GAO

United States General Accounting Office

Report to Congressional Requesters

August 2001 CHEMICAL RISK 

ASSESSMENT

Selected Federal 

Agencies’ Procedures, 

Assumptions, and 

Policies

GAO-01-810

Page 1 GAO-01-810 Chemical Risk Assessment

Contents

Letter 7

Results in Brief 9

Background 11

Context for Agencies’ Chemical Risk Assessments Is Important 18

Agencies’ Risk Assessment Procedures Share Common Features, But 

Substantive Differences Also Exist 23

Agencies’ Risk Assessment Procedures Often Include Precautionary 

Assumptions and Methods 30

Risk Characterization Policies and Practices Emphasize Transparency 43

Conclusions 46

Agency Comments and Our Evaluation 48

Appendixes Appendix I: Objectives, Scope, and Methodology 50

Appendix II: Chemical Risk Assessment at the Environmental 

Protection Agency 55

Context for EPA Chemical Risk Assessment 56

Risk Assessment Procedures 64

Guidelines 65

Agencywide Risk Assessment Procedures 67

Hazard Identification 68

Dose-response Assessment 71

Exposure Assessment 79

Ecological Risk Assessment 81

Program-specific Risk Assessment Procedures 84

Office of Pesticide Programs 85

Office of Pollution Prevention and Toxics 90

Office of Emergency and Remedial Response (Superfund 

Program) 94

Office of Solid Waste 99

Chemical Emergency Preparedness and Prevention Office 103

Office of Air and Radiation 107

Office of Water 112

Risk Assessment Assumptions and Methodological Choices 118

Risk Characterization 151

Appendix III: Chemical Risk Assessment at the Food and Drug 

Administration 153

Context for FDA Chemical Risk Assessment 154

Risk Assessment Procedures 158

Differences in Risk Assessment Among FDA Product Centers 159

CFSAN Risk Assessment Procedures 162
Contents

Page 2 GAO-01-810 Chemical Risk Assessment

CVM Risk Assessment Procedures 166

CDRH Risk Assessment Procedures 167

Risk Assessment Assumptions and Methodological Choices 170

Risk Characterization 182

Appendix IV: Chemical Risk Assessment at the Occupational Safety 

and Health Administration 184

Context for OSHA Chemical Risk Assessment 184

Risk Assessment Procedures 186

General Approach 186

Hazard Identification 187

Dose-response Assessment 188

Exposure Assessment 193

Risk Assessment Assumptions and Methodological Choices 194

Risk Characterization 199

Appendix V: Chemical Risk Assessment at the Department of 

Transportation’s Research and Special Programs 

Administration 201

Context for RSPA Chemical Risk Assessment 201

Risk Assessment Procedures 204

Guidance 204

Risk Assessment Approach 205

Identifying Hazards 206

Analyzing the Consequences and Probabilities of Risks 212

Risk Assessment Assumptions and Methodological Choices 216

Risk Characterization 218

Glossary 220

Tables Table 1: Comparison of Selected Major Assumptions or Methods 

Used in EPA, FDA, and OSHA Risk Assessments 41

Table 2: Chemical Risk Statutes, Tasks, and Mandates for EPA

Offices 57

Table 3: EPA’s 1986 Classification System for Characterization of 

Carcinogenicity 68

Table 4: Summary of EPA’s Ecological Risk Assessment Process 83

Table 5: EPA Risk Assessment Assumptions and Methodological

Choices 120

Table 6: Differences in FDA Chemical Risk Assessment Factors 160

Table 7: FDA Risk Assessment Assumptions and Methodological 

Choices 171
Contents

Page 3 GAO-01-810 Chemical Risk Assessment

Table 8: OSHA Risk Assessment Assumptions and Methodological 

Choices 194

Table 9: UN Classification System for Transport of Dangerous 

Goods 207

Table 10: Hazard Classification System of RSPA’s Hazardous

Materials Regulations 208

Table 11: Example of a Hazardous Materials Risk Assessment 

Matrix 215

Figures Figure 1: Typical Sequence of Risk Assessment and Risk 

Management Processes 13

Figure 2: Full Toxicity Data Is Available for Only a Small Portion 

of High-Production- Volume Chemicals 15

Figure 3: Extrapolation for Carcinogens 74

Figure 4: Derivation of a Reference Dose Using the Benchmark 

Dose Approach 78
Contents

Page 4 GAO-01-810 Chemical Risk Assessment

Abbreviations

ADI acceptable daily intake

AWQC ambient water quality criteria

BAF bioaccumulation factor

BAT best available technology

CAA Clean Air Act

CAAA Clean Air Act Amendments

CEPPO Chemical Emergency Preparedness and Prevention Office

CERCLA Comprehensive Environmental Response, Compensation, and 

Liability Act

CSFII Continuing Survey of Food Intakes by Individuals

CWA Clean Water Act

DES diethylstilbestrol

DOT Department of Transportation

ED effective dose

EPA Environmental Protection Agency

EPCRA Emergency Planning and Community Right-to-Know Act

FAA Federal Aviation Administration

FDA Food and Drug Administration

FDAMA Food and Drug Administration Modernization Act

FFDCA Federal Food, Drug, and Cosmetic Act

FHWA Federal Highway Administration

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act

FQPA Food Quality Protection Act

FRA Federal Railroad Administration

FTA Federal Transit Administration

GHS globally harmonized system

HAZMAT hazardous materials

HHS Department of Health and Human Services

HMIS Hazardous Materials Information System

HPV high production volume

IRIS Integrated Risk Information System

ISO International Organization for Standardization

LED lowest effective dose

LOAEL lowest observed adverse effect level

LOEL lowest observed effect level

MACT maximum achievable control technology

MCL maximum contaminant level

MCLG maximum contaminant level goal

MEI maximally exposed individual

MLE maximum likelihood estimate
Contents

Page 5 GAO-01-810 Chemical Risk Assessment

NAAQS national ambient air quality standards

NAS National Academy of Sciences

NCTR National Center for Toxicological Research

NOAEL no observed adverse effect level

NOEL no observed effect level

NRC National Research Council

OAQPS Office of Air Quality Planning and Standards

OAR Office of Air and Radiation

OERR Office of Emergency and Remedial Response

OHMS Office of Hazardous Materials Safety

OHMT Office of Hazardous Materials Technology

OPP Office of Pesticide Programs

OPPT Office of Pollution Prevention and Toxics

OPPTS Office of Prevention, Pesticides and Toxic Substances

ORD Office of Research and Development

OSHA Occupational Safety and Health Administration

OSW Office of Solid Waste

OW Office of Water

PBPK physiologically based pharmacokinetic

PEL permissible exposure limit

PMN premanufacture notification

POD point of departure

RCRA Resource Conservation and Recovery Act

RfC reference concentration

RfD reference dose

RSC relative source contribution

RSPA Research and Special Programs Administration

SAR structure-activity relationship

SARA Superfund Amendments and Reauthorization Act

SDWA Safe Drinking Water Act

SOPs standard operating procedures

STEL short-term exposure limit

TI tolerable intake

TSCA Toxic Substances Control Act

TWA time-weighted average

UCL upper confidence limit

UN United Nations

USCG United States Coast Guard

USDA United States Department of Agriculture
Contents

Page 6 GAO-01-810 Chemical Risk Assessment
Page 7 GAO-01-810 Chemical Risk Assessment

United States General Accounting Office

Washington, D.C. 20548 Letr

August 6, 2001

The Honorable W. J. (Billy) Tauzin

Chairman, Committee on Energy and Commerce

House of Representatives

The Honorable Paul E. Gillmor

Chairman, Subcommittee on Environment 

and Hazardous Materials

Committee on Energy and Commerce

House of Representatives

As used in public health and environmental regulation, risk assessment is 

the systematic, scientific description of potential adverse effects of 

exposures to hazardous substances or situations. It is a complex but 

valuable set of tools for federal regulatory agencies, helping them to 

identify issues of potential concern, select regulatory options, and estimate 

the range of a forthcoming regulation’s benefits. For example, the 

Environmental Protection Agency (EPA) used risk assessment information 

in a 1998 final rule to conclude that disinfection byproducts (e.g., 

chloroform) in drinking water could cause as many as 9,300 bladder cancer 

cases a year, and that a 24-percent reduction in those byproducts could 

result in monetized health benefits of about $4 billion.1

 However, risk 

assessments are also sometimes controversial, as evidenced by the fact 

that the disinfection byproduct rule was successfully challenged in court 

over whether the agency used the best scientific evidence available in 

support of certain assumptions.2

 Given the significant yet controversial 

nature of risk assessments, it is important that policymakers understand 

how risk assessments are conducted, the extent to which risk estimates 

produced by different agencies and programs are comparable, and the 

reasons for differences in agencies’ risk assessment approaches and 

results.

1

“National Primary Drinking Water Regulations: Disinfectants and Disinfection Byproducts”

(63 FR 69390, Dec. 16, 1998). The Food and Drug Administration published a related rule on 

disinfection byproducts in bottled water on March 28, 2001 (66 FR 16858).

2

Chlorine Chemistry Council v EPA, 206 F.3d 1286 (D.C. Cir. 2000). In March 2001, EPA 

announced that it would propose a new assessment for chloroform, the disinfection 

byproduct that was the subject of the dispute, using an approach based upon different 

assumptions.
Page 8 GAO-01-810 Chemical Risk Assessment

You asked us to provide information on selected federal agencies’ risk 

assessment procedures and the similarities and differences in how the 

agencies’ personnel are directed to conduct risk assessments. As you 

requested, our review focused on the human health and safety (and, to a 

lesser extent, ecological) risk assessment procedures of the following four 

agencies with primary responsibility for regulating or managing risks from 

potential exposure to chemicals: (1) EPA; (2) the Food and Drug 

Administration (FDA) within the Department of Health and Human 

Services (HHS); (3) the Occupational Safety and Health Administration 

(OSHA) within the Department of Labor; and (4) the Department of 

Transportation’s (DOT) Research and Special Programs Administration 

(RSPA). These agencies regularly conduct chemical risk assessments in 

support of regulatory activities and/or illustrate the diversity of risk 

assessment procedures. Our primary objectives were to identify and 

describe (1) the general context for the agencies’ chemical risk assessment 

activities; (2) what the agencies view as their primary procedures for 

conducting risk assessments; (3) what the agencies view as their major 

assumptions or methodological choices in their risk assessment 

procedures; and (4) the agencies’ procedures or policies for characterizing 

the results of risk assessments. In addressing each of these objectives, we 

also identified similarities and differences between and within the 

agencies. To the extent feasible, we were also asked to identify as part of 

the third objective, (a) at what stages of the risk assessment process the 

assumptions are used, (b) the reasons given for their selection, (c) their 

likely effects on risk assessment results, and (d) how they compare to the 

assumptions and choices used by other agencies or programs in similar 

circumstances. 

We addressed these objectives by reviewing agencies’ general guidance 

documents or, if there were no such documents, specific examples of 

agencies’ risk assessment procedures. We also reviewed previous reports 

on agencies’ procedures, interviewed agency officials, and provided 

detailed descriptions of the relevant procedures to agency officials for their 

review and comment. Our review focused on chemical risk assessments in 

selected agencies, and therefore did not cover all types of risk assessments 

or even all agencies or programs that conduct chemical risk assessments. 

Also, our review did not evaluate how the selected agencies’ procedures 

and policies are applied in individual risk assessments, or how risk 

assessment results are used in making regulatory decisions (risk 

management). We provided a draft of this report to five risk assessment 

experts to ensure technical accuracy. We also provided a draft to officials 

in each of the four agencies for their review and comment. The comments 
Page 9 GAO-01-810 Chemical Risk Assessment

that we received from both the experts and the agencies are reflected in the 

“Agency Comments and Our Evaluation” section of this letter. We 

conducted this review between February 2000 and March 2001 in 

accordance with generally accepted government auditing standards. 

Details of our scope and methodology are presented in appendix I.

Results in Brief The context in which chemical risk assessments are conducted plays an 

important role in determining what type of assessments federal regulatory 

agencies perform and why certain approaches are used. The statutory and 

legal context determines the general focus and goals of an agency’s risk 

assessment activities and also may shape how risk assessments for those 

activities are supposed to be conducted. The specific tasks and purposes 

for which an agency will use the results of a particular risk assessment 

determine the questions that the assessment needs to address and its scope 

and level of detail. For example, risk assessments used by OSHA to set 

occupational health standards must demonstrate that a significant risk 

exists and that the proposed standard would reduce that risk. However, in 

different contexts, FDA and EPA might use risk assessment procedures to 

estimate the dose of a chemical that people could consume daily without 

harmful effect, and not necessarily need to estimate the actual risk 

associated with exposure to that chemical. In other words, the focus of 

federal agencies’ “risk” assessments can sometimes be characterized more 

accurately as safety assessment (i.e., estimating an exposure level below 

which no significant risk will occur) rather than as risk assessment (i.e., 

simply describing the likelihood of a risk).

All four of the agencies included in our review have standard procedures 

for conducting risk assessments involving chemical agents, although the 

agencies vary in the extent to which they have documented their 

procedures in written guidance. There are more similarities than 

differences in the overall chemical risk assessment procedures developed 

by three of the agencies—EPA, FDA, and OSHA. These agencies’

procedures generally follow four-step process recommended by the 

National Academy of Sciences (NAS) of hazard identification, doseresponse assessment, exposure assessment, and risk characterization. 

However, there are variations both among and within the agencies in the 

details of those steps, particularly during the exposure assessment step 

because agencies’ regulatory authorities regarding chemical agents tend to 

vary according to the kinds or sources of exposure. The risk assessment 

procedures in DOT’s RSPA are not based on the NAS four-step process 

because of the particular regulatory context in which RSPA operates. 
Page 10 GAO-01-810 Chemical Risk Assessment

Instead, a classification system that is harmonized with international 

agreements defines what is to be considered a hazardous material for 

transportation purposes according to the general physical characteristics 

of the material (e.g., whether it is explosive, flammable, or toxic). RSPA’s 

analyses of risks then focus on identifying the potential circumstances 

under which unintentional releases of hazardous materials could occur 

during transit (e.g., due to transportation accidents) and assessing their 

consequences and probability of occurrence. 

Assumptions are an unavoidable part of risk assessment because science 

cannot always provide definitive answers to questions raised at various 

stages of an assessment. Agency guidelines and officials we contacted 

during our review identified a large number and wide variety of 

assumptions that may be used, in the absence of adequate information, 

during the first three steps of a risk assessment. The agencies frequently 

indicated that particular assumptions were chosen on the basis of their 

evaluation of available scientific information, precedents established in 

prior assessments, or policy decisions related to the agencies’ regulatory 

missions or mandates. In about half of the assumptions and 

methodological choices identified, the agencies described their likely 

effects on risk assessment results, most commonly (particularly at EPA and 

FDA) indicating that they were precautionary in nature.3

 Agencies use 

precautionary assumptions to ensure that a risk assessment will not 

underestimate risks. Consequently, they have the effect of raising the 

agencies’ estimates of risk, compared to less precautionary options, and 

potentially lowering the chemical doses or exposure levels at which 

agencies might take regulatory action. Precautionary assumptions are 

particularly common in the agencies’ procedures for initial screening risk 

assessments, when the primary task is to determine whether a risk might 

exist and more detailed analysis is needed. Agency guidelines and related 

documents indicate that subsequent assessments should involve more 

rigorous analyses and fewer precautionary assumptions. There are both 

similarities and differences in the assumptions and methods identified by 

EPA, FDA, and OSHA. RSPA, given its focus on analyzing transportation 

accident scenarios rather than chemical toxicity, uses different 

3

These are also referred to as “conservative” or “public-health conservative” assumptions. 

For consistency, we use the term precautionary throughout this letter. However, in the 

technical appendices on individual agencies we use the terms expressed in agency 

documents or by agency officials.
Page 11 GAO-01-810 Chemical Risk Assessment

assumptions and methods because it tends to deal with different analytical 

issues.

Both EPA and DOT have written, agencywide risk characterization policies 

that emphasize clear, complete, and transparent disclosure of the data, 

methods, assumptions, and limitations of their risk assessments. The 

policies also encourage agency personnel to characterize their risk 

estimates in terms of ranges or distributions rather than simply providing a 

single point estimate of risks. Both agencies also encourage the use of peer 

review to obtain the views of other scientists and experts on the agencies’

risk assessments. Although FDA and OSHA do not have written risk 

characterization policies, officials of those agencies said that in practice 

they tend to emphasize comprehensive characterizations of risk 

assessment results, discussions of limitations and uncertainties, and 

disclosure of the data and analytic methodologies on which the agencies 

relied.

The complexity and diversity of risk assessment policies, procedures, 

assumptions, and other choices affecting risk estimates underscore the 

importance of transparency in both individual risk assessments and 

agencies’ general guidance documents. That transparency is particularly 

important with regard to disclosing why certain data, methods, and default 

assumptions are selected, and under what conditions the agency would 

depart from its default assumptions or methods. Prudent use of risk 

assessment results in formulating public policy requires policymakers to be 

aware of the assumptions and methods used in the preparation of the 

assessments. 

Background Risk assessments are conducted to estimate whether and/or how much 

damage or injury can be expected from exposures to a given risk agent and 

to assist in determining whether these effects are significant enough to 

require action, such as regulation. The effects of concern can be diseases 

such as cancer, reproductive and genetic abnormalities, workplace injuries, 

or various types of ecosystem damage. The risk agent analyzed in an 

assessment can be any number of things, including chemicals, radiation, 

transportation systems, or a manufacturing process. The product of a risk 

assessment is a quantitative and/or qualitative statement regarding the 

probability that an exposed population will be harmed and to what degree.

Risk assessment, particularly quantitative risk assessment, is a relatively 

new discipline, developed in the first half of the 20th century to establish 
Page 12 GAO-01-810 Chemical Risk Assessment

various health and safety codes and standards. The role of risk assessment 

in the regulatory process was accelerated by the enactment of various 

health, safety, and environmental statutes in the early 1970s. The 

development of chemical risk assessment procedures has traditionally 

followed two different tracks—one for assessments of cancer risks and 

another for assessments of noncancer risks. The procedures associated 

with cancer risks have historically assumed that there is no “threshold”

below which an agent would not cause adverse effects. In contrast, 

procedures for assessments of noncancer risks were largely developed 

under the assumption that there is such a threshold—that exposures up to 

a certain level would not be expected to cause harm.

In 1983, NAS identified four steps in the risk assessment process: 

(1) hazard identification (determining whether a substance or situation 

could cause adverse effects), (2) dose-response assessment (determining 

the relationship between the magnitude of exposure to a hazard and the 

probability and severity of adverse effects), (3) exposure assessment

(identifying the extent to which exposure actually occurs), and (4) risk 

characterization (combining the information from the preceding analyses 

into a conclusion about the nature and magnitude of risk).4

 This paradigm, 

originally intended to address assessments of long-term health risks, such 

as cancer, has become a standard model for conducting risk assessments, 

but is not the only model (e.g., different models are used for ecological risk 

assessments). According to NAS, the results of the risk assessment

process should be conceptually distinguished from how those results are 

used in the risk management process (e.g., the decision on where to 

establish a particular standard). As illustrated by figure 1, the risk 

management decision considers other information in addition to the risk 

characterization. 

4

Risk Assessment in the Federal Government: Managing the Process (commonly referred 

to as the “Red Book”), National Research Council of the National Academy of Sciences 

(National Academy Press, 1983).
Page 13 GAO-01-810 Chemical Risk Assessment

Figure 1: Typical Sequence of Risk Assessment and Risk Management Processes

Source: EPA Office of Research and Development.

More recent reports have updated and expanded on these original 

concepts. In 1996, NAS urged risk assessors to update the original concept 

of risk characterization as a summary added at the end of a risk 

assessment.5

 Instead, the report suggested that risk characterization 

should be a “decision-driven” activity directed toward informing choices 

and solving problems and one that involves decision makers and other 

stakeholders from the very inception of a risk assessment. In this updated 

view, the nature and goals of risk characterization are dictated by the goals 

of the risk management decisions to be made. Similarly, the 

Presidential/Congressional Commission on Risk Assessment and Risk 

Management (hereinafter referred to as the Presidential/Congressional 

Commission) recommended in 1997 that the performance of risk 

assessments be guided by an understanding of the issues that will be 

important to risk management decisions and to the public’s understanding 

of what is needed to protect public health and the environment.6

5

Understanding Risk: Informing Decisions in a Democratic Society, National Research 

Council of the National Academy of Sciences (National Academy Press, 1996).

6

Risk Assessment and Risk Management in Regulatory Decision-Making, The 

Presidential/Congressional Commission on Risk Assessment and Risk Management, (Final 

Report, Volume 2, 1997).

Hazard

identification

Risk

management

decisions

Control

options Legal

considerations

Other economic

and social factors

Exposure

assessment

Dose-response

assessment

Risk assessment Risk management

Risk

characterization
Page 14 GAO-01-810 Chemical Risk Assessment

Data on Chemical Health 

Effects and Exposures Are 

Limited

Substantial numbers and amounts of chemical substances and mixtures are 

produced, imported, and used in the United States. For example, there are 

over 70,000 commercial chemicals in EPA’s Toxic Substances Control Act 

(TSCA) Chemical Substances Inventory, and the agency receives about 

1,500 petitions each year requesting the approval of new chemicals or new 

uses of existing chemicals.7

 However, there is relatively little empirical 

data available on the toxicity of most chemicals and the extent to which 

people or the environment might be exposed to the chemicals. For 

example, we previously reported that EPA’s Integrated Risk Information 

System (IRIS), which is a database of the agency’s consensus on the 

potential health effects of chronic exposure to various substances found in 

the environment, lacks basic data on the toxicity of about two-thirds of 

known hazardous air pollutants.8

 Furthermore, to the extent that data on 

health effects are available, the data are more often from toxicological 

studies involving animal exposures than from epidemiological studies 

involving human exposures. As a consequence, chemical risk assessments 

must rely often on extrapolation from animal studies and are quite different 

from risk assessments that use epidemiological studies or actuarial data 

(such as accident statistics). 

7

Excluding polymers (which are considered unlikely to present significant risk concerns), 

EPA’s TSCA inventory identified about 15,000 chemicals produced or imported at levels 

above 10,000 pounds per year. There are also other categories of chemical substances (such 

as drugs, cosmetics, food additives, and pesticides) that are exempt from TSCA but subject 

to control under other federal statutes. The number of chemicals actually in commerce 

varies as new chemicals are added and other chemicals are withdrawn.

8

Major Management Challenges and Program Risks: Environmental Protection Agency

(GAO/OCG-99-17, Jan. 1999).
Page 15 GAO-01-810 Chemical Risk Assessment

The limited nature of information on chemical toxicity was illustrated in a 

1998 EPA report on the data that were publicly available on approximately 

3,000 high-production-volume (HPV) chemicals.9

 For each of these 

chemicals, EPA examined the available data corresponding to six basic 

tests that have been internationally agreed to as necessary for a minimum 

understanding of a chemical’s toxicity.10 As shown in figure 2, the agency 

concluded that the full set of basic toxicity data was available for only 

about 200 (7 percent) of the chemicals, and that 43 percent of the 

chemicals did not have publicly available data for any of the six tests.

Figure 2: Full Toxicity Data Is Available for Only a Small Portion of High-ProductionVolume Chemicals

Source: EPA, Chemical Hazard Data Availability Study: What Do We Really Know About the Safety of 

High Production Volume Chemicals? (April 1998).

9

High-production-volume chemicals are those imported or produced at volumes of more 

than 1 million pounds per year. Note that, for regulatory approval purposes, some offices 

within EPA have access to confidential business information on commercial chemicals and 

pesticides that would not be reflected in this study of “publicly available” toxicity data.

10The six tests are acute toxicity, chronic toxicity, developmental/reproductive toxicity, 

mutagenicity, ecotoxicity, and environmental fate. Collectively, these tests are known as the 

Screening Information Data Set program.

 Have one to five of these tests

Have all six of basic tests for 

minimum understanding of 

toxicity per the international 

Screening Information Data 

Set 

Are missing all of these tests

7%

50% 43%

N= 2863 HPV chemicals
Page 16 GAO-01-810 Chemical Risk Assessment

There are also significant gaps in the available data on the extent to which 

people are exposed to chemicals. For example, last year we reviewed 

federal and state efforts to collect human exposure data on more than 1,400 

naturally occurring and manmade chemicals considered by HHS, EPA, and 

other entities to pose a threat to human health.11 We reported that, taken 

together, HHS and EPA surveys measured the degree of exposure in the 

general population for only 6 percent of those chemicals. Even for those 

chemicals that were measured, information was often insufficient to 

identify smaller population groups at high risk (e.g., women, children, and 

the elderly). 

Uncertainty Contributes to 

Controversy about 

Chemical Risk Assessment

There is an ongoing debate about the appropriate application of risk 

assessment in federal regulation. In 1990, Congress mandated that a 

commission be formed to “make a full investigation of the policy 

implications and appropriate uses of risk assessment and risk management 

in regulatory programs under various Federal laws to prevent cancer and 

other chronic human health effects which may result from exposure to 

hazardous substances.” The Presidential/Congressional Commission 

published its final report in 1997, and noted that often “the controversy 

arises from what we don’t know and from what risk assessments can’t tell 

us.”

12 NAS has also emphasized that science cannot always provide 

definitive answers to questions raised during the course of conducting a 

risk assessment, so risk assessors must use assumptions throughout the 

process that reflect professional judgments and policy choices.13

11Toxic Chemicals: Long-Term Coordinated Strategy Needed to Measure Exposures in 

Humans (GAO/HEHS-00-80, May 2, 2000). See also Environmental Information: EPA 

Needs Better Information to Manage Risks and Measure Results (GAO-01-97T, Oct. 3, 

2000). 

12Framework for Environmental Health Risk Management, The Presidential/Congressional 

Commission on Risk Assessment and Risk Management, (Final Report, Volume 1, 1997), p. 

23.

13See Risk Assessment in the Federal Government: Managing the Process (1983) and 

Science and Judgment in Risk Assessment (1994).
Page 17 GAO-01-810 Chemical Risk Assessment

One focus of the risk assessment debate has been agencies’ use of 

precautionary assumptions and analytical methods. The term 

“precautionary” refers to the use of methods and assumptions that are 

intended to produce estimates that should not underestimate actual risks. 

Some critics of federal risk assessment practices believe agencies use 

assumptions that are unjustifiably precautionary in the face of new 

scientific data and methods, thereby producing estimates that overstate 

actual risks. The critics contend that this effect is compounded when 

multiple precautionary assumptions are used. Others, however, criticize 

agency practices for not being precautionary enough in the face of 

scientific uncertainties, failing, for example, to adequately account for the 

synergism of exposures to multiple chemicals or the risks to persons most 

exposed or most sensitive to a particular toxic agent.14 Other observers, 

including NAS, have expressed concerns about whether the agencies’

procedures and assumptions are sufficiently transparent, thereby providing 

decision makers and the public with adequate information about the 

scientific and policy bases for agencies’ risk estimates as well as the 

limitations and uncertainties associated with those estimates.

14Proposals have been introduced in Congress regarding this issue. For example, H.R. 199, 

proposed in the 106th Congress, would have required the EPA Administrator to evaluate, 

among other things, environmental health risks to vulnerable subpopulations (e.g., children, 

pregnant women, and the elderly) and to ensure that all EPA standards protect such 

subpopulations with an adequate margin of safety.
Page 18 GAO-01-810 Chemical Risk Assessment

We have discussed these issues in several previous reports. For example, in 

1993, we noted that EPA used precautionary assumptions throughout the 

process that it used to assess risk at Superfund hazardous waste sites, and 

that the agency had been criticized for overstating risk by combining 

precautionary estimates.15 In September 2000, we reported on EPA’s use of 

precautionary “safety factors” pursuant to the Food Quality Protection Act 

of 1996.16 In October 2000, we said that three factors influenced EPA’s use 

of precautionary assumptions in assessing health risks: (1) the agency’s 

mission to protect human health and safeguard the natural environment, 

(2) the nature and extent of relevant data (e.g., animal versus human 

studies), and (3) the nature of the health risk being evaluated (e.g., cancer 

versus noncancer risks).17 

Context for Agencies’

Chemical Risk 

Assessments Is 

Important 

The context in which chemical risk assessments are conducted plays an 

important role in determining what type of assessments federal regulatory 

agencies perform and why certain approaches are used. Two dimensions 

seem particularly important to understanding the context for an agency’s 

chemical risk assessment activities: (1) the general statutory and legal 

framework underlying the agency’s regulation of chemicals and (2) how the 

agency plans to use the risk assessment information.18 The statutory and 

legal framework determines the general focus and goals of an agency’s 

chemical risk assessment activities and also can shape how risk 

assessments for those activities are supposed to be conducted. The 

specific tasks and purposes for which an agency will use the results of a 

particular risk assessment determine the questions that the assessment 

needs to address and the scope and level of detail of the assessment.

15Superfund: Risk Assessment Process and Issues (GAO/T-RCED-93-74, Sept. 30, 1993). 

16Children and Pesticides: New Approach to Considering Risk Is Partly in Place

(GAO/HEHS-00-175, Sept. 11, 2000).

17Environmental Protection Agency: Use of Precautionary Assumptions in Health Risk 

Assessments and Benefits Estimates (GAO-01-55, Oct. 16, 2000).

18Other contextual factors, such as the data limitations and scientific uncertainty, are also 

important. On a practical level, the availability of resources (e.g., staff, schedule, funding, 

data) also affects the scope and level of detail that an agency can provide in any given risk 

assessment. However, such factors are either so broadly applicable or so case specific that 

they do not distinctively characterize the risk assessment procedures of an agency or 

program. 
Page 19 GAO-01-810 Chemical Risk Assessment

Statutory and Legal 

Framework

A diverse set of statutes addresses potential health, safety, and 

environmental risks associated with chemical agents. These statutory 

mandates generally focus on different types and sources of exposure to 

chemicals, such as consumption of pesticide residues in foods, 

occupational exposures to chemicals, or inhalation of toxic air pollutants. 

Therefore, different agencies (and different offices within those agencies) 

have distinctive concerns regarding chemical risks. For example, each 

major program office within EPA (e.g., the Office of Air and Radiation or 

the Office of Water) is responsible for addressing the risk-related mandates 

of one or more statutes (e.g., the Clean Air Act, the Clean Water Act, or the 

Safe Drinking Water Act). Also, international agreements provide 

important legal context for transportation risk assessment activities. For 

example, criteria for classifying dangerous chemicals in transportation 

have been internationally harmonized through the United Nations’

Recommendations on the Transport of Dangerous Goods. 

The legal framework underlying chemical regulation influences both the 

extent to which risk assessment is needed for regulatory decision making 

and how risk assessments are supposed to be conducted. Some statutes 

require regulatory decisions to be based solely on risk (considering only 

health and environmental effects), some require technology-based 

standards (such as requiring use of the best available control technology), 

and still others require risk balancing (requiring consideration of risks, 

costs, and benefits). For example, section 112 of the Clean Air Act (CAA), 

as amended, has a technology-based mandate requiring the use of the 

maximum achievable control technology to control emissions of hazardous 

air pollutants. A risk assessment is not needed to determine such 

technology, but would be used to evaluate residual risks that remain after 

that technology is in use. Some statutes also place the primary 

responsibility for conducting risk assessments and compiling risk-related 

data for a particular chemical or source of exposure to chemical agents 

with industry, states, or local entities, rather than with the federal 

regulatory agencies. For example, industry petitioners have the primary 

responsibility to provide the data needed to support registration and 

tolerances from EPA for their pesticides, including information on the 

toxicological effects of the pesticides.19

19 Registration involves the licensing of pesticides for sale and use in agriculture and 

extermination. No chemical may be sold in the United States as a pesticide without such 

registration, which establishes the conditions of legal use. Pesticide tolerances are the 

concentrations permitted to remain in or on food, as it is available to the consumer.
Page 20 GAO-01-810 Chemical Risk Assessment

Statutes can also affect risk assessment by specifically defining what will 

be considered a hazard, directing the agency to take certain 

methodological steps, or specifying the exposure scenario of regulatory 

concern. For example, in response to the “Delaney Clause” amendments to 

the Federal Food, Drug, and Cosmetic Act, FDA identifies any food additive 

for which an adequately conducted animal cancer study indicates that the 

additive produces cancer in animals as a carcinogen under the conditions 

of the study. No further corroboration or weight-of-evidence analysis is 

required. The Food Quality Protection Act of 1996 requires EPA to add an 

additional 10-fold safety factor to protect infants and children when 

deriving standards for allowable pesticide residues in foods, unless reliable 

data show that a different factor will be safe. Provisions in the 

Occupational Safety and Health Act focus OSHA’s risk assessments on 

estimating the risks to workers exposed to an agent for a working lifetime.

However, in most cases the statutes simply provide a general framework 

within which the agencies make specific risk assessment assumptions and 

methodological choices. For example, section 109 of the CAA requires EPA 

to set national ambient air quality standards that in the judgment of the 

EPA Administrator—and allowing for an “ample margin of safety”—are 

requisite to protect the public health.20 EPA risk assessors translate that 

general requirement into specific risk assessment assumptions and 

methods (e.g., whether to assume a threshold or no-threshold relationship 

between dose and response at low doses).

Use of Risk Assessment 

Results

The specific purpose or task of an assessment determines the kinds of risk 

information needed for the agency to make its risk management decisions, 

and can significantly influence the scope and level of detail required of a 

risk assessment. For example,

• If the agency’s task is to set a specific health-based standard (e.g., a 

national air quality standard), a rigorous and detailed estimate of risks at 

particular exposure levels might be required. 

• If the agency’s task is to decide whether to approve the production and 

use of commercial chemicals or pesticides, risk assessors may initially 

focus on potential upper-bound exposures (e.g., assuming that a 

chemical agent will be used at the maximum level permitted by law or 

20 An ambient air quality standard is a national target for an acceptable concentration of a 

specific pollutant in air.
Page 21 GAO-01-810 Chemical Risk Assessment

focusing on individuals who consume the greatest amounts of a food 

containing residues of the agent at issue). If such upper-bound 

estimates exhibit no cause for concern, the agency may have no need to 

complete a more comprehensive and refined risk assessment. 

• A decision on whether to add or remove a chemical from the list of 

potential hazards might focus the risk assessors on determining whether 

the potential risk is above or below a specific threshold level, such as 

the risk of 1 extra cancer case over the lifetime of 1 million people.

The influence of the specific regulatory task at hand is illustrated by a 

method commonly used by agencies for risk assessments of noncancer 

health effects. Agencies such as EPA and FDA have historically attempted 

to identify a dose level of a chemical associated with no observed adverse 

effect level (NOAEL) in animal experiments—or the lowest observed 

adverse effect level (LOAEL) in the study, if every tested dose exhibited 

some effect.21 They then divided that NOAEL or LOAEL dose by multiple 

“safety” or “uncertainty” factors to account for the possibility that humans 

may be more sensitive to the chemical than animals and other 

uncertainties. This procedure is designed to identify a dose not likely to 

result in harm to humans, not to provide an explicit quantitative estimate of 

the risks associated with a given chemical. In other words, sometimes the 

focus of federal agencies’ “risk” assessments could more accurately be 

described as a safety assessment (i.e., estimating a “safe” level of exposure 

to chemical agents or a dose below which no significant risk is expected to 

occur) rather than a risk assessment (i.e., estimating the actual risks 

associated with exposures to chemical agents).

Implications of Contextual 

Differences

Because of contextual differences, the risk assessment procedures used, 

the resulting risk estimates (and regulatory actions based upon those 

estimates), and even whether a substance would be subject to risk 

assessment, can vary among different agencies and programs within the 

same agency. The following examples illustrate how contextual 

differences affect the conduct of risk assessments.

• Because regulation of certain wastes may be impractical or otherwise 

undesirable, regardless of the hazards that the waste might pose, 

21FDA often determines a no observed effects level (NOEL) rather than a NOAEL because 

many significantly altered, standard toxicological endpoints are assumed to be adverse to 

animals and/or humans even in the absence of data affirming that assumption.
Page 22 GAO-01-810 Chemical Risk Assessment

Congress and EPA exempted certain materials (e.g., agricultural or 

mining and mineral processing wastes) from the definitions of 

hazardous wastes. If a material meets one of the categories of 

exemptions, it cannot be identified as a hazardous waste even if it 

otherwise meets the criteria for listing as a hazardous waste. For 

example, according to EPA’s RCRA Orientation Manual, wastes 

generated in raw material, product storage, or process (e.g., 

manufacturing) units are exempt from EPA’s hazardous waste regulation 

while the waste remains in such units. However, OSHA might assess 

and regulate risks associated with such materials as part of its mission 

to protect the health of employees in the workplace.

• FDA and EPA both assess potential human health risks associated with 

ingestion of chemical substances. If a substance is being assessed by 

FDA as a food additive and results from any adequate study indicate that 

the substance produces cancer in animals, FDA labels that additive as a 

carcinogen without considering other scientific evidence (per the 

Delaney clause of the Federal Food, Drug, and Cosmetic Act, as 

amended). However, when assessing the risks associated with 

consumption of residues from animal drugs (FDA) and pesticides (EPA) 

the agencies may need to consider many scientific studies in 

determining whether and under what conditions an agent might cause 

cancer or other adverse health effects in humans. 

• EPA’s risk assessments of commercial chemicals under TSCA vary 

depending on whether the chemical at issue is “existing” or “new.” For 

EPA to control the use of an existing chemical, the agency must make a 

legal finding that the chemical will present an unreasonable risk to 

human health or the environment. EPA said this standard requires the 

agency to have conclusive data on risks associated with that particular 

chemical. By comparison, newly introduced chemicals can be regulated 

based on whether they may pose an unreasonable risk, and this finding 

of risk can be based on data for structurally similar chemicals, not just 

data on that particular chemical. Because industrial chemicals in 

commerce were “grandfathered” under TSCA into the inventory of 

existing chemicals more than 20 years ago, without considering whether 

they were hazardous, there are situations in which existing chemicals 

might not be controlled while, at the same time, EPA would act to 

control a new chemical of similar or less toxicity.

