potency estimates. For estimating HQs, this typically involves identifying and evaluating reference 

values that match the characterization of the exposure scenario from Figure 2 (i.e., acute, subchronic, 

or chronic reference values). 

This section provides guidance for the selection of toxicity values appropriate for assessing risk 

under inhalation exposure scenarios. It describes sources for the most current inhalation data and 

provides guidance for proceeding when published inhalation toxicity data are not available. 

4.1 Sources for Inhalation Toxicity Data 

The OSWER Directive, Human Health Toxicity Values in Superfund Risk Assessment (USEPA, 

2003), provides a recommended hierarchy of toxicological data sources to guide risk assessors when 

selecting appropriate toxicity values. This document sets out a recommended three-tiered 

framework for selecting human toxicity values. Tier 1 consists of EPA’s IRIS, Tier 2 consists of 

EPA’s PPRTVs, and Tier 3 includes other toxicity values as recommended by NCEA, such as the 

California EPA toxicity values, the Agency for Toxic Substances and Disease Registry’s (ATSDR’s) 

Minimal Risk Levels (MRLs), and Health Effects Assessment Summary Table (HEAST) toxicity 

values. Priority in Tier 3 should be given to sources that are the most current and those that are peer 

reviewed. Consultation with the Superfund Headquarters office is recommended regarding the use 

of Tier 3 values for Superfund response decisions when the contaminant appears to be a risk driver 

for the site. 

The most up-to-date information on Superfund-supported cancer potency estimates and chronic and 

subchronic cancer and non-cancer reference values for inhaled contaminants are available on the 

Superfund risk assessment website (www.epa.gov/oswer/riskassessment/superfund_toxicity.htm). 

Superfund-recommended sources for acute non-cancer toxicity values can be found at 

www.epa.gov/oswer/riskassessment/superfund_acute.htm.

31 

In situations where the desired reference value (e.g., acute, subchronic, chronic) is not available, risk 

assessors may use a reference value based on the next longer duration of exposure as a conservative 

estimate that would be protective for a shorter-term ED (USEPA, 2002c). For example, if a risk 

assessor determines that an ED at a site is subchronic, but no subchronic toxicity value is available, a 

chronic RfC can be used to assess hazard. 

EPA recommends that toxicity values published in Superfund-supported sources should generally be 

used in the risk equations presented in this guidance, without modification. This includes IURs on 

IRIS that were calculated from oral values using a default ventilation rate and BW (see Appendix B 

for a list of these chemicals). It is not generally appropriate to make adjustments to these values 

31 In selecting an acute toxicity value, risk assessors should consider the duration associated with their estimate of 

exposure (e.g., a 1-hour versus a 24-hour air sample). Use of a toxicity value specified for a longer duration than that of 

the exposure estimate may overestimate hazard, while the use of a shorter duration acute reference value may 

underestimate hazard. 

20
based on IR and BW using the intake equation, because the amount of the chemical that reaches the 

target site through the inhalation pathway is not a simple function of these parameters (see Section 

1.2). Use of the toxicity values listed in Appendix B should be noted in the uncertainty section of 

the risk assessment (see Section 9). 

4.2 Recommended Procedures for Assessing Risk in the Absence of Inhalation Toxicity Values 

The following section provides guidance on recommended procedures for situations where 

inhalation toxicity values are not available in any of the toxicity data sources described in Section 

4.1. 

If RfC and IUR values are not available for an inhaled contaminant, risk assessors should first 

contact NCEA’s STSC for guidance.32 Risk assessors working on Superfund sites can contact STSC 

to determine whether a provisional peer-reviewed toxicity value (PPRTV) exists for a contaminant; 

if not, the risk assessor, in cooperation with the appropriate EPA Regional office may request that 

STSC develop a PPRTV document or that STSC develop an inhalation toxicity value as a “consult”. 

The latter would be specific to the site in question only. Additional information on STSC’s current 

process for developing alternative toxicity values is described in Appendix C. 

If STSC indicates that no quantitative toxicity information for the inhalation route is available, the 

risk assessor should conduct a qualitative evaluation of this exposure route. The risk assessor should 

discuss in the uncertainty section of the risk assessment report the implications of not quantitatively 

assessing risks due to inhalation exposures to chemicals lacking inhalation toxicity data. See the 

section on Risk Characterization (Section 9) in this guidance for more information. 

Performing simple route-to-route extrapolation without the assistance of STSC is generally not 

appropriate because hazard may be misrepresented when data from one route are substituted for 

another without any consideration of the pharmacokinetic differences between the routes (USEPA, 

1998). The following circumstances, outlined in the Inhalation Dosimetry Methodology (page 4-6), 

are specific examples of situations when route-to-route extrapolation from oral toxicity values might 

not be appropriate, even for use during screening: 

• When groups of chemicals are expected to have different toxicity by the two routes − for 

example, metals, irritants, and sensitizers; 

• When a first-pass effect by the respiratory tract is expected; 

• When a first-pass effect by the liver is expected; 

• When a respiratory tract effect is established, but dosimetry comparison cannot be clearly 

established between the two routes; 

• When the respiratory tract was not adequately studied in the oral studies; and 

• When short-term inhalation studies, dermal irritation, in vitro studies, or characteristics of 

the chemical indicate the potential for portal-of-entry effects at the respiratory tract, but 

studies themselves are not adequate for inhalation toxicity value development. 

32 All contact with STSC should be performed by an EPA regional risk assessor. States and other entities should first 

contact their EPA regional risk assessor with questions on inhalation toxicity values. Regional risk assessors can then 

contact STSC on their behalf. 

21
The Cancer Guidelines (USEPA, 2005a) includes the following statement regarding route-to-route 

extrapolation: 

“When a qualitative extrapolation can be supported, quantitative extrapolation may still be 

problematic due to the absence of adequate data. The differences in biological processes among 

routes of exposure (oral, inhalation, dermal) can be great because of, for example, first-pass effects 

and different results from different exposure patterns. There is no generally applicable method for 

accounting for these differences in uptake processes in a quantitative route-to-route extrapolation of 

dose-response data in the absence of good data on the agent of interest. Therefore, route-to-route 

extrapolation of dose data relies on a case-by-case analysis of available data” (page 3-10). 

5. ESTIMATING RISKS 

This section provides updated equations recommended for estimating excess cancer risks and HQs 

from inhaled contaminants of concern at Superfund sites. Please see Section 8.2.1 of RAGS, Part A 

for further information about how to interpret calculated excess cancer risks and HQs. 

5.1 Cancer Risks Characterized by an Inhalation Unit Risk 

The excess cancer risk for a receptor exposed via the inhalation pathway can be estimated with the 

following equation: 

Risk = IUR x EC (Equation 11) 

Where: IUR (μg/m3

)

-1 = Inhalation Unit Risk; and 

EC (μg/m3

) = exposure concentration (See Equation 6). 

When estimated ECs are above the POD used for the low dose extrapolation described in Section 

2.3, a linear concentration-response relationship may not hold.33 In such situations, the risk assessor 

should not use toxicity values developed through low dose extrapolation techniques. Instead, the 

risk assessor may report semi-quantitative risk estimates (e.g., risks are greater than 10-2) or estimate 

risk using the original model underlying the toxicity value, which can be found in the technical 

support document for the value (e.g., IRIS profile, PPRTV Assessment). 

When estimating cancer risks for children, risk assessors should be aware of chemicals that pose a 

higher risk of cancer when exposure occurs during early life. If evidence exists suggesting 

differences in risk across age groups for a chemical, this typically will be considered in the 

derivation of the toxicity value and described in the chemical’s technical support document. 

33 Reviews of chemical-specific IRIS files indicate that the risk level corresponding to the concentration level above 

which the IUR should not be used often falls at or near 10-2. However, this risk level varies by chemical and, therefore, 

risk assessors should refer to the toxicity value’s technical support document for information on the concentration range 

for which the IUR was intended to be used. 

22
Chemicals that have been determined to cause cancer by a mutagenic mode of action (MOA) are 

thought to pose a higher risk during early life. An EPA-recommended procedure exists for assessing 

risks from these chemicals. Figure 3 summarizes the recommendations of the Supplemental 

Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens (USEPA, 2005b; 

hereafter Supplemental Cancer Guidelines) on how to adjust childhood risk calculations to account 

for chemicals with a mutagenic MOA for carcinogenicity. Please refer to the Supplemental Cancer 

Guidelines (USEPA, 2005b) for a list of chemicals with a mutagenic MOA that were used in the 

development of that document. 

In addition, EPA’s website for the “Handbook for Implementing the Supplemental Cancer Guidance 

at Waste and Cleanup Sites” contains an up-to-date list of chemicals that EPA has determined to 

have a mutagenic MOA (http://www.epa.gov/oswer/riskassessment/sghandbook/index.htm). As 

chemicals receive new assessments for mutagenicity, this information will appear in the IRIS profile 

or PPRTV assessment. 

FIGURE 3 

GUIDANCE ON ASSESSING RISK FROM EARLY-LIFE EXPOSURES FOR 

CHEMICALS ACTING BY A MUTAGENIC MODE OF ACTION FOR 

CARCINOGENICITY 

If a chemical has been determined to cause cancer by a mutagenic MOA, it is possible that exposures 

to that chemical in early-life may result in higher lifetime cancer risks than a comparable duration 

adult exposure. 

In risk assessments of exposure to chemicals for which a mutagenic MOA for carcinogenicity has 

been determined by EPA and a linear low-dose extrapolation performed, one of the following 

generally pertains: 

1) If chemical-specific data on susceptibility from early-life exposures were available for 

derivation of CSFs, those slope factors are used for risk characterization, and Age 

Dependent Adjustment Factors (ADAFs) are not applied. 

2) If chemical-specific data on susceptibility from early-life exposures were not available, 

the ADAFs are applied in calculating or estimating risks associated with early-life 

exposures (USEPA, 2005c). 

If the latter case applies, the Supplemental Guidance for Assessing Susceptibility from Early-Life 

Exposure to Carcinogens (USEPA, 2005b) recommends the following default ADAFs be applied in 

risk assessments: 

• 10-fold adjustment for exposures during the first 2 years of life; 

• 3-fold adjustment for exposures from ages 2 to <16 years of age; and 

• No adjustment for exposures after turning 16 years of age. 

 In such cases, Equation 11 can be altered to include the ADAFs in the following way: 

 Risk = (IUR x EC<2 x ADAF<2) + (IUR x EC2-16 x ADAF2-16) + (IUR x EC>16) 

Sources: USEPA, 2005b and USEPA, 2005c. 

Note: All communications and factsheets pertaining to the implementation of the 2005 Cancer 

Guidelines can be found at www.epa.gov/osa/spc/cancer_guidelines.htm. 