• Within EPA’s Office of Water, risk assessments vary depending on 

whether the assessment is done to establish drinking water standards or 

standards for ambient water (e.g., bodies of water such as lakes and 

rivers). Risk assessments for drinking water standards focus solely on 

human health effects, but assessments used to establish ambient water 
Page 23 GAO-01-810 Chemical Risk Assessment

quality criteria consider both human health and ecological effects. Even 

when considering just the human health risks, an important difference 

between the ambient and drinking water risk assessments is an 

additional focus for ambient water on exposures to contaminated water 

through consumption of contaminated fish or shellfish. This additional 

factor is a primary reason for potential differences in drinking water and 

ambient water risk estimates and standards for the same chemical.

Appendices II through V describe the relevant contextual factors for each 

of the four selected agencies in greater detail.

Agencies’ Risk 

Assessment 

Procedures Share 

Common Features, But 

Substantive 

Differences Also Exist 

All four of the agencies included in our review have standard procedures 

for conducting risk assessments, although the agencies vary in the extent 

to which their procedures are documented in written guidance. In general, 

there are more similarities than differences across EPA, FDA, and OSHA 

procedures, because each of these agencies generally follows the four-step 

NAS risk assessment process. The procedures address the same basic 

questions regarding hazard identification, dose-response assessment, and 

exposure assessment. The specific analytical methods and approaches in 

those procedures are also very similar (e.g., extrapolating from animal 

study data to model dose-response relationships in humans, and generally 

using different procedures for assessing cancer and noncancer risks). The 

most substantive differences across and within these agencies are related 

to exposure assessment, reflecting the diversity in the agencies’ regulatory 

authorities regarding chemical agents across different kinds or sources of 

exposure. For example, both OSHA and EPA consider methylene chloride 

(also known as dichloromethane) to be a probable human carcinogen. 

However, this same chemical can be identified as a significant hazard by 

one agency in one exposure setting (OSHA for purposes of assessing health 

risks associated with occupational exposures) but as a low hazard by 

another agency in a different setting (EPA for purposes of Superfund 

hazard ranking screening).22 RSPA, although sharing a concern over 

identifying risks and analyzing their consequences and probabilities of 

22 EPA has taken other actions regarding exposures to methylene chloride. For example, 

EPA requires that releases of methylene chloride of 1,000 pounds or more be reported to the 

federal government. EPA also has guidelines on how much of this chemical people can be 

exposed to without harming their health (e.g., EPA recommends that children not drink 

water that contains more than 13.3 parts of methylene chloride per million parts of water for 

longer than 1 day or with more than 1.5 parts per million for longer than 10 days).
Page 24 GAO-01-810 Chemical Risk Assessment

occurrence, has a different structure to its risk assessments than the other 

three agencies because of its focus on risks associated with unintentional 

releases of hazardous materials during transportation. In general, all four 

agencies are incorporating more complex analytical models and methods 

into their risk assessment procedures. However, some of the advanced 

models require much more detailed information than may be currently 

available for many chemicals.

Risk Assessment 

Procedures at EPA

EPA has extensive written internal risk assessment procedures. For 

example, EPA has agencywide guidelines, policy memoranda, and 

handbooks covering the following aspects of risk assessment:

• carcinogen risk assessment,

• neurotoxicity risk assessment,

• reproductive toxicity risk assessment,

• developmental toxicity risk assessment,

• mutagenicity risk assessment,

• health risk assessment of chemical mixtures,

• exposure assessment,

• ecological risk assessment,

• evaluating risk to children,

• use of probabilistic analysis in risk assessment,

• use of the benchmark dose approach in health risk assessment, and

• use of reference dose and reference concentration in health risk 

assessment.

EPA also has numerous program-specific guidelines and policy documents, 

such as the Risk Assessment Guidance for Superfund series and a set of 

more than 20 science policy papers and guidelines from the Office of 

Pesticide Programs in response to the Food Quality Protection Act of 1996. 

Many of the agency’s guidance documents are draft revisions to earlier 

documents or procedures or draft guidance on new issues that have not 

previously been addressed by EPA. Although such drafts are not yet final, 

official statements of agency policies or procedures, they may better 

represent the current practice of risk assessment in EPA than earlier “final”

documents.
Page 25 GAO-01-810 Chemical Risk Assessment

EPA generally follows the NAS four-step risk assessment process. (The 

major exception is the agency’s Chemical Emergency Preparedness and 

Prevention Office, which follows a different set of procedures because of 

its focus on risks associated with accidental chemical releases from fixed 

facilities. See app. II for a discussion of this office’s risk assessment 

procedures.) EPA’s risk assessment activities generally involve both the 

program offices (e.g., the Office of Air and Radiation or the Office of Solid 

Waste) and the Office of Research and Development (ORD), which is the 

principal scientific and research arm of the agency. ORD often does risk 

assessment work for EPA program offices that focuses on the first two 

steps in the four-step NAS process—hazard identification and doseresponse assessment—in particular, the development of “risk per unit 

exposed” numbers.23 Preparation of the final two steps in the process—

exposure assessment and risk characterization—tends to be the 

responsibility of the relevant program offices. Several programs, for 

example, frequently use a single hazard assessment, but for different 

exposure scenarios. There are, however, exceptions to this generalization. 

For example, ORD carries out all steps for highly complex, precedentsetting risk assessments, such as those for dioxin and mercury. There are 

also instances when EPA program offices carry out all four steps of the 

process. In some situations, EPA agencywide procedures also depart 

slightly from the NAS paradigm. For example, when assessing noncancer 

health effects, EPA’s normal practice is to do hazard identification in 

conjunction with the analysis of dose-response relationships, rather than as 

distinct steps. According to EPA’s guidelines, this is because the 

determination of a hazard is often dependent on whether a dose-response 

relationship is present. In the case of ecological risk assessments, EPA’s 

guidelines suggest a three-step process consisting of (1) problem 

formulation, (2) analysis, and (3) risk characterization, rather than the fourstep process used for health risk assessments.

23ORD also manages EPA’s IRIS database that contains agency-consensus information on 

human health effects that may result from exposure to various chemicals in the 

environment.
Page 26 GAO-01-810 Chemical Risk Assessment

EPA has identified several new directions in its approach to exposure 

assessment. First is an increased emphasis on total (aggregate) exposure 

to a particular agent via all pathways. EPA policy directs all regulatory 

programs to consider in their risk assessments exposures to an agent from 

all sources, direct and indirect, and not just from the source that is subject 

to regulation by the office doing the analysis.24 Another area of growing 

attention is the consideration of cumulative risks, when individuals are 

exposed to many chemicals at the same time. The agency is also increasing 

its use of probabilistic modeling methods to analyze variability and 

uncertainty in risk assessments and provide better estimates of the range of 

exposure, dose, and risk to individuals in a population than are provided by 

single point estimates. EPA’s guidance on probabilistic methods outlines 

standards that exposure data prepared by industry or other external 

analysts must meet to be accepted by EPA.

Risk Assessment 

Procedures at FDA and 

OSHA

FDA and OSHA also generally follow the NAS risk assessment paradigm, 

but neither FDA nor OSHA had written internal guidance specifically on 

conducting risk assessments at the time of our review. However, both 

agencies’ standard procedures are well documented in the records of 

actual risk assessments and in summary descriptions that have appeared in 

scientific and professional literature. In addition, FDA has published 

volumes of guidance on risk assessments for use by external parties 

affected by the agency’s regulations (e.g., animal drug manufacturers 

seeking FDA approval for their products). According to FDA officials, the 

documents are meant to represent the agency’s current thinking on the 

scientific data and studies considered appropriate for assessing the safety 

of a product, and sometimes include detailed descriptions of the risk 

assessment methods deemed appropriate to satisfy FDA’s requirements 

under various statutory provisions. However, these guidelines do not 

preclude the use of alternative procedures by either FDA or external 

parties.

The responsibility for conducting risk assessments in FDA is divided 

among the agency’s program offices. For example, FDA’s Center for Food 

24The Presidential/Congressional Commission noted that, traditionally, risk assessments 

have largely focused on assessing the risks of just one chemical in one medium at a time. 

Although some EPA offices, such as the Office of Pesticide Programs and Office of Water, 

conduct more comprehensive risk assessments, the Commission pointed out that few other 

regulatory agencies consider exposures or risks comprehensively, and EPA often does not 

do so because of resource or statutory limitations.
Page 27 GAO-01-810 Chemical Risk Assessment

Safety and Applied Nutrition (CFSAN) is responsible for assessing risks 

posed by food additives and contaminants, while the Center for Veterinary 

Medicine (CVM) is responsible for assessing risks posed by animal drug 

residues in food. In addition, FDA’s National Center for Toxicological 

Research conducts scientific research to support the agency’s regulatory 

needs, including research aimed at understanding the mechanisms of 

toxicity and carcinogenicity and at developing and improving risk 

assessment methods. FDA officials said that there are variations in the risk 

assessment approaches used among the agency’s different product centers 

and, in some cases, within those centers. In general, those variations are 

traceable to differences in factors such as the substances being regulated, 

the nature of the health risks involved (particularly carcinogens versus 

noncarcinogens), and whether the risk assessment is part of the process to 

review and approve a product before it can be marketed and used 

(premarket) or part of the process of monitoring risks that arise after a 

product is being used (postmarket). For example, risk assessments by 

CFSAN’s Office of Food Additive Safety and Office of Nutritional Products, 

Labeling and Dietary Supplements are mandatory for new dietary 

ingredients (and are used for premarket review of such ingredients) but 

discretionary for other food (and are associated with postmarket review). 

A unique characteristic of the hazard identification phase of risk 

assessment in FDA is that, by statute, if there is an adequate study that 

indicates a food additive can cause cancer in animals, that additive is 

labeled as a carcinogen under the conditions of the study. No additional 

corroboration or weight-of-evidence analysis is required in such cases, and 

there is no need to complete the other three risk assessment steps before 

proceeding to a regulatory decision. FDA’s CVM is permitted to allow the 

use of carcinogenic drugs in food-producing animals under the DES 

proviso of the Federal Food, Drug, and Cosmetic Act, as amended, 

provided that “no residue of such drug will be found.”
Page 28 GAO-01-810 Chemical Risk Assessment

OSHA’s Directorate of Health Standards Programs is primarily responsible 

for conducting the agency’s chemical risk assessments. Such assessments 

focus specifically on the potential risks to workers associated with 

exposures to chemicals in an occupational setting. In contrast to agencies 

regulating environmental exposures to toxic substances, OSHA frequently 

has relevant human data available on occupational exposures. Even when 

the agency assesses risks based on animal data, OSHA said that the 

workplace exposures of concern are often not far removed from levels 

tested in the animal studies. Therefore, OSHA’s risk assessments do not 

extrapolate as far beyond the range of observed toxicity as might be 

necessary to characterize environmental exposure risks. OSHA’s risk 

assessment procedures have also evolved to consider data from advanced 

physiologically based pharmacokinetic (PBPK) models on the relationship 

between administered doses and effective doses (i.e., the amounts that 

actually reach a target organ or tissue).25 However, PBPK models are 

complicated and require substantial data, which may not be available for 

most chemicals. OSHA therefore developed a set of 11 criteria to judge 

whether available data are adequate to permit the agency to rely on PBPK 

analysis in place of administered exposure levels when estimating human 

equivalent doses.

25Pharmacokinetics is the study of the absorption, distribution, metabolism, and elimination 

of chemicals in humans and animals. It is the basis for developing what are believed to be 

more realistic and accurate models of the movement and interactions of a chemical with 

blood, tissues, and organs once it enters the body, including consideration of the body’s 

ability to repair damage caused by a chemical. 
Page 29 GAO-01-810 Chemical Risk Assessment

Risk Assessment 

Procedures at RSPA

The applicable risk assessment guidance for RSPA is generally documented 

within broader DOT-wide guidance on conducting regulatory analyses and 

also in materials describing the agency’s Hazardous Materials Safety 

Program. Because of the particular regulatory context in which it operates, 

RSPA does not apply the NAS four-step paradigm for risk assessment used 

by EPA, FDA, and OSHA. RSPA is primarily concerned with potential risks 

associated with the transportation of hazardous materials. In particular, it 

is concerned with short-term or acute health risks due to relatively high 

exposures from unintentional release of hazardous materials. For its 

purposes, RSPA identifies chemicals as hazardous materials according to a 

regulatory classification system that is harmonized with internationally 

recognized criteria and EPA-defined hazardous substances. This 

classification system defines the type of hazard associated with a given 

material according to chemical, physical, or nuclear properties (e.g., 

whether it is an explosive, a flammable liquid, or a poisonous substance) 

that can make it dangerous in or near transporting conveyances. 

Therefore, a chemical’s toxicity is only one of its characteristics of concern 

to RSPA, rather than being the primary focus of analysis as in assessments 

of the other three agencies. The risk analyses by RSPA focus on identifying 

the potential circumstances under which unintentional releases of 

hazardous materials could occur during transit (e.g., due to transportation 

accidents) and assessing their consequences and probability of occurrence. 

Analysis of different modes (e.g., via truck, rail, or aircraft) and routes of 

transportation is an important component of RSPA’s consequence and 

probability analyses.26 Through DOT databases, directly relevant data on 

the incidence and severity of hazardous materials transportation accidents 

are available to assist RSPA in identifying and analyzing hazard scenarios.

Appendices II through V provide more detailed descriptions of the standard 

procedures for chemical risk assessments in each of the four selected 

agencies. 

26Assessment and regulation of risks associated with substances transported by bulk marine 

carriers are the responsibility of the United States Coast Guard.
Page 30 GAO-01-810 Chemical Risk Assessment

Agencies’ Risk 

Assessment 

Procedures Often 

Include Precautionary 

Assumptions and 

Methods

Assumptions and methodological choices are an integral and inescapable 

part of risk assessment. They are often intended to address uncertainty in 

the absence of adequate scientific data. However, those assumptions and 

methods may also reflect policy choices, such as how to address variability 

in exposures and effects among different individuals and populations, or 

particular contextual requirements. To the extent that the four agencies 

identified the specific reasons for selecting their major assumptions or 

methods, they most often attributed their choices to an evaluation of 

available scientific data, the precedents established in prior risk 

assessments, or policy decisions related to their regulatory missions. 

Agencies’ statements regarding the likely effects of their preferred 

assumptions and methods most often addressed the extent to which the 

default options would be considered precautionary. Some of the major 

assumptions and methodological choices of EPA, FDA, and OSHA address 

similar issues and circumstances during the risk assessment process, 

especially regarding assessment of a chemical’s toxicity.

Agencies’ Assumptions and 

Methodological Choices 

Vary

Agency procedural guidelines and officials we contacted during our review 

identified a large number and wide variety of major assumptions and 

methodological choices that they might use when conducting chemical risk 

assessments, in the absence of information that would indicate the 

particular assumption or method is not valid in a given case. Some of these 

assumptions and methodological choices were very broad (e.g., the 

common assumption that, in the absence of evidence to the contrary, 

substances that produce adverse health effects in experimental animals 

pose a potential threat to humans). Other assumptions and choices were 

more specific, covering particular details in the analytical process (e.g., 

identifying the preferred options for extrapolating high dose-response 

relationships to low doses). EPA and OSHA identified some of their choices 

as the default assumptions and methods of their agencies. FDA officials 

said that their agency does not require the use of specific default 

assumptions or risk assessment methods, but there are assumptions and 

methods that typically have been used as standard choices in FDA risk 

assessments. Although assumptions are also needed in RSPA’s risk 

assessments, RSPA officials said that they do not have any default 

assumptions. Instead, they said that their assumptions are specific to, and 

must be developed as part of, each risk assessment.

Appendices II through V present detailed information on some of what the 

agencies identified as their major assumptions and methodological choices 
Page 31 GAO-01-810 Chemical Risk Assessment

in chemical risk assessments. The tables illustrate both the number and 

variety of assumptions that agencies may use when conducting those 

assessments.

The following sections summarize information that was available from the 

four agencies’ procedures and related documents on (a) when the agencies 

employ major assumptions and methods, (b) their reasons for selecting 

these options, (c) the likely effects on risk assessment results of these 

options, and (d) how they compare to the assumptions and choices used by 

other agencies or programs in similar circumstances. In some cases the 

agencies’ documents did not contain this information, but there is no 

requirement that the agencies do so. Also, the reason for using a particular 

assumption and its effect on risk assessment results can vary on a case-bycase basis, and therefore might not be addressed in general risk assessment 

guidance. Nevertheless, both NAS and the Presidential/Congressional 

Commission recommended greater transparency regarding the procedures, 

assumptions, and results of agencies’ risk assessments. Also, as will be 

discussed more fully later in this report, the agencies’ own risk 

characterization policies and practices emphasize the value of such 

transparency in communicating information about risk assessment 

procedures and results. Recent regulatory reform proposals considered by 

Congress have had provisions requiring transparency in the use of 

assumptions.27

When Assumptions and 

Methods Are Used

As previously mentioned, NAS and the Presidential/Congressional 

Commission have both emphasized that science cannot always provide 

definitive answers to questions raised during a risk assessment. For 

example, in 1983, NAS identified at least 50 points during the course of a 

cancer risk assessment when choices had to be made on the basis of 

professional judgment, not science. EPA’s guidelines similarly point out 

that, because there is no instance in which a set of data on an agent or 

exposure is complete, all risk assessments must use general knowledge 

and policy guidance to bridge data gaps. Except in the case of RSPA, 

default or standard assumptions and methods may be used by agencies to 

27For example, S. 746, proposed in the 106th Congress, provided that when a risk assessment 

involves a choice of assumptions the agency must (1) identify significant assumptions and 

their scientific and policy bases, (2) explain the basis for any choices among assumptions, 

and (3) describe reasonable alternative assumptions not selected that would have had a 

significant effect on the results of the assessment.
Page 32 GAO-01-810 Chemical Risk Assessment

address these gaps in knowledge, and to encourage consistency in the 

efforts of agencies’ risk assessors to address such basic issues as:

• uncertainty in the underlying data, model parameters, or state of 

scientific understanding of how exposure to a particular chemical could 

lead to adverse effects;

• variability in the potential extent of exposure and probability of adverse 

effects for various subgroups or individuals within the general 

population;28 and 

• statutory requirements (and the related general agency missions) to be 

protective of public health and the environment (e.g., to set standards 

with “an adequate margin of safety”).

However, agency risk assessors have considerable flexibility regarding 

whether to use particular assumptions and methods, even when the agency 

has default or standard options. For example, EPA stated that its revised 

guidelines for carcinogen risk assessment were intended to be both explicit 

and more flexible than in the past concerning the basis for making 

departures from defaults, recognizing that expert judgment and peer 

review are essential elements of the process. The Executive Director of 

ORD’s Risk Assessment Forum pointed out that, although EPA’s guidelines 

always permitted such flexibility, without detailed guidance on departing 

from default assumptions there had been a tendency for analysts to not do 

so. He also stated that when determining whether to use a default, the 

decision maker must consider available information on an underlying 

scientific process and agent-specific data, and that scientific peer review, 

peer consultation workshops, and similar processes are the principal ways 

of determining the strength of thinking and the general acceptance of these 

views within the scientific community. FDA officials emphasized that their 

agency does not presume that there is a “best way” of doing a risk 

assessment and does not require the use of a specific risk assessment 

protocol or of specific default assumptions, but they are continually 

updating procedures and techniques with the goal of using the “best 

available science.”

28There is a conceptual difference between uncertainty and variability. Uncertainty is a 

property of a lack of knowledge and may be reduced through study and additional 

information. Variability is a property of a system or population (e.g., every person has 

different physical characteristics) and can only be understood, not reduced, through further 

study. See Adam Finkel, “A Second Opinion on an Environmental Misdiagnosis,” New York 

University Environmental Law Journal, Volume 3 (1995), p. 299.
Page 33 GAO-01-810 Chemical Risk Assessment

Agencies identified assumptions and methodological choices throughout 

the risk assessment process, and each of the first three steps in the process 

can have its own set of issues and choices that risk assessors need to 

address. During hazard identification, agencies must make choices about 

which types of data to use and what types of adverse effects and evidence 

will be considered in their analyses. For example, risk assessors need to 

decide whether data on benign tumors should be used along with data on 

malignant tumors as the basis for quantitative estimates of cancer risks, or 

whether only data on malignant tumors should be used. During doseresponse assessment, agencies may need to make assumptions when 

extrapolating effects from animals to humans (e.g., how to determine 

equivalent doses across different species). In particular, choices among 

assumptions and methods are needed when estimating dose-response 

relationships at doses that are much lower than those used in the scientific 

studies that provided the data for quantitative analysis. During exposure 

assessments, assumptions might be needed to address issues such as when 

exposures occur (e.g., in infancy or childhood versus as an adult), how long 

exposures last (e.g., short versus long term and continuous versus 

episodic), differences in exposures and effects for the population as a 

whole versus those affecting subpopulations and individuals, and questions 

about the concentration and absorption of chemical agents. Assumptions 

about human behavior also affect the relative likelihood of different 

exposure scenarios. For example, in assessing children’s residential 

exposures to a pesticide, risk assessors might need to make assumptions 

about how long children play in a treated area, the extent to which they are 

wearing clothing, and potential hand-to-mouth exposure to treated soil, 

among other factors.
Page 34 GAO-01-810 Chemical Risk Assessment

Why Particular Assumptions 

and Methods Are Selected

Agencies generally indicated that they use their major assumptions and 

methodological choices in risk assessments when professional judgments 

or policy choices must substitute for scientific information that is not 

available or is inconclusive. We examined risk assessment guidance 

documents and procedures in the four agencies to determine whether the 

agencies stated a specific scientific or policy basis for their choices, as 

recommended by NAS and the Presidential/Congressional Commission. In 

approximately three-quarters of the choices that we reviewed, the agencies 

provided at least some rationale for the use of particular assumptions or 

methods. The reasons most commonly cited were (1) an evaluation of 

available scientific data, (2) the precedents established in prior risk 

assessments, and (3) policy decisions related to their regulatory mandates. 

In some instances, the agencies cited more than one reason in support of 

their choices. For example, officials from FDA’s Center for Veterinary 

Medicine said they assume that an adult weighs 60 kilograms when 

converting an acceptable daily intake (ADI) to an intake level of residues in 

food because of historical precedent and because this assumption should 

protect women, growing adolescents, and the elderly.29

29According to FDA officials, if there is a need to convert an ADI (expressed as milligrams 

per kilogram body weight per day) to an intake level (expressed as the number of milligrams 

of an additive that would be acceptable on a daily basis), they multiply the ADI by the 

assumed weight of a person. Officials from FDA’s Center for Food Safety and Applied 

Nutrition said they assume values of 60 kilograms for adults and 15 kilograms for children, 

based on historical precedents which were based on population-based surveys.
Page 35 GAO-01-810 Chemical Risk Assessment

Of the three reasons, the agencies most often cited their evaluation of 

available scientific evidence as a reason for selecting particular 

assumptions or analytical methods. For example, one of the default 

assumptions in EPA’s carcinogen risk assessment guidance is that positive 

effects in animal cancer studies indicate that the agent under study can 

have carcinogenic potential in humans. EPA cited scientific research 

supporting this assumption, such as the evidence that nearly all agents 

known to cause cancer in humans are carcinogenic in animals in tests with 

adequate protocols. Other EPA guidelines stated that, in general, a 

threshold is assumed for the dose-response curve for agents that produce 

developmental toxicity. EPA’s guidelines noted that this assumption is 

based on the known capacity of the developing organism to compensate for 

or repair a certain amount of damage at the cellular, tissue, or organ level. 

OSHA cited scientific evidence and the views of the Office of Science and 

Technology Policy on chemical carcinogenesis (the origin or production of 

a tumor) to support its choice to combine data on benign tumors with the 

potential to progress to malignancies with data on malignant tumors 

occurring in the same tissue and the same organ site.30

30The National Science and Technology Policy, Organization, and Priorities Act of 1976 

created the Office of Science and Technology Policy within the Executive Office of the 

President to provide advice to the President on issues relating to science and to coordinate 

federal efforts in science and technology.
Page 36 GAO-01-810 Chemical Risk Assessment

Even when basing a choice upon available scientific studies and data, 

professional judgment may still be required regarding which particular 

method or assumption to choose among competing alternatives. The 

scientific evidence might show a range of assumptions or methods that 

provide plausible results and may, in specific cases, vary in terms of which 

one best fits the available evidence. For example, different mathematical 

models can be used for estimating the low-dose effects of exposure to 

suspected carcinogens. A basic problem for risk assessors is that, while 

the results produced by different models may be similar at higher doses, 

the estimates can vary dramatically at the low doses that are of concern to 

agency regulators. One study of 5 dose-response models showed that all of 

the models produced essentially the same dose-response curves at higher 

doses, but the models’ estimates differed by 3 or 4 orders of magnitude 

(values 1,000 to 10,000 times different) at lower doses.31 Because the 

mechanism of carcinogenesis is not sufficiently understood, none of the 

mathematical procedures for extrapolation has a fully adequate biological 

basis.32 Furthermore, because of the limitations in the ability of toxicologic 

or epidemiologic studies to detect small responses at very low doses, doseresponse relationships in the low-dose range are practically unknowable.

Agencies can encounter similar problems in attempting to determine how 

much of a chemical will produce the same effect in humans that was 

observed in animals. An interagency group of federal scientists that 

studied this issue noted that, although many alternatives had been 

developed for such cross-species scaling, and despite considerable study 

and debate, “no alternative has emerged as clearly preferable, either on 

empirical or theoretical grounds.”

33 The group noted further that the 

various federal agencies conducting chemical risk assessments therefore 

developed their own preferences and precedents, and this variation “stands 

among the chief causes of variation among estimates of a chemical’s 

potential human risk, even when assessments are based on the same data.” 

For purposes of consistency in federal risk assessments, the group 

recommended a method intermediate between the two methods most 

31 See “Criteria for Evidence of Chemical Carcinogenicity,” Interdisciplinary Panel on 

Carcinogenicity, Science 225 (1984), pp. 682-687.

32 See, for example, General Principles for Evaluating the Safety of Compounds Used in 

Food-Producing Animals, DHHS/FDA/CVM (revised July 1994).

33 “Draft Report: A Cross-Species Scaling Factor for Carcinogen Risk Assessment Based on 

Equivalence of mg/kg3/4/Day,” 57 FR 24152 (June 5, 1992). No final report has been issued. 
Page 37 GAO-01-810 Chemical Risk Assessment

commonly used by federal agencies, but reiterated that methodologies in 

use “have not been shown to be in error.”

Other reasons cited by the agencies for selecting assumptions or methods 

included the precedents established in prior risk assessments and policy 

decisions related to their regulatory missions and mandates. For example, 

FDA officials said that their practice of using the most sensitive species and 

sex when calculating the ADI of animal drug residues in food was based on 

historical precedents dating back to at least 1954. In other instances, FDA 

said that its use of precautionary assumptions was based on the agency’s 

statutory responsibility to ensure to a “reasonable certainty” that the public 

will not be harmed. Similarly, EPA guidelines pointed out that the default 

assumptions used in the agency’s risk assessments were chosen to be 

health protective because EPA’s overall goal is public health protection. 

For example, EPA’s neurotoxicity guidelines said that a choice to use the 

most sensitive animal species to estimate human risk “provides a 

conservative estimate of sensitivity for added protection to the public.”

Effects of Agencies’

Assumptions and Methods 

on Risk Estimates

The agencies provided information in their guidelines on the likely effects 

of using particular assumptions or methods in about half of the examples 

that we reviewed. When that information was provided, it was usually in 

the context of whether and to what extent the agencies’ choices could be 

considered precautionary. In a number of cases, EPA and FDA 

characterized their assumptions and methods as precautionary in that they 

were intended to avoid underestimating risks in the interest of protecting 

public health. Such assumptions tend to raise an agency’s estimate of risk 

and lower the levels of exposure that are of regulatory concern. 

Precautionary assumptions and methodological choices were a common 

component of programs that have “tiered” approaches for conducting risk 

assessments (e.g., EPA’s Superfund and pesticides programs). In these 

tiered risk assessment approaches, agencies move from initial rough 

screening efforts to increasingly more refined and detailed levels of 

analyses. The initial screening assessments will typically involve very 

precautionary “upper-bound” or even “worst-case” assumptions to 

determine whether there is cause for concern. Successive tiers of 

assessment, if deemed necessary, are characterized in agency documents 

as more detailed and focused assessments that require more extensive data 

and rigorous analysis. For example, EPA indicated that its screening 

assessments might well use precautionary upper-bound point estimates of 

exposures (e.g., that a chemical is used on 100 percent of the eligible crop 

and at the maximum permissible limit). However, subsequent tiers of 
Page 38 GAO-01-810 Chemical Risk Assessment

assessments might refine those estimates through the use of probability 

distributions of exposure parameters or the use of monitoring data on 

actual exposures, when feasible.

OSHA and RSPA also use precautionary assumptions in certain parts of 

their risk assessment procedures. However, these agencies identified few 

of their risk assessment assumptions and methods as precautionary. In 

fact, OSHA sometimes selected assumptions or methods that it explicitly 

characterized as less precautionary than those used by other agencies in 

similar circumstances. For example, OSHA stated that its standard 

approach to low-dose extrapolation can be much less precautionary than 

EPA’s or FDA’s approaches because it tends to use central estimates of 

potency rather than upper-bound confidence limits. OSHA officials also 

noted that the algorithm they use is less precautionary because it may lead 

to models that are sublinear at low doses.

The effect on risk estimates of using any one assumption is likely to be less 

significant than that of applying a series of assumptions while conducting a 

risk assessment, particularly if the assessment is compounding a string of 

largely precautionary assumptions. As we previously pointed out, 

assumptions and choices may be needed at many points during each step of 

an agency’s analysis. The agency’s policy may well be to use precautionary 

choices at most, if not all, of those points, if adequate information is not 

available to indicate that the precautionary choice is invalid in a specific 

case. The potential for such a string of precautionary assumptions is 

illustrated by the set of standard choices identified by FDA for risk 

assessments of carcinogenic animal drug residues in foods consumed by 

humans.

1. Regulation is based on the target tissue site exhibiting the highest 

potential for cancer risk for each carcinogenic compound.

2. If tumors are produced at more than one tissue site, the minimum 

concentration of the compound that produced a tumor is used.
Page 39 GAO-01-810 Chemical Risk Assessment

3. Cancer risk estimates are generally based on animal bioassays, using 

upper 95-percent confidence limits of carcinogenic potency.34

4. Low-dose extrapolation is done using a nonthreshold, conservative, 

linear-at-low-dose procedure (i.e., assuming that there is no dose that 

would not cause cancer and that effects vary in proportion to the 

amount of the dose).

5. It is assumed that the carcinogenic potency in humans is the same as 

that in animals.

6. The concentration of the residue in the edible product is at the 

permitted concentration.

7. Consumption is equal to that of the 90th percentile consumer.

8. All marketed animals are treated with the carcinogen.

9. In the absence of information about the composition of the total 

residue in edible tissue, assume that the entire residue is of 

carcinogenic concern.

FDA’s description of its risk assessment procedures acknowledged that 

these assumptions “result in multiple conservatisms” and stated that some 

of these choices are likely to overestimate risk by an unknown amount 

(although the fourth assumption could also underestimate risk by an order 

of magnitude). However, the agency also said that these assumptions are 

prudent because of the uncertainties involved and cited its statutory 

responsibility to ensure to a reasonable certainty that the public will not be 

harmed. It is important to keep in mind that the primary purposes for 

preparing such assessments are to identify safe concentration levels in 

edible tissues and residue tolerances (the amount permitted to remain on 

food) for postmarket monitoring rather than to produce a general estimate 

of the risk posed by use of the animal drug. 

34 Bioassay refers to the use of living organisms to measure the effect of a risk agent or 

condition—for example, a test for carcinogenicity in laboratory animals that includes nearlifelong exposure to the agent being tested.
Page 40 GAO-01-810 Chemical Risk Assessment

Comparison of Agencies’

Assumptions 

Agency documents very rarely made direct comparisons of their 

assumptions and methodological choices to those used by other agencies, 

and there is no requirement that they do so. Our review indicated that EPA, 

FDA, and OSHA risk assessment procedures have many basic assumptions 

in common—for example, that one can use results of animal experiments 

to estimate risks to humans, and that most potential carcinogens do not 

have threshold doses below which adverse effects would not occur. There 

are other default or standard assumptions and models in the three 

agencies’ risk assessment procedures that are similar, but not identical. 

For example, all three agencies employ a linear mathematical model for 

low-dose extrapolation (in the absence of information indicating that a 

linear model is inappropriate in a particular case). However, the agencies 

prefer different options in the details of fitting such models, such as the 

point of departure to low doses. EPA and FDA also consider similar, but 

not identical, sets of uncertainty or safety factors when using the NOAEL 

approach for noncancer risk assessments. Finally, as the discussion above 

regarding low-dose extrapolation illustrates, there are also instances in 

which the agencies use different assumptions in similar circumstances.

Table 1 compares and contrasts some of the risk assessment assumptions 

or analytical methods identified in the guidelines or other descriptive 

documents of EPA, FDA, and OSHA for use under similar circumstances.35 

(Note that, for comparability, the examples in table 1 all focus on 

carcinogen risk assessments based on animal studies, but the agencies’

major assumptions and methods are not limited to only carcinogen risk 

assessments. Note also that the “circumstances” listed in the table also 

include that the assumption or method would be used in the absence of 

data to the contrary.)

35RSPA is not included in this table because it uses a different process for risk assessments, 

and its assessments do not focus on the carcinogen risk assessment issues highlighted in the 

table. However, RSPA’s risk assessment methods are similar to EPA’s Chemical Emergency 

Preparedness and Prevention Office, which also focuses primarily on short-term risks 

associated with accidental releases of chemicals.
Page 41 GAO-01-810 Chemical Risk Assessment

Table 1: Comparison of Selected Major Assumptions or Methods Used in EPA, FDA, and OSHA Risk Assessments

Source: GAO analysis

Circumstance EPA FDA OSHA

Which species/sex to use in 

animal studies.

Use most sensitive species/sex. Use most sensitive species/sex. Use most sensitive species/sex 

for tumor sites appropriate for 

routes of exposure experienced 

by workers.

Whether to include data on 

benign tumors in a cancer 

assessment.

Include data on benign tumors if 

they have the capacity to 

progress to the malignancies 

with which they are associated. 

Benign tumors that are not 

observed to progress to 

malignancy are assessed on a 

case-by-case basis.

Include data on benign tumors if 

they have the capacity to 

progress to the malignancies 

with which they are associated. 

Benign tumors that are not 

observed to progress to 

malignancy are assessed on a 

case-by-case basis.

Combine data on benign tumors 

with the potential to progress to 

malignancies with data on 

malignant tumors occurring in 

the same tissue and the same 

organ site.

Preferred cancer low-dose 

extrapolation method if a 

mathematical model is used.

Default depends on the agent’s 

mode of action. For example, if 

mode is not understood or 

believed to be linear, a linear 

approach is recommended. 

When data supports a nonlinear 

mode of action, the default 

changes to a margin of exposure 

analysis.

 

Use a no-threshold, linear 

extrapolation method.

Use a particular no-threshold, 

linear approach known as the 

“maximum likelihood estimate in 

the Crump-Howe 

reparameterization of the 

multistage model.” (This 

particular approach may lead to 

models that are sublinear at low 

doses.)

Point of departure in preferred 

approach to low-dose 

extrapolation (i.e., the data point 

from which the agency 

extrapolates to lower, 

unobserved dose-response 

relationships).

Use the lower 95-percent limit of 

the doses that are estimated to 

cause a 10-percent response 

(i.e., an effect in 10 percent of 

exposed subjects). (This dose is 

referred to as the LED10.)

Use data at the upper 95- 

percent confidence limit.

According to agency officials, 

OSHA does not use a point of 

departure. OSHA tends to use 

central estimates of potency, 

such as the maximum likelihood 

estimate of the parameterized 

dose-response function.

Preferred method for crossspecies scaling of equivalent 

doses (i.e., how the agency 

converts data from doses given 

to one species, such as rats in a 

toxicological study, to doses 

presumed to have an equivalent 

effect on another species, such 

as humans).

For oral exposure, recommends 

use of a scaling factor of body 

weight to the 3⁄4 power.

Recommends use of scaling 

factor of body weight to the 3⁄4 

power. (However, risk assessors 

may also use the default of body 

weight scaling.)

Assumes that equivalent doses 

scaled by body weight would 

lead to equivalent risks. 

(However, it may in the future 

move to 3⁄4 -power scaling.)
Page 42 GAO-01-810 Chemical Risk Assessment

There appears to be some convergence in the agencies’ risk assessment 

assumptions in at least one area where there had been significant 

differences—their methods for cross-species dose scaling. In the absence 

of adequate information on differences between species, EPA’s standard 

practice in carcinogenic risk assessments had been to scale daily 

administered doses by body surface area, whereas FDA’s and OSHA’s 

standard practice had been to scale doses by body weight. Recently, the 

agencies have either adopted, or consider as one of their options, the 

expression of doses in terms of daily amount administered per unit of body 

weight to the 3⁄4 power.36

All four of the agencies included in our review have also been incorporating 

more complex analytical methods and models into their risk assessment 

procedures. Some of these methods (such as the use of probabilistic 

analyses to provide distributions of exposure parameters) help to address 

issues of uncertainty and variability in risk assessments and lessen the 

need for some precautionary assumptions. Other advances, such as the use 

of PBPK models, can provide better insights into how and to what extent a 

chemical might produce adverse effects in humans. One outcome of the 

integration of these methods into agencies’ procedures is a diminishing of 

the traditional distinction between cancer and noncancer risk assessment 

methods. EPA, in particular, has noted that it is less likely to consider 

cancer and noncancer endpoints in isolation as it develops and 

incorporates more advanced scientific methods to measure and model the 

biological events leading to adverse effects. According to EPA, the science 

of risk assessment is moving toward a harmonization of the methodology 

for cancer and noncancer assessments.