23
5.2 Hazard Quotients 

The HQ for the inhalation pathway can be calculated with the following general equation: 

HQ = EC/(Toxicity Value1 x 1000 μg/mg) (Equation 12) 

Where: HQ (unitless) = Hazard Quotient; 

EC (μg/m3

) = exposure concentration (See Equations 7 or 8); 

Toxicity Value (mg/m3

) = Inhalation toxicity value (e.g., RfC) that is 

appropriate for the exposure scenario (acute, subchronic, or chronic). 

1

 Risk assessors should refer to the flowchart (Figure 2) to select an appropriate inhalation toxicity value for the 

exposure scenario at a site in order to calculate the HQ. 

6. EXAMPLE EXPOSURE SCENARIOS 

This section of the guidance includes examples of the types of exposure scenarios risk assessors may 

encounter when evaluating inhalation exposures at waste sites. Each scenario includes sample 

values for exposure parameters and reviews the process of estimating the EC and risks for cancer 

and other health effects. These examples are provided for illustrative purposes only and are not 

representative of every exposure scenario that could be encountered at a site. Furthermore, risk 

assessors should use site-specific values for exposure parameters if practicable when estimating ECs 

and risk levels or HQs. This would typically require some information on activity patterns for the 

specific site or the use of professional judgment. If default values are to be used for certain exposure 

parameters, please consult the Superfund website for up-to-date information on Superfundrecommended default exposure parameters.34 

6.1 Residential Receptor 

An example of a residential scenario could consist of inhalation exposure for up to 24 hours per day, 

up to 350 days per year for 6 to 30 years. When estimating cancer risk for this type of scenario, 

Equation 6 is recommended to calculate an EC and Equation 11 is recommended to estimate risk. 

For estimating hazard quotients for cancer or non-cancer effects, this scenario can be evaluated using 

the steps outlined in Figure 2. The duration of this scenario ranges from 6 to 30 years, which can be 

considered chronic (because it consists of repeated exposures for approximately 10 percent of a 

receptor’s lifespan). The frequency of this scenario is generally as frequent as a chronic toxicity test 

and therefore Equation 8 is recommended to derive a chronic EC and Equation 12 with a chronic 

toxicity value is recommended to calculate an HQ. If information about multiple MEs is available, 

risk assessors should proceed according to Section 3.4 to estimate ECs to use in estimating cancer 

risks or HQs. 

When assessing the risk under the residential scenario for children, the risk assessor should keep in 

mind that exposure parameters, specifically those related to activity patterns (e.g., exposure time, 

frequency, and duration) may be different for children and adults at the same site. For example, due 

34 http://www.epa.gov/oswer/riskassessment/superfund_hh_exposure.htm. 

24
to outdoor play patterns, children may spend more time near the source of contamination than adults, 

and thus would have higher exposure time and/or exposure frequency values than adults living in the 

same location.35 For indoor vapor intrusion from the subsurface, very young children might be more 

highly exposed due to substantial time spent indoors. 

Beyond the consideration of activity patterns, MEs, and chemicals with a mutagenic MOA for 

carcinogenicity (as described in Section 5.1), no additional adjustments to account for specific child 

receptors should be made to the default values. Appendix A of this document is intended to 

illustrate that the use of default values sufficiently covers age-related variation in DAF or HEC 

values derived using the EPA Inhalation Dosimetry Methodology’s default approach. 

6.2 Commercial-Industrial/Occupational Receptor 

An example of a commercial-industrial or occupational inhalation exposure scenario could be 

characterized by full-time workers (e.g., 8 hours per day, 5 days per week) in an indoor setting, such 

as an office building, exposed via vapor intrusion of subsurface contamination on a daily basis for 5 

to 25 years. When estimating cancer risk for this type of scenario, Equation 6 is recommended to 

calculate an EC and Equation 11 is recommended to estimate risk. Following the flowchart in 

Figure 2, the duration and exposure pattern of this scenario would typically be considered chronic. 

Therefore, Equation 8 is recommended to derive a chronic EC and Equation 12 is recommended 

(with a chronic RfC) when calculating an HQ for cancer or non-cancer effects. If information about 

multiple MEs is available, risk assessors should proceed according to Section 3.4 when deriving ECs 

to use in estimating cancer risks or HQs. Exposure parameters should be adjusted to consider the 

exposure time, frequency and duration for this scenario, which may differ from a residential 

scenario. Risk assessors should also use appropriate exposure parameters for outdoor workers who, 

similar to children, may spend more time near a source of contamination than indoor workers. 

6.3 Construction Worker 

One example of a construction worker scenario could involve a long-term project (1-2 years) with 

workers exposed regularly to contaminant vapors and fugitive dust (8 hours per day, 5 days per 

week). When estimating cancer risk for this type of scenario, Equations 6 and 11 are recommended 

to calculate an EC and the risk estimate, respectively. Following the flowchart in Figure 2, the 

duration of this exposure scenario would typically be considered subchronic. In addition, this 

exposure is generally as frequent as a subchronic toxicity test. Therefore, Equation 8 is 

recommended to derive a subchronic EC, and Equation 12 is recommended for use with a 

subchronic toxicity value to calculate the HQ. If information about multiple MEs is available, risk 

assessors should proceed according to Section 3.4 when deriving ECs to use in estimating cancer 

risks or HQs. 

6.4 Trespasser/Recreational Receptor 

An example trespasser/recreational scenario could consist of an exposure of 1 to 2 hours per day, for 

100 days per year or less. When estimating cancer risk for this type of scenario, Equations 6 and 11 

35 For additional information about early-lifestage age groups to consider when assessing children’s exposure to 

environmental contaminants, please consult EPA’s Guidance on Selecting Age Groups for Monitoring and Assessing 

Childhood Exposures to Environmental Contaminants (EPA, 2005d). 

25
are recommended to calculate an EC and the risk estimate, respectively. Following the steps in 

Figure 2 for cancer or non-cancer effects characterized by an RfC, each exposure period should be 

assessed separately because this exposure lasts only one to two hours each day for an average of two 

days per week. Therefore, Equation 7 is recommended to derive acute ECs for each exposure 

period. In addition, Equation 12 is recommended for use with an acute toxicity value to calculate 

HQs for each exposure period. 

7. TARGET CONCENTRATIONS FOR SCREENING ANALYSIS OF INHALATION 

PATHWAYS 

For purposes of this guidance, risk-based screening levels are values that may be compared to the 

contaminant concentration in air to help risk assessors identify potential contaminants of concern. 

Screening levels can also be calculated for comparison with samples from source media at a site, 

such as soil. Screening levels are generally not appropriate for use as clean-up levels; they are 

intended to aid in initial evaluation of contaminants and exposure pathways of concern prior to 

proceeding with a baseline risk assessment.36 If contaminant concentrations in air exceed the riskbased screening levels appropriate for the receptor population of interest, risk assessors should 

gather site-specific information to determine the need for any remedial action. The following 

sections outline a recommended approach for calculating screening levels in air as well as source 

media. 

7.1 Target Contaminant Concentrations in Air 

The equations recommended for estimating ECs and risk (Equations 6 through 12) can be used to 

calculate target contaminant concentrations in air by following the four steps outlined below in Table 

4.37 

If air samples from a site are found to be below the target concentration, the risk assessor can 

generally conclude that this pathway does not pose an unacceptable level of risk from the 

contaminant. If the concentrations are found to exceed the screening levels, the risk assessor should 

evaluate the inhalation pathway further by gathering additional site-specific data on contaminant 

levels, site conditions, and receptor characteristics. 

7.2 Screening Levels for Other Media 

Inhalation risk-based screening levels may also be calculated for media other than air, including 

soils, tap water, soil gas, and ground water. The soil gas and ground water values may be derived 

specifically to address concerns about vapor intrusion from subsurface contamination into indoor 

spaces. 

36 EPA regions, states, or other agencies may support unique screening levels for specific purposes that may differ from 

the method presented in this document. Generally, when using screening levels it is important that risk assessors 

understand the target risks, toxicity, and exposure assumptions as well as migration-attenuation assumptions on which 

they are based, and to apply them for their intended use. 

37 Target contaminant concentrations in air calculated according to the procedure outlined in this document are generally 

protective for direct inhalation exposures. This process should not be used to calculate concentrations in air to be 

protective of indirect exposures (e.g., ingestion of crops contaminated through air delivery or vapor phase transfer, 

ingestion of livestock or fish contaminated indirectly through air deposition or vapor phase transfer). 

26
TABLE 4 

RECOMMENDED PROCEDURE FOR CALCULATING RISK-BASED SCREENING 

CONCENTRATIONS FOR CONTAMINANTS IN AIR 

Cancer Risk-Based Hazard-Based1 

Step 1: Select Target Levels Select target cancer risk (e.g., 1 x 10­

6

). 

Select target HQ (e.g., 1). 

Step 2: Identify Toxicity Value2 Identify inhalation cancer potency 

value (e.g., IUR). If none exists, 

proceed with hazard-based screening 

level calculation. 

Identify inhalation reference value 

(e.g., RfC) to match exposure scenario 

(acute, subchronic, or chronic). If 

none exist, proceed with cancer 

screening level calculation. 

Step 3: Calculate CA Using target cancer risk from Step 1 

along with the receptor- and 

scenario-specific exposure 

parameter values, calculate CA; the 

following equation is recommended: 

CA = (AT x Target Risk)/(IUR x ET 

x EF x ED) 

Using target HQ from Step 1 along 

with the receptor- and scenariospecific exposure parameter values, 

calculate CA; the following equation 

is recommended: 

CA = (AT x Target HQ x RfC x 1000 

μg/mg)/(ET x EF x ED) 

Step 4: Select Screening 

Concentration 

Select minimum of predicted cancer risk- and hazard-based values as 

screening concentrations.3

 Repeat for each receptor/scenario combination of 

interest. 1 Hazard-based screening concentrations are typically derived from reference values such as RfCs. These values may 

be available for non-cancer effects but may include cancer, if a nonlinear MOA is thought to operate for a chemical. 2 If no inhalation toxicity value is available for a chemical, contact STSC for further direction on how to proceed. 

3

 Screening levels estimated from the equations presented in Step 3 could yield concentrations that exceed the 

maximum possible vapor concentration for a chemical. In such cases, it may be useful to calculate the maximum 

possible vapor concentration of the pure contaminant at the temperature of interest, using the following formula: Cmax = 

S x H x 103

 L/m3, where S = solubility at 25◦C (or temperature of interest) and H (unitless) = Henry’s Law Constant at 

25◦

 C (or temperature of interest). This equation is based on an established relationship (see, for example, 

Schwartzenbach et al. 1993), that allows the Henry’s Law Constant to be estimated as the ratio of a compound’s vapor 

pressure and aqueous solubility for compounds that are slightly to moderately soluble in water. When the 

dimensionless Henry's Law constant, H, is used, the relationship described above can be used to calculate the vapor 

concentration of a saturated solution of a given compound, assuming equilibrium between the vapor and aqueous 

phases. 

7.2.1 Soil Screening Levels 

When evaluating risk in a source medium, such as soil, it is typically possible to calculate screening 

levels for that medium that are expected to be protective of inhalation exposures based on the 

expected transfer of a contaminant from the source medium to the air. Soil Screening Levels (SSLs) 

can be described as “risk-based soil concentrations derived for individual chemicals of concern from 

standardized sets of equations. These equations combine EPA chemical toxicity data with 

parameters defined by assumed future land uses and exposure scenarios, including receptor 

characteristics and potential exposure pathways” (USEPA, 2002b). These SSLs may be used for 

screening analyses and may serve as the basis for the development of Preliminary Remediation 

Goals (PRGs). Refer to the Soil Screening Guidance (USEPA, 1996) and the Supplemental 

Guidance for Developing Soil Screening Levels for Superfund Sites (USEPA, 2002b) for 

recommended equations that can be used to calculate SSLs for volatilization of chemicals from soil 

to air and for particulate emissions. 

27
7.2.2 Tap Water Screening Values 

Contaminated tap water may pose risk by the inhalation route if the contaminants present are 

volatile. Screening levels can be calculated for tap water that account for inhalation exposures 

resulting from the household use of water (e.g., showering, laundering, dishwashing). Risk 

assessors should consult their local EPA regional risk assessor for direction on how to calculate 

appropriate screening levels for tap water. 

7.2.3 Soil Gas or Ground Water Screening Values for Vapor Intrusion 

If there is concern at a site about the possibility of migration of vapor-forming chemicals from 

contaminated soil gas or ground water into the indoor air of overlying buildings (“vapor intrusion”), 

screening values can be calculated for these media. Risk assessors should first follow the procedure 

outlined in Section 7.1 and Table 4 to calculate a risk-based target concentration for the contaminant 

in air. 

For the calculation of a soil gas screening-level concentration, the target air concentration is then 

divided by an assumed screening-level attenuation factor. The attenuation factor (the ratio of indoor 

air divided by subsurface source concentration) represents the factor by which subsurface vapor 

concentrations migrating into indoor air spaces are reduced due to a variety of attenuating 

mechanisms. 

For the calculation of a ground water screening-level concentration, the target air concentration is 

divided by an assumed screening-level attenuation factor, and the resulting soil gas concentration is 

converted to a corresponding ground water concentration, assuming equilibrium between the 

aqueous and vapor phases at the water table. 

Risk assessors should consult their local EPA regional risk assessor for direction on how to calculate 

appropriate screening levels for soil gas and ground water when vapor intrusion is an issue at a site. 

8. DEVELOPING AGGREGATE AND CUMULATIVE RISK ESTIMATES 

EPA’s current approach to estimating cumulative risk or hazard at a site from multiple chemicals, set 

forth in RAGS, Part A (USEPA, 1989), is not affected by the Inhalation Dosimetry Methodology and 

therefore is not being updated at this time. In addition, the aggregation of risks and hazards across 

multiple exposure routes should remain unchanged. The recommended approaches for aggregating 

risk and hazard estimates are outlined below. 

8.1 Estimating Cumulative Risks and Hazards Across Multiple Chemicals 

The recommended method for estimating cumulative risk and hazard at a site from exposure to 

multiple chemicals is described in RAGS, Part A, Section 8.2.2. This method is based on the default 

approaches described in Guidelines for the Health Risk Assessment of Chemical Mixtures (USEPA, 

1986). Additional information on this method was subsequently published in the Supplementary 

Guidance for Conducting Health Risk Assessment of Chemical Mixtures (USEPA, 2000b). The 

recommended methods to use with quantitative cancer risk estimates as well as with HQs are 

outlined below. 

28
8.1.1 Cancer Risks 

When evaluating predicted cancer risks from multiple contaminants, risk assessors should estimate 

the cancer risk for each substance and then sum these risks. This yields an estimate of total cancer 

risk, which represents the cumulative predicted cancer risk for the chemicals at a site. 

Risk assessors should note, however, that this recommended method assumes “independence of 

action by the compounds involved (i.e., that there are no synergistic or antagonistic chemical 

interactions and that all chemicals produce the same effect, i.e., cancer)” (USEPA, 1989). In 

addition, this simple additive approach is generally most appropriate for total cancer risks less than 

0.1. If these assumptions are incorrect, over- or under-estimation of actual multiple-substance risk 

could result (USEPA, 1989). 

8.1.2 Hazard Quotients 

When the evaluation involves multiple chemicals assessed via HQs, risk assessors typically first 

calculate the HQ for each substance, and then sum the individual HQ values. This generally yields 

an estimated hazard index (HI) for the multiple chemicals assessed via a hazard-based approach. 

Separate HIs should be calculated for each type of exposure period (i.e., chronic, subchronic, acute). 

If an HI is greater than 1, it is generally appropriate to derive separate HIs for each target organ of 

concern (for more information, see RAGS, Part A, page 8-14).38 When multiple acute exposures are 

present at a site, risk assessors should evaluate each acute exposure event separately. Hazards from 

multiple chemicals generally should be summed only when the exposures to these chemicals occur 

simultaneously.39 

8.2 Aggregating Risk and Hazard Quotients Across Exposure Routes 

Guidance for combining the multi-chemical risk estimates and hazard quotients across exposure 

pathways is described in RAGS, Part A, Section 8.3 (USEPA, 1989). In order to determine whether 

risks or HIs should be combined across exposure pathways, risk assessors should first identify 

reasonable exposure pathway combinations. Then, risk assessors should examine whether it is likely 

that the same individuals would consistently face the reasonable maximum exposure (RME) by more 

than one pathway. 

38 This recommended method assumes that “the dose for each individual component is at a level at which effects are not 

expected to occur, be observable, or be of concern; however, when the doses are combined, effects of concern may be 

expected or observed in response to the higher dose level of the mixture” (EPA, 2000b, page 12). Another assumption of 

the HI approach is that the compounds induce the same effect by the same mechanism of action. Therefore, “application 

of the HI equation to a number of compounds that are not expected to induce the same type of effects or that do not act 

by the same mechanism, although appropriate as a screening-level approach, could overestimate the potential for effects” 

(EPA, 1989, page 8-14). This is generally less of a concern if one to two substances are responsible for driving the HI 

above 1. 

39 In cases where a single chemical is present at a site and receptors are exposed through a series of acute exposure 

events, the highest single EC should be compared to an acute reference value of the appropriate duration to assess 

hazard. 

29
The recommended approach for estimating excess cancer risk from exposure via multiple routes is to 

first estimate cancer risk from each exposure pathway and then sum across the multiple routes.40 

For the effects assessed via a reference value, risk assessors should calculate the HI for each 

exposure pathway and sum across the multiple routes. Separate total HIs should be calculated for 

each type of exposure period (i.e., chronic, subchronic or acute). If the HI exceeds one, there may be 

concern for potential adverse effects and risk assessors should consider deriving separate HIs for 

each target organ of concern. 

9. RISK CHARACTERIZATION 

Risk characterization is the final, summarizing step in conducting a risk assessment. Generally, the 

purpose of the risk characterization section of a report is to:41 

• Describe the key findings of the risk assessment in a transparent manner, including 

identifying hazard, characterizing the dose-response relationship, and describing receptor 

exposures; 

• Identify and describe the scientific and policy assumptions used in the assessment; 

• Characterize uncertainties in results; and 

• Provide an overall conclusion about the risks present at a site (USEPA, 2000c). 

A well-crafted risk characterization section puts risk calculations into context for risk managers so 

that they may effectively weigh and interpret risk assessment results (i.e., it is the interface between 

risk assessment and risk management). A few of the key issues and uncertainties involved in 

calculating risks from inhalation exposures are outlined below. 

9.1 Highly Exposed or Susceptible Populations and Life Stages 

EPA recommends that the risk characterization portion of the risk assessment explain any particular 

susceptibilities to inhaled toxicants or potential for increased inhalation exposures among the various 

receptor groups at a site.42 We discuss below two possible examples, children and worker receptors, 

though this discussion could apply to other receptor characteristics as well (e.g., age, disease, gender, 

genetic characteristics). 

9.1.1 Children 

One population group that could potentially be more highly exposed to inhalation exposures at a site 

is children. As discussed in Section 6.2, exposure parameters related to activity patterns (e.g., 

exposure time, frequency, and duration) and MEs, may vary across age groups. For example, due to 

outdoor play patterns, children may spend more time near the source of contamination than adults, 

40 Note that this approach is generally most appropriate for total cancer risks of less than 0.1 (EPA, 1989). 

41 For specific information on the format of risk characterizations, refer to Elements to Consider when Drafting EPA Risk 

Characterizations (EPA, 1995c). 

42 EPA’s IRIS glossary defines susceptibility as the following: “Increased likelihood of an adverse effect, often discussed 

in terms of relationship to a factor that can be used to describe a human subpopulation (e.g., life stage, demographic 

feature, or genetic characteristic)” (EPA, 2008b). 

30
and thus would have higher exposure time and/or exposure frequency values than adults living in the 

same location. Therefore, it is important to carefully describe site-specific exposures to children, 

and assumptions made in risk calculations.43 

If chemical-specific data on susceptibility to the toxic effects from early life exposures are available, 

these data are considered when developing toxicity values that specifically address differential 

toxicity to the young (e.g., vinyl chloride) (USEPA, 2005c). Toxicity values derived using the 

default approach from the Inhalation Dosimetry Methodology are developed for the human 

population as a whole, including sensitive subgroups. Therefore, as described in Section 6 of 

Appendix A, no quantitative adjustment of toxicity values derived using the default approach in the 

Inhalation Dosimetry Methodology is recommended for specific age groups to account for different 

ventilation rates or body weights of specific age groups. 

When evaluating risk to carcinogenic chemicals with a demonstrated mutagenic MOA but which 

lack chemical-specific information on susceptibility from early life exposures, EPA recommends a 

quantitative adjustment of the toxicity value to account for early life susceptibility, as described in 

the Supplemental Cancer Guidelines (see USEPA, 2005b & 2005c; and Section 5.1 of this guidance 

for further information). 

9.1.2 Workers 

Workers could have increased exposure under certain occupational scenarios. Some outdoor 

workers might spend more time near a source of contamination in the course of their job and this 

should be reflected in adjustments to the exposure parameters (e.g., ET, Exposure Frequency (EF), 

and ED) describing the worker exposure scenario. Toxicity values derived using the Inhalation 

Dosimetry Methodology are developed for the human population as a whole, including sensitive 

populations and life stages. In the default Inhalation Dosimetry Methodology approach, typical 

variation in IRs between periods of high activity and rest is considered. However, if workers have 

especially high levels of exertion with correspondingly high ventilation rates, these workers could be 

at the upper end of the risk range, particularly if they are exposed to Category 1 gases, which have 

direct effects in the respiratory tract. This implication should be recognized in the risk 

characterization section. 