The use of newer, more complex models and methods also opens up a new 

range of choices and assumptions in the analysis—along with the potential 

for risk estimates to diverge because of the different assumptions that 

might be used. For example, in its methylene chloride final rule OSHA 

reported on the results of its analyses as well as risk assessments 

submitted to OSHA by other risk assessors.37 Although most of the risk 

assessments used a linearized multistage model to predict risk, there were 

differences in the estimates produced by these assessments. OSHA 

36 Across the range of plausible values, the body weight approach is generally considered the 

least precautionary, surface area scaling the most precautionary, and (body weight)3/4 the 

midpoint value.

37“Occupational Exposure to Methylene Chloride,” 62 FR 1494 (Jan. 10, 1997).
Page 43 GAO-01-810 Chemical Risk Assessment

pointed out that the differences in risk estimates were not generally due to 

the dose-response model used, but to whether the risk assessor used PBPK 

modeling to estimate target tissue doses and what assumptions were used 

in the PBPK modeling.

Appendices II through V present more detailed information on some of the 

major assumptions and methodological choices in each of the four selected 

agencies.

Risk Characterization 

Policies and Practices 

Emphasize 

Transparency 

In the risk characterization step of a risk assessment, agencies bring 

together the results of the preceding analyses in the form of estimates and 

conclusions about the nature and magnitude of a potential risk. Agencies’

risk characterizations play a crucial role in explaining to decision makers 

and other interested parties what the agency’s risk assessors have 

concluded and on what basis they reached those conclusions. Both EPA 

and DOT have agencywide written policies on risk characterization that 

emphasize the importance of providing comprehensive and transparent 

characterizations of risk assessment results. Although FDA and OSHA do 

not have written risk characterization policies, officials of those agencies 

pointed out that, in practice, they also tend to emphasize comprehensive 

characterizations of risk assessment results, discussions of limitations and 

uncertainties, and disclosure of the data and analytic methodologies on 

which the agencies relied.
Page 44 GAO-01-810 Chemical Risk Assessment

EPA’s program offices are generally responsible for completing risk 

characterizations, and EPA’s agencywide guidance on this issue includes a 

risk characterization policy, a guidance memorandum, and a handbook. 

EPA’s policy stipulates that risks should be characterized in a manner that 

is clear, transparent, reasonable, and consistent with other risk 

characterizations of similar scope. EPA said that all assessments “should 

identify and discuss all the major issues associated with determining the 

nature and extent of the risk and provide commentary on any constraints 

limiting fuller exposition.” EPA’s policy documents also recommend that 

risk characterization should (1) bridge the gap between risk assessment 

and risk management decisions; (2) discuss confidence and uncertainties 

involving scientific concepts, data, and methods; and (3) present several 

types of risk information (e.g., a range of exposures and multiple risk 

descriptors such as high-end estimates and central tendencies). It is also 

EPA’s policy that major scientifically and technically based work products 

related to the agency’s decisions normally should be peer-reviewed.38

In its guidelines for carcinogen risk assessment, EPA also suggests 

preparing separate “technical” characterizations to summarize the findings 

of the hazard identification, dose-response assessment, and exposure 

assessment steps. The agency’s risk assessors are then to use these 

technical characterizations to develop an integrative analysis of the whole 

risk case, followed by a less extensive and nontechnical summary intended 

to inform the risk manager and other interested readers. EPA identified 

several reasons for preparing separate characterizations of each analysis 

phase before preparing the final integrative summary. One is that different 

people often do the analytical assessments and the integrative analysis. 

The second is that there is very often a lapse of time between the conduct 

of hazard and dose-response analyses and the conduct of the exposure 

assessment and integrative analysis. Thus, according to EPA, it is 

necessary to capture characterizations of assessments as the assessments 

are done to avoid the need to go back and reconstruct them. Finally, 

several programs frequently use a single hazard assessment for different 

exposure scenarios.

38 Peer review generally takes one of two forms: (1) internal peer review by a team of 

relevant experts from within EPA who have no other involvement with respect to the work 

product that is to be evaluated or (2) external peer review by a review team that consists 

primarily of independent experts from outside EPA.
Page 45 GAO-01-810 Chemical Risk Assessment

DOT’s policy principles regarding how the results of its risk or safety 

assessments should be presented are straightforward and encourage 

agency personnel to: 

• make public the data and analytic methods on which the agency relied 

(for replication and comment); 

• state explicitly the scientific basis for significant assumptions, models, 

and inferences underlying the risk assessment, and explain the rationale 

for these judgments and their influence on the risk assessment;

• provide the range and distribution of risks for both the full population at 

risk and for highly exposed or sensitive subpopulations and encompass 

all appropriate risk to health, safety, and the environment;

• place the nature and magnitude of risks being analyzed in context 

(including appropriate comparisons to other risks); and

• use peer review for issues with significant scientific dispute.

FDA does not have a written risk characterization policy, but FDA officials 

said that, in practice, the agency uses a standard approach that is similar to 

EPA’s official policy. They said that FDA’s general policy is to reveal the 

risk assessment assumptions that have the greatest impact on the results of 

the analysis, and to state whether the assumptions used in the assessment 

were conservative. FDA officials also said that their risk assessors attempt 

to show the implications of different distributions and choices (e.g., the 

results expected at different levels of regulatory intervention). FDA may 

employ probabilistic methods, such as Monte Carlo analysis, to provide 

additional information on the effects of variability and uncertainty on 

estimates of risk, and there are some differences in FDA risk 

characterization procedures depending on the products being regulated 

and the nature of the risks involved.39

Although OSHA does not have written risk characterization policies, in 

recent rules the agency emphasized (1) comprehensive characterizations of 

risk assessment results; (2) discussions of assumptions, limitations, and 

uncertainties; and (3) disclosure of the data and analytic methodologies on 

which the agency relied. The agency devoted considerable effort to 

addressing uncertainty and variability in its risk estimates. Such efforts 

39Monte Carlo analysis involves a repeated random sampling from the distribution of values 

for each of the parameters in a calculation (such as average daily exposure) to derive a 

distribution of estimates of exposures for a population. According to FDA, because Monte 

Carlo modeling is a probabilistic technique that can use all the available data, it will result in 

more accurate estimates at upper percentiles of exposure. 
Page 46 GAO-01-810 Chemical Risk Assessment

included performing sensitivity analyses and providing estimates produced 

by alternative analyses and assumptions (including analyses by risk 

assessors outside of OSHA). In its risk characterizations, OSHA provided 

both estimates of central tendency and upper limits (such as the 95th

percentile of a distribution).

Appendices II through V provide more detailed descriptions of the risk 

characterization policies or approaches of each of the four selected 

agencies. 

Conclusions Risk assessment is an important, but extraordinarily complex, element in 

federal agencies’ regulation of potential risks associated with chemicals. 

The assessments can help agencies decide whether to regulate a particular 

chemical, select regulatory options, and estimate the benefits associated 

with regulatory decisions. Scientific studies in such areas as toxicology 

and epidemiology are often used to produce the information needed for 

risk assessment decisions. However, assessors frequently must produce 

estimates of risk without complete scientific information about the extent 

of exposures to potentially hazardous substances and the effects of those 

exposures on human health and safety or the environment. Therefore, 

professional judgment with regard to assumptions and methodological 

choices is an inherent part of conducting risk assessments. The 

appendices to this report identify many of the major assumptions and 

methods that can be used in risk assessments prepared for EPA, FDA, 

OSHA, and RSPA. The number and variety of those assumptions and 

methods illustrate the range of issues that risk assessors confront during 

the course of their analyses.

Although there were more similarities than differences in the general risk 

assessment procedures of three of the four agencies, there were also some 

notable differences in the agencies’ specific approaches, methods, and 

assumptions. These differences can significantly affect the results and 

conclusions drawn from the assessments. Therefore, risk estimates 

prepared by different agencies, or by different program offices within those 

agencies, may not be directly comparable, even if the same chemical agent 

is the subject of the risk assessment. In some cases, the reasons for those 

differences are readily apparent, such as when agencies focus on different 

types of adverse effects (e.g., cancer versus noncancer) or different types 

and sources of exposure. For example, the same chemical (e.g., methylene 

chloride) might be identified as a significant hazard by one agency in one 

exposure setting (OSHA for occupational exposures) but as a low hazard 
Page 47 GAO-01-810 Chemical Risk Assessment

by another agency in a different setting (EPA for Superfund hazard ranking 

screening). In other cases, the reasons for different estimates may be more 

subtle and harder to discern within the many layers of analyses and 

professional judgments used to prepare the risk assessment. 

Because of the range of assumptions and methods that are scientifically 

plausible in a given situation, the risk characterization phase of the risk 

assessment process takes on added importance. In their risk 

characterization policies or procedures, the four agencies acknowledge the 

importance of clearly communicating not only their conclusions about the 

nature and likelihood of a given risk but also disclosing (1) the 

assumptions, methods, data, and other choices that had the greatest impact 

on risk estimates; (2) why those choices were made; and (3) the effect that 

alternative choices would have had on the results of a risk assessment. 

Transparency is important with regard to both individual risk assessments 

and in agencies’ general procedures regarding how the assessments should 

be conducted. Those procedures encourage consistency in how agencies 

conduct risk assessments and provide insights into agencies’ decision 

making when analyzing risks. For example, frameworks delineated by EPA 

and OSHA for departing from certain default assumptions inform both 

agency personnel and external parties as to whether particular data or 

analyses are acceptable to the agency.

Our review focused on describing the framework for agencies’ chemical 

risk assessments. We did not evaluate how that framework is applied in 

practice, or how risk assessment results affect risk management decisions 

by agencies and other policymakers. Nevertheless, our report highlights 

the value of policymakers and other interested parties becoming aware of 

the underlying risk assessment context, procedures, assumptions, and 

policies when using risk assessment data for risk management and other 

public policy decisions. For example, prudent use of risk data requires the 

user to be aware of the extent to which the data:

• represent estimates from screening assessments (which may rely 

heavily on precautionary assumptions) or estimates from subsequent, 

more rigorous assessments (which are likely to rely on more detailed 

and case-specific data and analyses);

• show the distribution of exposures and potential adverse effects across 

the population, including the extent to which the data address risks of 

the most exposed or sensitive subgroups of the population, or focus on 

only part of that distribution;
Page 48 GAO-01-810 Chemical Risk Assessment

• were produced using directly relevant scientific data that were available 

or had to rely on general assumptions and models; and

• reflect the flexibility permitted in agencies’ standard procedures or 

guidelines to depart from past precedent and default choices to use 

alternative assumptions and models, when appropriate.

In our review we also found that, although the underlying statutes specified 

the use of particular methods or assumptions in only three instances, the 

legal and situational context within which an agency is conducting a 

chemical risk assessment has a major effect on the specific focus, scope, 

and level of detail of the resulting assessment. Comparison of risk 

assessment estimates from different agencies and programs therefore 

requires careful consideration of these contextual differences. 

Because the central purpose of our review was to describe the framework 

for selected agencies’ chemical risk assessments, rather than to evaluate 

and critique how that framework is applied in practice, we are not making 

any recommendations in this report.

Agency Comments and 

Our Evaluation

At the end of our review, we sent a draft of this report to five experts in the 

field of risk assessment to ensure the technical accuracy of the report. The 

three experts who provided comments were (1) the Executive Director of 

the Presidential/Congressional Commission, (2) the individual who 

prepared the Survey of Methods for Chemical Health Risk Assessment 

Among Federal Regulatory Agencies for the Commission, and (3) an 

expert in risk assessment at Resources for the Future. The experts 

generally indicated that the report had no material weaknesses, but 

provided a number of technical suggestions that we incorporated as 

appropriate. For example, two of the reviewers suggested that the report’s 

discussion of the NAS four-step risk assessment paradigm, although 

reflecting the definitions generally relied upon by federal agencies, should 

also identify an updated view regarding the concept of risk 

characterization. The updated view is that risk characterization should be 

a decision-driven activity performed as part of the risk management 

decision making process rather than a stand-alone activity at the end of a 

risk assessment. We included this perspective in the report’s background 

section.

During our review, we obtained technical comments from officials in each 

of the four agencies on a draft of the appendices to this report, which we 

incorporated as appropriate. On June 18, 2001, we sent a draft of the full 
Page 49 GAO-01-810 Chemical Risk Assessment

report to the Secretaries of Health and Human Services, Labor, and 

Transportation, and the Administrator of EPA for their review and 

comment. None of the agencies provided formal comments on the report, 

but we received additional technical comments and suggestions from all 

four of the agencies, which we incorporated as appropriate.

As arranged with your office, unless you publicly announce the contents of

this report earlier, we plan no further distribution until 30 days after the 

date of this report. At that time, we will send copies of this report to the 

Ranking Minority Member, House Committee on Energy and Commerce; 

the Ranking Minority Member, Subcommittee on Environment and 

Hazardous Materials, House Committee on Energy and Commerce; the 

Secretaries of Health and Human Services, Labor, and Transportation; and 

the Administrator of EPA. We will also make copies available to others on 

request.

If you have any questions concerning this report, please call me or Curtis 

Copeland at (202) 512-6806. Key contributors to this assignment were 

Timothy Bober and Aaron Shiffrin.

Victor S. Rezendes

Managing Director, Strategic Issues
Page 50 GAO-01-810 Chemical Risk Assessment

Appendix I

Objectives, Scope, and Methodology ApApenednxidexiIs

Scope and Objectives As requested, our review focused on the chemical risk assessment 

procedures, assumptions, and policies of four federal agencies with 

responsibilities for regulating or managing risks from potential exposure to 

chemicals—the Environmental Protection Agency (EPA), the Food and 

Drug Administration (FDA) within the Department of Health and Human 

Services (HHS), the Occupational Safety and Health Administration 

(OSHA) within the Department of Labor, and the Department of 

Transportation’s (DOT) Research and Special Programs Administration 

(RSPA—in particular the Office of Hazardous Materials Safety). Our 

specific objectives were to identify and describe (1) the general context for 

the agencies’ chemical risk assessment activities; (2) what the agencies 

view as their primary procedures for conducting risk assessments; (3) what 

the agencies view as the major assumptions or methodological choices in 

their risk assessment procedures; and (4) the agencies’ procedures or 

policies for characterizing the results of risk assessments. To the extent 

feasible, we were also asked to identify for the assumptions and choices 

identified in the third objective (a) at what stages of the risk assessment 

process they are used, (b) the reasons given for their selection, (c) their 

likely effects on risk assessment results, and (d) how they compare to the 

assumptions and choices used by other agencies or programs in similar 

circumstances.
Appendix I

Objectives, Scope, and Methodology

Page 51 GAO-01-810 Chemical Risk Assessment

Methodology To address our objectives, we relied primarily on a detailed review and 

analysis of agencies’ general guidance documents on chemical risk 

assessment or, if there were no guidance documents, reviews of specific 

examples of agency risk assessments. We supplemented that information 

with material from secondary source reports on risk assessment and 

interviews with agency officials. Among the secondary sources that we 

used were relevant reports by the Congressional Research Service, 

National Academy of Sciences (NAS), and the Presidential/Congressional 

Commission on Risk Assessment and Risk Management (hereinafter 

referred to as the Presidential/Congressional Commission). In particular, 

as a starting point for our review we used a report on federal agencies’

chemical risk assessment methods that was prepared by Lorenz Rhomberg 

for the Presidential/Congressional Commission.1

 That report provided the 

baseline descriptions of some of the chemical risk assessment procedures 

at EPA, FDA, and OSHA.2

 We asked officials of those agencies to review 

Rhomberg’s report to identify information that was still relevant to 

addressing the objectives of this report as well as information that they felt 

should be revised or added to reflect the agencies’ current procedures.

There are several important limitations to our review. First, chemical risk 

assessment is just one of several types of risk assessment being conducted 

in federal agencies. Therefore, our review cannot be used to characterize 

other types of risk assessments (e.g., risks associated with radiation 

exposure). In fact, FDA officials considered risk assessments related to the 

human drug approval process to be outside the scope of our review 

because a completely different protocol is used in those assessments. 

However, limiting the scope of our review to chemical risk assessments 

makes comparisons among the agencies included more relevant and 

meaningful. Second, our review did not include all agencies or programs 

that conduct risk assessments involving chemicals. For example, we did 

not include the Consumer Product Safety Commission, which periodically 

assesses products with potential risks from chemicals. Nor did we include 

the Agency for Toxic Substances and Disease Registry, which prepares 

“health assessments” that closely resemble risk assessments but has no 

regulatory authority. We focused on the risk assessment procedures in four 

federal agencies that regularly conduct chemical risk assessments in 

1

A Survey of Methods for Chemical Health Risk Assessment Among Federal Regulatory 

Agencies, Lorenz Rhomberg (1996).

2

RSPA was not included in the scope of Rhomberg’s report.
Appendix I

Objectives, Scope, and Methodology

Page 52 GAO-01-810 Chemical Risk Assessment

support of regulatory activities and/or could illustrate the diversity of risk 

assessment procedures. However, the results of our review cannot be 

considered representative of chemical risk assessments in all federal 

agencies. Third, our review does not describe every chemical risk 

assessment procedure or assumption used by the agencies we reviewed. 

The material describing the agencies’ procedures is both voluminous and 

extremely complex. The detailed information that we provide on agency 

assumptions is illustrative of the assumptions included in agencies’

procedures, but not a compendium of all such assumptions. In addition, 

we concentrated primarily on the human health and safety risk assessment 

procedures of the four agencies and, to a lesser extent, on ecological risk 

assessment procedures. Fourth, this report describes agencies’ general 

procedures and policies, but it is not a compliance review of how well 

those procedures and policies are applied with regard to individual 

assessments. The agencies’ guidelines represent suggested procedures and 

are not binding, so the agencies’ practices may justifiably vary from the 

general frameworks we describe. In practice, risk assessments do not 

follow a simple recipe or formula. Each assessment has unique issues or 

characteristics that require case-specific resolutions. Finally, this report 

does not address risk management issues—e.g., using the results of a risk 

assessment to determine what level of exposure to a risk agent represents 

an acceptable or an unacceptable risk and deciding what control options 

should be used.

We conducted this review between February 2000 and March 2001 in the 

Washington, D.C., headquarters offices of the selected agencies in 

accordance with generally accepted government auditing standards. We 

obtained technical comments on our descriptions of the agencies’

procedures, assumptions, and policies in the appendices from 

knowledgeable agency personnel. We then provided the draft report to 

external experts in risk assessment, including the Center for Risk Analysis 

at the Harvard School of Public Health in Boston, MA; Resources for the 

Future in Washington, D.C.; the Executive Director of the 

Presidential/Congressional Commission; and Lorenz Rhomberg, the analyst 

who surveyed federal agencies’ chemical risk assessment procedures for 

the Commission. After incorporating their comments, we provided a draft 

of this report to the Secretaries of Health and Human Services, Labor, and 

Transportation; and the Administrator of the Environmental Protection 

Agency for their review and comment. 
Appendix I

Objectives, Scope, and Methodology

Page 53 GAO-01-810 Chemical Risk Assessment

Organization of 

Appendices on 

Chemical Risk 

Assessment at Selected 

Federal Agencies

In the following appendices, we provide more detailed information 

regarding the framework and methods applicable to chemical risk 

assessment activities of EPA, FDA, OSHA, and RSPA. There is a separate 

technical appendix covering each of these four agencies, along with their 

relevant offices, programs, or centers that are involved in conducting 

chemical risk assessments.

For consistency and ease of presentation, we have generally organized the 

appendices on each agency according to a standard format with four major 

sections. 

1. We describe the general context for the chemical risk assessment 

activities of each agency. This includes a summary of the primary risk 

statutes, mandates, and tasks related to potential risks from exposure 

to chemical agents.

2. We identify and summarize the standard risk assessment procedures of 

each agency and, if applicable, each agency’s various offices, programs, 

or centers. This section is generally organized by the major analytical 

steps of the risk assessment process: hazard identification, doseresponse assessment, and exposure assessment. These correspond to 

the first three steps of the four-step paradigm for risk assessment as 

defined by NAS and used by three of the four agencies covered by our 

review. (We address the fourth step of the process, risk 

characterization, as a separate objective in the final section of each 

agency appendix.) Within the descriptions of those steps, we often 

distinguish between the procedures used for assessing cancer and 

noncancer effects. Given developments in risk assessment methods, 

these distinctions are sometimes more artificial than real.3

3. We present additional information about major assumptions and 

methodological choices in the agencies’ standard risk assessment 

procedures. For EPA, FDA, and OSHA, the primary focus of this 

section is a detailed table identifying some of the major agencywide or 

program-specific assumptions that may be used in chemical risk 

assessments. To the extent that such information was available, each 

3

 For example, agencies may omit or combine some of the steps in certain situations. Also, 

with increasing research attention on the modes of action of chemical agents, the line 

between procedures for identifying carcinogenic and noncancer effects is blurring.
Appendix I

Objectives, Scope, and Methodology

Page 54 GAO-01-810 Chemical Risk Assessment

of these tables also includes information on the agency’s reason(s) for 

selecting a particular assumption, when in the risk assessment process 

the agency would apply the assumption, and the likely effect of using 

the assumption on risk assessment results. (Because agencies very 

rarely made direct comparisons of their choices to those of other 

agencies in their risk assessment guidelines or related documents, we 

have not included a separate column on that topic in the appendix 

tables. That objective is, however, addressed in the letter portion of 

this report.) The appendix on RSPA does not include all of these 

elements because of differences in its context and approach to 

chemical risk assessment.

4. The final section of each appendix addresses each agency’s approach 

or policies for characterizing the results of risk assessments for agency 

decision makers and other interested parties. In particular, we describe 

the agency’s policies or practices with regard to the transparency of 

risk assessment results, such as reporting the range and distribution of 

risks and identifying the uncertainties in the risk analysis and 

underlying data.

To avoid repetition in the appendices on agencies’ risk assessment 

procedures, our most detailed descriptions of basic methods and issues 

appear in the EPA appendix under the discussion of agencywide 

procedures. Descriptions of procedures used by other agencies or 

programs, including the individual program offices within EPA, then 

reference the EPA-wide descriptions of those particular methods, if they 

are similar. 

Although we provide much more detailed technical information in these 

appendices than in the main body of the report, it is still important to 

recognize that agencies’ risk assessment methods are more involved and 

complex than we have described in this report. In particular, the tables of 

assumptions do not represent a comprehensive listing of all assumptions 

and choices of the agencies. Agencies might use many different types and 

numbers of assumptions in any given assessment, and the assumptions are 

being altered over time to reflect scientific improvements and changes in 

risk approaches and the regulatory context. However, the information 

presented is intended to illustrate the types and diversity of procedures and 

assumptions employed by the agencies we examined.
Page 55 GAO-01-810 Chemical Risk Assessment

Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency ApendxiI

Chemical risk assessment at the Environmental Protection Agency (EPA) is 

a complex and diverse undertaking. The variety and range of the relevant 

regulatory authorities and activities has a major effect on the organization 

and conduct of risk assessment at the agency. An expanding set of agency 

guidelines reflects the evolving nature of EPA’s risk assessment 

procedures. EPA generally follows the four-step risk assessment process 

identified by the National Academy of Sciences (NAS). Changes are 

occurring in EPA’s approaches to cancer, noncancer, and exposure 

assessments, with a general trend toward the development and application 

of more complex and comprehensive methodologies. To a greater extent 

than the other agencies we reviewed, EPA has established a set of default 

assumptions (often precautionary in nature) and standard data factors for 

use by its risk assessors. In the “tiered” risk assessment approaches 

commonly employed by EPA’s program offices, precautionary default 

assumptions are most often used during initial screening assessments, 

when the primary task generally is to determine whether a risk might exist 

and more rigorous analysis is needed. However, the information necessary 

for more detailed analysis is not always available, so for regulatory 

purposes the agency may be limited to using results from its initial tiers of 

risk assessments. In presenting the results of its risk assessments, it is 

EPA’s policy that risk characterizations should be prepared in a manner 

that is clear, transparent, reasonable, and consistent with other risk 

characterizations of similar scope prepared across the programs in the 

agency.

The following sections describe for EPA and its component offices, the 

context for chemical risk assessment, the general procedures for 

conducting risk assessments, major assumptions and methodological 

choices in those procedures, and the agency’s policy for risk 

characterization. Because chemical risk assessment at EPA is such a 

complex and diverse activity, this appendix can only summarize and 

illustrate the range of contexts, procedures, assumptions and methods, and 

policies that affect the conduct of EPA risk assessments. For example, as 

in our report as a whole, this appendix focuses primarily on human health 

and safety risk assessment and less on ecological risk assessment. 

However, we have included a brief section on EPA’s ecological risk 

assessment guidelines under our discussion of agencywide risk assessment 

procedures and illustrated the role played by ecological risk assessment in 

the risk assessment activities of some, but not all, of EPA’s program offices 

under our discussion of program-specific procedures. As a practical 

matter, this appendix reflects risk assessment topics that were addressed 

in agencywide or program-specific guidelines or descriptions of chemical 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 56 GAO-01-810 Chemical Risk Assessment

risk assessment at EPA. To the extent that such activities were not 

explicitly addressed in the agency’s risk assessment guidelines and related 

documents, there may be little information on them in this appendix. 

Context for EPA 

Chemical Risk 

Assessment

EPA is responsible for a wide range of regulatory—and related risk 

assessment—activities pertaining to potential health, safety, and 

environmental risks associated with chemical agents. This range of 

activities reflects an equally broad and diverse range of underlying 

environmental statutes. According to EPA, close to 30 provisions within 

the major environmental statutes require decisions based on risk, hazard, 

or exposure assessment, with varying requirements regarding the scope 

and depth of the agency’s analyses. In general, EPA’s regulatory authority 

regarding chemical agents is compartmentalized according to the various 

kinds and sources of exposure—such as pesticides, drinking water 

systems, or air-borne pollutants—and reflected in the agency’s organization 

into various program offices—such as the Office of Air and Radiation, 

Office of Solid Waste, and Office of Water. Table 2 summarizes the 

principal statutes, regulatory tasks, and risk mandates associated with 

chemical risk assessment activities of EPA’s offices.
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 57 GAO-01-810 Chemical Risk Assessment

Table 2: Chemical Risk Statutes, Tasks, and Mandates for EPA Offices

Office or program Major risk-related statute(s) Primary risk-related tasks Primary risk-related mandate(s)

Chemical Emergency 

Preparedness and 

Prevention Office (CEPPO)

Emergency Planning and 

Community Right-to-Know Act 

(EPCRA) in the Superfund 

Amendments and 

Reauthorization Act of 1986 

(SARA), Title III

Clean Air Act Amendments of 

1990 (CAAA)

Under EPCRA, evaluates 

substances for toxicity, reactivity, 

volatility, dispersability, 

combustibility, or flammability to 

develop and maintain a list of 

extremely hazardous substances 

and threshold quantities. Also 

develops regulatory requirements 

for reporting accidental releases 

and for emergency planning.

Under Section 112(r) of the 

amended Clean Air Act (CAA), 

evaluates substances for acute 

adverse health effects, likelihood 

of accidental release, and 

magnitude of exposure to 

develop a list of substances for 

prevention of accidental release. 

Evaluates accidental chemical 

release risk management and 

prevention practices for 

development of accidentprevention and risk-reduction 

regulations at industrial facilities.

Also under the CAAA, 

investigates chemical incidents, 

evaluates the risks associated 

with accidental releases, and 

conducts research on risk 

analysis and assessment.

Under EPCRA, the EPA list of 

extremely hazardous substances 

and their thresholds, along with 

reporting requirements, are used by 

state and local entities to manage 

the risks associated with chemical 

emergencies at the local level.

Under Section 112(r) of the 

amended CAA, EPA must develop a 

list of at least 100 substances that 

pose the greatest risk of causing 

death, injury, or serious adverse 

effects to human health or the 

environment from accidental 

releases. EPA must also develop 

regulations for preparation and 

submission of risk management 

programs and plans by industrial 

facilities handling these listed 

substances.

Also under the amended CAA, for 

clean air research, EPA shall develop 

methods and techniques necessary 

to identify and assess the risks to 

human health from accidental 

exposures.
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 58 GAO-01-810 Chemical Risk Assessment

Office of Air and Radiation 

(OAR − air quality side)

Clean Air Act; Clean Air Act 

Amendments of 1990

Regulation of emissions of airborne pollutants, including

• setting national ambient air 

quality standards (NAAQS) for 

six “criteria” pollutants, and

• setting standards for regulating 

emissions of hazardous air 

pollutants (toxic chemicals other 

than the criteria pollutants).

Under the CAA, EPA is also 

required to review the scientific 

data upon which air quality 

standards are based and revise 

the standards, if necessary, every 

5 years.

For criteria air pollutants, set 

standards to protect public health 

with an adequate margin of safety.

For hazardous air pollutants, set 

standards using maximum 

achievable control technology 

(MACT) for a specified list of 

chemicals identified in the CAAA. 

However, if applying the MACT is 

found to lower risks insufficiently, 

EPA may pursue further regulation to 

control the residual risk, applying the 

pre-CAAA standard of providing an 

ample margin of safety.

Office of Emergency and 

Remedial Response 

(OERR − Superfund)

Comprehensive Environmental 

Response, Compensation, and 

Liability Act of 1980 (CERCLA); 

Superfund Amendments and 

Reauthorization Act of 1986

Remediation of hazardous waste 

sites, including

• defining hazardous substances 

and the amounts of release that 

must be reported to EPA,

• screening and ranking risks 

posed by hazardous waste sites 

and identifying action priorities 

among them,

• evaluating need for action at 

hazardous waste sites, and

• evaluating effectiveness of 

options for remediation.

Remedial actions are authorized at a 

site whenever any hazardous 

substance is released or there is a 

substantial threat of such a release 

into the environment, or when there 

is a release or substantial threat of 

release into the environment of any 

pollutant or contaminant which may 

present an imminent and substantial 

danger to the public health or 

welfare.

Remedial action priorities are to be 

based on relative risk or danger to 

public health or welfare or the 

environment, taking into account the 

population at risk, the hazard 

potential of the hazardous 

substances, and the potential for 

contamination of air and drinking 

water, among other factors. Need for 

action is determined by evaluation of 

risks to human health and the 

environment; effectiveness is 

determined by meeting requirements 

of other laws or risk-based goals.

(Continued From Previous Page)

Office or program Major risk-related statute(s) Primary risk-related tasks Primary risk-related mandate(s)
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 59 GAO-01-810 Chemical Risk Assessment

Office of Pesticide 

Programs (OPP)

Federal Insecticide, Fungicide, 

and Rodenticide Act (FIFRA);

Federal Food, Drug, and 

Cosmetic Act (FFDCA);

Food Quality Protection Act 

(FQPA)

Regulation of pesticides, 

including

• approving the registration of 

pesticides to set allowable uses 

in agriculture and extermination, 

and

• setting tolerances for pesticide 

residues permitted to remain in 

or on foods available to the 

consumer.

For pesticide residues in all foods, 

determine whether there is 

reasonable certainty of no harm, with 

consideration of

• an additional safety factor to protect 

infants and children,

• aggregate exposure to a pesticide 

(including all exposures for which 

there is reliable information), and

• cumulative exposures to pesticides 

with a common mechanism of 

toxicity.

For other exposures, determine 

whether use of the pesticide would 

present any unreasonable risk to 

man or the environment.

Office of Pollution 

Prevention and Toxics 

(OPPT)

Toxic Substances Control Act 

(TSCA)

Evaluation and regulation of 

existing and new chemicals used 

in manufacturing and commerce 

to identify any potentially 

dangerous products or uses.

For chemicals listed on the inventory 

of “existing chemicals,” determine 

whether use of that chemical will 

present an unreasonable risk to 

human health or the environment.

For newly introduced chemicals, or 

significant new uses of existing 

chemicals, determine whether use 

may present an unreasonable risk to 

human health or the environment.

(Continued From Previous Page)

Office or program Major risk-related statute(s) Primary risk-related tasks Primary risk-related mandate(s)
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 60 GAO-01-810 Chemical Risk Assessment

Office of Solid Waste 

(OSW)

Resource Conservation and 

Recovery Act of 1976 (RCRA)

“Cradle-to-grave” regulation of 

hazardous waste management, 

including the use of risk 

assessment information in

• defining (and delisting) 

substances as hazardous 

wastes,

• evaluating the hazards posed 

by waste streams,

• assessing the need for 

corrective action at disposal 

sites, and

• granting waste disposal permits.

Hazardous waste is defined as a 

solid waste, or combination of solid 

wastes, which because of its 

quantity, concentration, or physical, 

chemical, or infectious 

characteristics may

• cause, or significantly contribute to, 

an increase in mortality or an 

increase in serious irreversible, or 

incapacitating reversible, illness; or

• pose a substantial present or 

potential hazard to human health or 

the environment when improperly 

treated, stored, transported, or 

disposed of, or otherwise 

managed.

Treatment, storage, or disposal of 

waste is to be conducted so as to 

minimize the present and future 

threat to human health and the 

environment.

(Continued From Previous Page)

Office or program Major risk-related statute(s) Primary risk-related tasks Primary risk-related mandate(s)
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 61 GAO-01-810 Chemical Risk Assessment

Office of Water (OW) Clean Water Act (CWA); Safe 

Drinking Water Act (SDWA); 

SDWA Amendments of 1996

Evaluation and regulation of 

ambient water and drinking water 

quality, including

• recommending water quality 

criteria and establishing 

national minimum effluent 

standards,

• prohibiting discharge of toxic 

pollutants in toxic amounts,

• establishing national drinking 

water standards for public water 

systems, and

• identifying subpopulations at 

elevated risk of health effects 

from exposure to contaminants 

in drinking water and 

conducting studies 

characterizing health risk to 

sensitive populations from 

contaminants in drinking water.

Under CWA, EPA is to establish 

criteria for ambient water quality on 

the basis of health and ecological 

effects and accurately reflecting the 

latest scientific knowledge on the 

kind and extent of all identifiable 

effects on health and welfare.

Also under CWA, effluent standards 

for toxic pollutants are to be at that 

level which the EPA Administrator 

determines will provide an ample 

margin of safety, so standards more 

stringent than those based on the 

best available technology 

economically achievable (the normal 

basis) may be named at EPA 

discretion.

 

Under SDWA, the EPA Administrator 

is to promulgate national primary 

drinking water regulations for each 

contaminant which may have any 

adverse effect on the health of 

persons and which is known or 

anticipated to occur in public water 

systems. Such regulations specify 

two levels of contamination

• a maximum contaminant level goal 

(MCLG) set solely on health 

grounds at a level at which no 

known or anticipated effects on the 

health of persons occur and which 

allows an adequate margin of 

safety, and

• a maximum contaminant level 

(MCL) set as close as feasible to 

the MCLG.

The 1996 amendments to SDWA 

require EPA, when developing 

drinking water regulations, to (1) use 

the best available, peer-reviewed 

science and supporting studies and 

data; and (2) make publicly available 

a risk assessment document that 

discusses estimated risks, 

uncertainties, and studies used in 

the assessment. 

(Continued From Previous Page)

Office or program Major risk-related statute(s) Primary risk-related tasks Primary risk-related mandate(s)
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 62 GAO-01-810 Chemical Risk Assessment

Source: EPA documents and comments provided by EPA officials.

A number of other contextual factors affect the extent of involvement by 

EPA offices in assessing and using risk assessment information in support 

of the various statutes, mandates, and tasks identified in table 2.

• Risk assessment information may not be the only, or even the primary, 

basis for the ultimate risk management decision. EPA statutes vary 

fundamentally by whether the basis for regulation is (1) risk (health and 

environmental) only, (2) technology-based, or (3) risk balancing 

(consideration of risks, costs, and benefits).

• For some chemical risk assessment activities, EPA has a secondary role. 

Instead, the main responsibility for determining the relative risk of a 

chemical, compiling and analyzing risk-related data, or completing other 

tasks associated with a particular statute might lie with industry, states, 

or local entities.

• In practical terms, the resources available for conducting a risk 

assessment for a given chemical might limit the depth and scope of 

EPA’s (or other parties’) analysis. Such resource limitations might 

include not only schedule and staffing constraints, but often the amount 

and quality of directly relevant scientific data available for analysis.

Office of Research and 

Development (ORD)

(Not applicable; supports the 

efforts of other EPA program 

offices.)

No direct regulatory authority, but 

supports risk-related activities of 

other EPA offices by:

• conducting the hazard 

identification and doseresponse assessment steps of 

risk assessments for specific 

chemicals at the request of 

program offices,

• preparing or assisting in the 

development of EPA risk 

assessment guidelines and 

policies, and

• conducting complex, precedentsetting risk assessments.

(Not applicable; supports the efforts 

of other EPA program offices.)

(Continued From Previous Page)

Office or program Major risk-related statute(s) Primary risk-related tasks Primary risk-related mandate(s)
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 63 GAO-01-810 Chemical Risk Assessment

Risk assessment activities involve both EPA’s program offices and its Office 

of Research and Development (ORD), which is the principal scientific and 

research arm of the agency. ORD often does risk assessment work for EPA 

program offices that focuses on the first two steps in the four-step NAS 

process—hazard identification and dose-response assessment—in 

particular, the development of “risk per unit exposed” numbers. The 

exposure assessment and risk characterization steps tend to be the 

responsibility of the various regulatory programs at EPA. However, 

according to agency officials, both program offices and ORD may conduct 

all of the risk assessment steps in particular cases. For example, OW’s 

Office of Science and Technology does all of the assessments for purposes 

of the SDWA, and, because of their particular statutory mandates, OPP and 

OPPT have developed the capability to conduct all steps of a risk 

assessment on their own.1

 ORD carries out all steps of highly complex, 

precedent-setting risk assessments of specific chemicals, such as dioxin 

and mercury.