9.2 Uncertainties in Inhalation Risk Assessment 

This guidance recommends including an assessment of the key uncertainties that may significantly 

impact risk estimates for inhaled chemicals. This should ensure transparency, clarity, reasonableness 

and consistency in risk assessments, as recommended by EPA’s Policy for Risk Characterization 

(USEPA, 1995a). Other sources of uncertainty may be present and other EPA documents provide 

guidance on characterizing uncertainty in risk the assessment process (USEPA, 1992, 1995a, 1995b, 

1995c, 1997a, 1997b). Key uncertainties related to inhalation risk assessment, which is the focus of 

this section, include the development of ECs, choice of toxicity value, lack of quantitative toxicity 

information via inhalation, and the approach to estimating and aggregating risks. According to 

EPA’s Guidance for Risk Characterization, the discussion of uncertainty “should reflect the type and 

complexity of the risk assessment, with the level of effort for analysis and discussion of uncertainty 

43 For additional information on children’s health risk assessment, please consult A Framework for Assessing Health 

Risks of Environmental Exposures to Children (EPA, 2006b). 

31
corresponding to the level of effort for the assessment” (USEPA, 1995b). Therefore, risk assessors 

should provide a qualitative and/or quantitative evaluation of key uncertainties pertaining to 

inhalation risk, and their impact on the outcome of the assessment, consistent with the level of effort 

of the specific risk assessment. 

9.2.1 Development of Exposure Concentrations 

As described in Section 3 of this guidance, with the exception of acute exposures, time-weighted 

averages are typically used to represent intermittent or variable inhalation exposures to receptors at a 

site. This recommended approach is consistent with the duration adjustment approach (based on 

Haber’s Law) that is generally used in deriving the toxicity values (see Section 2.1.1.1 for further 

information). As mentioned in Section 3, when evaluating situations in which the exposure is longterm, yet there are short periods of significantly higher exposure, those periods should also be 

assessed using appropriate short-term toxicity values. This ensures that periods of much higher 

exposure can be appropriately assessed and not “diluted out” in the assessment of longer-term 

exposure. 

When information on multiple MEs exists at a site, risk assessors may choose to estimate ECs as 

outlined in Section 3.4. However, this typically requires sufficient time-activity information of 

receptors at a site to accurately determine the time spent in each ME. Incomplete or low quality data 

on time-activity pattern may introduce uncertainty into the estimation of the ECs for MEs. Risk 

assessors should describe the quality and completeness of these data. 

The recommended method for determining the CA at a site can potentially introduce uncertainty into 

the EC calculations. For instance, if contaminant concentrations in air are measured, risk assessors 

should consider uncertainties related to how well the set of air samples available at a site represents 

the duration and time period being assessed as well as measurement uncertainty related to the 

methods and equipment used. In addition, risk assessors should describe any potential confounding 

of indoor air samples by other sources of contaminants (e.g., household products). If contaminant 

concentrations in air are modeled, (e.g., by EPA’s spreadsheet models for vapor intrusion) risk 

assessors should address model-related uncertainties and their potential impact on the estimate of 

contaminant concentrations in air. Considerations of particle size at the site versus particle size used 

to derive the toxicity value are also important. 

9.2.2 Toxicity Assessment 

Section 4.1 of this document indicates that some IURs on IRIS were developed through 

extrapolation from oral CSFs (see Appendix B of this document). The use of toxicity values derived 

through simple route-to-route extrapolation introduces additional uncertainty into risk calculations. 

Therefore, risk assessors should indicate when extrapolated IURs are used and should characterize 

the potential impact of the uncertainty associated with using these values, if known. 

Section 4.2 and Appendix C of this guidance recommends contacting STSC to help identify 

appropriate toxicity values for conducting a risk assessment at Superfund sites in the absence of 

published inhalation toxicity values. If STSC is unable to recommend a toxicity value, risk assessors 

should acknowledge the resulting uncertainty in risk associated with the chemical(s) lacking 

inhalation toxicity data. If STSC provides risk assessors with a toxicity value based on a PBPK 

32
model, model uncertainty should be discussed. In addition, if STSC provides risk assessors with one 

or more structurally analogous chemicals, risk assessors can use toxicity data for these chemicals to 

help characterize the potential magnitude of the inhalation risk associated with the chemical(s) 

lacking data. In this case, risk assessors should acknowledge the uncertainty associated with relying 

on toxicity data for analogous chemicals to characterize risk at the site. 

Risk assessors should also acknowledge chemicals that lack duration-appropriate toxicity values and 

discuss the potential impacts of substituting alternative toxicity values for HQ calculations. For 

instance, if the ED is determined to be subchronic but no subchronic inhalation RfC or analogous 

toxicity value is available for that chemical, the risk assessor should address the uncertainty 

associated with calculating an HQ using a toxicity value for a different duration, such as chronic, or 

the impact of not quantifying those risks. In addition, if risk assessors use an acute toxicity value 

that does not match the duration of the acute exposure being assessed, the possibility of under or 

overestimating hazard should be discussed. 

When conducting a screening-level risk assessment using screening values such as those described in 

Section 7, it is important to further evaluate and clearly describe the quality and uncertainties 

associated with the inhalation toxicity values used in the risk assessment if measured sample 

contaminant concentrations at a site exceed these screening values. 

9.2.3 Estimating Cancer Risks 

For high exposures, for example those within the range of epidemiological studies (usually those 

predicted to have risks greater than 10-2), the IUR derived from the linear extrapolation below the 

range of observation is generally not appropriate for use (see Section 5.1 of this document for further 

information).44 Risk assessors should provide specific information in the risk characterization 

describing how these high exposures were addressed in the risk assessment. For instance, if a risk 

assessor chose to provide a semi-quantitative approach (e.g., indicating that risks are above 10-2), 

this should be indicated, along with a description of the uncertainties involved in not fully 

quantifying risk associated with exposure to this chemical. If a risk assessor chose to use the 

original model in the IRIS file or other technical background document, the risk characterization 

section should include a description of any uncertainties in the model used and could contain 

examples of the risks estimated. 

9.2.4 Estimating Risk and Hazard from Multiple Chemicals and Exposure Pathways 

Risk assessors should also describe uncertainties involved in aggregating risk and hazard across 

multiple chemicals and exposure pathways. For instance, the approaches described in Section 8 of 

this document are associated with several assumptions (e.g., independence of action and doses for 

individual compounds at levels not expected to be of concern). If these assumptions are not met, 

aggregation may not be appropriate. This should be fully described in the risk characterization 

section and any uncertainties involved in the lack of quantitative information should be indicated. 

44 Also refer to Section 8.2.1 of RAGS, Part A for further discussion of this topic (EPA, 1989, page 8-6). 

33
10. REFERENCES 

Eaton, D.L. and Klaassen, C.D. (2001). “Principles of Toxicology” in Casarett and Doull’s 

Toxicology: The Basic Science of Poisons, Klaassen, C.D., editor. McGraw-Hill Publishing 

Division, 6th Edition, page 14. 

Gaylor, D.W. (2000). The Use of Haber’s Law in Standard Setting and Risk Assessment. Toxicology 

149:17-19. Johnson, P.C. and Ettinger, R.A. (1991). Heuristic Model for Predicting the 

Intrusion Rate of Contaminant Vapors into Buildings. Environmental Science and 

Technology 25: 1445-1452. 

http://www.epa.gov/oswer/riskassessment/airmodel/johnson_ettinger.htm 

Schwarzenbach, R.P., P.M. Gschwend, and D.M. Imboden. (1993). Environmental Organic 

Chemistry. John Wiley & Sons, Inc.: New York. 

U.S. EPA. (1986). Guidelines for Health Risk Assessment of Chemical Mixtures. Risk Assessment 

Forum, Washington, D.C. EPA/630/R-98/002. 

 http://www.epa.gov/ncea/raf/pdfs/chem_mix/chemmix_1986.pdf 

U.S. EPA. (1989). Risk Assessment Guidance for Superfund, Volume 1, Part A. Office of 

Emergency and Remedial Response, Washington, D.C. EPA/540/1-89/002. 

 http://www.epa.gov/oswer/riskassessment/ragsa/index.htm 

U.S. EPA. (1991). Risk Assessment Guidance for Superfund, Volume 1, Part B. Office of 

Emergency and Remedial Response, Washington, D.C. EPA/540/R-92/003. 

 http://www.epa.gov/oswer/riskassessment/ragsb/ 

U.S. EPA. (1992). Memorandum: Guidance on Risk Characterization for Risk Managers and Risk 

Assessors. From F. Henry Habicht II, Deputy Administrator, U.S. EPA, Washington, DC. 

http://www.epa.gov/oswer/riskassessment/pdf/habicht.pdf 

U.S. EPA. (1994). Methods of Derivation of Inhalation Reference Concentrations and Application 

of Inhalation Dosimetry. Office of Research and Development, Research Triangle Park, NC. 

EPA/600/8-90/066F. http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=71993. 

U.S. EPA. (1995a). Policy for Risk Characterization. From Carol Browner, Administrator, U.S. 

EPA, Washington, DC. 

U.S. EPA. (1995b) Guidance for Risk Characterization. Science Policy Council. February. 

http://www.epa.gov/osa/spc/pdfs/rcguide.pdf 

U.S. EPA. (1995c). Elements to Consider when Drafting EPA Risk Characterizations. March. 

http://www.epa.gov/osa/spc/pdfs/rcelemen.pdf 

U.S. EPA. (1996). Soil Screening Guidance: User’s Guide, Second Edition. Office of Solid Waste 

and Emergency Response, Washington, D.C. EPA/540/R95/128. 

http://www.epa.gov/superfund/resources/soil/ssg496.pdf 

U.S. EPA. (1997a). Exposure Factors Handbook. Office of Research and Development, 

34
Washington, DC. EPA/600/P-95/002Fa. http://www.epa.gov/ncea/pdfs/efh/front.pdf 

U.S. EPA. (1997b). Policy for Use of Probabilistic Analysis in Risk Assessment. From Fred Hansen, 

Deputy Administrator, Washington, DC. 

U.S. EPA. (1998). Route-to-Route Extrapolations. Memorandum from John E. Whalan and Hugh 

M. Pettigrew to Margaret Stasikowski. Office of Prevention, Pesticides, and Toxic 

Substances. October 10, 1998. 

U.S. EPA. (2000a). Integrated Risk Information System Summaries: Vinyl Chloride. Office of 

Research and Development, Washington, D.C. http://www.epa.gov/iris/subst/1001.htm 

U.S. EPA. (2000b). Supplementary Guidance for Conducting Health Risk Assessment of Chemical 

Mixtures. EPA/630/R-00/002. 

 http://www.epa.gov/ncea/raf/pdfs/chem_mix/chem_mix_08_2001.pdf 

U.S. EPA. (2000c). Risk Characterization Handbook. Science Policy Council, Washington, D.C. 