1

 Also, some of the material submitted by industry petitioners seeking regulatory approvals 

of chemicals is confidential business information, which precludes OPP and OPPT from 

sharing all of their risk assessment data with other parts of EPA.
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 64 GAO-01-810 Chemical Risk Assessment

ORD also helps to coordinate the development of EPA’s risk assessment 

methods, tools, models, and policies. In particular, much of EPA’s 

agencywide guidance on conducting risk assessments is developed and 

disseminated through ORD, with input from EPA’s program offices, Science 

Policy Council, and Science Advisory Board, as well as other external 

parties. Coordination of risk assessment activities also occurs through 

EPA’s Risk Assessment Forum and the agency workgroups that approve 

information for entry into EPA’s Integrated Risk Information System (IRIS). 

The Risk Assessment Forum is a standing committee of senior EPA 

scientists that was established to promote agencywide consensus on 

difficult and controversial risk assessment issues and to ensure that this 

consensus is incorporated into appropriate EPA risk assessment guidance. 

Managed by ORD, IRIS is a computerized database that contains 

information on human health effects that may result from exposure to 

various chemicals in the environment. IRIS was initially developed for EPA 

staff in response to a growing demand for consistent information on 

chemical substances for use in risk assessments, decision making, and 

regulatory activities. The entries in IRIS on individual chemicals represent 

a consensus opinion of EPA health scientists representing the program 

offices and ORD and have been subject to EPA’s peer review policy since its 

issuance in 1994.2

Risk Assessment 

Procedures

There are agencywide risk assessment procedures that EPA’s various 

program offices generally follow, but each office also has different 

statutory mandates and risk assessment tasks associated with its 

regulatory authority. These contextual differences contribute to some 

program-specific variations in the conduct of chemical risk assessments. 

In addition, EPA’s procedures are in transition from more simplistic 

traditional methods for identifying and assessing risks to increasingly 

complex models and methods. It is particularly important to recognize 

that, while most EPA guidelines (and this appendix) distinguish between 

cancer and noncancer procedures, this distinction is becoming increasingly 

blurred as new scientific methods are being developed and applied. In 

general, EPA follows the NAS four-step process for human health risk 

assessments: (1) hazard identification, (2) dose-response assessment, 

(3) exposure assessment, and (4) risk characterization. However, for 

ecological risk assessment, EPA’s guidelines recommend a three-step 

2

 IRIS does not, however, incorporate OPP or OPPT risk assessment data from confidential 

business data.
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 65 GAO-01-810 Chemical Risk Assessment

process: (1) problem formulation, (2) analysis, and (3) risk 

characterization.

Guidelines To a much greater extent than the other agencies we reviewed, EPA has 

documented its risk assessment procedures and policies in a voluminous 

and expanding set of guidelines, policy papers, and memoranda. These 

documents are primarily intended as internal guidance for use by risk 

assessors in EPA and those consultants, contractors, or other persons who 

perform work under EPA contract or sponsorship.3

 However, the 

documents also make information on the principles, concepts, and 

methods used in EPA’s risk assessments available to other interested 

parties. EPA’s guidelines undergo internal and external peer review.

Beginning in 1986, EPA published a series of risk assessment guidelines to 

set forth principles and procedures to guide EPA scientists in the conduct 

of agency risk assessments, and to inform agency decision makers and the 

public about these procedures. In general, EPA adopted the guiding 

principles of fundamental risk assessment works, such as the 1983 Red 

Book by the NAS’ National Research Council (NRC).4

 EPA’s guidelines 

supplement these principles. Five sets of guidelines were finalized in 1986, 

including guidelines for carcinogen risk assessment, mutagenicity risk 

assessment, health risk assessment of chemical mixtures, health 

assessment of suspect developmental toxicants, and estimating exposures.5

 

In part to respond to advances and changes in risk assessment methods—

but also in response to criticisms of its guidelines by NRC, among others—

EPA has revised most of these guidelines, in either proposed or final form, 

and produced additional guidance documents.

3

 Guidelines are not rules, are not binding on either EPA or any outside parties, and do not 

alter applicable EPA statutes and regulations.

4

 NRC is the principal operating agency and research arm of NAS in advising and providing 

services to the federal government, the public, and the scientific community.

5

 Mutagenicity risk assessment focuses on analysis of agents that may cause genetic 

mutations. Developmental toxicity risk assessment focuses on risk to human development, 

growth, survival, and function because of exposure to environmental agents prior to 

conception, prenatally, or to infants and children.
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 66 GAO-01-810 Chemical Risk Assessment

Statutory changes have also prompted revisions and expansions of EPA’s 

risk assessment guidelines and policy papers. In the Clean Air Act 

Amendments of 1990, for example, Congress directed EPA to revise its 

carcinogen risk assessment guidelines, taking into consideration the NAS 

recommendations, before making any determinations of the “residual 

risks” associated with emissions of hazardous air pollutants.6

 The results 

of the NAS study appeared in the 1994 NRC report, Science and Judgment 

in Risk Assessment. Among other things, NRC recommended that EPA 

better identify the inference (default) assumptions in its guidelines, explain 

the scientific or policy bases for selecting them, and provide guidance on 

when it would be appropriate to depart from the assumptions. 

The current set of agencywide risk assessment guidelines and policies 

includes the following major topics:7

• carcinogen risk assessment,

• neurotoxicity risk assessment,

• reproductive toxicity risk assessment,

• developmental toxicity risk assessment,

• mutagenicity risk assessment,

• health risk assessment of chemical mixtures,

• guidelines for exposure assessment,

• guidelines for ecological risk assessment,

• other risk assessment tools and policies,

• probabilistic analysis in risk assessment,

• use of the benchmark dose approach in health risk assessment,

• reference dose (RfD) and reference concentration (RfC),

• evaluating risk to children, and

• EPA risk characterization program.

In addition to these agencywide documents, there are also numerous 

program-specific guidelines and policy documents. For example, the Risk 

Assessment Guidance for Superfund series covers various stages of 

human health evaluation as well as ecological risk assessment and 

probabilistic risk assessment. There are also guidelines and policy 

memoranda at the headquarters and regional office level that supplement 

6

 Residual risks are those remaining after the maximum achievable control technology is in 

effect.

7

 There are other documents, but they are mostly on narrow topics—the assessment of 

thyroid follicular cell tumors, for example.
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 67 GAO-01-810 Chemical Risk Assessment

these general Superfund guidelines. Similarly, OPP, with input from ORD, 

has developed a series of science policy papers specifically on issues 

related to pesticide risk assessments, in response to provisions of the Food 

Quality Protection Act of 1996. 

Describing EPA’s risk assessment procedures with any certainty is a 

difficult task, given the sheer volume of EPA guidance documents, the 

continuing evolution of risk assessment practices, and the extent to which 

many of EPA’s revisions are currently draft in nature. For example, the 

official guidelines for cancer risk assessment are still the 1986 version, but 

the agency published a proposed revision of those guidelines in 1996, and 

continued to revise them in 1999, but the revised guidelines have not yet 

been made final by EPA.8

 Although the various revisions since 1986 do not 

represent official agency policy at this stage, the approaches that they 

describe are likely to provide a more accurate reflection of current 

practices and directions in EPA risk assessments. To some extent EPA is 

already applying these newer approaches, for example in the Office of 

Water’s revised methodology for deriving ambient water quality criteria for 

the protection of human health and the Office of Pesticide Programs’

Cancer Peer Review Committee. 

Agencywide Risk 

Assessment Procedures

The following sections summarize the basic elements of EPA’s agencywide 

procedures for conducting risk assessments. Because most of EPA’s 

guidelines focus on human health risks, this section also focuses primarily 

on health assessments in describing EPA’s general approach. EPA 

generally uses the NAS four-step process for those assessments. However, 

a separate short section on EPA’s approach to ecological risk assessment 

appears at the end of this agencywide summary. Also, while this appendix 

(and most of the source material from which it was derived) discusses 

procedures for assessing cancer and noncancer effects separately, this 

distinction is increasingly artificial. As EPA noted in its Strategy for 

Research on Environmental Risks to Children, the agency is less likely to 

consider cancer and noncancer endpoints in isolation as it develops and 

incorporates more advanced scientific methods to measure and model the 

biological events leading to adverse effects.9

 According to EPA, the science 

8

 A particular focus of changes in the 1999 version is additional attention to issues of human 

variability, especially risks to children versus adults.

9

 EPA/600/R-00-068 (August 2000).
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 68 GAO-01-810 Chemical Risk Assessment

of risk assessment is moving toward a harmonization of the methodology 

for cancer and noncancer assessments.

Hazard Identification Carcinogens

EPA’s approach to hazard identification changed significantly between the 

agency’s 1986 guidelines and its proposed revision. In its 1986 guidelines, 

EPA defined a hierarchical classification scheme for hazard identification 

of chemical agents (see table 3). In this scheme, analysis of whether an 

agent is a potential human carcinogen proceeds through distinct steps 

based on the type of human, animal, or “other” evidence available and its 

quality (whether such evidence is sufficient, limited, or inadequate), 

resulting in classification of the agent in one of six alphanumeric 

categories. 

Table 3: EPA’s 1986 Classification System for Characterization of Carcinogenicity

Source: Adapted from EPA’s 1986 Guidelines for Carcinogen Risk Assessment and other agency 

documents that describe the agency’s classification system.

Group Description Weight of evidence for carcinogenicity

A Human carcinogen Sufficient evidence from epidemiologic (human) studies

B1 Probable human carcinogen Limited evidence from epidemiologic studies

B2 Probable human carcinogen Sufficient evidence from animal studies and inadequate evidence or no data from 

epidemiologic studies 

C Possible human carcinogen Limited evidence in animals and absence of adequate human data

D Not classifiable Inadequate or no data

E Evidence of noncarcinogenicity for 

humans

No evidence in adequate studies in at least two species or in both epidemiologic 

and animal studies
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 69 GAO-01-810 Chemical Risk Assessment

In response to further developments in the understanding of 

carcinogenesis, and to address limitations of its 1986 scheme, EPA 

proposed a revised approach that melds the separate human-animal-other 

processes into a single comprehensive evaluation. In this approach, 

weighing the evidence and reaching conclusions about the carcinogenic 

potential of an agent would be accomplished in a single step after assessing 

all individual lines of evidence. Compared to the 1986 guidelines, the 

proposed revision also encourages fuller use of all biological information—

instead of relying primarily on tumor findings—and emphasizes analysis of 

the agent’s mode of action in leading to tumor development.10 

EPA’s proposed revision replaces the 1986 alphanumeric classifications 

with a “weight of evidence” narrative to provide more complete 

information not only on the likelihood of human carcinogenic effects but 

also the conditions under which such effects may be expressed. To provide 

some measure of consistency in the narratives, standard descriptors are to 

be utilized to express the conclusion regarding the weight of evidence for 

carcinogenic hazard potential. These descriptors have also been 

undergoing some changes, but, according to EPA’s July 1999 discussion 

draft, would include:

1. carcinogenic to humans,

2. likely to be carcinogenic to humans,

3. suggestive evidence of carcinogenicity but not sufficient to assess 

human carcinogenic potential,

4. data are inadequate for an assessment of human carcinogenic potential, 

and

5. not likely to be carcinogenic to humans.

The narrative might also reflect more than one conclusion for a given 

agent. For example, a narrative could say that an agent is likely to be 

carcinogenic by inhalation exposure but not likely to be carcinogenic by 

oral exposure.

Noncancer effects

10 “Mode of action” is defined as a series of key events and processes, starting with 

interaction of an agent with a cell and proceeding through operational and anatomical 

changes resulting in cancer formation.
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 70 GAO-01-810 Chemical Risk Assessment

EPA starts with a review and assessment of the toxicological database to 

identify the type and magnitude of possible adverse health effects 

associated with a chemical. Exposure to a given chemical might result in a 

variety of toxic effects, so EPA has produced separate guidelines for the 

assessment of mutagenicity, developmental toxicity, neurotoxicity, and 

reproductive toxicity.11 However, assessments for these noncancer health 

effects may also overlap. For example, developmental effects might be 

traced to exposures and factors also covered by reproductive toxicity 

assessments, and developmental exposures may result in genetic damage 

that would require evaluation of mutagenicity risks. The EPA guidelines 

for noncancer effects are not step-by-step manuals, and they do not 

prescribe a hazard identification classification scheme. Instead, they focus 

on providing general advice to risk assessors on different types of toxicity 

tests or data and on the appropriate toxicological interpretation of test 

results (e.g., which outcomes should be considered adverse effects).

In addition to considering the types and severity of potential adverse 

effects, hazard identification would also consider and describe the nature 

of exposures associated with these effects. A review of the full range of 

possibilities would consider:

• acute effects—generally referring to effects associated with exposure to 

one dose or multiple doses within a short time frame (less than 24 hours, 

for example);

• short-term effects—associated with multiple or continuous exposure 

occurring within a slightly longer time frame, usually over a 14-day to 28-

day time period;

• subchronic effects—associated with repeated exposure over a limited 

period of time, usually over 3 months; and

• chronic effects—associated with continuous or repeated exposure to a 

chemical over an extended period of time or a significant portion of the 

subject’s lifetime.

Procedurally, there is an important variation from the distinct four steps of 

the risk assessment paradigm. In its guidelines, EPA notes that its normal 

practice for assessments of noncancer health effects is to do hazard 

11 Neurotoxicity focuses on adverse changes in the structure or function of the central or 

peripheral nervous system following exposure to a chemical, physical, or biological agent. 

Reproductive toxicity focuses on toxic effects on the male and female reproductive 

systems, including outcomes of pregnancy and lactation. Mutagenicity and developmental 

toxicity were described in a previous footnote.
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 71 GAO-01-810 Chemical Risk Assessment

identification in conjunction with the analysis of dose-response 

relationships. This is because the determination of a hazard is often 

dependent on whether a dose-response relationship is present. According 

to EPA, this approach has the advantages of (1) reflecting hazards in the 

context of dose, route, duration, and timing of exposure; and (2) avoiding 

the potential to label chemicals as toxicants on a purely qualitative basis.

Dose-Response Assessment Carcinogens

Risk assessors conducting dose-response assessments must make basic 

choices regarding which data to base analyses upon and which models and 

assumptions to use for extrapolation of study results to the potential 

human exposures of regulatory interest. Data choices focus on the 

availability and quality of human or animal studies. Three of the more 

important extrapolation tasks are estimation of low-dose relationships (i.e., 

those that fall below the range of observation in the studies supporting the 

agency’s analysis), calculation of toxicologically equivalent doses when 

dose-response data from animal studies are applied to human exposures, 

and extrapolating results from data on one route of exposure to another 

route.12 

• Data choices

The two main types of studies that provide data useful in a quantitative 

dose-response assessment are (1) epidemiological studies of human 

populations and (2) toxicological laboratory studies using animals or, 

sometimes, human cells. Epidemiological studies examine the occurrence 

of adverse health effects in human populations and attempt to identify the 

causes. At a minimum, such studies can establish a potential link between 

exposures to chemical agents and the occurrence of particular adverse 

effects by comparing differences in exposed and nonexposed populations. 

If there is adequate information on the exposure levels associated with 

adverse effects, these studies can also provide the basis for a doseresponse assessment. Because such data obviate the need to extrapolate 

from animals to humans, EPA (like other agencies) prefers to use data from 

epidemiological studies, if available.

12Risk assessors might also need to make other types of extrapolations (e.g., when 

estimating effects for less than a full lifetime).
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 72 GAO-01-810 Chemical Risk Assessment

Often, however, the available data for dose-response assessment will come 

from animal studies. A common assumption underlying risk assessments 

by EPA (and other agencies) is that an agent that produces adverse effects 

in animals will pose a potential hazard to humans. EPA’s guidelines 

emphasize that case-specific judgments are necessary in considering the 

relevance of particular studies and their data. However, in the absence of 

definitive information to the contrary, EPA’s guidelines establish some 

standard default choices to assist risk assessors in selecting which studies 

and data to use. (See the section on assumptions in this appendix for more 

information on such default choices and assumptions.) 

• Extrapolation to low doses

Quantifying risks engenders another set of issues and choices. In 

particular, some type of low-dose extrapolation is usually necessary, given 

that the doses observed in studies tend to be higher than the levels of 

exposure of regulatory concern. There are limits to the ability of both 

epidemiological and toxicological studies to detect changes in the 

likelihood of health effects with acceptable statistical precision, especially 

at the low-dose exposures typical of most environmental exposures and 

given practical limits to the sizes of research studies.

A number of different models might be used for extrapolation, all giving 

plausible results. In its proposed revision of the carcinogen risk 

assessment guidelines, EPA identifies use of a biological extrapolation 

model as the preferred approach for quantifying risk. Such models 

integrate events in the carcinogenic process throughout the dose-response 

range from high to low doses and include physiologically based 

pharmacokinetic (PBPK) and biologically based dose-response models. 

PBPK models address the exposure-dose relationship in an organism taken 

as a whole, estimating the dose to a target tissue or organ by taking into 

account rates of absorption into the body, metabolism, distribution among 

target organs and tissues, storage, and elimination of an agent. Biologically 

based dose-response models describe specific biological processes at the 

cellular and molecular levels that link target-organ dose to the adverse 

event. These models are useful in extrapolation between animals and 

humans and between children and adults because they allow consideration 

of species- and age-specific data on physiological factors affecting dose 

levels and responses. However, biological models require substantial 

quantitative data and adequate understanding of the carcinogenic process 

for a specific agent. EPA cautions that the necessary data for using such 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 73 GAO-01-810 Chemical Risk Assessment

models will not be available for most chemicals. Therefore, the agency’s 

guidelines describe alternative methods.

Dose-response assessment is a two-step process when a biologically based 

model is not used. The first step is the assessment of observed data to 

derive a point of departure, and the second step is extrapolation from that 

point of departure to lower (unobserved) exposures. According to EPA 

guidelines, the agency’s standard point of departure for animal studies is 

the effective dose (ED) corresponding to the lower 95-percent confidence 

limit on a dose associated with 10-percent extra risk (LED10) compared to 

the control group.13 EPA may use a lower point of departure for data from 

human studies of a large population or from animal studies when such data 

are available. For the extrapolation step, EPA’s proposed guidelines 

provide three default approaches which assume, respectively, that the 

dose-response relationship is linear, nonlinear, or both. The choice of 

which default approach to apply is to be based on the available information 

on the mode(s) of action of the chemical agent.

In the absence of sufficient mode of action information, or if the available 

mode of action information indicates that the dose-response curve at low 

doses is expected to be linear, the default is to use a linear approach for the 

extrapolation step. The assumption of linearity is generally considered a 

conservative, public-health protective default, intended to avoid 

underestimating risks at low doses. It is rooted in EPA’s traditional 

assumption for suspected carcinogens that no threshold exists regarding 

adverse effects (i.e., any exposure to carcinogenic substances, no matter 

how small, poses some risk of developing cancer). A linear, no-threshold 

model generally assumes that adverse health effects are proportional to 

exposure for any dose above zero. The linear approach is to draw a 

straight line between the point of departure from observed data—typically 

the LED10—and the origin (zero incremental dose, zero incremental 

response). (See fig. 3 below.) According to EPA’s guidance, this linear 

default approach is thought to generally provide an upper-bound 

calculation of potential risk at low doses. The agency also pointed out that 

it gives numerical results about the same as a linearized multistage 

approach, which is the default approach under the 1986 cancer guidelines.

13 According to EPA, the LED10 is chosen to account protectively for experimental variability 

and is an appropriate representative of the lower end of the observed range, because the 

limit of detection in studies of tumor effects is about 10 percent. 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 74 GAO-01-810 Chemical Risk Assessment

Figure 3: Extrapolation for Carcinogens

Source: EPA Proposed Guidelines for Carcinogen Risk Assessment.

The default changes to a “margin of exposure” analysis when (1) adequate 

data on mode of action show that linearity is not plausible, and (2) the data 

provide sufficient evidence to support a nonlinear mode of action for the 

general population and any sub-populations of concern. Rather than 

estimating the probability of effects at low doses, a margin of exposure 

analysis compares the point of departure from study data with the dose 

associated with the environmental exposure(s) of interest by computing 

the ratio between the two. (See fig. 3 for a graphical representation of 

these two points.) If the available evidence indicates that the doseresponse may be adequately described by both a linear and a nonlinear 

approach, EPA’s default is to present both the linear and the margin of 

exposure analysis.

Extrapolation range Observed range

(Confidence limit on dose)

ED10

Response

10%

LED10

Human

exposure

of interest

x

x

x

(Central estimate)

MOE Dose

Projected linear

0%

LED10 = Lower 95 percent confidence limit on a dose associated with a 10 percent extra risk

ED10 = Dose associated with a 10 percent extra risk

MOE = Margin of exposure

= Central estimate of dose-response curve

= Confidence limit

= Linear low-dose extrapolation
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 75 GAO-01-810 Chemical Risk Assessment

• Extrapolation from animal to human-equivalent doses

When dose-response relationships are being extrapolated from the 

observed results of animal studies, it is also necessary to estimate what 

doses are of equivalent risk in the experimental animals (usually mice or 

rats) and humans. The objective of this interspecies “scaling” is to define 

dose units that are presumed to lead to equivalent risk across species. Not 

only are rodents much smaller in size than humans, but they have shorter 

life spans and quicker metabolisms, all of which affect the equivalent dose. 

For carcinogens, EPA’s historical default had been to assume that end-oflife cancer risks will be equivalent across species when lifetime dosing is 

proportional to each species’ body surface area. In practice, this “surface 

area scaling” was calculated by using daily milligrams scaled by the 2/3-

power of the species’ body weight. EPA’s draft revision of the carcinogen 

guidelines presents a default for oral dose of scaling daily applied doses in 

proportion to body weight raised to the 3/4- power. This would be 

consistent with the 1992 recommendation from an interagency group.14 

Scaling by this method generally results in human risk estimates that are 

slightly lower than those obtained from surface area scaling.

For cross-species scaling of inhalation exposures, EPA uses a different 

approach—its reference concentration (RfC) methodology—to determine 

what is toxicologically equivalent. In the RfC approach, the agency 

estimates the respiratory deposition of particles and gases and the internal 

doses of gases with different absorption characteristics. EPA uses this 

approach because it is the concentration needed to produce an equivalent 

rate of loading the target tissue with deposited or absorbed chemical agent 

that is important in inhalation exposures, not simply the dose in the air.

14 FDA and OSHA traditionally used an alternative assumption that risks are equivalent 

when dosing is proportional to each species’ body weight but are now also using or 

considering (body weight)3/4.
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 76 GAO-01-810 Chemical Risk Assessment

• Extrapolation to different routes of exposure

Exposure to a chemical agent may occur through inhalation, oral ingestion, 

or dermal contact. However, the data being used for a risk assessment may 

only reflect one of these routes of exposure, and that route may be 

different than the route of concern to agency regulators in a particular 

case. For example, available animal study data might indicate that 

ingestion of a chemical substance is associated with cancer, but risk 

assessors may need to consider the relevance of this ingestion data to the 

prediction of risks associated with inhalation exposures. In general, it is 

EPA’s position that adverse effects manifested through one route of 

exposure are relevant to consideration of any other route of exposure. 

However, EPA’s guidelines also caution that such route-to-route 

extrapolation should be consistent with existing biological information.15

Noncancer effects

In contrast to its assessments of cancer risks, EPA’s traditional view of 

noncancer toxic effects has been that a threshold exists. In other words, 

the agency typically assumes that noncancer adverse effects occur only 

after a threshold level of exposure to an agent has been exceeded.16 For 

noncancer effects, the primary objective of the agency’s assessment is to 

derive an RfD or, in the case of inhalation exposures, an RfC representing a 

concentration of the agent in the air rather than a dose. This RfD or RfC is 

an estimate of a daily exposure to an agent by the human population 

(including sensitive sub-groups) that is expected to be without an 

appreciable risk of deleterious effects during a lifetime. For most of its 

history, EPA has relied on a no observed adverse effect level (NOAEL) 

approach to estimate the RfD. However, the agency may also use other 

approaches, such as the benchmark dose approach, depending on the 

quality and type of data available. The NOAEL and benchmark dose 

approaches are described in more detail below.

15 For example, a chemical that acts as a carcinogen because of the way the body 

metabolizes it via one route—such as ingestion into the stomach transforming the chemical 

into a toxin—may not be metabolized in the same way by another route. Carcinogenic 

effects, therefore, would not be expected via another route of exposure that does not 

produce this same metabolite.

16 There are, however, exceptions to this general rule, such as reproductive toxicants that 

may act through genetic mutation mechanisms. In such cases, EPA will use the nothreshold approach described for suspected carcinogens.
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 77 GAO-01-810 Chemical Risk Assessment

Similar to other agencies, EPA’s traditional procedure for addressing 

noncancer effects has been to define a NOAEL from experimental data and 

then apply uncertainty factors to estimate an RfD or RfC. In this approach, 

toxicologists first seek to identify the top of the range of dose levels 

without any observed adverse effect in animals.17 Then, to estimate a dose 

to humans that will be similarly without effect, this dose level is divided by 

a set of uncertainty factors, typically factors of 10.18 These uncertainty 

factors are used to account for the possibility of greater sensitivity among 

humans than in experimental animals, of greater sensitivity in some 

humans compared to average humans, and for other concerns. One such 

concern is if there was no dose in a study at which harmful effects were not 

detected. In such cases, extrapolation is instead based on the lowest 

observed adverse effect level (LOAEL), but an additional uncertainty factor 

would then be incorporated in the agency’s estimated dose. The choice and 

size of factors (e.g., 10 or 3) can vary from case to case, and EPA’s 

guidelines note that professional scientific judgment must be used in 

assigning uncertainty and modifying factors. EPA typically uses two or 

three factors (a division of the NOAEL dose by 100- to 1000-fold), and, 

under current policy, generally will use a maximum uncertainty factor of no 

greater than 3,000.19 However, EPA may also reduce the standard 

uncertainty factors if it has more informative pharmacokinetic data about 

variability among humans or across species. An additional “modifying”

factor may also be used when the areas of scientific uncertainty addressed 

with uncertainty factors do not represent all of the uncertainties in the 

estimation of a reference dose or concentration.

EPA may also use the benchmark dose approach to identify a dose without 

appreciable effect from an experimental study. Unlike the NOAEL 

approach, the benchmark dose approach uses the entire set of available 

data on doses and responses; it is not limited to only considering the 

specific dose levels tested in the study. In this benchmark dose approach, 

17 Sometimes, a no observed effect level (NOEL) is used instead of a NOAEL.

18 These are often referred to as “safety factors” by other agencies and in general risk 

assessment literature. EPA, however, uses the term uncertainty factor instead of safety 

factor because of concerns that the latter implies an absolutely safe level, an assurance that 

the agency does not believe it can provide.

19 It is EPA’s opinion that toxicity databases that are weaker and would result in uncertainty 

factors in excess of 3,000 are too uncertain as a basis for quantification. In such cases, EPA 

no longer estimates an RfD. Before this policy was in place, factors of 10,000 were applied 

for a few chemicals.
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 78 GAO-01-810 Chemical Risk Assessment

researchers fit a dose-response curve using all of the data in the observed 

experimental range. EPA would typically use the modeled LED10 dose as a 

point of departure to derive an RfD, and the agency would still apply 

uncertainty factors to this dose, as in the NOAEL approach. (See fig. 4.)

Figure 4: Derivation of a Reference Dose Using the Benchmark Dose Approach

Source: EPA Methodology for Deriving Ambient Water Quality Criteria for the Protection of Human 

Health (2000); Technical Support Document Volume 1: Risk Assessment.

100

90

80

70

60

50

40

30

20

10

0

Increasing response

0 50 100 150 200 250 300 350

UFs

RfD

LED10 ED10

LED10 = Lower 95 percent confidence limit on a dose associated 

 with a 10 percent extra risk

ED10 = Dose associated with a 10 percent extra risk

RfD = Reference dose

UFs = Uncertainty factors

= Central estimate of dose-response curve

= Confidence limit

Dose
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 79 GAO-01-810 Chemical Risk Assessment

Exposure Assessment EPA’s program offices usually perform the exposure assessment step, given 

the different exposure scenarios of interest for the separate regulatory 

programs.20 However, EPA has published agencywide guidelines for 

exposure assessment that describe general principles and practices for 

conducting such assessments. The focus of EPA’s guidelines is on human 

exposures to chemical substances, but the agency noted that much of the 

guidance also applies to wildlife exposure to chemicals or human exposure 

to biological, physical (e.g., noise), or radiological agents.21 EPA points out, 

though, that assessments in these other areas must consider additional 

factors that are beyond the scope of the exposure assessment guidelines.

EPA’s guidelines establish a broad framework for agency exposure 

assessments by describing the general concepts of exposure assessment, 

standardizing the terminology (such as defining concepts of exposure, 

intake, uptake, and dose), and providing guidance on the planning and 

implementation of an exposure assessment. The guidelines are not, 

however, intended to serve as a detailed instructional guide. EPA’s 

guidance prescribes no standard format for presenting exposure 

assessment results, but recommends that all exposure assessments, at a 

minimum, contain a narrative exposure characterization section that

• provides a statement of purpose, scope, level of detail, and approach 

used in the assessment, including key assumptions;

• presents the estimates of exposure and dose by pathway and route for 

individuals, population segments, and populations in a manner 

appropriate for the intended risk characterization;

• provides an evaluation of the overall quality of the assessment and the 

degree of confidence the authors have in the estimates of exposure and 

dose and the conclusions drawn; 22

• interprets the data and results; and

20 As mentioned earlier in this appendix, sometimes ORD may do the entire risk assessment, 

including the exposure assessment step.

21 The guidelines also discuss the implications for exposure assessment if the assessment is 

to be used for purposes other than risk assessment (e.g., to determine whether exposure 

occurs, to monitor status and trends, or to establish exposure-incidence in epidemiologic 

studies).

22 The guidelines note that it is common for the single largest source of uncertainty in an 

exposure assessment to be the estimate of the duration of an individual’s contact with a 

chemical at a given concentration. The concentration of the chemical in the media (e.g., air, 

soil, or water) often is known with more certainty than the activities of the exposed 

individual(s).
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 80 GAO-01-810 Chemical Risk Assessment

• communicates the results of the exposure assessment to the risk 

assessor, who can then use this information with the results from other 

risk assessment elements to develop the overall risk characterization.

The guidelines encourage agency staff to use multiple “descriptors” of both 

individual and population risks, rather than a single descriptor or risk 

value. The exposure guidelines also emphasize the use of more realistic 

estimates of high-end exposures than had been the case in some previous 

practices. In the past, EPA sometimes relied on exposure estimates 

derived from a hypothetical “maximally exposed individual” who might 

spend, for example, a 70-year lifetime drinking only groundwater with the 

highest concentrations of contaminants detected. According to the 1997 

report of the Presidential/Congressional Commission, this approach was 

often based on such unrealistic assumptions that it impaired the scientific 

credibility of risk assessments. Now, however, EPA has adopted the use of 

distributions of individual exposures as the preferred practice. EPA’s 

guidance indicates that risk assessments should include both central 

estimates of exposure (based on either the mean or median exposure) and 

estimates of the exposures that are expected to occur in small, but 

definable, high-end segments of the population. EPA states that a high-end 

exposure estimate is to be a plausible estimate of the individual exposure 

for those persons at the upper end of an exposure distribution. The 

agency’s intent is to convey an estimate of exposure in the upper range of 

the distribution, but to avoid estimates that are beyond the true 

distribution.23

EPA has identified several new directions in its approach to exposure 

assessment. First is an increased emphasis on total (aggregate) exposure 

via all pathways. EPA policy directs all regulatory programs to consider in 

their risk assessments exposures to an agent from all sources, direct and 

indirect, and not just from the source that is subject to regulation by the 

office doing the analysis. Another area of growing attention is the 

consideration of cumulative risks, when individuals are exposed to many 

chemicals at the same time. The agency is also increasing its use of 

probabilistic modeling methods, such as Monte Carlo analysis, to analyze 

variability and uncertainty in risk assessments and provide better estimates 

of the range of exposure, dose, and risk in individuals in the population. 

23 The guidelines state that, conceptually, the high end of the distribution means above the 

90th percentile of the population distribution, but not higher than the individual in the 

population who has the highest exposure.
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 81 GAO-01-810 Chemical Risk Assessment

EPA policy directs regulatory programs to pay special attention to the risks 

of children and infants.

EPA has produced some reference documents for exposure assessments, 

such as the Exposure Factors Handbook.

24 This handbook is intended to 

provide parameter values for use across the agency and to encourage use 

of reasonable exposure estimates by providing appropriate data sources 

and suggested methods. The handbook provides a summary of available 

statistical data on various factors used to assess human exposure to toxic 

chemicals. These factors include: drinking water consumption; soil 

ingestion; inhalation rates; dermal factors including skin area and soil 

adherence factors; consumption/intake of fruits and vegetables, fish, 

meats, dairy products, homegrown foods, and breast milk; human activity 

patterns, such as time spent performing household tasks; consumer 

product use; and residential characteristics. EPA provides recommended 

values for the general population and also for various segments of the 

population who may have characteristics different from the general 

population (e.g., by age, gender, race, or geographic location). EPA 

guidance cautions, though, that these general default values should not be 

used in the place of known, valid data that are more relevant to the 

assessment being done. The default values used in EPA risk assessments, 

however, sometimes vary slightly from the recommended values appearing 

in the handbook. For example, while the handbook’s mean recommended 

value for adult body weight is 71.8 kilograms (kg), the handbook also noted 

that a value of 70 kg has been commonly assumed in EPA’s risk 

assessments. Similarly, the recommended value to reflect average life 

expectancy of the general population is 75 years, but 70 years also has been 

commonly assumed in EPA risk assessments. Officials from EPA program 

offices pointed out that they may use different exposure factors in their 

risk assessments because they sometimes develop exposure assessment 

methods specific to their programs using different data sources or 

population characteristics than those used by ORD for the Exposure 

Factors Handbook.

Ecological Risk Assessment Ecological risk assessment is different from human health risk assessment 

in that it may examine entire populations of species and measure effects on 

partial or whole ecosystems. Often, the focus is on not just a single 

ecological entity, but on the potential adverse effects on multiple species 

24 The agency also has a Wildlife Exposure Factors Handbook for ecological risk 

assessments, and a Children’s Exposure Factors Handbook is also in development.
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 82 GAO-01-810 Chemical Risk Assessment

and their interactions (for example, on the food chain). While human 

health risk assessment is primarily concerned with an agent’s toxicity to 

humans, ecological risk assessment might consider a range of adverse 

effects on natural resources (such as crops, livestock, commercial 

fisheries, and forests), wildlife (including plants), aesthetic values, 

materials or properties, and recreational opportunities. For example, a 

chemical agent could be considered a risk to wildlife if exposure to it 

caused death, disease, behavioral abnormalities, mutations, or deformities 

in the members of a species or their offspring. It could be considered a risk 

to aesthetic values if it affected the color, taste, or odor of a water source.

By EPA’s definition, ecological risk assessment is a process that evaluates 

the likelihood that adverse ecological effects may occur or are occurring as 

a result of exposure to one or more “stressors.” In other words, ecological 

risk assessments may be prospective or retrospective, and, in many cases, 

both approaches are included in a single risk assessment. Chemicals are 

only one of the possible ecological stressors that EPA might consider, along 

with physical and biological ones.25 EPA’s guidance focuses on stressors 

and adverse ecological effects generated or influenced by human activity, 

which could be addressed by the agency’s risk management decisions.

In comparison to human health risk assessment procedures, the 

approaches for ecological risk assessment are more recent and less well 

developed. However, as these methods have changed to incorporate and 

better characterize dynamic, interconnected ecological relationships, EPA 

has updated its guidance documents on the subject, with input from 

multiple interested internal and external parties. According to EPA, the 

solicitation of input from an array of sources is based, in part, on the need 

to establish a framework for characterizing risks based on numerous 

stressors, interconnected pathways of exposure, and multiple endpoints 

(adverse effects).

25 For example, the alteration of a wildlife habitat would be a physical stressor and the 

introduction of a nonnative invasive species would be a biological stressor.
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 83 GAO-01-810 Chemical Risk Assessment

The most recent version of EPA’s framework appears in Guidelines for 

Ecological Risk Assessment, published in 1998.26 EPA’s guidelines describe 

an iterative three-phase process consisting of problem formulation, 

analysis, and risk characterization. These guidelines incorporate many of 

the concepts and approaches called for in human health risk assessments. 

However, particularly in the addition of a problem formulation phase, the 

ecological risk assessment framework deviates from the standard four-step 

process used for human health risk assessments. EPA pointed out that, 

unlike human health assessments where the species of concern and the 

endpoints (e.g., cancer) have been predetermined, ecological risk 

assessments need a phase that focuses on the selection of ecological 

entities and endpoints that will be the subject of the assessment. Table 4 

summarizes the activities and expected outcomes for each of the three 

phases of an ecological risk assessment. Prior to these phases, according 

to EPA, a planning stage occurs during which risk assessors, risk managers, 

and other interested parties are to have a dialogue and scope the problem.

Table 4: Summary of EPA’s Ecological Risk Assessment Process

Source: EPA Guidelines for Ecological Risk Assessment.

Among the things considered during problem formulation is the selection 

of assessment endpoints, which are “explicit expressions of the actual 

environmental value that is to be protected.” This is unlike human health 

26 EPA has published other, more detailed guidance documents addressing specific 

ecological risk assessment topics relevant to its program offices. For example, Ecological 

Risk Assessment Guidance for Superfund: Process for Designing and Conducting 

Ecological Risk Assessments from 1997 is specific to EPA’s Superfund Program requirement 

for an ecological risk assessment.

Phase Actions Products

Problem formulation • Articulate purpose for assessment

• Define problem

• Determine plan for analyzing and characterizing risk

• Integrate available information on sources, stressors, effects, and 

ecosystem and receptor characteristics

• Assessment endpoints

• Conceptual models

• Analysis plan

Analysis • Characterize exposure

• Characterize ecological effects

• Exposure profile

• Stressor-response profile

Risk characterization • Estimate risk

• Summarize assumptions, scientific uncertainties, and strengths and 

limitations of the analyses

• Risk description
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 84 GAO-01-810 Chemical Risk Assessment

assessments, where the species of concern and the endpoints have been 

predetermined. The selection of endpoints at EPA has traditionally been 

done internally by program offices, but more recently, affected parties or 

communities are assisting in the selection of endpoints with their selection 

based on ecological relevance, susceptibility, and relevance to management 

goals. Furthermore, conceptual models are developed during the problem 

formulation phase. Such models contain risk hypotheses in the form of 

written descriptions and visual representations, outlining predicted 

relationships between ecological entities and the stressors to which they 

may be exposed. According to EPA the hypotheses are in effect 

assumptions, being based on theory and logic, empirical data, 

mathematical models, probability models, and professional judgment.

Subsequently, during the analysis phase data are selected that will be used 

on the basis of their utility for evaluating risk hypotheses. The major items 

considered during this phase are the sources and distribution of stressors 

in the environment, the extent of contact and stressor-response 

relationships, the evidence for causality, and the relationship between what 

was measured and the assessment endpoint(s). Field studies involving 

statistical techniques (i.e., correlation, clustering, or factor analysis), 

surveys, the formation of indices, and the use of models are approaches to 

evaluating the determined risk hypotheses. (EPA’s guidance on the risk 

characterization phase of an ecological risk assessment is discussed in the 

final section of this appendix.)

Program-Specific Risk 

Assessment Procedures

EPA’s various program offices generally follow the agencywide risk 

assessment procedures and guidelines described above. The major 

exception to this is the Chemical Emergency Preparedness and Prevention 

Office, which does not follow the NAS four-step process for its risk 

assessment procedures because of its focus on risks associated with 

accidental chemical releases. Overall, there is great diversity in the context 

for risk assessment activities across EPA’s program offices. Each program 

has different statutory mandates and risk assessment tasks associated with 

its specific regulatory authority, and these contribute to variations in the 

way the offices conduct risk assessments. In particular, there are 

differences in the exposure assessment step across, and sometimes within, 

EPA’s program offices. This is not surprising, given that EPA’s regulatory 

authorities regarding chemical agents primarily vary according to types and 

sources of exposure. Although there are overlaps in these various 

exposures to chemicals, EPA’s program offices generally assess and 

regulate different aspects of the risks associated with exposures to humans 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 85 GAO-01-810 Chemical Risk Assessment

and/or the environment. There are also some variations in the conduct of 

hazard identification and dose-response analysis. The following sections 

summarize the risk assessment activities and procedures of those EPA 

program offices that are most likely to conduct assessments involving 

chemical risks. The descriptions highlight some of the major variations 

and similarities across the program offices. 

Office of Pesticide Programs OPP is part of EPA’s Office of Prevention, Pesticides and Toxic Substances 

(OPPTS). The primary risk assessment-related activities of OPP are the 

registration of pesticides and the setting of tolerances for pesticide 

residues.27 Registration involves the licensing of pesticides for sale and use 

in agriculture and extermination. No chemical may be sold in the United 

States as a pesticide without such registration, which establishes the 

conditions of legal use. All uses within the scope of the registration 

conditions and limits are permissible, although actual practice may vary. 

Pesticide tolerances are the concentrations (maximum pesticide residue 

levels) permitted to remain in or on food, as it is available to the consumer. 

Registrations and tolerances are obtained through petitions to OPP. The 

petitioner has the primary responsibility to provide the data needed to 

support registration and tolerances, including information on the 

toxicological effects of the pesticide.

There are three major risk statutes affecting EPA’s actions regarding 

pesticides. Registration is carried out under the Federal Insecticide, 

Fungicide, and Rodenticide Act (FIFRA). Tolerances are established under 

the Federal Food, Drug, and Cosmetic Act (FFDCA).28 In 1996, Congress 

amended both FIFRA and FFDCA through the FQPA, which mandated 

some key changes in risk assessment of pesticides.

Major features and characteristics of chemical risk assessment by OPP are 

summarized below.

• OPP conducts all steps of risk assessments. Because OPP generally 

follows the NAS four-step process for human health risk assessment and 

27 The term “pesticide” includes many kinds of ingredients used in products, such as 

insecticides, fungicides, rodenticides, insect repellants, weed killers, antimicrobials, and 

swimming pool chemicals, which are designed to prevent, destroy, repel, or reduce pests of 

any sort.

28 While EPA administers the setting of pesticide tolerances, FDA has authority over 

enforcement of the tolerances.
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 86 GAO-01-810 Chemical Risk Assessment

the EPA-wide risk assessment guidelines, most of its procedures mirror 

those used elsewhere in the agency.

• OPP officials noted that, over the last three decades, their office has 

developed a rigorous process to support the development of chemical 

risk assessments. This process includes regulations to establish 

baseline data requirements and published guidelines for conducting 

required studies. OPP officials emphasized the transparency of the 

process used to develop EPA’s risk assessment procedures and the 

transparency of the procedures EPA uses to make decisions on the risk 

of individual pesticides. As an example, they noted that their program 

has consulted with outside experts and asked for public comment on its 

guidelines for reviewing studies, science policies for assessing the 

significance of study data, and standard operating procedures for 

implementing these policies in the development of a hazard 

identification or exposure assessment for a chemical. They also pointed 

out that OPP adopted a public participation process for reregistration 

and tolerance reassessment decisions on registered pesticides and that 

they publish for public comment proposed tolerances for proposed new 

uses of pesticides. In some circumstances, OPP consults with outside 

experts concerning a risk assessment of an individual pesticide.

• Pesticide registration decisions are based primarily on OPP’s evaluation 

of the test data provided by petitioners (applicants). EPA has 

established a number of requirements, such as the Good Laboratory 

Practice Standards, to ensure the quality and integrity of pesticide data. 

OPPTS has also developed harmonized test guidelines for use in the 

testing of pesticides and toxic substances and the development of test 

data that must be submitted to EPA for review under federal 

regulations.29 Depending on the type of pesticide, OPP can require more 

than 100 different tests to determine whether a pesticide has the 

potential to cause adverse effects to humans, wildlife, fish, and plants.

29 OPPTS developed these guidelines through a process of harmonization that blended the 

testing guidance and requirements that existed in OPP, OPPT, and guidelines published by 

the Organization for Economic Cooperation and Development. The purpose of harmonizing 

these guidelines into a single set of OPPTS guidelines was to minimize variations among the 

testing procedures that must be performed to meet EPA data requirements under FIFRA 

(for OPP) and TSCA (for OPPT). The pesticide data requirements are set out in 40 CFR 158.
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 87 GAO-01-810 Chemical Risk Assessment

• The FQPA established a single, health-based standard—“reasonable 

certainty of no harm”—for pesticide residues in all foods.30 All existing 

tolerances that were in effect when the FQPA was passed are to be 

reevaluated by 2006 to ensure that they meet the new safety standard. 

The law requires EPA to place the highest priority for tolerance 

reassessment on pesticides that appear to pose the greatest risk. To 

make the finding of “reasonable certainty of no harm” OPP considers:

1. the toxicity of the pesticide and its break-down products;

2. how much of the pesticide is applied and how often; and

3. how much of the pesticide remains in or on food by the time it is 

marketed and prepared (the residue).

• Among other key changes affecting OPP’s risk assessments when setting 

tolerances, the FQPA requires the agency to:

1. Explicitly address risks to infants and children and to publish a specific 

safety finding before a tolerance can be established. It also requires an 

additional tenfold uncertainty factor (unless reliable data show that a 

different factor will be safe) to account for the possibly greater 

sensitivity and exposure of children to pesticides.

2. Consider aggregate exposure from a pesticide, including all anticipated 

dietary and all other exposures for which there is reliable information. 

These include exposures through food, drinking water, and nondietary 

exposures encountered through sources in the home, recreational 

areas, and schools.31

3. Consider cumulative exposures to pesticides with a common 

mechanism of toxicity, which previously had been considered 

separately.32

30 This eliminated problems caused by prior differences in the standards that applied to raw 

versus processed foods.

31 Occupational exposures are regulated separately.

32 See Children and Pesticides: New Approach to Considering Risk Is Partly in Place

(GAO/HEHS-00-175, Sept. 11, 2000) for more detailed information on EPA’s progress in 

implementing the FQPA provisions.
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 88 GAO-01-810 Chemical Risk Assessment

• Title III of the FQPA also requires certain data collection activities of the 

Secretary of Agriculture, in consultation or cooperation with the 

Administrator of EPA and the Secretary of Health and Human Services, 

regarding food consumption patterns, pesticide residue levels, and 

pesticide use that, according to EPA, affect its risk assessments when 

setting tolerances.

• Also as a result of the FQPA, OPP uses a population adjusted dose 

(PAD), which involves dividing the acute or chronic reference dose by 

the FQPA uncertainty factor. According to OPP officials, this allowed 

OPP to be consistent with the rest of the agency regarding setting RfDs, 

but still use the FQPA factor for regulating pesticides.

• OPP is concerned with both cancer and noncancer toxicity. However, 

for noncancer effects, OPP has paid special attention to neurotoxicity 

(because many pesticides work through this mechanism) and, more 

recently, to endocrine disrupting effects (those affecting the body’s 

hormone system).33

• OPP officials noted that, while their agency has made important use of 

“real life” monitoring or incident data, it primarily relies on studies 

conducted in laboratory animals and on laboratory or limited field 

studies. They stated that, in their experience, “real life” data have 

profound limitations and that such data are inconsistent, expensive, 

inconclusive, and are not available for premarket decision making. 

They said that, most importantly, by the time there are observable health 

or environmental effects, it is too late to prevent the harm that could 

have been predicted from judicious use of animal or environmental fate 

studies conducted in the laboratory. 

• During the exposure assessment step, OPP is concerned with a variety 

of routes, sources, and types of exposure. The three routes by which 

people can be exposed to pesticides are inhalation, dermal (absorbing 

33 Because of the potentially serious consequences of human exposure to endocrine 

disrupting chemicals, Congress included specific provisions on this topic in both the FQPA 

and the 1996 amendments to the Safe Drinking Water Act. In response to the FQPA 

language, EPA developed its Endocrine Disruptor Screening Program, which focuses on 

providing methods and procedures to detect and characterize endocrine activity of 

pesticides, commercial chemicals, and environmental contaminants. EPA uses a tiered 

approach for these risk assessments, sorting chemicals into four categories on the basis of 

the existing scientific data.
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 89 GAO-01-810 Chemical Risk Assessment

pesticides through the skin), and oral (getting pesticides in the mouth or 

digestive tract). Depending on the situation, a pesticide could enter the 

body by any one or all of these routes. Typical sources of pesticide 

exposure include food, home and personal use of pesticides, drinking 

water, and work-related exposure to pesticides (in particular, to 

pesticide applicators or vegetable and fruit pickers). In its approach to 

exposure assessment, OPP distinguishes between residential and 

occupational types of exposures. OPP officials noted that their 

program is further developing procedures to conduct drinking water 

exposure assessments and residential exposure assessments and that 

they have new procedures for ecological risk assessments.

• OPP calculates estimates of acute (i.e., short-term) pesticide exposure 

slightly differently from those for chronic (i.e., longer-term) exposures. 

This is because an acute assessment estimates how much of a pesticide 

residue might be consumed in a single day, while a chronic assessment 

estimates how much might be consumed on a daily basis over the 

course of a lifetime. In an important difference, acute assessments are 

based on high-end individual exposure assumptions, while chronic 

assessments use average exposure assumptions. 

• In assessing both acute and chronic risks, OPP uses a tiered approach, 

starting with an initial screening tier and proceeding through 

progressively more elaborate risk assessments, if needed. The 

analytical tiers proceed from more conservative to less conservative 

assumptions. For the first-tier risk assessment, OPP uses “worst-case”

assumptions (e.g., that pesticide residues are at tolerance levels and that 

100 percent of the food crop is treated with the pesticide) that give only 

an upper-bound estimate of exposure. For more refined analyses, OPP 

officials noted that they have new procedures for conducting 

probabilistic dietary exposure assessments. Generally, the level of 

resources and the data needed to refine exposure estimates increase 

with each tier. Typically, if risks from pesticide residues are not of 

concern using lower-tier exposure estimates, OPP does not make 

further refinements through additional tiers. However, with the 

aggregate and cumulative exposure assessments now required by the 

FQPA, EPA notes that it is likely that higher-tier exposure estimates will 

be needed.

• The agency has developed procedures for modeling the environmental 

fate of pesticides. OPP officials said that these models use real data on 

the physical and chemical properties of the pesticide, information on the 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 90 GAO-01-810 Chemical Risk Assessment

proposed or actual uses of the pesticide, and real data on the movement 

of pesticides or other materials through soil, air, water, skin, textiles, or 

other media to predict potential exposures to a pesticide. These models 

are guided by scientific judgments that are based upon data and 

scientists’ experience in drawing inferences from these data.

Office of Pollution Prevention 

and Toxics

OPPT (formerly the Office of Toxic Substances) is also part of OPPTS. 

OPPT was established to implement the Toxic Substances Control Act 

(TSCA), which authorizes EPA to screen existing and new chemicals used 

in manufacturing and commerce to identify potentially dangerous products 

or uses.34 TSCA focuses on the properties of a chemical and paths of 

exposure to that chemical. Risk assessment activities are primarily related 

to four sections of TSCA:

• Section 4 directs EPA to require manufacturers and processors to 

conduct tests for existing chemicals when: (1) their manufacture, 

distribution, processing, use, or disposal may present an unreasonable 

risk of injury to health or the environment; or (2) they are to be 

produced in substantial quantities and the potential for environmental 

release or human exposure is substantial or significant. Under either 

condition, EPA must issue a rule requiring testing if existing data are 

insufficient to predict the effects of human exposure and environmental 

releases and testing is necessary to develop such data. Rhomberg 

pointed out that these conditions require OPPT to do some preliminary 

risk assessment and that, unlike testing mandates under other statutes 

(e.g., regarding pesticides), the agency has the burden of showing that 

such testing is necessary.35

• Section 5 addresses future risks through EPA’s premanufacture 

screening—the premanufacture notification (PMN) process. This also 

applies to a “significant new use” of an existing chemical.

• Section 6 directs EPA to control unreasonable risks presented or that 

will be presented by existing chemicals.

34 15 U.S.C. 2601 et seq. In addition to its original role to implement TSCA, OPPT has been 

given responsibility for pollution prevention programs; regulation of specific toxic 

substances, including asbestos, radon, and lead; and administration of the Toxics Release 

Inventory.

35Lorenz Rhomberg, A Survey of Methods for Chemical Health Risk Assessment Among 

Federal Regulatory Agencies, a report prepared for the Presidential/Congressional 

Commission on Risk Assessment and Risk Management (1996).
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 91 GAO-01-810 Chemical Risk Assessment

• Section 8 requires EPA to gather and disseminate information about 

chemical production, use, and possible adverse effects to human health 

and the environment. This section requires EPA to develop and 

maintain an inventory of all chemicals, or categories of chemicals, 

manufactured or processed in the United States. All chemicals not on 

the inventory are, by definition, “new” and subject to the notification 

provisions of section 5. Once a chemical enters commerce through the 

section 5 process, it is listed as an existing chemical.

Although TSCA gives EPA general authority to seek out and regulate any 

“unreasonable risk” associated with new or existing chemicals, there are 

two major limitations on the agency’s regulatory actions. First, as 

implemented by EPA, regulation under TSCA involves consideration of 

both risks and applying the least burdensome requirement needed to 

regulate the risk. The term “unreasonable risk” is not defined in TSCA. 

However, according to EPA, the legislative history indicates that 

unreasonable risk involves the balancing of the probability that harm will 

occur, and the magnitude and severity of that harm, against the effect of a 

proposed regulatory action on the availability to society of the expected 

benefits of the chemical substance. The second major limitation on EPA’s 

authority under TSCA is a requirement to defer to other federal laws. 

Generally, if a risk of injury to health or the environment could be 

eliminated or reduced to a sufficient extent by actions taken under another 

federal law, that other law must be deferred to unless it can be shown to be 

in the public interest to regulate under TSCA.

The major distinction in the procedures that apply to OPPT risk 

assessments is between the evaluation of potential risks associated with 

exposures to new versus existing chemicals. For EPA to control the use of 

a chemical listed on the inventory of existing chemicals, according to 

OPPT, a legal finding has to be made that the chemical will present an 

unreasonable risk to human health or the environment. According to 

OPPT, this standard requires the agency to have conclusive data on that 

particular chemical. The agency noted, in comparison, that newly 

introduced chemicals (or uses) can be regulated under TSCA based on 

whether they may present an unreasonable risk, and this finding of risk can 

be based on data for structurally similar chemicals. Because industrial 

chemicals in commerce in 1975-1977 were “grandfathered” into the 

inventory without considering whether they were hazardous, there are 

situations in which existing chemicals might not be controlled, while EPA 

would act to control a new chemical of similar or less toxicity under the 

PMN program. Additional information on the major features and 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 92 GAO-01-810 Chemical Risk Assessment

characteristics of assessments for new versus existing chemicals is 

presented below.

Premanufacture notification for new chemicals or significant new uses

• TSCA requires manufacturers, importers, and processors to notify EPA 

at least 90 days prior to introducing a new chemical into the U.S. or 

undertaking a significant new use of a chemical already listed on the 

TSCA inventory. If available, test data and information on the 

chemical’s potential adverse effects on human health or the 

environment are to be submitted to EPA. Much of this submission must 

be kept confidential by OPPT. However, there is no defined toxicity data 

set required before PMN, and, unless EPA promulgates a rule requiring 

the submission of test data, TSCA does not require prior testing of new 

chemicals. Consequently, according to EPA, less than half of the PMNs 

submitted include toxicological data. OPPT reviews approximately 

1,500 PMNs annually.

• EPA has 90 days after notification to evaluate the potential risk posed by 

the chemical. EPA must then decide whether to (1) permit manufacture 

and distribution (the default if EPA takes no action), (2) suspend 

manufacture and distribution or to restrict use pending the development 

of further data, or (3) initiate rulemaking to regulate manufacture or 

distribution.

• OPPT typically has very limited chemical-specific data on toxic effects 

and exposure associated with new chemicals. When no data exist on 

the effects of exposure to a chemical, EPA may make its determination 

on what is known about the chemical’s molecular structure (called the 

structure-activity relationship, or SAR) and the effects of other 

chemicals that have similar structures and are used in similar ways. 

OPPT’s New Chemicals Program has issued a document entitled 

Chemical Categories that describes information for numerous classes 

of chemicals. In assessing exposures for new chemicals where 

exposure monitoring data are unavailable, OPPT uses several screeninglevel approaches, including (1) estimates based on data on analogous 

chemicals; (2) generic scenarios (i.e., standardized approaches for 

assessing exposure and release for a given use scenario); (3) 

mathematical models based on empirical and theoretical data and 

information; and (4) assumptions of compliance with regulatory limits, 

such as OSHA Permissible Exposure Limits (PELs). 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 93 GAO-01-810 Chemical Risk Assessment

• Rhomberg noted that OPPT cannot require full testing for all chemicals, 

because of statutory limitations under TSCA. He therefore 

characterized OPPT’s assessments as “rough screens” designed to flag 

situations in which further testing should be required.

Assessments of existing chemicals

• Chemicals that OPPT assesses for regulation under sections 4 or 6 of 

TSCA are subject to a more rigorous risk assessment process. 

Compared to PMN reviews, such assessments are much more similar to 

those conducted elsewhere in EPA, so the EPA-wide guidelines 

generally apply.

• For hazard identification and dose-response assessment of carcinogens 

and noncancer effects, OPPT follows EPA-wide procedures. Because 

TSCA focuses on the properties of a chemical, rather than on a specific 

pathway or mode of exposure, OPPT considers the potential hazards 

posed through multiple routes of exposure. In lieu of information to the 

contrary, OPPT typically presumes that the results for one route are 

applicable to other routes.

• Similarly, in exposure assessment OPPT considers a variety of types and 

routes of exposure. Unlike other programs that focus on exposure 

through one medium, assessments under TSCA must assess all potential 

exposures to a chemical that may lead to unreasonable risk, 

considering, for example, both residential and occupational exposures. 

These risks may be assessed separately for each mode of exposure, even 

if occurring in the same setting. Overall, OPPT aims to provide both 

central estimates and upper-bound estimates of exposure, and it 

considers population risks as well as individual risks.

• OPPT shares overlapping concerns about a number of different kinds of 

exposure with other federal regulatory agencies. However, some 

aspects of OPPT’s exposure assessments may differ from those of other 

programs or agencies concerned with similar exposures. For example, 

with regard to occupational exposures OPPT assumes that a working 

lifetime is 40 years, rather than the 45 years assumed by OSHA. Another 

example is the assumption of body weight; OPPT uses 70kg, whereas 

ORD recommends a value of 71.8 kg in its Exposure Factors Handbook.
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 94 GAO-01-810 Chemical Risk Assessment

In addition to the assessment of chemicals for regulation under sections 4 

and 6 of TSCA, OPPT has recently launched a new program to voluntarily 

add screening-level hazard information on approximately 2,800 highproduction-volume industrial chemicals and has proposed a second new 

voluntary program to address the risks of certain industrial chemicals to 

which children may be exposed. These two new programs operate under 

the same risk assessment processes used in the other OPPT programs 

noted above.

Office of Emergency and 

Remedial Response (Superfund 

Program)

OERR is part of EPA’s Office of Solid Waste and Emergency Response 

(OSWER). Risk assessments are a required component of a larger 

remediation process established by the Comprehensive Environmental 

Response, Compensation, and Liability Act of 1980 (CERCLA or 

Superfund), as amended by the Superfund Amendments and 

Reauthorization Act of 1986 (SARA).36 Congress enacted CERCLA to 

facilitate the cleanup of hazardous waste sites. The act gave EPA broad 

authority to respond to releases of hazardous substances. SARA requires 

EPA to emphasize cleanup remedies that treat—rather than simply 

contain—contaminated waste to the maximum extent practicable and to 

use innovative waste treatment technologies.

Hazardous substances are defined by CERCLA to include substances 

identified under the Solid Waste Disposal Act, the Clean Water Act, the 

Clean Air Act, and the Toxic Substances Control Act, or designated by EPA. 

After investigating potentially hazardous sites, EPA ranks them according 

to the severity of their waste problems and places the worst on its National 

Priorities List for Superfund cleanup. Under CERCLA section 105, EPA 

uses a Hazard Ranking System to decide which sites to include on the list. 

Section 105 states that priorities are to be based upon relative risk or 

danger to public health or welfare or the environment, taking into account 

the population at risk, the hazard potential of the hazardous substances, 

and the potential for contamination of air and drinking water, among other 

factors.

OERR has developed a human health and environmental evaluation 

process as part of its remedial response program. Major features and 

characteristics of the Superfund risk assessment procedures are 

summarized below.

36 42 U.S.C. 9601-9675.
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 95 GAO-01-810 Chemical Risk Assessment

• Overall, the risk scenarios for Superfund can be very complex. 

Superfund sites are often associated with multiple potential pathways 

and routes of exposure, and mixtures of chemicals at Superfund sites 

are common. In addition, the Superfund program is required to consider 

ecological as well as human health risks.

• A risk assessment is performed after a particular site has been identified 

according to the National Contingency Plan, EPA’s regulation outlining 

requirements relevant to response action(s) for hazardous substances. 

The remedial response process under the National Contingency Plan—

and the role of risk information in the process—is summarized in the 

following seven steps:

1. Site discovery or notification:

• report determinations about which substances are hazardous.

2. Preliminary assessment and site inspection:

• collect and review all available information to evaluate the 

source and nature of hazardous substances.

3. Hazard ranking system:

• compile data from steps one and two in a numerical scoring 

model to determine a relative risk measure.

4. Possible inclusion of site on the National Priorities List based on one 

of the following criteria:

• the release scores sufficiently high pursuant to the Hazard 

Ranking System,

• a state designates a release as its highest priority, or

• the release satisfies all of the following criteria:

• the Agency for Toxic Substances and Disease Registry has issued 

a health advisory that recommends dissociation of individuals 

from the release,37

• EPA determines that the release poses a significant threat to 

public health, and

37The Agency for Toxic Substances and Disease Registry within the Department of Health 

and Human Services has an oversight role but no regulatory authority. It prepares “health 

assessments” rather than risk assessments that tend to be qualitative in nature, site specific, 

and focused on medical and public health perspectives. Exposures to site contaminants are 

presented in terms of sensitive populations, mechanisms of toxic chemical action, and 

possible disease outcomes. In contrast, EPA’s human health evaluation, which is more 

quantitative, is a characterization of the potential for adverse effects from human exposures 

to environmental hazards.
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 96 GAO-01-810 Chemical Risk Assessment

• EPA anticipates that it will be more cost effective to use its 

remedial authority than to use removal authority to respond to 

the release.

5. Remedial investigation and feasibility study:

• characterize the contamination at site where data is obtained to 

identify, evaluate, and select cleanup alternatives.

6. Selection of a remedy:

• choose remedy that is protective of human health and the 

environment by eliminating, reducing, or controlling risks posed 

through each pathway, and

• utilize risk information obtained during step five.

7. 5-year review.

One intended result of the remedial steps is the facilitation of a sitespecific baseline risk assessment, designed to support risk management 

decision making. Human health and ecological risk assessments occur 

during step five, the Remedial Investigation/Feasibility Study stage.

• For human health risk assessments, Superfund procedures approximate 

the NAS paradigm, using the following four stages.

1. A data collection and evaluation stage that involves:

• gathering and analyzing site data relevant to the human health 

evaluation, and

• identifying substances present at the site that are the focus of the risk 

assessment process.

2. An exposure assessment that involves:

• analyzing contaminant releases,

• identifying exposed populations,

• identifying potential exposure pathways and estimating exposure 

concentrations for pathways, and

• estimating contaminant intakes for pathways.

3. A toxicity assessment stage that considers:

• types of adverse health effects associated with chemical exposures,

• relationships between magnitude of exposure and adverse effects,

• related uncertainties such as the weight evidence of a particular 

chemical’s carcinogenicity in humans, and

• existing toxicity information developed through hazard identification 

and dose-response assessment.

4. A risk characterization that involves:

• characterizing potential for adverse health effects (cancer or 

noncancer) to occur,
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 97 GAO-01-810 Chemical Risk Assessment

• evaluating uncertainty, and

• summarizing risk information.

• For ecological risk assessments, EPA’s guidelines suggest that 

Superfund remedial actions generally should not be designed to protect 

organisms on an individual basis, but should protect local populations 

and communities of biota.38 Furthermore, except for a few very large 

sites, Superfund ecological risk assessments typically do not address 

effects on entire ecosystems. Instead, they gather data regarding the 

effects on individuals in order to predict or postulate potential effects 

on local wildlife, fish, invertebrate, and plant populations and 

communities that occur or that could occur in specific habitats at sites 

(e.g., a wetland, floodplain, stream, estuary, or grassland). Specifically, 

the guidelines recommend that ecological risk assessments performed 

at every site follow an eight-step process:

1. Screening-level problem formulation and ecological effects evaluation:

• site history,

• site visit,

• problem formulation, and

• ecological effects evaluation.

2. Screening-level exposure estimate and risk calculation:

• exposure estimate, and

• risk calculation.

3. Baseline risk assessment problem formation:

• ecotoxicity literature review,

• exposure pathways,

• assessment endpoints and conceptual model, and

• risk questions.

4. Measurement endpoints and study design.

5. Verification of field sampling design.

6. Site investigation and data analysis.

7. Risk characterization.

8. Risk management.

• OERR uses a tiered approach for Superfund risk assessments, in which 

the agency employs more conservative methods and assumptions in the 

initial screening phases, followed by a more rigorous, multistage risk 

assessment if screening results indicate the need. Under Superfund, 

38 An exception would be actions affecting designated protected status resources that could 

be exposed to site releases. Such resources include treaty-protected species and species 

that are listed as or candidates for threatened or endangered status.
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 98 GAO-01-810 Chemical Risk Assessment

decisions generally are made on a site-by-site basis. According to 

agency officials, early activities at Superfund sites are often based on 

initial tier screening. However, they pointed out that the remedial 

cleanup decision is supported by a site-specific risk assessment that is 

usually quite detailed with either site-specific exposure assumptions or 

national default assumptions appropriate to the site which result in 

“high-end” reasonable risk estimates. Although the Superfund program 

initially employed an approach of using a hypothetical “worst case”

scenario for exposure assessments, EPA’s exposure assessment 

guidance now emphasizes use of a more realistic upper-bound exposure 

scenario. The EPA guidelines emphasize that this exposure scenario 

should be in the range of plausible real exposures, and also call for a 

central tendency case. In addition, guidelines put forth by the 

Superfund program office emphasize streamlining the process and 

reducing the cost and time required, focusing on providing information 

necessary to justify action and select the best remedy for a Superfund 

site. In doing so, Superfund guidelines suggest using standardized 

assumptions, equations, and values wherever appropriate.

• The Superfund program uses extensive additional program-specific 

guidance documents addressing human health and ecological risk 

assessments, as well as analytical tools, such as probabilistic analysis. 

These documents supplement applicable EPA-wide guidelines. The 

Superfund guidelines for human health risk assessment, for example, 

cover developing a baseline risk assessment (Part A), developing or 

refining preliminary remediation goals (Part B), performing a risk 

evaluation of remedial alternatives (Part C), and standardizing, 

planning, reporting, and completing a review (Part D). There are also 

other headquarters and regional office documents that further 

supplement the program-specific guidelines and manuals. 

Office of Solid Waste The Office of Solid Waste, like OERR, is part of OSWER. OSW regulates the 

management of solid waste and hazardous waste through federal programs 

established by the Resource Conservation and Recovery Act of 1976, as 

amended (RCRA).39 Congress enacted RCRA to protect human health and 

the environment from the potential hazards of waste disposal, conserve 

energy and natural resources, reduce the amount of waste generated, and 

ensure that wastes are managed in a manner that is protective of human 

health and the environment. The act defines solid and hazardous waste, 

39 42 U.S.C. 6901-6991k.
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 99 GAO-01-810 Chemical Risk Assessment

authorizes EPA to set standards for facilities that generate or manage 

hazardous waste, and establishes a permit program for hazardous waste 

treatment, storage, and disposal facilities. The RCRA hazardous waste 

program has a “cradle to grave” focus, regulating facilities that generate, 

transport, treat, store, or dispose of hazardous waste from the moment it is 

generated until its ultimate disposal or destruction.

RCRA regulations interact closely with other environmental statutes, 

especially CERCLA. EPA notes that both programs are similar in that they 

are designed to protect human health and the environment from the 

dangers of hazardous waste, but each has a different regulatory focus. 

RCRA mainly regulates how wastes should be managed to avoid potential 

threats to human health and the environment. On the other hand, 

according to EPA, CERCLA is relevant primarily when mismanagement 

occurs or has occurred, such as when there has been a release or a 

substantial threat of a release in the environment of a hazardous substance.

Regulatory activity under RCRA focuses primarily on specifying 

procedures and technology to be used to ensure proper handling and 

disposal of wastes, but risk assessments play a role in several supporting 

tasks, particularly those involving hazardous waste regulation under RCRA 

Subtitle C. For example, risk assessment information may be used in the 

processes for defining (and delisting) substances as hazardous wastes, 

evaluating the hazards posed by waste streams, assessing the need for 

corrective action at disposal sites, and granting waste disposal permits 

(such as incinerator permits). In its RCRA Orientation Manual, OSW 

expressed an increasing emphasis on making the RCRA hazardous waste 

program more risk based (with the intention of ensuring that the 

regulations correspond to the level of risk posed by the hazardous waste 

being regulated). Major features and characteristics of risk assessment for 

hazardous waste regulation are summarized below.

• Making the determination of whether a substance is a hazardous waste 

is a central component of the waste management program. The Subtitle 

C program includes procedures to facilitate this identification and 

classification of hazardous waste. Under the RCRA framework, 

hazardous wastes are a subset of solid wastes.40 In RCRA §1004(5), 

Congress defined hazardous waste as a solid waste, or combination of 

40 Despite the name, solid wastes actually may be solids, semi-solids, liquids, or sludges.
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 100 GAO-01-810 Chemical Risk Assessment

solid wastes, which because of its quantity, concentration, or physical, 

chemical, or infectious characteristics may:

• cause, or significantly contribute to, an increase in mortality or an 

increase in serious irreversible, or incapacitating reversible, illness; 

or

• pose a substantial present or potential hazard to human health or the 

environment when improperly treated, stored, transported, or 

disposed of, or otherwise managed.

EPA developed more specific criteria for defining hazardous waste using 

two different mechanisms: (1) listing certain specific solid wastes as 

hazardous and (2) identifying characteristics (physical or chemical 

properties) which, when exhibited by a solid waste, make it hazardous. 

The agency has done so, and risk assessment information may be used to 

support both mechanisms.41

• “Listed wastes” are wastes from generic industrial processes, wastes 

from certain sectors of industry, and unused pure chemical products 

and formulations. EPA uses four criteria to decide whether or not to list 

a waste as hazardous.

1. The waste typically contains harmful chemicals (and exhibits other 

factors, such as risk and bioaccumulation potential) which indicate that 

it could pose a threat to human health and the environment in the 

absence of special regulation. Such wastes are known as toxic listed 

wastes.

2. The waste contains such dangerous chemicals that it could pose a 

threat to health or the environment even when properly managed. 

These wastes are fatal to humans and animals even in small doses and 

are known as acute hazardous wastes.

3. The waste typically exhibits one of the four characteristics of 

hazardous waste: ignitability, corrosivity, reactivity, and toxicity.

4. EPA has cause to believe that, for some other reason, the waste 

typically fits within the statutory definition of hazardous waste.

41 In addition, there are some wastes that are specifically excluded from Subtitle C 

regulation and wastes that may be exempted when recycled.
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 101 GAO-01-810 Chemical Risk Assessment

Listed hazardous wastes can exit Subtitle C regulation through a sitespecific delisting process initiated by a petition from a waste handler to an 

EPA region or a state. The petition must demonstrate that, even though a 

particular waste stream generated at a facility is a listed hazardous waste, it 

does not pose sufficient hazard to merit RCRA regulation.

• “Characteristic wastes” are wastes that exhibit measurable properties 

that indicate they pose enough of a threat to deserve regulation as 

hazardous wastes. EPA established four hazardous waste 

characteristics.

1. Ignitability identifies wastes that can readily catch fire and sustain 

combustion.

2. Corrosivity identifies wastes that are acidic or alkaline. Such wastes 

can readily corrode or dissolve flesh, metal, or other materials.

3. Reactivity identifies wastes that readily explode or undergo violent 

reactions (e.g., when exposed to water or under normal handling 

conditions).

4. Toxicity is used in a rather narrow and specific sense under this 

program to identify wastes that are likely to leach dangerous 

concentrations of chemicals into ground water if not properly managed 

(and thus expose users of the water to hazardous chemicals and 

constituents).

EPA developed a specific lab procedure, known as the Toxicity 

Characteristic Leaching Procedure, to predict whether any particular waste 

is likely to leach chemicals into ground water at dangerous levels. In this 

procedure, liquid leachate created from hazardous waste samples is 

analyzed to determine whether it contains any of 40 different common 

toxic chemicals in amounts above specified regulatory levels. The 

regulatory levels are based on ground water modeling studies and toxicity 

data that calculate the limit above which these toxic compounds and 

elements will threaten human health and the environment.

• For OSW, the task of identifying and assessing hazardous wastes is 

made more difficult because waste may be in the form of a mixture of 

constituents, some of which may be hazardous and some not. (This is 

also a common issue for the Superfund program.) The EPA-wide 

guidelines on assessments of chemical mixtures therefore could come 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 102 GAO-01-810 Chemical Risk Assessment

into play in OSW risk assessments.

• For dose-response data on the toxicity and potency of hazardous 

substances, OSW largely relies on information from other EPA sources. 

For example, OSW may use the chemical-specific assessments prepared 

by ORD, data in EPA’s IRIS database, and regulatory standards from 

other EPA program offices, in particular the Office of Water. However, 

OSW combines this information with its own exposure analyses.

• Rhomberg categorized exposure assessment by OSW as either 

hypothetical or site specific. He noted that hypothetical exposures 

principally come into play when the agency is defining hazardous 

wastes and evaluating disposal options. These exposure analyses cover 

hypothetical waste-handling and disposal practices anywhere in the 

nation, and OSW focuses on the question of whether such practices 

might cause undue risks to individuals, not on characterizing the actual 

distribution of exposures across the population. One of the principal 

concerns in OSW exposure assessments is leaching to groundwater, but 

OSW evaluates other exposure pathways from virtually all treatment 

and disposal practices, with the specific pathways for any particular 

analysis being decided on a case-by-case basis. Site-specific exposure 

assessments might be needed when OSW is making regulatory decisions 

regarding actual waste disposal facilities, as when assessing the need for 

remedial action at a given site or permitting incineration or other 

disposal activities. In such cases, the office can focus exposure 

estimates on the off-site migration of the particular toxic compounds 

associated with that location. In general, an important part of OSW’s 

exposure assessments is evaluating the “relative contribution” of 

hazardous wastes to the overall exposure to a hazardous chemical 

(which is very similar to assessments by EPA’s Office of Water).

• In exposure assessments, OSW’s deterministic analyses follow EPA’s 

risk characterization guidance by setting only two sensitive parameters 

at high-end values, with the rest of the parameters being set at their 

central tendency values. According to OSW, this approach is meant to 

produce a risk estimate above the 90th percentile of the risk distribution 

but still on the actual distribution. 

Chemical Emergency 

Preparedness and Prevention 

Office

CEPPO is also part of OSWER. It provides leadership, advocacy, and 

assistance to: (1) prevent and prepare for chemical emergencies; (2) 

respond to environmental crises; and (3) inform the public about chemical 

hazards in their community. To protect human health and the environment, 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 103 GAO-01-810 Chemical Risk Assessment

CEPPO develops, implements, and coordinates regulatory and 

nonregulatory programs. It carries out this work in partnership with EPA 

regions, domestic and international organizations in the public and private 

sectors, and the general public.