EPA-100-B-00-002. http://www.epa.gov/osa/spc/pdfs/rchandbk.pdf 

U.S. EPA. (2001). Risk Assessment Guidance for Superfund, Volume 1, Part D. Office of 

Emergency and Remedial Response, Washington, D.C. Publication 9285.7-47. 

 http://www.epa.gov/oswer/riskassessment/ragsd/index.htm 

U.S. EPA. (2002a). Draft Guidance for Evaluating the Vapor Intrusion to Indoor Air Pathway from 

Groundwater and Soils (Subsurface Vapor Intrusion Guidance). Office of Solid Waste and 

Emergency Response, Washington, D.C. 

http://www.epa.gov/epawaste/hazard/correctiveaction/eis/vapor/complete.pdf 

U.S. EPA. (2002b). Supplemental Guidance for Developing Soil Screening Levels for Superfund 

Sites. Office of Solid Waste and Emergency Response, Washington, D.C. Publication 

9335.4-24. http://www.epa.gov/superfund/health/conmedia/soil/pdfs/ssg_main.pdf 

U.S. EPA. (2002c). A Review of the Reference Dose and Reference Concentration Processes. Risk 

Assessment Forum, Washington, DC, EPA/630/P-02/002F. 

http://cfpub.epa.gov/ncea/raf/recordisplay.cfm?deid=55365

U.S. EPA. (2003). Human Health Toxicity Values in Superfund Risk Assessment. Office of Solid 

Waste and Emergency Response, Washington, D.C. Publication 9285.7-53. 

http://rais.ornl.gov/homepage/hhmemo.pdf. 

U.S. EPA. (2004a). User’s Guide for Evaluating Subsurface Vapor Intrusion Into Buildings. Office 

of Emergency and Remedial Response, Washington, D.C. 

U.S. EPA. (2004b). Air Quality Criteria for Particulate Matter: Volume II. Office of Research and 

Development, Washington, D.C. EPA/600/P-95/001bF. 

U.S. EPA. (2005a). Guidelines for Carcinogen Risk Assessment, Risk Assessment Forum, 

Washington, D.C. EPA/630/P-03/001F. 

http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=116283

35
U.S. EPA. (2005b). Supplemental Guidance for Assessing Cancer Susceptibility from Early-Life 

Exposure to Carcinogens. Risk Assessment Forum, Washington, DC. EPA/630/R-30/003F. 

http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=160003 

U.S. EPA. (2005c). Implementation of the Cancer Guidelines and Accompanying Supplemental 

Guidance – Science Policy Council Cancer Guidelines Implementation Workgroup 

Communication I: Application of the mode of action framework in mutagenicity 

determinations for carcinogenicity. Memorandum from William H. Farland, Chair, Science 

Policy Council to Science Policy Council Steering Committee October 4, 2005. 

http://www.epa.gov/osa/spc/pdfs/canguid1.pdf 

U.S. EPA. (2005d). Guidance on Selecting Age Groups for Monitoring and Assessing Childhood 

Exposures to Environmental Contaminants. Risk Assessment Forum, Washington, DC. 

EPA/630/P-03/003F. http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=146583. 

U.S. EPA. (2006a). Approaches for the Application of Physiologically Based Pharmacokinetic 

(PBPK) Models and Supporting Data in Risk Assessment. National Center for Environmental 

Assessment, Washington, DC. EPA/600/R-05/043F. 

http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=157668. 

U.S. EPA. (2006b). A Framework for Assessing Health Risks of Environmental Exposures to 

Children. National Center for Environmental Assessment, Washington, DC. EPA/600/R05/093F. http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=158363. 

U.S. EPA. (2008a). Regional Screening Levels for Chemical Contaminants at Superfund Sites. 

http://www.epa.gov/reg3hwmd/risk/human/rb-concentration_table/index.htm. 

U.S. EPA. (2008b). Integrated Risk Information System, Glossary of Terms. Office of Research and 

Development. Searched September, 2008. http://www.epa.gov/iris/help_gloss.htm#content 

36
APPENDICES 
TABLE OF CONTENTS 

APPENDIX A: ANALYSIS OF DEFAULT APPROACH FOR HEC DERIVATION AS 

COMPARED TO POPULATION- AND LIFE STAGE-SPECIFIC CALCULATIONS 

INTRODUCTION ...................................................................................................................... A-1 

1. EXAMPLE 1: CATEGORY 1 GAS, EXTRATHORACIC EFFECTS, ACROLEIN ........... A-3 

2. EXAMPLE 2: CATEGORY 1 GAS, TRACHEOBRONCHIAL 

EFFECTS, HYPOTHETICAL CHEMICAL.......................................................................... A-4 

3. EXAMPLE 3: CATEGORY 1 GAS, PULMONARY EFFECTS, 

HYPOTHETICAL CHEMICAL ............................................................................................ A-5 

4. CATEGORY 3 GASES .......................................................................................................... A-7 

5. PARTICLE DEPOSITION ACROSS AGE GROUPS .......................................................... A-7 

6. CONCLUSIONS................................................................................................................... A-10 

7. REFERENCES CITED......................................................................................................... A-11 

8. ADDITIONAL SOURCES OF RELATED INFORMATION ............................................ A-13 

APPENDIX B: CHEMICALS ON IRIS WITH EXTRAPOLATED INHALATION UNIT 

RISKS 

APPENDIX C: STSC’S PROCESS FOR DERIVING ALTERNATIVE INHALATION 

TOXICITY VALUES 
LIST OF TABLES 

Table A-1 Calculation of LOAEL[HEC] Values for Humans of Different Ages 

and Activity Patterns for the Extrathoracic Region ................................................ A-4 

Table A-2 Calculation of NOAEL[HEC] Values for Humans of Different Ages 

 and Activity Patterns for the Tracheobronchial Region ......................................... A-5 

Table A-3 Calculation of NOAEL[HEC] Values for Humans of Different Ages 

 and Activity Patterns for the Pulmonary Region .................................................... A-6 

Table A-4 Particle Deposition Across Age Groups.................................................................... A-9 

Table B-1 Chemicals with Extrapolated Inhalation Unit Risks on Iris .......................................B-2 

LIST OF EQUATIONS 

Equation A-1 RGDRETh .............................................................................................................. A-3 

Equation A-2 RGDRTB ............................................................................................................... A-4 

Equation A-3 RGDRPU ............................................................................................................... A-5 

Equation A-4 Category 3 DAF ................................................................................................... A-7 

Equation A-5 RDDRr.................................................................................................................. A-7 

Equation A-6 RDDRER ............................................................................................................... A-8 
APPENDIX A 
APPENDIX A 

ANALYSIS OF DEFAULT APPROACH FOR HEC DERIVATION AS COMPARED TO 

POPULATION- AND LIFESTAGE-SPECIFIC CALCULATIONS

NOTE: The Agency’s inhalation dosimetry methodology (USEPA, 1994; hereafter, “the Inhalation Dosimetry 

Methodology”) is a technical report that describes the derivation of human equivalent concentrations (HECs) from 

animal (or human) studies, as well as the other steps involved in developing a chronic Reference Concentration (RfC). 

This appendix is included to illustrate the HEC derivation using the Inhalation Dosimetry Methodology’s default 

approach (with the recommended default values for humans), and to also illustrate the impact of substituting alternate 

age- and activity-specific human values into the default calculations. The default approach is employed for chemicals 

for which more chemical-specific dosimetric and pharmacokinetic data are not available, thus precluding the use of more 

advanced models for deriving the HEC. The calculations in this appendix do not represent a refined or optimal model for 

assessing intra-human variability (e.g., age- and activity-specific risks), and are not intended to imply that risk assessors 

should deviate from the Inhalation Dosimetry Methodology by substituting alternate values into the default calculations. 

Age-specific data are limited. Because of these limitations, the calculations made for different ages and exposure groups 

in this appendix are not recommended for use in quantitative risk assessment (i.e., they are only for the purpose of 

illustration), but may be useful in discussions of uncertainty and variability associated with the default approach. 

It is also noted that, as of this writing, the Agency is involved in a routine reevaluation of scientific advancements in 

the field, with consideration of the need for improvement to the Inhalation Dosimetry Methodology. Any revisions 

will consider current understanding of inhalation dosimetry and differences across and within species, as well as the 

Agency’s risk assessment needs. In order to transparently and quantitatively address children’s inhalation dosimetry 

and risk assessment, this guidance document will be updated (on-line) when Agency methodology updates are 

available that are specific to early life. Until that time, the 1994 Inhalation Dosimetry Methodology is the 

appropriate Agency methodology. 

INTRODUCTION 

This appendix consists of examples and discussions illustrating the current default chemical 

category-specific approach to inhalation dosimetry for the various categories of gases and particles 

as described in Methods for Derivation of Inhalation Reference Concentrations and Application of 

Inhalation Dosimetry (USEPA, 1994; hereafter, the Inhalation Dosimetry Methodology). This 

default inhalation dosimetry approach is used to convert toxicological and epidemiological study 

data to an HEC that can then be used to derive chronic RfCs for the human population (inclusive of 

susceptible populations and life stages, such as children) and also in the development of Inhalation 

Unit Risks (IURs) (USEPA, 2005). The default approach does not rely on age- or activity-specific 

values for physiological parameters when calculating HECs; however the default approach has been 

designed by EPA to derive reference values that are protective across the entire population. 

The appendix includes six sections. Sections 1 through 3 address Category 1 gases. These sections 

provide example calculations for Category 1 highly reactive, high water solubility gases that are 

typically absorbed in the upper airways, exhibiting adverse effects in the extrathoracic (ETh), 

tracheobronchial (TB), and pulmonary (PU) regions of the respiratory tract, respectively. These 

examples include comparisons of HEC calculations based on default parameters with those derived 

using age- and activity-specific parameters for the respiratory region affected. Section 4 addresses 

Category 3 low reactivity, limited water solubility gases that exhibit systemic effects outside the 

respiratory tract. Section 5 addresses changes in particle deposition in the respiratory tract across 

age groups. The conclusions are summarized in Section 6. 

A-1
When reviewing the examples, please note the following: 

• An RfC derived using the Inhalation Dosimetry Methodology is defined as “an estimate 

(with uncertainty spanning perhaps an order of magnitude) of a continuous inhalation 

exposure to the human population (including sensitive subgroups) that is likely to be 

without an appreciable risk of deleterious effects during a lifetime” (USEPA, 2008). 

• All examples in this appendix are based on the Inhalation Dosimetry Methodology. EPA is 

committed to periodically reviewing and updating the Inhalation Dosimetry Methodology to 

ensure that it reflects the current state of the science and that it yields toxicity values that 

sufficiently cover potential age- and activity-related variation in inhalation exposure. A 

review and update is currently underway. 

• The examples in this appendix are all based on calculating HECs from a point of departure 

(POD) for non-cancer effects (e.g., a No Observed Adverse Effect Level (NOAEL), Lowest 

Observed Adverse Effect Level (LOAEL), or Benchmark Concentration, Lower confidence 

limit (BMCL)). These calculations could also be performed in an identical manner for 

carcinogens using a POD for cancer risk estimate derivation (e.g., a Lower limit on the 

Effective Concentration (LEC) value). 