CEPPO is responsible for the risks associated with accidental chemical 

releases. Under the Emergency Planning and Community Right-to-Know 

Act (EPCRA) in Title III of the Superfund Amendments and 

Reauthorization Act of 1986, CEPPO must evaluate, develop, and maintain 

a list of chemicals and threshold quantities that are subject to reporting for 

emergency planning. In addition, CEPPO develops the emergency 

reporting and planning requirements, guidance for industry, and guidance 

and tools for use of the reporting information by Local Emergency Planning 

Committees. These reporting and planning requirements serve to provide 

the necessary information to be used at the local level to manage the risks 

associated with accidental chemical releases.

CEPPO is also responsible for accidental chemical release prevention. 

Under Section 112(r) of the Clean Air Act, as amended by the Clean Air Act 

Amendments of 1990, CEPPO must evaluate chemicals for acute adverse 

health effects, likelihood of accidental release, and magnitude of exposure 

to develop a list of at least 100 substances that pose the greatest risk of 

causing death, injury, or serious adverse effects to human health or the 

environment from accidental releases. Each listed substance must have a 

threshold quantity that takes into account the chemical’s toxicity, 

reactivity, volatility, dispersability, combustibility, or flammability.

Facilities handling a listed substance above its threshold quantity must 

implement a risk management program and develop a risk management 

plan. The risk management program must address a hazards analysis, 

prevention program, and emergency response program. According to 

CEPPO officials, they scaled these regulatory requirements according to 

the risk posed by the wide range of facilities subject to the requirements—

the greater the risk, the greater the risk management responsibilities. The 

facilities submit their risk management plans to EPA and to state and local 

officials for use in emergency planning and local risk management and 

reduction. CEPPO investigates chemical accidents, conducts research, and 

collects information about chemical and industrial process hazards to issue 

Chemical Safety Alerts and other publications to raise awareness about 

chemical accident risks. CEPPO also develops tools, methods, and 

guidance necessary to identify and assess the risks to human health from 

accidental releases.
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 104 GAO-01-810 Chemical Risk Assessment

Major features and characteristics of CEPPO’s risk assessment procedures 

are summarized below.

• The chemical risk assessments conducted by CEPPO are unique from 

the risk assessments conducted by other EPA offices. CEPPO’s 

procedures do not follow the NAS four-step risk assessment approach, 

but are similar to the chemical risk assessment approach used by the 

Department of Transportation’s (DOT) Research and Special Programs 

Administration (RSPA) in that hazards are identified and a measure of 

exposure (or consequence) is determined to yield a “threat” associated 

with an accidental release. While RSPA focuses on risks associated with 

accidents involving unintentional releases of hazardous materials during 

transportation, CEPPO focuses on risk associated with accidental 

releases from a fixed facility. According to CEPPO, for accidental 

release risks, because these events are high consequence and low 

probability, the hazard and exposure typically can be estimated with 

some degree of confidence. However, the likelihood or probability of an 

accidental release is very uncertain. Consequently, likelihood is 

addressed only in a limited way and the “threat” is judged to be a 

surrogate for risk.

• CEPPO’s approaches with respect to chemical accident risk are 

published mainly in two rulemakings—“List of Regulated Substances 

and Thresholds for Accidental Release Prevention and Risk 

Management Programs for Chemical Accident Release Prevention,” 59 

FR 4478 (Jan. 31, 1994) and “Accidental Release Prevention 

Requirements: Risk Management Programs under the Clean Air Act, 

Section 112(r)(7),” 61 FR 31668 (June 20, 1996)—and in guidelines, 

especially “Technical Guidance for Hazards Analysis, Emergency 

Planning for Extremely Hazardous Substances,” which was issued 

jointly by EPA, DOT, and the Federal Emergency Management Agency 

(Dec. 1987).

• For hazard identification, CEPPO identifies the hazards that pose a risk 

to human health and the environment from an analysis of chemical 

accidents and of the physical/chemical properties of substances that 

make them more likely to cause harm as a result of an accidental 

chemical release. For example, the catastrophic chemical release in 

Bhopal, India, in December 1984 involved methyl isocyanate, a chemical 

that is toxic when inhaled. CEPPO identified the criteria necessary to 

identify those substances that are so toxic that, upon exposure (i.e., 

inhalation, dermal contact, or ingestion) to a small amount, they cause 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 105 GAO-01-810 Chemical Risk Assessment

death or serious irreversible health effects in a short time (acute 

toxicity). CEPPO also has developed criteria to identify other 

substances, such as highly flammable substances that can trigger a 

vapor cloud explosion harming the public and environment. CEPPO is 

also working to understand the long-term (chronic) effects that might be 

generated by a single acute exposure.

• As part of its identification of hazards, CEPPO also evaluates the 

quantity of a chemical that would need to be released and travel off-site 

to establish a threshold quantity.42 If a facility handles more than this 

quantity, there is a presumption of risk triggering some action by the 

facility’s owner(s) and operator(s). The hazardous chemicals and 

threshold quantities identified by CEPPO are published in rulemakings.

• According to CEPPO, the exposure assessment (or consequence 

analysis) phase of a chemical accident release assessment is somewhat 

unique from the classical risk assessment approaches and procedures. 

The actual exposure to humans after an accidental release is often not 

known. In addition, the amount and rate of chemical released and the 

precise conditions (e.g., weather) are usually not known. However, 

these parameters can be estimated using engineering calculations and 

mathematical models to generate the concentration likely to have been 

present or that could be present in a certain type of accidental release. 

Using these techniques, chemicals that possess the physical/chemical 

properties most likely to harm the public or the environment can be 

evaluated to estimate the degree of “threat” that they may pose in an 

accidental release.

• CEPPO uses these exposure assessment (consequence analysis) 

techniques to understand the potential magnitude of exposure 

associated with a variety of hazardous chemicals. In addition, CEPPO 

publishes the techniques in guidelines and as software to assist facilities 

in their assessment of accidental release risk. According to CEPPO, 

industry has a fundamental responsibility to understand the risks 

associated with chemical accidents. In addition, the Risk Management 

Plan requirements under section 112(r) of the Clean Air Act require that 

this information be made available to the public so that industry and the 

42 A CEPPO official pointed out that his agency’s focus is the general public and environment 

outside the bounds of an industrial facility. The Occupational Safety and Health 

Administration is responsible for risk within the bounds of an industrial facility.
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 106 GAO-01-810 Chemical Risk Assessment

community can work together to manage the risks that might be 

present.

• CEPPO may characterize the risks associated with accidental releases 

using a number of parameters, such as the presence of a large quantity 

of a highly hazardous substance in proximity to a large facility that has 

had a number of accidental releases in the past. CEPPO uses these 

parameters to place more responsibility on such facilities (e.g., greater 

accidental release prevention measures under the Risk Management 

Program requirements), to investigate the underlying reasons for their 

accidental releases, or to assist in audits and inspections of their 

accident prevention programs.

Office of Air and Radiation OAR oversees the air and radiation protection activities of the agency. 

Radiation risk assessments conducted by OAR are outside the scope of this 

report, but chemical risk assessments do have a part in OAR’s efforts to 

preserve and improve air quality in the United States.43 Such air quality 

concerns are the primary mission of OAR’s Office of Air Quality Planning 

and Standards (OAQPS), which, among other activities, compiles and 

reviews air pollution data and develops regulations to limit and reduce air 

pollution. The Risk and Exposure Assessment and the Health and 

Ecosystem Effects Groups within OAQPS provide the scientific and 

analytical expertise to conduct and support human health and ecological 

risk assessments in this area, in coordination with ORD.

The Clean Air Act, as amended, provides the statutory basis for air-related 

risk assessments by OAR.44 The CAA requires EPA to establish national 

standards for air quality, but it gives states the primary responsibility for 

assuring compliance with the standards. Chemical risk assessments are 

primarily associated with regulation of (1) criteria air pollutants and (2) 

hazardous air pollutants, also referred to as “air toxics.”

45

43 See Radiation Standards: Scientific Basis Inconclusive, and EPA and NRC 

Disagreement Continues (GAO/RCED-00-152, June 30, 2000) for information regarding 

some of the procedures used by EPA in setting radiation standards.

44 42 U.S.C. 7401-7626. 

45 There are other distinct programs within OAR—for example, focusing on the regulation of 

mobile sources (including fuels and fuel additives), acid rain, and global climate change—

that also include consideration of chemicals.
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 107 GAO-01-810 Chemical Risk Assessment

The CAA requires EPA to set health-based air quality standards (National 

Ambient Air Quality Standards, or NAAQS) for criteria pollutants, which 

are common throughout the United States and mostly the products of 

combustion.46 Under the CAA, EPA is also required to review the scientific 

data upon which the standards are based and revise the standards, if 

necessary, every 5 years. The criteria pollutants are particulate matter, 

carbon monoxide, sulfur oxides, nitrogen dioxide, ozone, and lead. Of 

these pollutants, ozone is not directly emitted by a source, but rather is the 

product of the interaction of nitrogen oxide, volatile organic compounds, 

and sunlight. Therefore, regulations targeting ozone focus on controlling 

emissions of nitrogen oxide and volatile organic compounds. The CAA 

requires EPA to set health-based standards with an “adequate margin of 

safety,” but according to EPA it is not required to set air quality standards at 

a zero-risk level to achieve an adequate margin of safety, but simply at a 

level that avoids unacceptable risks. EPA therefore sets the standards to 

protect the substantial part of the national population, including sensitive 

or at-risk populations, but not necessarily the most sensitive or exposed 

individuals.

The CAA also contains provisions, first added in 1970, for the regulation of 

emissions to the atmosphere of hazardous air pollutants—toxic chemicals 

other than the six criteria pollutants. The 1970 amendments to the CAA 

required EPA to identify and control hazardous air pollutants so as to 

achieve “an ample margin of safety.” However, Congress passed another 

major set of amendments, the Clean Air Act Amendments of 1990 (CAAA), 

which revised the hazardous air pollutant provisions and substantially 

affected the application of risk assessment regarding air toxics. The 

amendments explicitly wrote into the act a list of 189 hazardous air 

pollutants to be regulated. In addition, the amendments replaced the 

former health-based criterion for standards with a criterion that is 

primarily technology based, mandating the maximum achievable control 

technology (MACT) for the specified list of chemicals.47 The act further 

mandates that EPA evaluate residual risks remaining after implementation 

46 The states are responsible for establishing procedures to attain and maintain the 

standards. They prepare State Implementation Plans (SIPs) on these procedures that are 

submitted to EPA for approval.

47 All new or existing sources of these pollutants are to require the use of MACT, which is 

judged to be “the best of the best” for new sources and at the top end (best 12 percent) of 

current emissions control performance for existing sources.
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 108 GAO-01-810 Chemical Risk Assessment

of the MACT standards to determine if additional standards are needed to 

protect the public health with an ample margin of safety.

Additional information on the major features and characteristics of 

chemical risk assessments related to these air quality protection activities 

is presented below.

Criteria air pollutants

• There are several unique features that affect risk assessments for 

criteria air pollutants. Compared to many other agents assessed by 

EPA, the agency generally has extensive human data available on health 

effects at relevant exposure levels. Therefore, risk assessments for 

criteria air pollutants require little extrapolation across species or to 

low doses and few default assumptions. These are the least likely of 

EPA’s risk assessments to use precautionary or conservative methods 

and assumptions, and the results are intended to be unbiased estimates 

without any built-in conservatism.

• For criteria air pollutants, “hazard identification” information on health 

effects appears primarily in air quality criteria documents prepared by 

ORD and staff papers prepared by OAQPS to support the review and 

development of national ambient air quality standards. These 

documents are intended to reflect the available scientific evidence on 

toxicity endpoints of concern. The definition of what responses 

constitute “adverse” outcomes is ultimately left to the Administrator’s 

judgment, informed by staff recommendations, advice from the Clean 

Air Scientific Advisory Committee (part of EPA’s Science Advisory 

Board), and public comments.

• EPA’s principal concern regarding criteria pollutants is for noncancer 

health effects. In contrast to most other EPA noncancer risk 

assessments, however, EPA does not apply a threshold approach in the 

case of criteria pollutants. Instead, the agency models response curves 

as though they have no threshold, recognizing that, as a practical matter, 

at least some members of the general population will have their 

thresholds exceeded at or near the lowest exposure levels. EPA 

characterizes these response relationships without any conservative 

upper-bound methods. However, probabilistic methods are used to 

characterize uncertainty in the fitted exposure-response relationships. 

In addition, there is temporal variation in pollution concentrations, so 

characterization of exposure-time relationships is also an important 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 109 GAO-01-810 Chemical Risk Assessment

component of EPA’s assessments of criteria pollutants.

• Although EPA’s exposure assessments (and risk characterization) for 

criteria pollutants focus on population risks, rather than individual 

risks, the agency does consider effects on more sensitive or exposed 

populations. Exposure assessments are also affected by the need to 

establish air quality standards for both annual and daily concentrations 

for some pollutants. The annual standards are intended to provide 

protection against typical day-to-day exposures as well as longer-term 

exposures, while the daily standards are intended to provide protection 

against days with high peak concentrations of pollutants. EPA’s 

exposure assessments therefore need to address these types of 

variations. Rhomberg noted that, because of the long history of analysis 

of standard pollutants, EPA’s exposure modeling has been continually 

improved and expanded, resulting in sophisticated models with 

capabilities well beyond models used in other situations that do not 

have the benefit of decades of experience and application.

• Finally, it is important to recognize that one of the most important uses 

of risk assessments regarding criteria air pollutants is to characterize 

the population exposure levels and health effects that would be 

expected given various specified air quality criteria. In other words, one 

of the primary uses of risk assessment is to estimate what the effects 

would be if standards were set at various specified levels, rather than 

using the tool simply to estimate what health risks these pollutants pose.

Hazardous air pollutants (air toxics)

• Although the Clean Air Act Amendments of 1990 shifted the focus in 

hazardous air pollutant regulation to technology-based controls, several 

activities may still involve risk assessments, including

• listing and delisting of hazardous air pollutants, which depends on 

whether a chemical may present a threat of adverse effects to 

humans and the environment;

• de minimis delisting of source categories, which requires sources be 

listed unless they pose less than a 10-6 risk to the maximally exposed 

individual (MEI);

• triggering the consideration of further regulation to address residual 

risks that remain after applying MACT standards (triggered if the MEI 

suffers a 10-6 or greater lifetime risk); and
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 110 GAO-01-810 Chemical Risk Assessment

• offset trading of one pollutant for another based on whether the 

increase in emissions is offset by an equal or greater decrease in a 

“more hazardous” air pollutant.

• According to section 112(o) of the amended CAA, prior to the 

promulgation of any residual risk standard, EPA shall revise its 

guidelines for carcinogen risk assessment or provide an explanation of 

the reasons regarding any NAS report section 112(o)(4) 

recommendations that have not been implemented.

• The amended act also had a major impact on hazard identification for 

air toxics. The amendments defined hazardous air pollutants as air 

pollutants listed pursuant to section 112(b) of the act. Section 112(b) 

included an initial list of 189 compounds incorporated by reference into 

the law.

• Dose-response analysis for air toxics has in the past been done largely 

through Health Assessment Documents produced by ORD for the air 

office, according to the methods discussed in the earlier section on EPAwide risk assessment procedures. Carcinogen potency calculations for 

de minimis delisting and residual risk determination will be done under 

the revised carcinogen assessment guidelines, once they are finalized. 

EPA addresses noncancer risks for hazardous air pollutants with its 

usual methodologies (e.g., NOAEL/LOAEL, benchmark dose, or others).
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 111 GAO-01-810 Chemical Risk Assessment

• With the 1990 amendments, exposure assessments for air toxics will 

focus on assessing the residual risk for the most exposed individual 

after MACT has been applied. OAR uses a population-based risk 

assessment to generate estimates of how risks are distributed within the 

population, not just for specific conservative scenarios. According to 

Rhomberg (and confirmed by OAR officials), OAR’s intent is to define 

the actual most exposed person in the population, rather than a 

hypothetical person with an unrealistically high estimated exposure. 

EPA has adopted a tiered approach to analyzing residual risk consistent 

with the recommendations from NAS and the 

Presidential/Congressional Commission.48 In the screening phase, 

default conservative assumptions are used to ensure that risks will not 

be underestimated. Sources and hazardous air pollutants that exceed 

some benchmark in the screening analysis will be evaluated further. 

According to OAR, the more refined assessments will utilize more sitespecific information and more realistic assumptions, especially as they 

relate to exposure. EPA estimates exposures to air toxics using a 

general-purpose model largely based on fate and transport 

considerations for stack emissions.49 OAR officials noted that they are 

updating their modeling methodology, updating their Human Exposure 

Model with the current state-of-the-art dispersion model (ISCST3), and 

will be updating the census data they use with the 2000 Census numbers 

when they become available.

Office of Water OW is responsible for the agency’s water quality activities, including 

development of national programs, technical and science policies, 

regulations, and guidance relating to drinking water, water quality, ground 

water, pollution source standards, and the protection of wetlands, marine, 

and estuarine areas. Chemical risk assessments are associated, in 

particular, with EPA’s ambient water quality criteria, under the CWA, and 

drinking water quality regulations, under the SDWA.50

The goal of CWA is to maintain and improve the cleanliness and biological 

integrity of the nation’s waters, including lakes, rivers, and navigable 

waters. Under CWA, EPA publishes water quality criteria defining the 

48 See Residual Risk Report to Congress, U.S. EPA (March 1999).

49 Fate and transport models are mathematical descriptions of the movement and 

transformation of substances through various media, such as air, soil, and water.

50 CWA is codified generally as 33 U.S.C. 1251-1387 and SDWA as 42 U.S.C. 300f-300j.
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 112 GAO-01-810 Chemical Risk Assessment

degree of water quality that is compatible with intended uses and states of 

different water bodies. The criteria are health based, but they are not rules 

and are themselves unenforceable. States use these criteria as guidance for 

developing state water quality standards and setting enforceable limits in 

permits for facilities that discharge pollutants into surface waters. CWA 

distinguishes “conventional” from “toxic” pollutants. Toxic water 

pollutants are evaluated as exposures to toxic chemicals (similar to EPA’s 

treatment of hazardous air pollutants).

The goal of SDWA is to protect the quality of public drinking water systems. 

The law focuses on all waters actually or potentially designed for drinking 

use, whether from above ground or underground sources. SDWA requires 

EPA to set drinking water standards to control the level of contaminants in 

drinking water provided by public water systems, which the water systems 

are required to meet.51 Congress passed extensive amendments to SDWA 

through the Safe Drinking Water Act Amendments of 1996 (PL 104-182). 

Among other key changes, the amendments increased regulatory flexibility, 

focused regulatory efforts on contaminants posing the greatest health 

risks, and added risk assessment and risk communication provisions to 

SDWA.

There are several risk-related mandates in these acts.

• Under CWA, EPA is to establish criteria for water quality solely on the 

basis of health and ecological effects and “accurately reflecting the 

latest scientific knowledge... on the kind and extent of all identifiable 

effects on health and welfare.” CWA defines a toxic pollutant as one 

that after discharge and upon exposure, ingestion, inhalation, or 

assimilation into any organism, either directly from the environment or 

indirectly by ingestion through food chains, will, on the basis of 

information available to the Administrator, cause death, disease, 

behavioral abnormalities, cancer, genetic mutations, physiological 

malfunctions (including malfunctions in reproduction), or physical 

deformities in such organisms or their offspring. Federal water quality 

criteria are unenforceable, but states develop enforceable permit limits 

51 Drinking water standards apply to public water systems that provide water to at least 15 

connections used by year-round residents or regularly serve at least 25 year-round residents. 

Private water wells serving fewer than 25 persons are not covered by these federal 

standards. EPA also sets Secondary Drinking Water Regulations, which are nonenforceable 

guidelines for contaminants that may cause cosmetic or aesthetic effects. 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 113 GAO-01-810 Chemical Risk Assessment

based on them.

• In contrast to the unenforceable federal water quality criteria, CWA also 

provides for the promulgation of enforceable federal performance 

standards for sources of effluent (waste discharged into a river or other 

water body) that do include consideration of technological and 

economic feasibility. Since 1977, establishment of effluent standards for 

toxic pollutants has been based on the best available technology (BAT) 

economically achievable by particular source category. The compounds 

to be regulated are specified in a list, and there are provisions for 

additions and deletions to the list. Standards must be at that level which 

the Administrator determines provides “an ample margin of safety,” so 

that standards more stringent than BAT may be named at EPA 

discretion.

• Under SDWA, the EPA Administrator is to “promulgate national primary 

drinking water regulations for each contaminant... which... may have 

any adverse effect on the health of persons and which is known or 

anticipated to occur in public water systems.” An important feature of 

such regulations, however, is that a standard specifies two levels of 

contamination. First, a maximum contaminant level goal (MCLG) is set 

solely on health grounds “at a level at which no known or anticipated 

adverse effects on the health of persons occur and which allows an 

adequate margin of safety.” For each such goal there is also a maximum 

contaminant level (MCL). This MCL is to be as close to the MCLG “as is 

feasible,” where feasible means “with the use of the best technology, 

treatment techniques and other means which... are available (taking 

cost into consideration).” The MCL is the enforceable standard.

• The 1996 amendments to SDWA added several provisions that increased 

the importance of risk assessment and risk communication in EPA’s 

regulation of drinking water quality. For example, the amendments

• Require EPA, when developing regulations, to (1) use the best 

available, peer-reviewed science and supporting studies and data and 

(2) make publicly available a risk assessment document that 

discusses estimated risks, uncertainties, and studies used in the 

assessment.

• Require EPA to conduct a cost-benefit analysis for every new 

standard to determine whether the benefits (health risk reduction) of 

a drinking water standard justify the costs.

• Permit consideration of “risk-risk” issues by authorizing EPA to set a 

standard other than the feasible level if the feasible level would lead 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 114 GAO-01-810 Chemical Risk Assessment

to an increase in health risks by increasing the concentration of other 

contaminants or by interfering with the treatment processes used to 

comply with other SDWA regulations.

• Require EPA to review and revise, as appropriate, each national 

primary drinking water regulation promulgated by the agency at least 

every 6 years. Of particular relevance to the use of risk assessment 

information, any revisions must “maintain, or provide for greater, 

protection of the health of persons.”

• Require EPA to identify subpopulations at elevated risk of health 

effects from exposure to contaminants in drinking water and to 

conduct studies characterizing health risk to sensitive populations 

from contaminants in drinking water.

Additional information on major features and characteristics of chemical 

risk assessments related to water quality protection activities is presented 

below.

• The various offices within OW—the Office of Ground Water and 

Drinking Water; Office of Science and Technology; Office of 

Wastewater Management; and Office of Wetlands, Oceans, and 

Watersheds—have developed extensive technical and analytical 

guidance on water quality monitoring and the development of water 

quality criteria. One recently finalized document particularly 

relevant for describing OW’s current risk assessment procedures is 

the revision to the methodology for deriving ambient water quality 

criteria (AWQC) for the protection of human health.52 Published 

pursuant to section 304(a)(1) of the CWA, OW noted that this revised 

methodology supersedes EPA’s 1980 guidelines and methodology on 

this subject. In addition to describing OW’s approach to developing 

new and revising existing AWQC, it defines the default factors that 

EPA will use in evaluating and determining consistency of state water 

quality standards with the requirements of the CWA.

• Although there are different statutory bases and risk mandates for 

the regulation of ambient and drinking water, OW’s risk assessment 

procedures in support of CWA and SDWA are mostly similar. 

52 Methodology for Deriving Ambient Water Quality Criteria for the Protection of Human 

Health, also referred to as the “2000 Human Health Methodology,” EPA-822-B-00-005 

(October 2000). The agency is also in the process of revising its methodology for deriving 

AWQC for the protection of aquatic life.
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 115 GAO-01-810 Chemical Risk Assessment

However, risk assessments in support of CWA consider not just 

human health effects but also the ecological effects associated with 

exposure to pollutants. With regard to human health risks, perhaps 

the most notable difference between the ambient water and drinking 

water parts of OW is the additional focus, during exposure 

assessments for CWA purposes, on exposures to contaminated water 

through consumption of contaminated fish or shellfish. (This is a 

primary reason for potential differences in the resulting drinking 

water and ambient water quality criteria or standards for the same 

chemical.)

• OW’s Office of Science and Technology does all of the risk 

assessments for SDWA maximum contaminant level goals and CWA’s 

AWQC. For cancer risk evaluation, OW has been applying the 

principles in EPA’s proposed revision of the carcinogen guidelines. 

• For hazard identification purposes, SDWA originally had specified a 

list of compounds to be regulated as toxic pollutants and required 

EPA to regulate an additional 25 contaminants every 3 years. 

However, the 1996 amendments eliminated that requirement and 

revised OW’s approach for listing, reviewing, and prioritizing the 

drinking water contaminant candidate list. The new risk-based 

contaminant selection process provides EPA the flexibility to decide 

whether or not to regulate a contaminant after completing a required 

review of at least five contaminants every 5 years. EPA must use 

three risk-related criteria to determine whether or not to regulate: 

(1) that the contaminant adversely affects human health; (2) it is 

known or substantially likely to occur in public water systems with a 

frequency and at levels of public health concern; and (3) regulation of 

the contaminant presents a meaningful opportunity for health risk 

reduction. The 1996 amendments also included specific 

requirements to assess health risks and set standards for arsenic, 

sulfate, radon, and disinfection byproducts.

• There are a number of important features regarding OW’s exposure 

assessments in support of CWA and SDWA regulations.

• OW’s primary exposure question during the criteria/standard-setting 

process for drinking or ambient water is hypothetical: What health 

effects might be expected if people consumed water and/or finfish 

and shellfish contaminated at the level of a candidate standard? The 

main function of exposure assessment is to link criteria or water 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 116 GAO-01-810 Chemical Risk Assessment

concentrations to doses of chemicals and the associated health 

effects that might be projected.

• For its exposure assessments, OW uses estimates of water and food 

ingestion in the United States based on a variety of surveys and 

studies. One of the major sources of per capita water and fish 

ingestion is the Department of Agriculture’s Continuing Survey of 

Food Intakes by Individuals (CSFII), which presents results for the 

general population and for certain subpopulations (e.g., pregnant and 

lactating women, children).53

• For assessing standards under SDWA, the linking of water 

concentration to dose is conducted through standardized 

consumption values. For example, the default exposure scenario of 

lifetime consumption by individuals is 2 liters of water per day. 

However, OW uses other default values to address consumption by 

sensitive subpopulations, especially children and infants. For 

assessing AWQC under the CWA, EPA uses the same water 

consumption rate as under SDWA. In addition, though, the agency 

adds the dose resulting from the daily average consumption of 17.5 

grams of fish. 

• An important change in EPA’s approach for developing AWQC, 

reflected in the 2000 Human Health Methodology, has been the 

move toward use of a bioaccumulation factor (BAF) to estimate 

potential human exposure to contaminants via the consumption of 

contaminated fish and shellfish. BAFs reflect the accumulation of 

chemicals by aquatic organisms from all surrounding media (e.g., 

water, food, and sediment). EPA’s 1980 method used a 

bioconcentration factor that reflected only absorption directly out of 

the water column, and therefore tended to underestimate actual 

contaminant levels in fish and shellfish. EPA’s revised methodology 

also gives preference to the use of high-quality field data over 

laboratory or model-derived estimates of BAFs.

• OW considers indirect exposures to a substance from sources other 

than drinking water (e.g., food and air) when establishing AWQC. 

This is particularly important for noncarcinogens, where the fact that 

53 The CSFII is a complex multistage probability sample of the entire United States 

conducted to survey food and beverage intake. 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 117 GAO-01-810 Chemical Risk Assessment

several exposure sources might individually be below the RfD level 

does not mean that collectively the exposure is below this 

presumably safe level. OW has revised and expanded its policy on 

accounting for nonwater sources of indirect exposures known as the 

“relative source contribution.” The procedures for calculating the 

relative source contribution vary depending on the adequacy of 

available exposure data, levels of exposure, sources and media of 

exposure relevant to the pollutant of concern, and whether there are 

multiple health-based criteria or standards for the same pollutant. 

(See table 5 in the next section for a more detailed description of 

these assumptions.)

Risk Assessment 

Assumptions and 

Methodological 

Choices

EPA’s risk assessment guidelines and other related documents identify 

many default assumptions, standardized data factors, and methodological 

choices that may be used in chemical risk assessments. As pointed out by 

NAS, assumptions and professional judgment are used at every stage of a 

risk assessment, because there are always uncertainties in risk 

assessments that science can not directly answer. For the most part, these 

assumptions and choices are intended to address various types of 

uncertainties—such as an absence or limited amount of available data, 

model uncertainty, and gaps in the general state of scientific knowledge—

or variability in the population. They are also intended to provide some 

consistency and transparency to agency risk assessments. Defaults are 

generally used in the absence of definitive information to the contrary, but 

also reflect policy decisions.

In its guidelines, EPA characterizes many of its choices as conservative or 

public-health protective in that they are intended to help the agency avoid 

underestimating possible risks. Agency guidelines often cited the scientific 

studies and other evidence that supported the agency’s choice and the 

plausibility of the resulting risk estimates. In our recent report on EPA’s 

use of precautionary assumptions, we identified three major factors 

influencing the agency’s use of such assumptions: (1) EPA’s mission to 

protect human health and safeguard the natural environment (including 

specific requirements in some of the underlying environmental statutes), 

(2) the nature and extent of relevant data, and (3) the nature of the risk 

being evaluated.54

54 Environmental Protection Agency: Use of Precautionary Assumptions in Health Risk 

Assessments and Benefits Estimates (GAO-01-55, Oct. 16, 2000).
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 118 GAO-01-810 Chemical Risk Assessment

EPA’s program offices commonly employ tiered risk assessment 

approaches that progress from rough screening assessments (for which 

only limited data may be available) through increasingly detailed and 

rigorous analyses, if needed. EPA’s guidelines and program-specific 

documents indicate that conservative default assumptions are most often 

used during initial screening assessments, when the primary task is to 

determine whether a risk might exist and further analysis is called for. 

Such screening assessments may use “worst case” assumptions to 

determine whether, even under those conditions, risk is low enough that a 

potential problem can be eliminated from further consideration. According 

to guidelines and related descriptive materials from the program offices, 

conservative assumptions are used less often in later tiers, as the agency 

attempts to gather and incorporate more detailed data into its analyses.

Several circumstances may lead to conservative choices playing a less 

prominent role in EPA risk assessments. For example, the development of 

more complex and sophisticated models for cancer and noncancer effects 

places more emphasis on using the full range of available data and 

characterizing the full range of potential adverse outcomes and effects. 

Similarly, the increased use of probabilistic analytical methods to derive 

parameter values will tend to reduce the “compounding” effect of picking 

conservative point values for each factor. As noted above, the use of tiered 

risk assessment approaches may also limit the use of default assumptions if 

more rigorous and case-specific analysis is done beyond initial screening 

assessments. However, all of these developments may require substantial 

additional effort and the availability of considerable data, which might not 

be possible in many cases.

Although not intended to be comprehensive, table 5 illustrates in detail 

some of the specific assumptions, default data values, or methodological 

choices that are used in EPA chemical risk assessments. The table 

concentrates primarily on default choices from EPA’s various agencywide 

risk assessment guidelines. However, to also provide a sense of how 

default choices are used at the program level, we have included examples 

of standard assumptions and values employed by two of EPA’s program 

offices. One set of examples illustrates assumptions and choices used by 

OPP. The second set presents more detailed descriptions of the standard 

assumptions and choices identified in OW’s risk assessment methodology 

for deriving AWQC for the protection of human health. OW’s policy reflects 

many of the same basic choices that would apply to assessments 

conducted across the agency, such as the use of uncertainty factors when 

estimating an RfD. 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 119 GAO-01-810 Chemical Risk Assessment

To the extent that EPA’s documents identified for each of these 

assumptions or choices a reason for its selection, when it would be applied 

in the risk assessment process, and its likely effect on risk assessment 

results, we have reported that information. However, it is important to 

recognize that there is no requirement that agencies provide such 

information in their guidelines (or even that they have guidelines). In 

particular with regard to the “likely effects” column, EPA officials 

cautioned that it is not always appropriate to characterize a single 

assumption separate from the rest and that it is not always possible to 

quantify the effect of each default assumption. They noted that, in general, 

their default assumptions are intended to be public-health protective. 

The information presented in table 5 was taken primarily from EPA risk 

assessment guidelines and related documents but also reflects additional 

comments provided by EPA officials. (GAO notes and comments appear in 

parentheses.)
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 120 GAO-01-810 Chemical Risk Assessment

Table 5: EPA Risk Assessment Assumptions and Methodological Choices

Assumption or methodological 

choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 

1. Agencywide (ORD) proposed carcinogen risk assessment guidelines

A carcinogen is a substance or agent that produces or incites cancerous growth. The following items reflect major assumptions or 

choices identified in the 1999 version of EPA’s proposed revision to its 1986 carcinogen risk assessment guidelines.

1.1

The guidelines use a combination of 

principles and process to describe a 

general framework for the application 

of, or departure from, default 

assumptions.

The proposed guidelines state that the 

decision to use a default, or not, is a 

choice considering available 

information on an underlying scientific 

process and agent-specific data, 

depending on which kind of data it is. 

Generally,

• If a gap in basic understanding exists, 

or if agent-specific data are missing, 

the default is used without pause.

• If data are present, their evaluation 

may reveal inadequacies that also 

lead to use of the default.

• If data support a plausible alternative 

to the default, but no more strongly 

than they support the default, both 

the default and its alternative are 

carried through the assessment and 

characterized by the risk manager.

• If the alternative to the default is 

strongly supported by data, the 

alternative may be used in place of 

the default.

(The discussion setting up this 

framework refers to reports by the 

National Academy of Sciences’

NRC. In particular, the guidelines 

note that, in 1994, NRC supported 

continued use of default 

assumptions as a reasonable way 

to deal with uncertainty about 

underlying mechanisms in 

selecting methods and models for 

use in risk assessment but also 

recommended that EPA should 

consider attempting to give 

greater formality to its criteria for a 

departure from default options.)

The framework of default 

assumptions allows risk 

assessment to proceed when 

current scientific theory or 

available case-specific data do not 

provide firm answers in a 

particular case.

(General framework outlined for 

determining whether or not to use 

default assumptions.)

(Not identified in the 

proposed guidelines.)
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 121 GAO-01-810 Chemical Risk Assessment

1.2

When cancer effects in exposed 

humans are attributed to exposure to 

an exogenous agent, the default 

assumption is that such data are 

predictive of cancer in any other 

exposed human population.

(Not identified in the proposed 

guidelines, but this is a standard 

assumption in risk assessment.)

When determining whether the 

presence or absence of effects 

observed in a human population is 

predictive of an agent posing a 

carcinogenic hazard to other 

exposed humans.

The guidelines caution 

that studies either 

attributing cancer 

effects in humans to 

exogenous agents or 

reporting no effects 

are often studies of 

occupationally 

exposed humans and, 

therefore, not 

representative of the 

general population 

exposed 

environmentally to the 

same agents. 

Therefore, the 

guidelines state that 

this assumption does 

not err on the side of 

public-health 

conservatism, 

because it could still 

underestimate the 

response of certain 

sensitive human 

subpopulations.

1.3

When cancer effects are not found in 

an exposed human population, this 

information by itself is not generally 

sufficient to conclude that the agent 

poses no carcinogenic hazard to this or 

other populations of potentially 

exposed humans, including sensitive 

subpopulations.

Epidemiologic studies usually 

have low power to detect and 

attribute responses and typically 

evaluate cancer potential in a 

restricted population (e.g., by age, 

occupation, etc.).

When determining whether the 

presence or absence of effects 

observed in a human population is 

predictive of an agent posing a 

carcinogenic hazard to other 

exposed humans.

(Not identified in the 

proposed guidelines.)

(Continued From Previous Page)

Assumption or methodological 

choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 122 GAO-01-810 Chemical Risk Assessment

1.4

Positive effects in animal cancer 

studies indicate that the agent under 

study can have carcinogenic potential 

in humans.

• To demonstrate that a response in 

animals is not relevant to any human 

situation, adequate data to assess 

the relevancy issue must be 

available.

The assumption is supported by 

the fact that nearly all of the 

agents known to cause cancer in 

humans are carcinogenic in 

animals in tests with adequate 

protocols [citations provided]. 

Moreover, almost one-third of 

human carcinogens were 

identified subsequent to animal 

testing [citations provided]. 

Further support is provided by 

research on the molecular biology 

of cancer processes, which has 

shown that the mechanisms of 

control of cell growth and 

differentiation are remarkably 

homologous among species and 

highly conserved in evolution.

• (Relevancy issue) There may be 

instances in which the use of an 

animal model would identify a 

hazard in animals that is not truly 

a hazard in humans [citation 

provided].

When determining whether the 

presence or absence of effects 

observed in an animal population 

is predictive of an agent posing a 

carcinogenic hazard to exposed 

humans, if no adequate human 

data are present.

Available mode of action 

information is studied for its 

implications in both hazard and 

dose-response assessment and its 

effect on default assumptions.

This assumption is a 

public-health 

conservative policy, 

and it is both 

appropriate and 

necessary given that 

we do not test for 

carcinogenicity in 

humans.

1.5

Effects seen at the highest dose tested 

are appropriate for assessment, but it 

is necessary that the experimental 

conditions be scrutinized.

• If adequate data demonstrate that the 

effects are solely the result of 

excessive toxicity rather than 

carcinogenicity of the tested agent 

per se, then the effects may be 

regarded as not appropriate to 

include in assessment of the potential 

for human carcinogenicity of the 

agent.

Animal studies are conducted at 

high doses in order to provide 

statistical power, the highest dose 

being one that is minimally toxic. 

Consequently, the question often 

arises whether a carcinogenic 

effect at the highest dose may be 

a consequence of cell killing with 

compensatory cell replication or of 

general physiological disruption, 

rather than inherent 

carcinogenicity of the tested 

agent. There is little doubt that 

this may happen in some cases, 

but skepticism exists among some 

scientists that it is a pervasive 

problem [citations provided].