• The default animal and human values for minute volume (Ve) and surface area (SA) used in 

these examples were obtained from Methods for Derivation of Inhalation Reference 

Concentrations and Application of Inhalation Dosimetry (USEPA, 1994).45 The age- and 

activity-specific Ve values were obtained from the International Commission on 

Radiological Protection (ICRP) Publication 66, Human Respiratory Tract Model for 

Radiological Protection (ICRP, 1994).46 Age-specific SA values used in Examples 1 and 2 

were calculated using scaled estimates for the mass and thickness of respiratory regionspecific target tissue from ICRP (1994); Values for Example 3 were calculated from an 

allometric scaling equation presented in a publication by Zeltner et al. (1987). EPA’s 

Office of Research and Development (ORD) selected these data following review of the 

available physiological data for the age groups indicated in the examples. 

• Chemical-specific data from the Integrated Risk Information System (IRIS) file for acrolein 

were used in the ETh example (Example 1). However, the other two examples, which 

focus on effects in the TB and PU regions, respectively, use hypothetical data for the POD 

because there are currently no chemicals on IRIS exhibiting Critical Effects (for RfC 

derivation) in those regions.47 The conclusions of these two examples are unaffected by the 

use of hypothetical data because the results are driven by the values of parameters that are 

not chemical-specific (i.e., SA and Ve). 

45 The minute volume is the total ventilation per minute and equals the product of the tidal volume (the air volume 

entering or leaving the lungs with a single breath) and the respiratory frequency. 

46 For further information on inhalation rates in humans under different scenarios, refer to Chapter 5 of EPA’s Exposure 

Factors Handbook (EPA, 1997). 

47 Hypothetical examples for the TB and PU regions were included in this appendix because currently no RfCs for gases 

on IRIS are calculated based on animal studies showing health effects occurring in these regions of the respiratory 

system 

A-2
1. EXAMPLE 1: CATEGORY 1 GAS, EXTRATHORACIC EFFECTS, ACROLEIN 

The Dosimetric Adjustment Factor (DAF) for a Category 1 gases, the Regional Gas Dose Ratio 

(RGDR), is based on the animal to human ratio of the Ve divided by the SA of the region of the 

respiratory tract where the effect occurs. For acrolein, the effect occurs in the ETh region. The DAF 

is typically calculated using the following equation (USEPA, 1994, Equation 4-18): 

⎛ V ⎞ e ⎜

⎜ ⎟

⎟ 0.14L/min 

⎝ SAETh ⎠animal 15cm2 

RGDRETh = ⎛ V ⎞ = 13.8L/min =0.14 (Equation A-1) 

e ⎜

⎜ ⎟

⎟ 2 ⎝SAETh ⎠human 200cm 

The default Inhalation Dosimetry Methodology-recommended values for the Ve and SAETh of the 

Wistar rat (the animal in the principal study for acrolein) are 0.14 L/min (0.20 m3/day) and 15 cm2, 

respectively (USEPA, 1994). EPA’s default human values are 13.8 L/min (20 m3/day) for Ve and 

200 cm

2

 for SAETh (USEPA, 1994). The RGDR for the ETh region (RGDRETh) was calculated using 

these values for the rat and the human as shown in Equation A-1. In the laboratory animal study on 

acrolein, the LOAEL adjusted for continuous exposure (LOAEL[ADJ]) of 0.16 mg/m3

 (USEPA, 2003) 

is used as the point of departure. The LOAEL[HEC] is the LOAEL[ADJ] multiplied by the RGDRETh. 

To illustrate any potential age- or activity-related variation in the LOAEL[HEC] that might result from 

using human parameter values other than the defaults, scaled estimates for the mass and thickness of 

ETh target tissue from ICRP (1994) at different ages are used to calculate the SAETh values in Table 

A-1. Age- and activity-related Ve reported in ICRP (1994) are based on daily time-budgeted 

reference values. Table A-1 shows little variation in the resultant LOAEL[HEC] across the groups in 

this example. The default procedure produces the lowest LOAEL[HEC] value in Table A-1 and is, 

therefore, sufficient to cover all of these groups. 

A-3
TABLE A-1 

COMPARISON OF THE HEC-DEFAULT (EPA, 1994) WITH EXAMPLE LOAEL[HEC] VALUES 

FOR HUMANS OF DIFFERENT AGES AND ACTIVITY PATTERNS 

FOR THE EXTRATHORACIC REGION 

Total Ve (human) 

(L/min)

a 

SAETh 

(human) 

(cm2)

b 

(Ve/SAETh)human 

(L/min-cm2) RGDRETh 

LOAEL[HEC] 

(mg/m3) 

Outdoor Worker, Male 17.5 470 0.037 0.25 0.04 

Sedentary Worker, Male 15.4 470 0.033 0.28 0.04 

Sedentary Worker, Female 12.6 407 0.031 0.30 0.05 

15 Year-Old Male 14.0 439 0.032 0.29 0.05 

15 Year-Old Female 10.9 397 0.027 0.35 0.06 

10 Year-Old 10.6 293 0.036 0.26 0.04 

5 Year-Old 6.1 198 0.031 0.30 0.05 

1 Year-Old 3.6 97.1 0.037 0.25 0.04 

3 Month-Old 2.0 65.8 0.030 0.31 0.05 

HEC - Default 13.8 200 0.069 0.14 0.02 a These values are from the ICRP publication, Tables 8, 27, B.16a, B.16b and B.17 (ICRP, 1994). b

 These values are from the ICRP publication, Tables 1 and 5 (ICRP, 1994). 

2. EXAMPLE 2: CATEGORY 1 GAS, TRACHEOBRONCHIAL EFFECTS, 

HYPOTHETICAL CHEMICAL 

The DAF for a Category 1 gas or vapor exhibiting effects in the TB region is based on the animal to 

human ratio of the Ve divided by the SA of the TB region for each species. The DAF is typically 

calculated using the following equation: 

⎛ V ⎞ e ⎜

⎜ ⎟⎟ 0.14 L/min 

RGDRTB = ⎝ SATB ⎠animal = 22.5 cm2 

=1.4 (Equation A-2)48 

⎛ V ⎞ 13.8 L/min e ⎜

⎜

SA ⎟

⎟ 3200 cm2 ⎝ TB ⎠human 

This example assumes that the hypothetical chemical has been tested on Wistar rats and therefore 

utilizes the EPA animal default values for that strain. The Ve value used is 0.14 L/min (0.20 m3/day) 

and the default SATB is 22.5 cm2 (USEPA, 1994). EPA’s default human values are 13.8 L/min (20 

m3/day) for Ve and 3200 cm2 for SATB (USEPA, 1994). The RGDR for the TB region (RGDRTB) is 

calculated using these values for the rat and the human, as shown in Equation A-2. The example 

also assumes a NOAEL adjusted for continuous exposure (NOAEL[ADJ]) of 0.16 mg/m3 as the point 

of departure. The NOAEL[HEC] is the NOAEL[ADJ] multiplied by the RGDRTB. 

Table A-2 shows little variation across age and activity groups in the NOAEL[HEC]. The variation 

from the default (less than a factor of 2) is less than the default value of 10 used for the uncertainty 

factor for intraspecies variability when deriving the RfC. Application of the normal procedure for 

48 This equation is the reduced, default version of Equation 4-19 of the Inhalation Dosimetry Methodology. 

Equation 4-19 is reduced to this form consistent with the derivation of the reduced form of the RGDR equation of 

extrathoracic effects described in section 4.3.6.1 and Appendix I of the Inhalation Dosimetry Methodology. 

A-4
determining the RfC will accommodate the observed variation. In addition, RfCs and IURs are 

developed for chronic exposure and will generally involve an exposure for multiple years. 

TABLE A-2 

COMPARISON OF THE HEC-DEFAULT (EPA, 1994) WITH EXAMPLE LOAEL[HEC] VALUES 

FOR HUMANS OF DIFFERENT AGES AND ACTIVITY PATTERNS 

FOR THE TRACHEOBRONCHIAL REGION 

Total Ve (human) 

(L/min)

a 

SATB (human) 

(cm2

)

b 

(Ve/SATB)human 

(L/min-cm2) 

RGDRTB NOAEL[HEC] 

(mg/m3) 

Outdoor Worker M 17.5 2660 0.0066 0.94 0.15 

Sedentary Worker M 15.4 2660 0.0058 1.1 0.18 

Sedentary Worker F 12.6 2640 0.0048 1.3 0.21 

15 year M 14.0 2520 0.0056 1.1 0.18 

15 year F 10.9 2250 0.0048 1.3 0.21 

10 Year 10.6 1830 0.0058 1.1 0.18 

5 Year 6.1 1340 0.0046 1.4 0.22 

1 Year 3.6 857 0.0042 1.5 0.24 

3 Months 2.0 712 0.0028 2.2 0.35 

HEC-default 13.8 3200 0.0043 1.4 0.22 a

 These values are from the ICRP publication, Tables 8, 27, B.16a, B.16b and B.17 (ICRP, 1994). b

 These values are from the ICRP publication, Tables 1 and 5 (ICRP, 1994). 

3. EXAMPLE 3: CATEGORY 1 GAS, PULMONARY EFFECTS, HYPOTHETICAL 

CHEMICAL 

The DAF for a Category 1 gas or vapor with an effect in the PU region is based on the animal to 

human ratio of the alveolar ventilation rate (Q-alv) divided by the SA of the PU region (SAPU) for 

each species. The Q-alv is approximately equal to the Ve multiplied by 0.7. This adjustment 

accounts for the anatomic/physiologic deadspace in the PU region, making the Q-alv equivalent to 

the amount of inspired air available for gas exchange (West, 2000). The DAF for this region of the 

respiratory tract is typically calculated using the following equation: 

⎛ ⎞

⎜

⎜

Q − alv 

⎟

⎟ 0.1L/min 

2 ⎝ SAPU ⎠ 0.34 m RGDRPU =

⎛ Q − alv ⎞

animal = 9.7 L/min =1.6 (Equation A-3)49 

⎜

⎜ ⎟

⎟ 2 ⎝ SAPU ⎠human 54 m 

This example assumes that the hypothetical chemical has been tested on Wistar rats and therefore 

utilizes the EPA animal default values for that strain. The Ve valued used is 0.14 L/min (0.20 

m3/day), which when multiplied by 0.7, yields a Q-alv of 0.1 L/min. The example uses the EPA 

default rat SAPU of 0.34 m2 (USEPA, 1994). EPA’s default human values are 13.8 L/min (20 

49 This equation is the reduced, default version of Equation 4-23 of the Inhalation Dosimetry Methodology. 

Equation 4-23 is reduced to this form consistent with the derivation of the reduced form of the RGDR equation of 

extrathoracic effects described in section 4.3.6.1 and Appendix I of the Inhalation Dosimetry Methodology. 

A-5
m3

/day) for Ve (which yields a Q-alv of 9.7 L/min) and 54 m2 for SAPU (USEPA, 1994). The RGDR 

for the PU region (RGDRPU) is calculated using these values for the rat and the human, as shown in 

Equation A-3. The example also assumes a NOAEL[ADJ] of 0.16 mg/m3 as the point of departure. 

The NOAEL[HEC] is the NOAEL[ADJ] multiplied by the RGDRPU. 

Table A-3 below provides the Q-alv values for humans based on the daily time-budgeted Ve for 

different ages and activity levels from the ICRP publication (1994). SA data for the PU region in the 

ICRP publication are estimated using an allometric scaling model fitted to data from a morphometric 

analysis of SAPU in a sample of seven children (ranging in age from 26 days to 5 years) and eight 

adults (Zeltner et al., 1987). ORD selected the Zeltner analysis for this example because these SAPU 

data are based on empirical morphometric measurements of human lungs as opposed to scaled 

estimates determined from lung models (such as those done by Yu and Xu, 1987 or Yu and Yoon, 

1991). In addition, the children and adult SAPU values calculated in the Zeltner analysis are 

supported by several independent studies that measured SAPU in children (Langston et al., 1984) or 

in adults using similar morphometric techniques (Crapo et al., 1982 & 1983; Stone et al., 1992; 

Mercer et al., 1994). 

Table A-3 shows little variation in the resultant NOAEL[HEC] across the groups in this example. The 

default procedure produces the lowest NOAEL[HEC] value in Table A-3 and is, therefore, sufficient to 

cover all of these groups. 

TABLE A-3 

COMPARISON OF THE HEC-DEFAULT (EPA, 1994) WITH EXAMPLE LOAEL[HEC] VALUES 

FOR HUMANS OF DIFFERENT AGES AND ACTIVITY PATTERNS 

FOR THE PULMONARY REGION 

Total Ve 

(L/min)

a 

Q-alv(human) 

(L/min)

b 

SAPU (human) 

(m2

) 

(Q-alv/SAPU)human 

(L/min-m2

) 

RGDRPU NOAELHEC 

(mg/m3) 

Outdoor Worker, 

Male 

17.5 12 139 0.088 3.3 0.53 

Sedentary Worker, 

Male 

15.4 11 139 0.078 3.7 0.59 

Sedentary Worker, 

Female 

12.6 8.8 114 0.077 3.8 0.61 

15 Year-Old Male 14.0 9.8 108 0.091 3.2 0.51 

15 Year-Old 

Female 

10.9 7.6 100 0.076 3.8 0.61 

10 Year-Old 10.6 7.4 62.0 0.12 2.4 0.38 

5 Year-Old 6.1 4.3 37.3 0.11 2.6 0.42 

1 Year-Old 3.6 2.5 18.5 0.14 2.1 0.34 

3 Month-Old 2.0 1.4 11.0 0.13 2.2 0.35 

HEC-Default 13.8 9.7 54.0 0.18 1.6 0.26 

a These values are from the ICRP publication, Tables 8, 27, B.16a, B.16b and B.17 (ICRP, 1994). b

 These values are from Zeltner et al. (1987). 

A-6
4. CATEGORY 3 GASES 

The DAF for a Category 3 gas or vapor is based on the ratio of the animal blood:gas partition 

coefficient to the human blood:gas partition coefficient and is typically calculated using the 

following equation: 

(H

DAF = b/ g )

animal 

( (Equation A-4) Hb /g )

human 

The blood:gas partition coefficient is primarily determined by the solubility of the gas in an aqueous 

medium as well as the protein and lipid content of the blood. There is little reason to suspect that the 

blood:gas partition coefficient for a non-metabolized chemical will vary greatly across the human 

population. The limited data available indicate no difference in the blood:gas partition coefficient 

with age for methylene chloride in mice (Thomas et al., 1996), and for sevoflurane, isoflurane, and 

halothane in humans (Malviya and Lerman, 1990). Two studies examining the solubility of volatile 

anesthetics (isoflurane, enflurane, halothane, and methoxyflurane) in the blood and body tissues 

found higher blood:gas partition coefficients in adults compared with children (Lerman, et al., 1984 

& 1986). Any variability in the blood:gas partition coefficient with age is expected to be less than 

the default value of 10 used for the uncertainty factor for intraspecies variability when deriving the 

RfC. Any variability in the blood:gas partition coefficient with age is also not expected to cause a 

large overestimate or underestimate in the calculated cancer risk. 

Because of the limited data available, the Inhalation Dosimetry Methodology makes the science 

policy decision to use a value of one for the ratio of the partition coefficients when the animal to 

human ratio exceeds one or when the animal or human value is unknown. At this time, all chemicals 

on IRIS for which both human and animal data are available have an animal to human ratio of 

partition coefficient greater than 1.50 Therefore, the default assumption of one is a conservative 

approach that is not likely to underestimate the chemical-specific DAF. 

5. PARTICLE DEPOSITION ACROSS AGE GROUPS 

The DAF for a particle causing an effect in the respiratory tract, the Regional Dose Deposition Ratio 

(RDDRr), is based on the animal to human ratio of the Ve and the fractional deposition of the particle 

in that region (Fr), divided by the surface area of the region where the effect occurs (SAr) (USEPA, 

1994). Inherent in this derivation is the assumption that 100 percent of the deposited dose remains in 

the respiratory tract and any clearance mechanisms are not considered. The RDDRr is typically 

calculated using the following equation: 

⎛ V ⎞ e ⎜

⎜

SA 

× Fr ⎟

⎟

RDDR = ⎝ r ⎠animal (Equation A-5) r ⎛ V ⎞ e ⎜

⎜ × Fr ⎟

⎟

⎝ SA r ⎠human 

50 While 1,4-dioxane has not yet been evaluated on IRIS, it provides an exception to this statement, in that the blood:gas 

partition coefficient is 2750 for mice, 1850 for rats, and 3650 for humans, yielding an animal to human ratio of 0.75 for 

mice and 0.51 for rats (Reitz et al., 1990). 

A-7
The DAF for a particle causing an extra-respiratory (ER) effect, the RDDRER, is based on the animal 

to human ratio of the Ve and the total deposition of the particle in the entire respiratory tract (Ftotal), 

divided by body weight (BW) (USEPA, 1994). The RDDRER assumes that 100 percent of the 

deposited dose in the entire respiratory tract is available for uptake into the systemic circulation. The 

following general equation can be used to estimate the RDDRER: 

⎛ Ve ⎞ ⎜ × ⎜ F

BW total ⎟

⎟ ⎝ ⎠ ER

animal RDDR = (Equation A-6) ⎛ V ⎞ ⎜ e × ⎜ F

BW total ⎟

⎟ ⎝ ⎠human 

The information on particle deposition in various age groups is quite limited. A discussion of the 

current state of the science can be found in the Air Quality Criteria for Particulate Matter Volume II, 

Section 6.2.3.2 (USEPA, 2004; hereafter, PM Criteria Document). 

Experimental and modeling results are summarized in Table A-4. The results for experimental 

studies are mixed, some suggesting higher deposition in children and others finding no difference 

across age groups. Bennett and Zeman (1998) and Schiller-Scotland et al. (1994) found no 

difference between total deposition of particles in the respiratory tract of children (aged 7 to14 and 6 

to12, respectively) and adults for 1 to 2 micrometer particles. Schiller-Scotland et al. did find twoto three-fold higher total particulate deposition in 6 to 12 year olds for particles of 2 to 3 

micrometers in size. In addition, Bennett et al. (1997) found that deposition in the ETh region was 

50 percent greater in children than adults. The PM Criteria Document concludes that “these...studies 

...do not provide unequivocal evidence for significant differences in deposition between adults and 

children” (USEPA, 2004, page 6-29). The document notes, however, that children may have 

higher activity levels and higher associated minute ventilation per lung size, potentially causing a 

greater size-specific dose of particles to the lung. 

Modeled results suggest a higher deposition of particles in the TB region of children when compared 

to adults, depending on the particle size (Xu and Yu (1986); Hofmann et al. (1989); Musante and 

Martonen (1999); Phalen and Oldham (2001); Asgharian et al. (2004); Jarabek et al. (2005); 

Ginsberg et al. (2005)). Mixed results again are found in modeling studies for total deposition and 

deposition in other respiratory regions. In general, where differences are observed in either 

experimental or modeled studies, variability in deposition between age groups has been reported to 

be most often in the range of 1- to 3-fold greater for children than for adults, but ranging from 

equivalency or less up to 7-fold greater.51 

51 A modeling analysis examining deposition fraction per unit area at various airway generations of the lung as a function 

of age for various particle sizes (ranging from 0.01 to 10 μm) reported comparisons between a 3-month old and 21-year 

old that ranged from equivalency up to a 14-fold difference in this metric for some specific airway generations 

(Asgharian et al., 2004). 

A-8
TABLE A-4 

PARTICLE DEPOSITION ACROSS AGE GROUPS 

Study Particle Size Results 

Experimental Studies 

Becquemin et al. (1991) Various Nasal deposition higher in adults (up to 1.8-fold higher at rest and up to 3.4-fold higher during exe

thoracic airways of children are less protected than those of adults. 

Bennett et al. (1997) 4.5 μm -ETh deposition of particles 50 percent greater in children (higher for younger ages). 

-No significant difference in total respiratory tract deposition. 

Bennett and Zeman (1998) 1-2 μm No difference between 7-14 year olds and adults in total deposition of particles in the respiratory tSchiller-Scotland et al. (1994) 1-2 μm No difference between 6-12 year olds and adults in total deposition of particles in the respiratory t

2-3 μm Two- to three-fold higher total deposition of particles in 6-12 year olds versus adults. 

Modeled Studies 

Asgharian et al. (2004) 0.01-10 μm -Up to 1.2-fold higher total deposition in 3 month olds compared to adults in the TB region. 

-Up to 1.5-fold higher total deposition in 8 year olds compared to adults in the alveolar region. Toand 23 month olds (up to 2-fold). -Estimates of deposition fraction per unit area at various airway generations of the lung and variouolds compared to adults (up to 14-fold). Higher deposition also seen for 23 month olds (up to 5-fo

compared with adults. No difference in deposition in 14 year olds compared to adults. 

Cheng et al. (1995) 0.0046-0.2 μm Nasal casts of children’s airways found increased deposition efficiency for ultrafine particles with 

children may receive a higher dose of ultrafine particles to the upper airways. 

Ginsberg et al. (2005) 0.001-10 μm -Higher deposition in 3 month olds compared with adults for coarse and fine particles in the upper 

fold) regions. -Higher deposition in adults in the lower TB region. 

Hoffmann et al. (1989) 1-2 μm -1.5- to 2-fold higher total deposition in the TB region for particles in resting 8 year olds versus ad

-40-50 percent lower total deposition of particles in 8 year olds under conditions of exercise. 