When determining whether the 

presence or absence of effects 

observed in an animal population 

is predictive of an agent posing a 

carcinogenic hazard to exposed 

humans, if no adequate human 

data are present.

This is a matter of expert 

judgment, considering all of the 

data available about the agent, 

including effects in other toxicity 

studies, structure-activity 

relationships, and effects on 

growth control and differentiation.

(Not identified in the 

guidelines.)

(Continued From Previous Page)

Assumption or methodological 

choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 123 GAO-01-810 Chemical Risk Assessment

1.6

When cancer effects are not found in 

well-conducted animal cancer studies 

in two or more appropriate species and 

other information does not support the 

carcinogenic potential of the agent, 

these data provide a basis for 

concluding that the agent is not likely 

to possess human carcinogenic 

potential, in the absence of human 

data to the contrary.

(Not identified in the guidelines. 

Instead, the discussion focuses on 

the limitations of this default 

assumption. EPA notes, for 

example, that it is recognized that 

animal studies and epidemiologic 

studies have very low power to 

detect cancer effects and, in some 

situations, the tested animal 

species may not be predictive of 

effects in humans (e.g., arsenic).) 

When determining whether the 

presence or absence of effects 

observed in an animal population 

is predictive of an agent posing a 

carcinogenic hazard to exposed 

humans, in the absence of human 

data to the contrary.

The guidelines note 

that this default 

assumption about lack 

of cancer effects has 

limitations. For 

example, in some 

situations, the tested 

animal species may 

not be predictive of 

effects in humans. 

Therefore, the 

guidelines discuss the 

importance of using 

supplementary data to 

support conclusions 

that negative results in 

animal studies indicate 

a lack of human 

hazard.

1.7

Target organ concordance is not a 

prerequisite for evaluating the 

implications of animal study results for 

humans.

• An exception to the basic default of 

not assuming site concordance exists 

in the context of toxicokinetic 

modeling. Site concordance is 

inherently assumed when these 

models are used to estimate 

delivered dose in humans based on 

animal data.

Target organs of carcinogenesis 

for agents that cause cancer in 

both animals and humans are 

most often concordant at one or 

more sites [citations provided]. 

However, concordance by site is 

not uniform.

When determining whether the 

presence or absence of effects 

observed in an animal population 

is predictive of an agent posing a 

carcinogenic hazard to exposed 

humans.

“It is appropriate under these 

guidelines to consider the 

influences of route of exposure, 

metabolism, and, particularly, 

hormonal modes of action that 

may either support or not support 

target organ concordance between 

animals and humans. When data 

allow, these influences are 

considered in deciding whether the 

default remains appropriate in 

individual instances.”

This is a public-health 

conservative science 

policy.

(Continued From Previous Page)

Assumption or methodological 

choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 124 GAO-01-810 Chemical Risk Assessment

1.8

The default is to include benign tumors 

observed in animal studies in the 

assessment of animal tumor incidence 

if they have the capacity to progress to 

the malignancies with which they are 

associated.

This default is consistent with the 

approach of the National 

Toxicology Program and the 

International Agency for Research 

on Cancer and is somewhat more 

protective of public health than not 

including benign tumors in the 

assessment. This treats the 

benign and malignant tumors as 

representative of related 

responses to the test agent, which 

is scientifically appropriate 

[citation provided].

When determining whether the 

presence or absence of effects 

observed in an animal population 

is predictive of an agent posing a 

carcinogenic hazard to exposed 

humans.

In assessing findings from animal 

studies, a greater proportion of 

malignancy is weighed more 

heavily than a response with a 

greater proportion of benign 

tumors.

This is a science policy 

decision that is 

somewhat more 

conservative of public 

health than not 

including benign 

tumors in the 

assessment.

1.9

Benign tumors that are not observed to 

progress to malignancy are assessed 

on a case-by-case basis.

(Not identified in the proposed 

guidelines.)

When determining whether the 

presence or absence of effects 

observed in an animal population 

is predictive of an agent posing a 

carcinogenic hazard to exposed 

humans.

(Not identified in the 

proposed guidelines.)

1.10

There is a similarity of the basic 

pathways of metabolism and the 

occurrence of metabolites in tissues in 

regard to the species-to-species 

extrapolation of cancer hazard and 

risk.

(Not identified in the proposed 

guidelines.)

When extrapolating from animal 

studies and considering how 

metabolic pathways relate across 

species.

(Not identified in the 

proposed guidelines.)

1.11

For oral exposure, a human equivalent 

dose for adults is estimated from data 

on another species by an adjustment 

of animal applied oral dose by a 

scaling factor of body weight to the 

0.75 power. 

• The same factor is used for children.

This adjustment factor is used 

because it represents scaling of 

metabolic rate across animals of 

different sizes. (Also see reason 

cited under next assumption, and 

note that an interagency 

committee recommended this 

scaling factor as a default 

approach for federal agencies.)

• The same factor is used for 

children because it is slightly 

more protective than using 

children’s body weight.

When estimating human 

equivalent doses in extrapolating 

from animal studies.

Because the factor adjusts for a 

parameter that can be improved on 

and brought into more 

sophisticated toxicokinetic 

modeling, when such data become 

available, the default assumption 

of 0.75 power can be refined or 

replaced.

(Not identified in the 

proposed guidelines. 

However, from other 

sources, this is 

generally considered 

to provide the midpoint 

of plausible values.)

(Continued From Previous Page)

Assumption or methodological 

choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 125 GAO-01-810 Chemical Risk Assessment

1.12

For inhalation exposure, a humanequivalent dose for adults is estimated 

by default methodologies that provide 

estimates of lung deposition and of 

internal dose.

• Because of the differences for infants 

and children, for gases and aerosols, 

an adjustment is made for their 

breathing rate and their body weight.

This default assumption, like the 

one with oral exposure, is selected 

in part because it lays a 

foundation for incorporating better 

data. The use of information to 

improve dose estimation from 

applied, to internal, to delivered 

dose is encouraged, including use 

of toxicokinetic modeling instead 

of any default, where data are 

available.

• The guidelines point out that the 

processes of absorption, 

distribution, and elimination have 

important differences among 

infants and adults [citation 

provided].

When extrapolating from animal 

studies and considering how 

toxicokinetic processes relate 

across species.

Health conservatism is 

not an element in 

choosing the default.

1.13

For a route-to-route exposure 

extrapolation, the default assumption is 

that an agent that causes internal 

tumors by one route of exposure will be 

carcinogenic by another route if it is 

absorbed by the second route to give 

an internal dose.

The rationale is that for internal 

tumors an internal dose is 

significant no matter what the 

route of exposure. Additionally, 

the metabolism of the agent will be 

qualitatively the same for an 

internal dose.

When extrapolating from one route 

of exposure to another route and 

considering how toxicokinetic 

processes relate across species.

This is a qualitative assumption. 

The issue of quantitative 

extrapolation of the dose-response 

relationship from one route to 

another is addressed case by 

case. Adequate data are 

necessary to demonstrate that an 

agent will act differently by one 

route versus another route of 

exposure.

This is a qualitative 

assumption and is 

considered to be 

public-health 

conservative.

(Continued From Previous Page)

Assumption or methodological 

choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 126 GAO-01-810 Chemical Risk Assessment

1.14

If sufficient data are available, a 

biologically based model for both the 

observed range and extrapolation 

below that range may be used. 

When a biologically based model is not 

used,

• The default procedure for the 

observed range of data is to use a 

curve-fitting model for incidence data.

• For extrapolation outside of the 

observed range, the choice of 

approach is based on the view of 

mode of action of the agent arrived at 

in the hazard assessment (covered 

by items 1.15 through 1.17 below).

While no standard biologically 

based models are in existence, 

one may be developed if extensive 

data exist in a particular case and 

the purpose of the assessment 

justifies the investment of 

resources needed.

(See more specific assumptions 

described below for rationales 

regarding extrapolation when a 

biologically based model is not 

used.)

When assessing the correlation of 

the observed dose-response 

relationship to the relationship at 

lower doses. [Low-dose 

extrapolation during doseresponse assessment.]

In the absence of data supporting 

a biologically based model for 

extrapolation outside of the 

observed range, the choice of 

approach is based on the view of 

the mode of action of the agent 

arrived at in the hazard 

assessment.

(See more specific 

assumptions 

described below.)

1.15

When the mode of action information is 

supportive of linearity or mode of 

action is not understood, the basic 

default is to assume linearity and use a 

linear default approach.

The linear approach is to draw a 

straight line between a point of 

departure from observed data, 

generally, as a default, the LED10, and 

the origin (zero incremental dose, zero 

incremental response). Other points of 

departure may be more appropriate for 

certain data sets; these may be used 

instead of the LED10.

(Although not mentioned in the 

proposed guidelines, the 

assumption of linearity for 

suspected carcinogens 

traditionally has been a standard 

default assumption for EPA.)

The LED10 is the lower 95-percent 

limit on a dose that is estimated to 

cause a 10-percent response. 

This level is chosen to account 

(conservatively) for experimental 

variability. Additionally, it is 

chosen because it rewards 

experiments with better designs in 

regard to number of doses and 

dose spacing, since these 

generally will have narrower 

confidence limits. It is also an 

appropriate representative of the 

lower end of the observed range 

because the limit of detection of 

studies of tumor effect is about 10 

percent.

Low-dose extrapolation during 

dose-response assessment, in the 

absence of data supporting a 

biologically based model.

This approach is 

generally considered 

to be public-health 

conservative. The 

linear default is 

thought to generally 

produce an upper 

bound on potential risk 

at low doses. This 

upper bound is thought 

to cover the range of 

human variability 

although, in some 

cases, it may not 

completely do so. EPA 

considers the linear 

default to be inherently 

conservative of public 

health, without 

addition of another 

factor for human 

variability.

(Continued From Previous Page)

Assumption or methodological 

choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 127 GAO-01-810 Chemical Risk Assessment

1.16

When adequate data on mode of 

action show that linearity is not 

plausible, and provide sufficient 

evidence to support a nonlinear mode 

of action for the general population and 

any subpopulations of concern, the 

default changes to a different 

approach—a margin of exposure 

analysis—which assumes that 

nonlinearity is more reasonable. (A 

margin of exposure analysis compares 

the dose at the point of departure with 

the dose associated with the 

environmental exposure(s) of interest 

by computing the ratio between the 

two.)

The departure point is again generally 

the LED10 when incidence data are 

modeled. When the data available are 

continuous data, such as blood levels 

of hormones or organ weight, a 

NOAEL/LOAEL procedure is typically 

used. 

In the nonlinear approach, the 

margin that exists between a 

human exposure of interest and 

the point of departure is examined 

for adequacy to protect public 

health. A margin of exposure 

analysis may be used as the basis 

to consider the protectiveness of a 

possible environmental criterion 

for regulation or to judge whether 

an existing exposure might 

present risk.

According to the guidelines, the 

NOAEL/LOAEL procedures are 

used with continuous data 

because modeling approaches for 

deriving a point of departure from 

continuous data are not yet 

available. 

Low-dose extrapolation during 

dose-response assessment, in the 

absence of data supporting a 

biologically based model.

As noted in the first column, this 

default is to be used when 

adequate data on mode of action 

(1) show that linearity is not 

plausible and (2) provide sufficient 

evidence to support a nonlinear 

mode of action. The guidelines 

also state that a sufficient basis to 

support this nonlinear procedure 

will include data on responses that 

are key events integral to the 

carcinogenic process. This means 

that the point of departure mostly 

will be from these precursor data 

rather than tumor incidence data.

(Not identified in the 

proposed guidelines.)

1.17

When the mode of action information 

indicates that the dose response may 

be adequately described by both a 

linear and a nonlinear approach, then 

the default is to present both the linear 

and margin of exposure analyses.

(No additional discussion in the 

proposed guidelines. See 

previous assumptions regarding 

linear and nonlinear approaches.)

Low-dose extrapolation during 

dose-response assessment, in the 

absence of data supporting a 

biologically based model.

As noted in the first column, this 

default is to be used when mode of 

action information indicates that 

both a linear and a nonlinear 

approach may adequately 

describe the dose response.

(No additional 

discussion in the 

proposed guidelines. 

See previous 

assumptions regarding 

linear and nonlinear 

approaches.)

1.18

A default assumption is made that 

cumulative dose received over a 

lifetime, expressed as a lifetime 

average daily dose, is an appropriate 

measure of dose (exposure to a 

carcinogen).

This assumes that a high dose of 

such an agent over a shorter 

period of time is equivalent to a 

low dose spread over a lifetime. 

This assumption has empirical 

support [citation provided].

When assessing the correlation of 

the observed dose-response 

relationship to the relationship at 

lower doses. [Low-dose 

extrapolation during doseresponse assessment.]

This is thought to be a 

relatively public-health 

conservative 

assumption.

(Continued From Previous Page)

Assumption or methodological 

choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 128 GAO-01-810 Chemical Risk Assessment

2. Agencywide (ORD) guidelines for neurotoxicity risk assessment 

Neurotoxicity is an adverse change in the structure or function of the central and/or peripheral nervous system following exposure to a 

chemical, physical, or biological agent.

2.1

It is assumed that an agent that 

produces detectable adverse 

neurotoxic effects in experimental 

animal studies will pose a potential 

hazard to humans.

This assumption is based on the 

comparisons of data for known 

human neurotoxicants [citations 

provided], which indicate that 

experimental animal data are 

frequently predictive of a 

neurotoxic effect in humans.

When extrapolating data from 

animal studies to humans.

Generally applied in the absence 

of data on the relevance of effects 

to potential human risk.

These assumptions 

are “plausibly 

conservative” in that 

they are protective of 

public health and are 

also well founded in 

scientific knowledge 

about the effects of 

concern.

2.2

It is assumed that behavioral, 

neurophysical, neurochemical, and 

neuroanatomical manifestations are of 

concern.

A biologically significant increase in 

any of the manifestations is considered 

indicative of an agent’s potential for 

disrupting the structure or function of 

the human nervous system.

In the past, the tendency has been 

to consider only neuropathological 

changes as endpoints of concern. 

Based on data on agents that are 

known human neurotoxicants 

[citations provided], there is at 

least one experimental species 

that mimics the types of effects 

seen in humans, but in other 

species tested, the neurotoxic 

effect may be different or absent.

When extrapolating data from 

animal studies to humans.

Generally applied in the absence 

of data on the relevance of effects 

to potential human risk.

(See general 

statement about these 

assumptions cited 

above.)

2.3

It is assumed that the neurotoxic 

effects seen in animal studies may not 

always be the same as those produced 

in humans. Therefore, it may be 

difficult to determine the most 

appropriate species in terms of 

predicting specific effects in humans.

The fact that every species may 

not react in the same way is 

probably due to species-specific 

differences in maturation of the 

nervous system, differences in 

timing of exposure, metabolism, or 

mechanisms of action. 

When extrapolating data from 

animal studies to humans.

Generally applied in the absence 

of data on the relevance of effects 

to potential human risk.

(See general 

statement about these 

assumptions cited 

above.)

2.4

It is also assumed that, in the absence 

of data to the contrary, the most 

sensitive species is used to estimate 

human risk.

This is based on the assumption 

that humans are as sensitive as 

the most sensitive animal species 

tested. This provides a 

conservative estimate of 

sensitivity for added protection to 

the public.

When extrapolating data from 

animal studies to humans.

Generally applied in the absence 

of data on the relevance of effects 

to potential human risk.

Provides a 

conservative estimate 

of sensitivity. (Also 

see general statement 

about these 

assumptions cited 

above.)

(Continued From Previous Page)

Assumption or methodological 

choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 129 GAO-01-810 Chemical Risk Assessment

2.5

As with other noncancer endpoints, it is 

assumed that there is a nonlinear 

dose-response relationship for 

neurotoxicants.

Although there may be a threshold 

for neurotoxic effects, these are 

often difficult to determine 

empirically. Therefore, a nonlinear 

relationship is assumed to exist for 

neurotoxicants.

When extrapolating data from 

animal studies to humans.

Generally applied in the absence 

of data on the relevance of effects 

to potential human risk.

(See general 

statement about these 

assumptions cited 

above.)

3. Agencywide (ORD) guidelines for reproductive toxicity risk assessment

Reproductive toxicity focuses on toxic effects regarding the male and female reproductive systems, including outcomes of pregnancy and 

lactation.

3.1

An agent that produces an adverse 

reproductive effect in experimental 

animals is assumed to pose a potential 

threat to humans.

This assumption is based on 

comparisons of data for agents 

that are known to cause human 

reproductive toxicity [citations 

provided]. In general, the 

experimental animal data 

indicated adverse reproductive 

effects that are also seen in 

humans.

When extrapolating data from 

experimental animal studies to 

humans, in the absence of 

adequate human data

(Not identified in the 

guidelines.)

3.2

Effects of xenobiotics on male and 

female reproductive process are 

assumed generally to be similar unless 

demonstrated otherwise. 

For developmental outcomes, the 

specific effects in humans are not 

necessarily the same as those seen in 

the experimental species. However, 

adverse developmental outcomes in 

laboratory mammalian studies are 

presumed to predict a hazard for 

adverse developmental outcome in 

humans.

Because similar mechanisms can 

be identified in the male and 

female of many mammalian 

species, effects of xenobiotics on 

male and female reproductive 

processes are assumed generally 

to be similar across species, 

unless demonstrated otherwise.

The assumption for developmental 

outcomes is made because of the 

possibility of species-specific 

differences in timing of exposure 

relative to critical periods of 

development, pharmacokinetics 

(including metabolism), 

developmental patterns, 

placentation, or modes of action.

When extrapolating data from 

experimental animal studies to 

humans, in the absence of 

adequate human data.

(Not identified in the 

guidelines.)

(Continued From Previous Page)

Assumption or methodological 

choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 130 GAO-01-810 Chemical Risk Assessment

3.3

In the absence of information to 

determine the most appropriate 

experimental species, data from the 

most sensitive species should be used.

It is assumed that the most 

sensitive species is most 

appropriate because, for a 

majority of agents known to cause 

human reproductive toxicity, 

humans appear to be as or more 

sensitive than the most sensitive 

animal species tested, based on 

data from studies that determined 

dose on a body weight or air 

concentration basis [citations 

provided].

When extrapolating data from 

experimental animal studies to 

humans, in the absence of 

adequate human data, and in the 

absence of sufficient information 

(e.g., pharmacokinetic data) to 

determine the most appropriate 

experimental species.

(Not identified in the 

guidelines.)

3.4

In the absence of information to the 

contrary, an agent that affects 

reproductive function in one sex is 

assumed to adversely affect 

reproductive function in the other sex.

This assumption for reproductive 

risk assessment is based on three 

considerations: 

1. For most agents, the nature of 

the testing and data available 

are limited, reducing 

confidence that the potential 

for toxicity to both sexes and 

their offspring has been 

examined equally.

2. Exposures of either males or 

females have resulted in 

developmental toxicity. 

3. Many of the mechanisms 

controlling important aspects 

of reproductive system 

function are similar in females 

and males, and therefore 

could be susceptible to the 

same agents.

When extrapolating data from 

experimental animal studies to 

humans, in the absence of 

adequate human data.

In the absence of information to 

the contrary.

(Not identified in the 

guidelines.)

(Continued From Previous Page)

Assumption or methodological 

choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 131 GAO-01-810 Chemical Risk Assessment

3.5

A nonlinear dose-response curve is 

assumed for reproductive toxicity.

This is based on known 

homeostatic, compensatory, or 

adaptive mechanisms that must 

be overcome before a toxic 

endpoint is manifested and on the 

rationale that cells and organs of 

the reproductive system and the 

developing organism are known to 

have some capacity for repair of 

damage. 

Although a threshold may exist for 

endpoints of reproductive toxicity, 

it usually is not feasible to 

distinguish empirically between a 

true threshold and a nonlinear 

low-dose relationship.

When extrapolating data from 

experimental animal studies to 

humans, in the absence of 

adequate human data.

In a quantitative dose-response 

analysis, mode of action, 

pharmacokinetic, and 

pharmacodynamic information 

should be used to predict the 

shape of the dose-response curve 

when sufficient information of that 

nature is available. When that 

information is insufficient, it has 

generally been assumed that there 

is a nonlinear dose response for 

reproductive toxicity.

(Not identified in the 

guidelines.)

4. Agencywide (ORD) guidelines for developmental toxicity risk assessment 

Developmental toxicity risk assessment focuses on risk to human development, growth, survival, and function because of exposure to 

environmental agents prior to conception, prenatally, or to infants and children.

4.1

It is assumed that an agent that 

produces an adverse developmental 

effect in experimental animal studies 

will potentially pose a hazard to 

humans following sufficient exposure 

during development.

This assumption is based on the 

comparisons of data for agents 

known to cause human 

developmental toxicity [citations 

provided] which indicate that, in 

almost all cases, experimental 

animal data are predictive of a 

developmental effect in humans.

When extrapolating data from 

animal studies to humans for 

hazard identification/doseresponse analysis.

Generally applied in the absence 

of adequate human data.

(Not identified in the 

guidelines.)

4.2

It is assumed that all of the four 

manifestations of developmental 

toxicity (death, structural 

abnormalities, growth alternations, and 

functional deficits) are of concern. A 

biologically significant increase in any 

of the four manifestations is considered 

indicative of an agent’s potential for 

disrupting development and producing 

a developmental hazard.

In the past, there has been a 

tendency to consider only 

malformations or malformations 

and death as endpoints of 

concern. From data on agents 

that are known to cause human 

developmental toxicity [citations 

provided], there is usually at least 

one experimental species that 

mimics the types of effects seen in 

humans, but in other species 

tested, the type of developmental 

perturbation may be different.

When extrapolating data from 

animal studies to humans for 

hazard identification/doseresponse analysis.

Generally applied in the absence 

of adequate human data.

(Not identified in the 

guidelines.)

(Continued From Previous Page)

Assumption or methodological 

choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 132 GAO-01-810 Chemical Risk Assessment

4.3

It is assumed that the types of 

developmental effects seen in animal 

studies are not necessarily the same 

as those that may be produced in 

humans.

This assumption is made because 

it is impossible to determine which 

will be the most appropriate 

species in predicting the specific 

types of effects seen in humans. 

The fact that every species may 

not react the same way could be 

due to species-specific differences 

in critical periods, differences in 

timing of exposure, metabolism, 

developmental patterns, 

placentation, or mechanisms of 

action.

When extrapolating data from 

animal studies to humans for 

hazard identification/doseresponse analysis.

Generally applied in the absence 

of adequate human data.

(Not identified in the 

guidelines.)

4.4

The most appropriate species is used 

to estimate human risk when data are 

available (e.g., pharmacokinetics). In 

the absence of such data, it is 

assumed that the most sensitive 

species is appropriate for use.

This assumption is based on 

observations that humans are as 

sensitive or more so than the most 

sensitive animal species tested for 

the majority of agents known to 

cause human developmental 

toxicity [citations provided].

When extrapolating data from 

animal studies to humans for 

hazard identification/doseresponse analysis.

Generally applied in the absence 

of adequate human data.

(Not identified in the 

guidelines.)

4.5

In general, a threshold is assumed for 

the dose-response curve for agents 

that produce developmental toxicity.

This is based on the known 

capacity of the developing 

organism to compensate for or to 

repair a certain amount of damage 

at the cellular, tissue, or organ 

level. In addition, because of the 

multipotency of cells at certain 

stages of development, multiple 

insults at the molecular or cellular 

level may be required to produce 

an effect on the whole organism.

When evaluating the doseresponse relationship.(Not identified in the 

guidelines.)

4.6

For developmental toxic effects, a 

primary assumption is that a single 

exposure at a critical time in 

development may produce an adverse 

developmental effect, i.e., repeated 

exposure is not a necessary 

prerequisite for developmental toxicity 

to be manifested.

(Not identified in the guidelines.) When doing dose-response 

evaluation.

(Not identified in the 

guidelines.)

(Continued From Previous Page)

Assumption or methodological 

choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 133 GAO-01-810 Chemical Risk Assessment

4.7

If absorption [of the administered dose 

of an agent] in the experimental 

species has been determined, but 

human absorption is not known, 

human absorption is generally 

assumed to be the same as that for the 

species with the greatest degree of 

absorption.

(Not identified in the guidelines, 

but this assumption is a variation 

on the inference assumption 

identified under item 4.4, and 

other related EPA guidelines are 

referenced as well.)

When doing dose-response 

evaluation using data from animal 

studies.

(Not identified in the 

guidelines.)

4.8

When determining the reference dose 

or reference concentration for 

developmental toxicity:

• The most sensitive developmental 

effect from the most appropriate 

and/or sensitive mammalian species 

is used for determining the NOAEL, 

LOAEL, or benchmark dose.

• Uncertainty factors for developmental 

and maternal toxicity generally 

include a 10-fold factor for 

interspecies variation and a 10-fold 

factor for intraspecies variation. 

Additional factors may be applied to 

account for other uncertainties or 

additional information that may exist 

in the database. In general, an 

uncertainty factor is not applied to 

account for duration of exposure.

(Not identified in the section on 

RfD and RfC, but the assumptions 

regarding use of the most 

sensitive effect and most 

appropriate and/or sensitive 

species are variations on 

inference assumptions described 

above.)

When determining the reference 

dose or concentration for 

developmental toxicity (the RfDDT

or RfCDT) − a level at or below which 

it is assumed that no significant 

risk occurs.

(Not identified in the 

guidelines.)

(Continued From Previous Page)

Assumption or methodological 

choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 134 GAO-01-810 Chemical Risk Assessment

5. Agencywide (ORD) guidelines for health risk assessment of chemical mixtures (1999 draft of supplemental guidance)

5.1

For the component chemicals that 

show similar toxicity, dose addition is 

recommended. (When the effect of the 

combination is the effect expected from 

the equivalent dose of an index 

chemical, the equivalent dose is the 

sum of the component doses scaled by 

their potency relative to the index 

chemical. This sum of the exposure 

levels is a weighted sum.)

Dose addition is different from 

response addition because two 

assumptions are made: that all of the 

components have similar uptake, 

pharmacokinetics, and toxicologic 

processes, and that the (log probit) 

dose-response curves of the 

components are parallel.

Several studies have 

demonstrated that dose (or 

concentration) addition often 

predicts reasonably well the 

toxicities of mixtures composed of 

a substantial variety of both similar 

and dissimilar compounds 

(citations provided).

The assessment of multiple 

toxicant exposure has been 

addressed by the American 

Conference of Governmental 

Industrial Hygienists, OSHA, the 

World Health Organization, and 

the NRC (citations provided). 

Although the focus and purpose of 

each group was somewhat 

different, all of the recommended 

approaches included some type of 

dose-additive model.

Used in dose-response 

assessment.

Dose addition is the default 

approach in situations where 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 are 

then expected or observed in 

response to the higher dose level 

of the mixture.)

(Not identified in the 

guidelines.)

(Continued From Previous Page)

Assumption or methodological 

choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 135 GAO-01-810 Chemical Risk Assessment

5.2

For the component chemicals in a 

mixture that show dissimilar toxicity, 

response addition is recommended. 

(Under response addition, the general 

procedure is to first determine the risks 

per exposure for the individual 

components; the mixtures risk is then 

estimated by adding the individual 

risks together.)

Response addition is different from 

dose addition in that it does not 

assume similar kinetics or a similar 

mode of action and does not assume 

parallel dose-response curves. It 

assumes that the components of the 

mixture are considered to be 

functionally independent of one 

another at low-exposure levels, so that 

the risks may be added together. (This 

sum of the effects of the individual 

chemicals is a conditional sum.)

Dose-additive models may not be 

the most biologically plausible 

approach if the compounds do not 

have the same mode of toxicologic 

action.

Used in dose-response 

assessment.

Response addition is the default 

approach when the component 

chemicals are functionally 

independent. It is most often 

applied when an effect that is of 

concern is expected to be present 

at low-dose levels for each of the 

component chemicals, even 

though it is highly unlikely to be 

observable at these low levels in 

either epidemiologic or toxicologic 

studies.

Because response addition does 

not require a similar mode of action 

across the chemicals in the 

mixture, it allows for combining 

risks across different types of 

endpoints.

(Not identified in the 

guidelines.)

5.3

If interactions data are available, the 

default recommendation is that they be 

incorporated into the risk assessment 

either by using the interactions based 

hazard index or by including a 

qualitative assessment of the direction 

and magnitude of the impact of the 

interaction data.

(Not identified in the guidelines.) Used in dose-response 

assessment.

(Not identified in the 

guidelines.)

(Continued From Previous Page)

Assumption or methodological 

choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 136 GAO-01-810 Chemical Risk Assessment

6. Agencywide (ORD) guidelines for ecological risk assessment

These guidelines focus on exposures to one or more anthropogenic chemical, physical, or biological stressors that may result in adverse 

ecological effects. In comparison to the NAS risk paradigm, the information here reflects the novel approaches and methodological 

choices advocated by EPA in ecological risk assessments. Only a subset of the primary methodological choices are presented—rather 

than specific default assumptions, reflecting the level of specificity in EPA’s ecological risk assessment guidance document.

6.1

EPA advocates tiering ecological risk 

assessments such that conservative 

approaches are first employed in both 

data and model use, followed by a 

more detailed assessment process (if 

warranted).

When a risk has been identified, 

subsequent tiers use additional data to 

address the uncertainties of the initial 

assessment(s).

Examples of methodological choices in 

first tier of a ecological risk 

assessment:

• use simple rather than complex 

models;

• analyze uncertainty propagation and 

how uncertainty in individual 

parameters can affect the overall 

uncertainty in the results (e.g., 

calculate error bounds on a point 

estimate); and

• conduct tests designed to evaluate 

effects such as lethality and 

immobility.

Allows determinations regarding 

how extensive a risk assessment 

should be, taking into 

consideration risk management 

goals.

The underlying assumptions and 

the risk scenarios can be carried 

through to risk characterization 

phase in a first-tier risk 

assessment, allowing their 

plausibility to be discussed and 

reevaluated.

Applied in most ecological risk 

assessments.

Precautionary 

approach maintaining 

a higher degree of 

conservatism in the 

risk assessment.

(Continued From Previous Page)

Assumption or methodological 

choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 137 GAO-01-810 Chemical Risk Assessment

6.2

Methodological choices regarding data 

issues:

• When existing data are few and new 

data cannot be collected, consider 

extrapolation from existing data when 

characterizing effects of stressors on 

assessment endpoints.

• Employ field-observational studies 

that represent exposures and effects 

better than estimates generated from 

laboratory studies or theoretical 

models.

• Use statistical tests (e.g., correlation, 

clustering, factor analysis) or indices 

to measure and evaluate effects.

• Directly measure environmental 

media (or a combination of modeling 

and direct measurement) if stressors 

have already been released into the 

environment, if possible.

• Use point estimate/descriptor 

approach when there is not enough 

information to describe a distribution.

Better characterization of stressorassessment endpoint 

relationships and better ability to 

accurately formulate and address 

risk hypotheses:

• Extrapolation of data collected 

from other locations or on 

organisms where similar 

circumstances exist can be a 

useful proxy—particularly when 

obtaining original data is 

unachievable.

• Field-observational studies 

(surveys) are necessary to 

measure biological changes in 

uncontrolled situations that best 

mimic the relationship between 

assessment endpoint and 

stressor [citations provided].

• Large-scale ecological 

processes are difficult to detect 

in laboratory settings.

General data considerations 

during early first- and subsequenttier risk assessment stages of 

problem formulation phase—

particularly when data or 

relationships cannot be defined in 

a traditional laboratory setting or 

where assessments of multiple 

stressors or site-specific factors 

significantly influence exposure.

Studies that minimize the amount 

of extrapolation are preferred.

Data choice(s) can 

effect a risk 

assessment in a 

variety of ways, for 

example:

• More accurate 

conclusions in 

laboratory settings 

may be possible; 

however, laboratory 

controls may limit the 

range of responses 

and/or may not 

reflect responses in 

the environment.

• Results can be 

presented as a 

series of point 

estimates with 

different aspects of 

uncertainty reflected 

in each (e.g., 

classical statistical 

methods such as 

confidence limits, or 

percentiles, can be 

employed).

(Continued From Previous Page)

Assumption or methodological 

choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 138 GAO-01-810 Chemical Risk Assessment

6.3

Generally, potential dose of a chemical 

is quantified as the amount of chemical 

ingested, inhaled, and/or applied 

dermally.

Specifically, potential average daily 

dose for ingested media is a function 

of:

• average contaminant concentration in 

the type of food (using modeled or 

measured values);

• fraction of intake of the food type that 

is from the contaminated area;

• normalized ingestion rate of the food 

type on a wet-weight basis;

• number of contaminated food types.

Allows for the establishment of a 

standardized approach in deriving 

values of exposure for ingested 

media (food or soil).

Determination of dose in analysis 

phase.

(Not indicated in 

guidelines.)

(Continued From Previous Page)

Assumption or methodological 

choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 139 GAO-01-810 Chemical Risk Assessment

6.4

In creating an exposure profile, 

estimates of exposure should be 

considered, at a minimum, along three 

dimensions: intensity, time, and space. 

These, and other exposure guidelines, 

are outlined below:

• Intensity may be expressed as the 

amount of chemical contacted per 

day or the number of pathogenic 

organisms per unit area.

• The temporal dimension of exposure 

is best addressed with the 

parameters of duration, frequency, 

and timing.

• In its simplest form, a stressor is 

quantified as a concentration, with 

the assumption that the chemical is 

well mixed or that the organism 

moves randomly through the 

medium.

• “High end” exposure should refer to 

estimates that are expected to fall 

between the 90th and 99.9th percentile 

of the exposure distribution.

• Bounding estimates should refer to 

those higher than any actual 

exposure.

EPA advocates such 

methodological choices regarding 

exposure profiles in order to allow 

a risk assessor to best estimate 

risks. The exposure profile, in 

turn, is combined with an effects 

profile to estimate risks.

Production of a summary exposure 

profile during analysis phase that:

• identifies the receptor (i.e., the 

exposed ecological entity);

• describes the course a stressor 

takes from the source to the 

receptor (i.e., the exposure 

pathway); and

• describes the intensity and 

spatial and temporal extent of cooccurrence or contact.

(Not indicated in 

guidelines.)

(Continued From Previous Page)

Assumption or methodological 

choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 140 GAO-01-810 Chemical Risk Assessment

6.5

When sufficient data are available to 

quantify exposure and effects 

estimates, the simplest approach for 

comparing the estimates is a ratio (or 

quotient).

A quotient addition approach assumes 

that toxicities are additive or 

approximately additive (this 

assumption may be mostly applicable 

when the modes of action of chemicals 

in a mixture are similar).

Quotient method is commonly 

used for chemical stressors, 

where reference or benchmark 

toxicity values are widely 

available.

Principal reasons for selecting 

quotient method:

• It is simple and quick to use and 

risk assessors and managers 

are familiar with its application.

• It provides an efficient, 

inexpensive means of identifying 

high- or low-risk situations that 

can allow risk management 

decisions to be made without the 

need for further information.

• Quotients can be used to 

integrate risks of multiple 

chemical stressors.

When performing activities of risk 

characterization phase (i.e., risk 

estimation, risk description, 

reporting risk).

(Not indicated in 

guidelines.)

The following sections illustrate the types of additional, program-specific assumptions and choices identified by individual program offices 

within EPA. We only provide examples from two of EPA’s offices—the Office of Pesticide Programs and the Office of Water. However, 

other offices can also have their own preferences with regard to risk assessment assumptions and methods tied to the particular

exposures of concern to their programs.

(Continued From Previous Page)

Assumption or methodological 

choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 141 GAO-01-810 Chemical Risk Assessment

7. Office of Pesticide Programs science policy papers and guidance documents regarding risk assessments for pesticides

OPP has published an expanding series of over 20 science policy papers—many still at the draft stage—on various issues related to 

regulation of pesticides in response to the Food Quality Protection Act of 1996. The following rows illustrate some of the major 

assumptions or choices described within those science policy papers or guidance documents.

7.1

Applying the FQPA tenfold safety factor

The FQPA requires EPA to apply, in the 

case of threshold effects, an additional 

tenfold margin of safety for the 

pesticide chemical residue and other 

sources of exposure for infants and 

children to take into account potential 

pre- and postnatal toxicity and 

completeness of data with respect to 

exposure and toxicity to infants and 

children. The Administrator of EPA 

may use a different margin of safety for 

the pesticide chemical residue only if, 

on the basis of reliable data, such a 

margin will be safe for infants and 

children. 

Where reliable data are available, OPP 

favors an approach that attempts to 

make a specific case-by-case 

determination as to the size of the 

additional factor rather than rely on the 

tenfold default value.

Statutory provision of the FQPA, in 

section 408(b)(2)(C).

(In draft policy papers on this 

subject, EPA cited a number of 

reasons regarding the agency’s 

preference for making a case-bycase determination of an 

appropriate safety factor. The 

agency pointed out, in particular, 

that because OPP’s approach to 

estimating exposure in the 

absence of extensive, specific 

data is typically very conservative, 

OPP can usually conclude, with a 

high degree of confidence, that its 

approach adequately protects 

infants and children. EPA is also 

revising its toxicology and 

exposure data requirements in 

response to the FQPA.)

(This is primarily a “risk 

management” issue when EPA is 

“establishing, modifying, leaving in 

effect, or revoking a tolerance or 

exemption for a pesticide chemical 

residue.” However, it affects risk 

assessment by OPP in that it calls 

for a determination of whether the 

available data are reliable and a 

different “margin of safety” will be 

safe for infants and children.)

(The intent of this 

additional “safety 

factor” is 

precautionary—to give 

special consideration 

with respect to 

exposure and toxicity 

to infants and 

children.)