Jarabek et al. (2005) 0.3-6 μm -Retained mass in the TB region normalized to regional SA was compared across age groups. 

-Up to 2-fold lower deposition in 3 month olds compared to adults. -Up to 2-fold higher deposition in 3 year olds and 14 year olds compared to adults. 

Musante and Martonen (1999) 0.25-5 μm -Total deposition was generally higher in children (ages 7, 22, 48, and 98 months) than adults (e.g

olds was 38 percent higher than adults for 1μm particles). -TB deposition monotonically decreased as a function of age (i.e., younger children had increased -PU deposition greatest in the 48 and 98-month children. 

Musante and Martonen (2000) 2 μm 3-fold higher deposition of particles in the PU region for 7 month olds versus adults. Oldham et al. (1997) Various Airway models of trachea and bronchial airways showed total deposition in children (ages 4 and 7

approximately 7-fold higher for 4 year olds compared to adults for 4.5 μm particles). 

Phalen and Oldham (2001) 0.1-10 μm -No difference in total deposition of particles in 2 year olds versus adults. 

-Somewhat higher (13-81 percent; depending on particle size) deposition of particles in the TB reg-Lower deposition of particles in the PU region. 

Xu and Yu (1986) Various Increased total deposition (up to 1.5-fold higher) in children aged 6 months, 2 years, and 8 years c

varying sizes. 

A-9
6. CONCLUSIONS 

The examples and discussions included in this appendix suggest that the Inhalation Dosimetry 

Methodology’s default approaches for derivation of the HEC for Category 1 gases with effects in the 

ETh, TB, and PU regions and for Category 3 gases typically are sufficient to cover variation across 

human age- and activity-level groups. The process for deriving an RfC from the HEC includes 

applying an uncertainty factor (UF) to account for within-species variability, adding further 

protection. When deriving an IUR for a carcinogen, UFs are not used. However the procedures for 

estimating an IUR incorporate conservative assumptions that would likely accommodate the degree 

of variation observed in these examples. 

Experimental and modeling results for particles suggest the potential for small differences in 

deposition of particles in the respiratory tract as a function of age. The assumption that 100 percent 

of the deposited dose is available for uptake into the systemic circulation (for remote acting 

toxicants), or for activity in the respiratory tract (for local toxicity) is likely to result in an 

overestimation of dose to the target tissue. Any small variation in deposition among age groups 

should be considered against the potential magnitude of such overestimation. These differences in 

calculated deposition are small relative to the default 10-fold UF that accounts for intra-species 

variability in the derivation of the RfC. In addition, RfCs and IURs are developed for chronic 

exposure and will generally involve an exposure for multiple years. No additional correction of the 

toxicity values for these age groups is needed when the RfC or IUR is used in a risk assessment. 

Calculations in these examples are based on empirical data from sources listed and referenced in 

ICRP Publication 66 (ICRP, 1994). While ORD selected the ICRP values as the best estimates for 

these examples, other published values for Ve and SA exist. The use of alternate values may change 

the LOAEL[HEC] calculated for the various populations and life stages and may show more or less 

variability in results across the age and activity groups. In addition, the examples for the TB and PU 

regions are based on a hypothetical chemical, since currently no RfCs for gases on IRIS are 

calculated based on animal studies showing health effects occurring in these regions of the 

respiratory system. Given the parameter values used in the default method for calculating the HEC, 

it is likely that the process would yield results sufficient to cover populations and life stages with 

varying activities and physiologic characteristics. 

Note that the available data, albeit limited, generally support these conclusions. As recommended by 

the Reference Dose (RfD)/RfC Technical Panel (USEPA, 2002), EPA has been exploring issues 

involving dose to the young from inhalation exposures, both theoretically and experimentally as well 

as further considering the existing animal-to-human extrapolation procedures described in current 

methodologies (e.g., USEPA, 1994). This is especially important because of the significant 

developmental changes that occur in the lung from birth well into adolescence (Pinkerton and Joad, 

2000). The review and updating of these methodologies will be based on the best available science. 

A-10
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A-11
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8. ADDITIONAL SOURCES OF RELATED INFORMATION 

De Winter-Sorkina. R., Cassee, F.R. (2002). From concentration to dose: factors influencing 

airborne particulate matter deposition in humans and rats. RIVM Report 650010031/2002. 

Gehr et al. (1978). The normal human lung: ultrastructure and morphometric estimation of the 

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diffusion capacity. Respiration Physiology 18: 519-522. 

Various Authors. (2008). EPA Workshop on Children’s Inhalation Dosimetry and Health Effects for 

Risk Assessment. Journal of Toxicology and Environmental Health, Part A 71:147-248. 

Zoetis, T., Hurtt, M.E. (2003). Species comparison of lung development. Birth Defects Research 68: 

121-124. 

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APPENDIX B 
APPENDIX B 

CHEMICALS ON IRIS WITH EXTRAPOLATED INHALATION UNIT RISKS 

Table B-1 contains chemicals on the Environmental Protection Agency’s (EPA’s) Integrated Risk 

Information System (IRIS) with Inhalation Unit Risk (IUR) values calculated by extrapolation using 

the default ventilation rate and body weight from the oral Cancer Slope Factor (CSF). These 

chemicals cause tumors remote from the respiratory tract. Also listed is the year EPA verified the 

cancer assessment. The list was compiled in September 2008. 

EPA recommends that extrapolated IURs should be used with risk Equations 6 and 11 in the main 

document without additional modification for calculation of cancer risk by the inhalation route of 

exposure. It is generally not appropriate to make adjustments based on ventilation rate and body 

weight using the intake equation, because the amount of the chemical that reaches the target site of 

the chemical through the inhalation pathway is not a simple function of the inhalation rate and body 

weight. Risk assessors should outline the uncertainties involved in using extrapolated IURs in the 

risk characterization section of the risk assessment. 

B-1
TABLE B-1 

CHEMICALS WITH EXTRAPOLATED INHALATION UNIT RISKS 

ON IRIS 

Chemical Year of Verification 

Acrylamide1

 1988 

Aldrin 1987 

Aramite 1991 

Azobenzene 1988 

Bromoform 1989 

Chlordane 1997 

Chloroform1

 1987 

DDT 1987 

1,2-Dichloroethane 1986 

Dieldrin 1987 

1,2-Diphenylhydrazine 1986 

Heptachlor 1987 

Heptachlor epoxide 1987 

Hexachlorobenzene 1989 

Hexachlorobutadiene1

 1986 

Alpha-hexachlorocyclohexane 1986 

Beta-hexachlorocyclohexane 1986 

Technical-hexachlorocyclohexane 1986 

Hexachlorodibenzo-p-dioxin mixture 1987 

Hexachloroethane 1986 

N-nitroso-di-n-butylamine 1986 

N-nitrosodiethylamine 1986 

N-nitrosodimethylamine 1986 

N-nitrosopyrrolidine 1986 

Polychlorinated biphenyls 1996 

1,1,2,2-Tetrachloroethane 1986 

1,1,1,2-Tetrachloroethane 1988 

Toxaphene 1987 

1,1,2-Trichloroethane 1986 

2,4,6-Trichlorophenol 1989 1 Note that this chemical’s IUR is currently under review. 

B-2
APPENDIX C 
APPENDIX C 

STSC’s PROCESS FOR DERIVING ALTERNATIVE INHALATION TOXICITY 

VALUES 

If Reference Concentration (RfC) and/or Inhalation Unit Risk (IUR) values for an inhaled 

contaminant are not available from the sources in the Environmental Protection Agency’s (EPA’s) 

Office of Solid Waste and Emergency Response (OSWER) hierarchy, risk assessors should first 

contact the National Center for Environmental Assessment’s (NCEA’s) Superfund Health Risk 

Technical Support Center (STSC) for guidance.52 Risk assessors working on Superfund sites can 

contact STSC to determine whether a provisional peer-reviewed toxicity value (PPRTV) exists for a 

contaminant; if not, the risk assessor, in cooperation with the appropriate EPA Regional office may 

request that STSC develop a PPRTV document or that STSC develop an inhalation toxicity value as 

a “consult.” The latter would be specific to the site in question only. 

As a first choice, if human or whole animal studies exist providing a suitable No Observable 

Adverse Effect Level (NOAEL)/Lowest Observable Adverse Effect Level (LOAEL) or Point of 

Departure (POD) from a Benchmark Dose (BMD) analysis, this data normally will be used by STSC 

to develop an inhalation toxicity value. If, in addition, a suitable human inhalation physiologically 

based pharmacokinetic (PBPK) model exists that can be utilized to refine the dose metric to the 

target organ, then this information generally will be included in developing an inhalation toxicity 

value. 

If no appropriate whole animal or human studies exist, but an appropriate peer reviewed human 

inhalation PBPK model exists that has been validated by experimental results, then STSC usually 

will attempt to derive an inhalation toxicity value from this model. If none exists, but a suitable 

PBPK animal inhalation models exists, STSC may attempt developing a human model and deriving 

an inhalation value. 

PBPK modeling quantitatively describes the absorption/metabolism/distribution and elimination of 

the chemical from a point of entry (oral, inhalation, dermal) to the target organ(s). In some cases, an 

oral PBPK model can be extrapolated to the inhalation pathway, but care must be taken to consider 

direct pulmonary effects that may not be evident by oral dosing. 

As a next approach, STSC typically will evaluate development of an inhalation toxicity value using a 

suitable surrogate chemical based on a quantitative structure-activity relationship (QSAR) model 

with structural selection criteria and solubility/toxicity considerations. STSC may evaluate possible 

surrogate chemicals based on several available structural models and provide a comparison. 

Selection of the appropriate surrogate may depend on the weight of evidence of these models. 

52 All contact with STSC should be performed by an EPA regional risk assessor. States and other entities should 

first contact their EPA regional risk assessor with questions on inhalation toxicity values. Regional risk assessors 

can then contact STSC on their behalf. 

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If STSC uses any of the methods for developing toxicity values other than from human or whole 

animal data, the value normally will be presented as a “screening” value with the caveat that it 

should not be used as a risk driver for a site without consultation with the STSC. The uncertainties 

associated with using toxicity values derived through PBPK modeling or QSAR, or with using a 

surrogate value should be described in the risk characterization portion of the risk assessment (see 

Section 9). Risk assessors are discouraged from performing simplistic route-to-route extrapolations 

from oral data using default assumptions about Inhalation Rate (IR) and body weight (BW).

53 

53 If STSC indicates that no quantitative toxicity information for the inhalation route is available, the risk assessor should 

conduct a qualitative evaluation of this exposure route. The risk assessor should discuss in the uncertainty section of the 

risk assessment report the implications of not quantitatively assessing risks due to inhalation exposures to chemicals 

lacking inhalation toxicity data. See the section on Risk Characterization (Section 9) in the main text of this guidance for 

more information. 

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