(Continued From Previous Page)

Assumption or methodological 

choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 142 GAO-01-810 Chemical Risk Assessment

7.2

Dietary exposure estimates (draft):

For regulatory purposes, acute and 

chronic dietary exposure to pesticides 

in foods are estimated using indirect 

modeling approaches that consider 

pesticide residues in food and the 

amount of food consumed. EPA 

assesses dietary exposure using a 

tiered approach, proceeding from 

conservative to more refined 

assumptions and varying by acute 

(short-term) and chronic (long-term) 

assessments. Initially, EPA uses 

deterministic assessments based on 

various assumptions about the 

concentration of pesticide residue in 

the food. For more refined dietary 

assessments, EPA uses probabilistic 

exposure assessments. (See details 

for these various tiers in rows 7.2.1 

through 7.2.4 below.]

The tiered approach is used to 

conserve limited resources.

When assessing dietary exposures 

to pesticides. Analysis proceeds 

through more rigorous tiers, as the 

overall risk assessment situation 

requires, when data exist.

(EPA characterizes the 

initial tiers, especially 

tier 1, as producing 

conservative exposure 

estimates. The higher 

level tiers are 

characterized as 

producing more 

accurate, and less 

conservative, 

exposure 

assessments.)

7.2.1

Tier 1 approach to estimating dietary 

risk from pesticides in foods (draft):

• Both acute and chronic assessments 

use deterministic values (point 

estimates) for exposure, assuming 

residues on foods to be at maximum 

legal tolerance levels and that 100 

percent of the crop is treated with the 

pesticide.

The tiered approach is used to 

conserve limited resources.

When assessing dietary exposures 

to pesticides. Analysis proceeds 

through more rigorous tiers, as the 

overall risk assessment situation 

requires, when data exist.

Tolerance levels for 

residues used in Tier 1 

dietary exposure 

estimates are not 

expected to accurately 

reflect actual residues 

in ready-to-eat foods; 

rather, they are 

intended to provide 

inputs for “worst-case”

exposure estimates. 

Residue data for Tier 1 

assessments meet the 

criterion for 

conservative exposure 

factors.

(Continued From Previous Page)

Assumption or methodological 

choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 143 GAO-01-810 Chemical Risk Assessment

7.2.2

Tier 2 approach to estimating dietary 

risk from pesticides in foods (draft):

• Acute assessments use deterministic 

values for exposure and assume that 

residues on single-serving size items 

are at maximum legal tolerance 

levels, residues for blended 

commodities are based on average 

residue from field trials or monitoring 

data, and 100 percent of the crop is 

treated with the pesticide. 

• Chronic assessments use 

deterministic values and assume 

residues are at tolerance levels, but 

use actual percentage of the crop 

treated.

The tiered approach is used to 

conserve limited resources.

When assessing dietary exposures 

to pesticides. Analysis proceeds 

through more rigorous tiers, as the 

overall risk assessment situation 

requires, when data exist.

Assessments are 

refined in Tier 2 using 

more realistic values 

for pesticide residues.

(In its guidance for 

performing aggregate 

exposure 

assessments, OPP 

noted that field trial 

data, which are 

traditionally the 

primary source of 

residue data in foods, 

overestimate the 

residues that are likely 

to occur in foods as 

actually consumed. 

According to the 

agency, this is 

because they reflect 

the maximum 

application rate and 

shortest pre-harvest 

interval, and represent 

residue levels “at the 

farm gate.” OPP 

pointed out that data 

more reflective of 

residues on foods as 

consumed are often 

available from 

monitoring data in 

which food samples 

are obtained closer to 

the dinner table in the 

chain of commerce 

and analyzed.)

(Continued From Previous Page)

Assumption or methodological 

choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 144 GAO-01-810 Chemical Risk Assessment

7.2.3

Tier 3 approach to estimating dietary 

risk from pesticides in foods (draft):

• Acute assessments use probabilistic 

values (distributional estimates), an 

empirical distribution frequency from 

field trials for single-serving items, 

average residue data from field trials 

or monitoring data for blended 

commodities, and actual percentage 

of the crop treated. These 

assessments also consider food 

processing factors.

• Chronic assessments use 

deterministic values, average residue 

data from field trials or monitoring 

data for both blended and singleserving commodities, and actual 

percentage of the crop treated. 

Again, food processing factors are 

considered.

 

The tiered approach is used to 

conserve limited resources.

When assessing dietary exposures 

to pesticides. Analysis proceeds 

through more rigorous tiers, as the 

overall risk assessment situation 

requires, when data exist.

In Tiers 3 and 4, 

pesticide residue data 

are combined with 

assumptions on actual 

pesticide application 

rates, stability, etc., to 

refine further residue 

estimates in foods as 

they are consumed.

(See note on field trial 

and monitoring data in 

row 7.2.2 above.)

7.2.4

Tier 4 approach to estimating dietary 

risk from pesticides in foods (draft):

• Acute assessments use probabilistic 

values, market basket survey data on 

consumption, actual percentage of 

the crop treated, and consider 

cooking, residue decline, residue 

degradation, and other factors that 

may affect residues in foods as they 

are consumed.

• Chronic assessments use the same 

types of data as acute assessments, 

but with deterministic values. 

The tiered approach is used to 

conserve limited resources.

When assessing dietary exposures 

to pesticides. Analysis proceeds 

through more rigorous tiers, as the 

overall risk assessment situation 

requires, when data exist.

In Tiers 3 and 4, 

pesticide residue data 

are combined with 

assumptions on actual 

pesticide application 

rates, stability, etc., to 

refine further residue 

estimates in foods as 

they are consumed.

(Continued From Previous Page)

Assumption or methodological 

choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 145 GAO-01-810 Chemical Risk Assessment

7.3 Assessing Residential Exposures

EPA notes that although its residential 

exposure assessments “are designed 

to be as realistic as possible,” the 

assessments also are “generally 

conservative.” Specific assumptions 

include:

a. Assume high amounts of pesticide 

residues will transfer to a person. 

(EPA generally assumes 20-50 

percent of the residues will 

transfer.)

b. Assume no residue dissipation. In 

other words, all the residues 

available initially are available 

throughout the time a person is 

exposed.

c. Assume that a person has no 

clothing on to protect from 

exposure.

d. Assume 2 to 8 hours of continuous 

contact.

(Note that EPA was reviewing and 

considering whether to update some of 

the detailed exposure scenario 

assumptions in its standard operating 

procedures (SOPs) for residential 

assessments.)

This conservatism adds an extra 

measure of safety when regulating 

pesticides.

Explanations for the specific 

assumptions include:

a. The highest reasonably 

possible transfer rate must be 

assumed for safety.

b. Dissipation rate is based on 

many factors (heat, sunlight, 

and rain, etc.) so EPA says it 

must include the conservative 

prospect that in a given case 

there is no residue 

dissipation.

c. Assumed because little or no 

clothing is a possible realistic 

scenario in some 

circumstances.

d. (No additional explanation 

provided.)

When assessing risks associated 

with residential exposures to 

(residential uses of) pesticides.

EPA said that when 

scientists have studied 

people in the real 

world (including the 

children of 

farmworkers) they 

have generally found a 

person’s exposure to 

be less than that 

predicted by EPA’s 

exposure 

assessments.

(In other guidance 

documents, EPA 

points out that its 

residential SOPs are 

by nature designed to 

produce screeninglevel assessments that 

are intentionally 

conservative in 

nature.)

(Continued From Previous Page)

Assumption or methodological 

choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 146 GAO-01-810 Chemical Risk Assessment

7.4 Guidance for Performing 

Aggregate Exposure and Risk 

Assessment

Aggregate exposure and risk 

assessment involves the analysis of a 

single chemical exposure by multiple 

pathways of exposure (i.e., food, 

drinking water, and residential, 

nonoccupational), and all relevant 

routes of exposure (i.e., oral, dermal, 

and inhalation). EPA’s revised 

guidelines support an approach in 

which an analyst assesses exposure 

on an individual-by-individual basis, 

culminating in a representative 

population of interest. This approach 

differs from EPA’s interim guidelines. 

(According to the interim guidelines, 

aggregate assessments most 

frequently added the “high-end” or 

upper-bound point estimates from the 

drinking water and residential 

exposure pathways to a point on the 

distribution of food ingestion exposure, 

e.g., the 99.9th percentile.) 

Aggregate exposure and risk 

assessments will be more realistic to 

the extent that the appropriate 

temporal, spatial, and demographic 

factors that affect exposure to an 

individual are understood and 

accounted for. When these data are 

not available, reasonable assumptions 

that do not underestimate exposure 

can be used. Once an aggregate 

exposure and risk assessment is 

completed for one individual and 

repeated for many individuals, 

population and subpopulation 

distributions of total exposures and risk 

may be constructed by probabilistic 

techniques. Distributional data 

analysis is preferred.

(EPA revised its approach to 

aggregate exposure and risk 

assessment in response to the 

FQPA’s requirement that the 

agency consider aggregate 

exposure in its decision making.)

EPA noted in the guidance that 

aggregate exposure assessments 

built individual by individual, 

culminating in a total exposure to 

the population, may allow for 

probabilistic treatment of data 

incorporating all pathways of 

exposure, (i.e., food, drinking 

water, and residential).

Distributional data analysis is 

preferred as this tool allows an 

aggregate exposure assessor to 

more fully understand the 

uncertainty and variability inherent 

in the data set.

When performing aggregate 

exposure and risk assessments

(Not directly 

addressed in the 

general discussion in 

the revised guidance. 

The inference from 

EPA’s comparison to 

the interim guidance is 

that the revised 

practices should result 

in less conservative 

estimates than the 

interim practices. 

However, the revised 

guidance also 

emphasizes the use of 

“reasonable 

assumptions that do 

not underestimate 

exposure” when data 

are not available, so 

there still may be a 

precautionary 

element.)

(Continued From Previous Page)

Assumption or methodological 

choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 147 GAO-01-810 Chemical Risk Assessment

8. Office of Water Risk Assessments

OW has published a collection of guidance documents relating to water quality issues, based primarily on mandates derived from the 

Clean Water Act (CWA) and Safe Drinking Water Act (SDWA). For illustrative purposes, emphasis here is on assumptions and 

methodological choices taken from Methodology for Deriving Ambient Water Quality Criteria for the Protection of Human Health, EPA822-B-00-005 (October 2000). This document provides detailed guidance on developing Ambient Water Quality Criteria (AWQC), with 

organized procedures for evaluating cancer risk, noncancer health effects, human exposure, and bioaccumulation potential in fish. In this 

guidance, EPA states that protective assumptions are made regarding potential human exposure intakes at an appropriate level of

conservatism where uncertainties exist. Furthermore, criteria are derived to be protective, not predictive, of an exact percentile of the 

total population that is protected.

8.1

EPA has identified a number of 

standard or default exposure factors:

• All drinking water consumed is 

contaminated at the criteria level.

• All fish consumed is contaminated at 

the criteria level and all fish may 

come from one water body.

• Body weight of a child ages 1 to 3 is 

13 kg (when the age group is ages 1 

to 14, body weight is 30 kg).

• Body weight of an adult is 70 kg.

• Body weight of a woman of 

childbearing age is 67 kg.

• Daily untreated surface water 

consumed is 2 liters.

• Daily fish consumption is 17.5 g for 

general adult population and 

(average) sport fishers; 142.4 g for 

subsistence fishers.

• Criteria generally represent ambient 

pollutant concentrations that are 

acceptable based on a lifetime (70 

years) of exposure.

Body weight, water intake, and 

fish intake are default parameters 

specific to target populations that 

are considered important when 

determining AWQC values.

Drinking water and fish intake 

values are 90th percentile 

estimates, based on most recent 

USDA survey data reflecting the 

90th percentile of the general 

population (1994-96 CSFII data), 

and are percentiles selected to 

ensure protection of the majority 

of consumers of drinking water 

and fish.

Used in the derivation of AWQC, 

and also, to be consistent with 

Section 101(a) of CWA which 

specifies possible water body uses 

(e.g., consumption of fish).

Conservative 

assumptions in 

choosing exposure 

parameters support 

the goal of protecting 

the majority of the 

population.

(Continued From Previous Page)

Assumption or methodological 

choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 148 GAO-01-810 Chemical Risk Assessment

8.2

In setting RfDs for noncarcinogens, 

EPA advocates the use of uncertainty 

factors and, if needed, a modifying 

factor to account for areas of scientific 

uncertainty in toxicity databases. EPA 

recommends a default of 10 for 

uncertainty factors and a default of 1 

for modifying factors when lacking 

other information.

Specifically, EPA recommends 

applying a 1-, 3-, or 10-fold uncertainty 

factor when: 

a. extrapolating from valid data in 

studies using long-term exposure 

to average healthy humans;

b. extrapolating from valid results of 

long-term studies on experimental 

animals when results of studies of 

human exposure are not available 

or inadequate;

c. extrapolating from less-thanchronic results on experimental 

animals when there are no useful 

long-term human data; or

d. deriving an RfD from an 

“incomplete” database.

EPA recommends a 3- or 10-fold 

uncertainty factor when:

e. deriving an RfD from a LOAEL, 

instead of a NOAEL.

EPA advocates using professional 

judgment in determining the modifying 

factor, the magnitude of which is 

greater than zero and less than or 

equal to 10, being dependent on 

assessment of uncertainties of relevant 

studies and databases.

Uncertainty factors listed in the 

previous column are used to more 

accurately determine an RfD by 

more closely identifying and 

incorporating, respectively:

a. interhuman variability (to 

account for variation in 

sensitivity among the 

members of the human 

population);

b. experimental animal-tohuman extrapolation 

(interspecies variation);

c. subchronic to chronic 

extrapolation (to account for 

uncertainty in extrapolating 

from less-than-chronic 

NOAELs or LOAELs to 

chronic NOAELs);

d. database completeness (to 

account for the inability of any 

single study to adequately 

address all possible adverse 

outcomes); and

e. LOAEL-to-NOAEL 

extrapolation.

A modifying factor is to be used 

when the areas of scientific 

uncertainty addressed with 

uncertainty factors do not 

represent all of the uncertainties in 

the estimation of a RfD.

Deriving water quality criteria for 

the protection of human health 

from noncancer effects (i.e., 

noncarcinogenic chemicals) via 

the determination RfDs.

Specifically, the RfD is used with 

additional information regarding 

exposure and the bioaccumulation 

potential of the substance to derive 

an AWQC for noncancer effects.

According to EPA, the “[c]hoice of 

appropriate uncertainty factors and 

modifying factors must be a caseby-case judgment by experts and 

should account for each of the 

applicable areas for uncertainty 

and nuances in the available data 

that impact uncertainty.”

Conservative 

approach resulting in 

lower RfD values.

(Continued From Previous Page)

Assumption or methodological 

choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 149 GAO-01-810 Chemical Risk Assessment

8.3

EPA identified both 10-6 and 10-5 as 

appropriate cancer target risk levels, 

and said that highly exposed 

populations should not exceed a 10-4

cancer risk level.

Cancer risk level of 10-6 is based on a 

fish intake rate of 17.5 g/day for 

general population and sport anglers, a 

fish intake rate of 142.4 g/day for 

subsistence fishers, and a drinking 

water intake rate of 2 liters per day for 

each of these groups.

Such values reflect appropriate 

target risk levels for health 

protection of the general 

population.

The cancer risk levels increase the 

degree of consistency between 

the drinking water program, 

ambient water program, and other 

EPA programs.

(None given.) (None given.)

8.4

Under some circumstances, it may be 

appropriate to use a point within an 

RfD range as the basis for deriving 

AWQC, rather than the single point 

default estimate of the RfD, when the 

uncertainty factor is 100 or greater and 

the range is either a quarter or half log 

unit to either side of the calculated RfD.

This methodological choice offers 

some flexibility for site-specific or 

contaminant-specific situations but 

remains protective of public 

health.

Where either new risk assessment 

studies or site-specific information 

support derivation of an AWQC 

from a point within RfD range.

AWQC may increase 

or decrease.

8.5

Consideration of nonwater sources of 

exposure (e.g., ingestion and/or 

inhalation exposure) is recommended 

when determining a relative source 

contribution (RSC) factor to apply to a 

nonlinear carcinogen point-ofdeparture (POD) or a RfD.

Apply an estimate of the RSC factor 

(between 20 and 80 percent) to the 

RfD when adequate exposure data do 

not exist, using an exposure decision 

tree approach.

In deriving RfD, use of RSC allows 

for assessing total human 

exposure to a contaminant and 

apportions the RfD among the 

media of concern.

• Use of “Exposure Decision Tree”

approach allows for use of either 

subtraction or percentage 

methods, depending on 

chemical circumstances, within 

the 20- to 80- percent range.

Derivation or revision of an AWQC 

based on RfDs or nonlinear 

carcinogen PODs.

Conservative and 

protective approach 

when known or 

anticipated nonwater 

sources of exposure 

are anticipated.

(Continued From Previous Page)

Assumption or methodological 

choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 150 GAO-01-810 Chemical Risk Assessment

Source: Compiled from GAO review of EPA risk assessment guidelines and related documents and 

from additional comments provided by agency officials.

Risk Characterization As with exposure assessment, the program offices typically are responsible 

for completing the risk characterization. EPA does, however, have several 

documents that provide agencywide guidance on how such 

characterization is to be done. The guidance includes a February 26, 1992, 

memorandum from the EPA Deputy Administrator entitled, “Guidance on 

Risk Characterization for Risk Managers and Risk Assessors,” and a March 

21, 1995, document issued by the EPA Administrator entitled, “Policy for 

Risk Characterization at the U.S. Environmental Protection Agency.” EPA 

also has developed a Risk Characterization Handbook to provide more 

detailed guidance to agency staff. 

In the statement accompanying its 1994 report Science and Judgment in 

Risk Assessment, NRC said that although EPA’s overall approach for 

assessing risks was fundamentally sound, the agency “must more clearly 

establish the scientific and policy basis for risk estimates and better 

describe the uncertainties in its estimates of risk.” In March 1995, the EPA 

Administrator issued the agency’s risk characterization policy and 

guidance, which reaffirmed the principles and guidance in the agency’s 

1992 policy. EPA’s guidance document defined risk characterization as the 

final step in the risk assessment process that (1) integrates the individual 

characterizations from the hazard identification, dose-response, and 

exposure assessments; (2) provides an evaluation of the overall quality of 

the assessment and the degree of confidence the authors have in the 

estimates of risk and conclusions drawn; (3) describes the risks to 

individuals and populations in terms of extent and severity of probable 

harm; and (4) communicates the results of the risk assessment to the risk 

8.6

EPA recommends using a 

bioaccumulation factor (BAF) rather 

than a bioconcentration factor as 

previously set forth in the 1980 

Methodology.

This change was made in order to 

reflect the uptake of a contaminant 

by aquatic organisms from all 

sources (e.g., water, food, 

sediment) rather than just from the 

water column.

BAF values are used in 

calculations of AWQC for 

carcinogens (in both linear and 

nonlinear approaches) and for 

noncarcinogens.

The ambient water 

quality criteria for 

highly bioaccumulative 

pollutants may be up 

to 2 orders of 

magnitude lower than 

criteria derived with 

bioconcentraton 

factors.

(Continued From Previous Page)

Assumption or methodological 

choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 151 GAO-01-810 Chemical Risk Assessment

manager. Discussing “guiding principles” for risk characterization, EPA 

emphasized that the integration of information from the three earlier stages 

of risk assessment, discussion of uncertainty and variability, and 

presentation of information to risk managers requires the use of both 

qualitative and quantitative information. For example, when assumptions 

are made in exposure assessment, EPA said that the source and general 

logic used to develop the assumptions should be described, as well as the 

confidence in the assumptions made and the relative likelihood of different 

exposure scenarios. 

In the 1995 policy statement, EPA said that risks should be characterized in 

a manner that is clear, transparent, reasonable, and consistent with other 

risk characterizations of similar scope. EPA said that all assessments 

“should identify and discuss all the major issues associated with 

determining the nature and extent of the risk and provide commentary on 

any constraints limiting fuller exposition.” The policy also said risk 

characterization should (1) bridge the gap between risk assessment and 

risk management decisions; (2) discuss confidence and uncertainties 

involving scientific concepts, data, and methods; and (3) present several 

types of risk information (i.e., a range of exposures and multiple risk 

descriptors such as high ends and central tendencies). The policy stated 

that each risk assessment used in support of decision making at EPA 

should include a risk characterization that follows the principles and 

reflects the values outlined in the policy. However, the policy statement 

went on to say that it and the associated guidance did not establish or 

affect legal rights or obligations.

Some of EPA’s other risk assessment guidelines also discuss and 

recommend certain approaches to the risk characterization phase. For 

example, EPA’s proposed guidelines for carcinogen risk assessment call for 

greater emphasis on the preparation of “technical” characterizations to 

summarize the findings of the hazard identification, dose-response 

assessment, and exposure assessment steps. The agency’s risk assessors 

are then to use these technical characterizations to develop an integrative 

analysis of the whole risk case. That integrative analysis is in turn used to 

prepare a less extensive and nontechnical Risk Characterization Summary 

intended to inform the risk manager and other interested readers. EPA 

identified several reasons for individually characterizing the results of each 

analysis phase before preparing the final integrative summary. One is that 

the analytical assessments are often done by different people than those 

who do the integrative analysis. The second is that there is very often a 

lapse of time between the conduct of hazard and dose-response analyses 
Appendix II

Chemical Risk Assessment at the 

Environmental Protection Agency

Page 152 GAO-01-810 Chemical Risk Assessment

and the conduct of the exposure assessment and integrative analysis. 

Thus, according to EPA, it is necessary to capture characterizations of 

assessments as the assessments are done to avoid the need to go back and 

reconstruct them. Finally, several programs frequently use a single hazard 

assessment for different exposure scenarios. The guidelines also point out 

that the objective of risk characterization is to call out any significant 

issues that arose within the particular assessment being characterized and 

inform the reader about significant uncertainties that affect conclusions, 

rather than to recount generic issues that are covered in agency guidance 

documents.

In another example, EPA’s ecological risk guidelines emphasize that risk 

characterization is a means for clarifying relationships between stressors, 

adverse effects, and ecological entities. In addition, this phase of the risk 

assessment process is a time to reach conclusions regarding the 

occurrence of exposure(s) and the adversity of existing or anticipated 

effects. Specifically, EPA guidance describes three ecological risk 

characterization activities: (1) risk estimation (i.e., integrating exposure 

and effects data and evaluating uncertainties); (2) risk description (i.e., 

interpreting and discussing available information about risks to the 

assessment endpoints); and (3) risk reporting (i.e., estimating risks 

indicating the overall degree of confidence in such estimates, citing lines of 

evidence to support risk estimates, and addressing assumptions and 

uncertainties). Similar to EPA-wide guidance on risk characterization, 

EPA’s ecological risk characterization guidelines emphasize open 

communication with risk managers and other interested parties to clearly 

convey information needed for decision making in a risk management 

context.

It is also EPA’s policy that major scientifically and technically based work 

products related to the agency’s decisions normally should be peer 

reviewed to enhance the quality and credibility of the agency’s decisions. 

With regard to EPA’s chemical risk assessments, peer review can be used 

for evaluating both specific assessments and the general methods EPA uses 

in its risk assessments. Peer review generally takes one of two forms: 

(1) internal peer review by a team of relevant experts from within EPA who 

have no other involvement with respect to the work product that is to be 

evaluated or (2) external peer review by a review team that consists 

primarily of independent experts from outside EPA. In December 2000, 

EPA released a revised edition of its Peer Review Handbook for use within 

the agency.
Page 153 GAO-01-810 Chemical Risk Assessment

Appendix III

Chemical Risk Assessment at the Food and 

Drug Administration ApendxiI

The Food and Drug Administration (FDA) within the Department of Health 

and Human Services regulates the safety of a large number and wide 

variety of consumer products, including foods, cosmetics, human and 

animal medicines, medical devices, biologics (such as vaccines and blood 

products), and radiation-emitting products (such as microwave ovens). 

Chemical risk assessments are primarily conducted by three of FDA’s five 

product-oriented centers—the Center for Food Safety and Applied 

Nutrition (CFSAN), the Center for Veterinary Medicine (CVM), and the 

Center for Devices and Radiological Health (CDRH). The chemical risk 

assessment activities of these centers vary depending on factors such as 

the underlying statutory requirements, the substances being regulated, 

whether cancer or noncancer effects are of concern, and whether a 

product is under pre- or postmarket scrutiny. FDA officials said that the 

agency generally follows the National Academy of Sciences’ (NAS) fourstep risk assessment process, although it has not developed written 

internal guidelines. FDA often incorporates conservative assumptions into 

its assessments when information essential to a risk assessment is not 

known, but such assumptions are supposed to be scientifically plausible 

and consistent with agency regulations or policies. For example, CFSAN 

assumptions are expected to be reasonably protective of human health. 

FDA does not have an official policy on how risk assessment results should 

be characterized and communicated to policymakers and the public. 

However, FDA officials said that, in practice, they use a standard approach 

that typically highlights the assumptions with the greatest impact on the 

results of an analysis, states whether the assumptions used were 

conservative, and shows the implications of different choices.
Appendix III

Chemical Risk Assessment at the Food and 

Drug Administration

Page 154 GAO-01-810 Chemical Risk Assessment

Context for FDA 

Chemical Risk 

Assessment

FDA’s regulatory authority is primarily derived from the Federal Food, 

Drug, and Cosmetic Act, as amended (FFDCA), although several related 

public health laws (e.g., the Food and Drug Administration Modernization 

Act of 1997, or FDAMA) provide additional authority. FDA administers its 

regulatory responsibilities through its five product-oriented centers: (1) 

CFSAN, (2) CVM, (3) CDRH, (4) the Center for Drug Evaluation and 

Research, and (5) the Center for Biologics Evaluation and Research. FDA 

officials said that, although each of these five product centers conducts 

some type of risk assessments, the first three primarily conduct the 

chemical risk assessments that are the focus of this report.1

 Each of these 

centers has different responsibilities, authorities, and constraints on its 

regulatory and risk assessment activities. 

1

Some of the offices focused on in this appendix also conduct other, nonchemical, types of 

risk assessments. For example, the Center for Devices and Radiological Health also uses 

risk assessments to determine the carcinogenic, genetic, and/or reproductive health risks 

associated with radiation-emitting products. The Center’s reviews of medical devices are 

also likely to consider engineering risk assessments and the potential adverse effects of 

exposure to microbial contamination. The Center for Veterinary Medicine and the Center 

for Food Safety and Applied Nutrition also carry out microbiological risk assessments.
Appendix III

Chemical Risk Assessment at the Food and 

Drug Administration

Page 155 GAO-01-810 Chemical Risk Assessment

• CFSAN is responsible for the regulation of food additives, color 

additives used in food, and cosmetic additives.2

 Under the FFDCA, the 

regulation of substances intentionally added to food or used in contact

with food must be based solely on the safety of the substances for their 

intended uses (i.e., consideration of benefits and costs is not allowed). 

A food containing an unapproved food or color additive is considered 

“unsafe” unless FDA issues a regulation approving its use or, in the case 

of a food contact substance, there exists an effective notification.3

 To 

obtain an authorizing regulation or an effective notification, the sponsor 

of a food or color additive must show that it is safe for its intended use. 

FDA regulations under the FFDCA define a product as safe if there is “a 

reasonable certainty in the minds of competent scientists that the 

substance is not harmful under the intended conditions of use.”

4

 For 

food additives and color additives that are not themselves carcinogenic 

but contain carcinogenic impurities, CFSAN uses a quantitative risk 

assessment to determine whether the risk posed by a carcinogenic 

impurity is acceptable (i.e., a lifetime risk below one per million) under 

the FFDCA’s general safety clause of “reasonable certainty of no harm.” 

Nevertheless, if the food or color additive itself is a known carcinogen, 

under the “Delaney Clause” amendments to FFDCA, it cannot be 

deemed safe and is prohibited from use in food.5

 CFSAN is also 

involved with substantial activities in the area of postmarket concerns 

with contaminants and naturally occurring toxicants. For example, in 

the past year, CFSAN participated in a number of major, international 

chemical risk assessments in the areas of dioxins and various 

mycotoxins.

2

FDA’s responsibility in the food area covers all food except meat, poultry, and egg products, 

which are under the authority of the U.S. Department of Agriculture. Generally, FDA 

regulates food products sold in interstate commerce, whereas products made and sold 

entirely within a state are regulated by that state.

3

Section 309 of FDAMA of 1997.

4

21 CFR 170.3(i).

5

21 U.S.C. 348 (c)(3)(A) on food additives and 379e(b)(5)(B) on color additives. The Food 

Quality Protection Act of 1996 eliminated application of the Delaney proviso to pesticides.
Appendix III

Chemical Risk Assessment at the Food and 

Drug Administration

Page 156 GAO-01-810 Chemical Risk Assessment

• CVM’s primary role is to implement the FFDCA requirement that animal 

drugs and medicated feeds are safe and effective for their intended uses 

and that food from treated animals is safe for human consumption. 

Under the FFDCA, the regulation of residues of animal drugs that 

become a part of food because of the use of the animal drug must be 

based solely on health factors (i.e., consideration of benefits and costs is 

not allowed). A carcass or any of its parts that contain residues of an 

unapproved drug, or residues of an approved drug above approved 

levels, is considered to be unsafe and the carcass is considered 

adulterated. CVM uses risk assessment to help develop safe 

concentration levels in edible tissues, residue tolerances for postmarket 

monitoring, and withdrawal periods for slaughter following drug 

treatment. For noncancer effects, the applicable safety standard under 

FFDCA is that that these concentrations, tolerances, and withdrawal 

periods should represent a “reasonable certainty of no harm.” FFDCA 

includes provisions that permit FDA to authorize extralabel uses of an 

animal drug that would pose a “reasonable probability” of risk to human 

health if residues of the drug are consumed. The agency may establish a 

safe level for the residue and require that the drug sponsor provide an 

analytical method for detecting residues of such a compound.6

 

However, the act prohibits use in food-producing animals of any 

compound found to induce cancer when ingested by people or animals 

unless it can be determined that “no residue” of that compound will be 

found in the food produced from those animals under conditions of use 

reasonably certain to be followed in practice.7

 FDA has interpreted the 

intention of the “no residue” language in the statute as meaning that any 

remaining residues should present an insignificant risk of cancer to 

people. As a matter of policy, FDA accepts a lifetime risk below one per 

million as an insignificant level.

6

21 U.S.C. 360b(a)(4)(B).

7

21 U.S.C. 360b(d)(1)(I) on new animal drugs. This is known as the DES (diethylstilbestrol) 

proviso to the Delaney Clause. The Center for Veterinary Medicine’s regulation found in 21 

CFR 500.80 outlines how the center regulates carcinogenic drugs and feed additives under 

the DES proviso.
Appendix III

Chemical Risk Assessment at the Food and 

Drug Administration

Page 157 GAO-01-810 Chemical Risk Assessment

• CDRH administers the medical device provisions of FFDCA, and 

assesses risks posed by chemicals that might leach out from medical 

devices (e.g., breast implants) into surrounding tissue. The center’s 

basic mission is to protect the public health by ensuring that there is 

reasonable evidence of the safety and effectiveness of medical devices 

intended for human use. CDRH usually evaluates risks in the context of 

a premarket review system, and the decision to clear or approve a 

product to treat a specific condition is based on a benefit-risk analysis 

for the intended population and use (not just on the basis of safety or 

human health as in the case of food regulation). Because all medical 

products are associated with risks, CDRH considers a medical product 

to be safe if it has reasonable risks given the magnitude of the benefit 

expected and the alternatives available.8

Another unit of FDA, the National Center for Toxicological Research 

(NCTR), has an important supporting role in the risk-related activities of 

the product centers. NCTR conducts much of the agency’s methodological 

research on risk assessment methods and helps to develop and modify 

FDA’s quantitative methods, in conjunction with experts from the various 

product centers. NCTR also provides toxicology research supporting all 

components of FDA. It performs fundamental and applied research 

designed specifically to define biologic mechanisms of action underlying 

the toxicity of products regulated by FDA.

8

This applies to all medical products, including drugs and biological products, not just to 

devices.
Appendix III

Chemical Risk Assessment at the Food and 

Drug Administration

Page 158 GAO-01-810 Chemical Risk Assessment

Risk Assessment 

Procedures

Although FDA has long been a pioneer in the development of risk 

assessment methods, the agency has not developed written internal 

guidance specifically on conducting risk assessments. 9

 FDA officials 

noted that much of their work is done before products are placed on the 

market and, in those instances, the burden of proof is on sponsors seeking 

FDA approval for new products.10 In keeping with this requirement, FDA 

produces extensive external guidance documents that are primarily 

directed at those sponsors.11 The documents are meant to represent the 

agency’s current thinking on the scientific data and studies considered 

appropriate for assessing the safety of a product. However, the guidance 

documents are not legal requirements and do not preclude the use of 

alternative procedures or practices by either FDA or external parties. 

Some of these guidelines include detailed descriptions of risk assessment 

methods deemed appropriate to satisfy FDA’s reviews under various 

statutory provisions. FDA has also adopted a number of domestic and 

international consensus standards that prescribe certain risk assessment 

methods (e.g., approaches for assessing the safety of medical devices and 

default consumption values for meat products).

9

FDA published “Procedures for the Appraisal of Toxicity of Chemicals in Food,” the 

agency’s first guidance to industry, in 1949. In the 1950s, FDA initially developed the general 

NOAEL (or NOEL)/safety factor approach to noncancer risk assessment that has been used 

by most regulatory bodies (e.g., EPA’s reference dose approach).

10This is not true with regard to dietary supplements. The Dietary Supplement Health and 

Education Act of 1994 created a new framework for FDA’s regulation of dietary 

supplements, which do not have to undergo preapproval by FDA to determine their safety or 

efficacy. FDA officials said they currently have no standard procedures for dietary 

supplement risk assessment.

11Examples of such guidelines include “Redbook 2000: Toxicological Principles for the 

Safety of Food Ingredients,” “Estimating Exposure to Direct Food Additives and Chemical 

Contaminants in the Diet,” and “General Principles for Evaluating the Safety of Compounds 

Used in Food-Producing Animals.”
Appendix III

Chemical Risk Assessment at the Food and 

Drug Administration

Page 159 GAO-01-810 Chemical Risk Assessment

FDA risk assessment procedures have also been described by individuals 

and organizations from within and outside of the agency in scientific and 

professional journal articles. For example, a 1997 journal article written by 

a panel of officials from across FDA summarized the risk assessment 

approaches of each of FDA’s product centers.12 A 1996 report on federal 

agencies’ chemical risk assessment methods described CFSAN’s methods, 

but did not describe the approaches used by the other centers within 

FDA.13 FDA’s food safety risk assessment procedures were also described 

in “Precaution in U.S. Food Safety Decisionmaking: Annex II to the United 

States’ National Food Safety System Paper,” which was prepared for the 

Organization for Economic Cooperation and Development in March 2000.14 

FDA officials said that the agency generally follows the four-step risk 

assessment process identified by NAS: hazard identification, dose-response 

assessment (which FDA prefers to call “hazard characterization”), 

exposure assessment, and risk characterization. They said that they also 

rely on past precedent and other seminal works on risk assessment, such 

as the 1985 Office of Science and Technology Policy guidance document on 

cancer risk assessment. However, they emphasized that FDA does not 

presume there is a “best way” of doing a risk assessment and is continually 

updating its procedures and techniques with the goal of using the “best 

available science.” 

Differences in Risk 

Assessment Among FDA 

Product Centers

FDA officials also said that there are variations in the risk assessment 

approaches used among the agency’s different product centers and, in 

some cases, within those centers. In general, those variations are traceable 

to differences in the following factors:

• the substances being regulated,

12D.W. Gaylor, J.A. Axelrad, R.P. Brown, J.A. Cavagnaro, W.H. Cyr, K.L. Hulebak, R.J. 

Lorentzen, M.A. Miller, L.T. Mulligan, and B.A. Schwetz, “Health Risk Assessment Practices 

in the U.S. Food and Drug Administration,” Regulatory Toxicology and Pharmacology 26 

(1997).

13Lorenz R. Rhomberg, A Survey of Methods for Chemical Health Risk Assessment Among 

Federal Regulatory Agencies, a report prepared for the National Commission on Risk 

Assessment and Risk Management (1996).

14Hereinafter referred to as Precaution in U.S. Food Safety Decisionmaking. This paper 

also addresses risk assessment practices of other federal agencies involved in food safety, 

such as the Department of Agriculture and EPA.
Appendix III

Chemical Risk Assessment at the Food and 

Drug Administration

Page 160 GAO-01-810 Chemical Risk Assessment

• the nature of the health risks involved (particularly carcinogens versus 

noncarcinogens),

• statutory and regulatory requirements,

• whether the risk assessment is part of the process to review and 

approve a product before it can be marketed and used (premarket) or 

whether the assessment is for risks that might arise during monitoring 

of a product once it is being used (postmarket), and

• the nature and extent of the scientific information available.

The nature and extent of scientific information varies on a case-by-case 

basis. The other factors, however, are more generic, and table 6 illustrates 

how they are similar or different across CFSAN, CVM, and CDRH. The 

subsections following the table describe more specifically how CFSAN, 

CVM, and CDRH conduct the first three stages of risk assessment.

Table 6: Differences in FDA Chemical Risk Assessment Factors 

Nature of chemical 

health risk Statutory/regulatory requirements

Stage of product 

review

Product center

(Endpoint of 

concern)

Substances being 

regulated Safety standard

Risk assessment 

mandated?

(Premarket/

Postmarket review)

CFSAN − Office of 

Food Additive Safety

Noncancer 

toxicological 

endpoints

Food contact 

substances, direct 

and indirect food 

additives, color 

additives, and 

impurities

Reasonable 

certainty of no harm

Mandatory Primarily premarket

CFSAN − Office of 

Food Additive Safety 

and Office of 

Nutritional Products, 

Labeling and Dietary 

Supplements

Various toxicological 

endpoints, including 

cancer

Industrial and 

naturally occurring 

chemical 

contaminants, 

dietary supplements

May render injurious 

to health

In addition, for 

dietary supplements, 

significant or 

unreasonable risk of 

illness or injury

Mandatory for new 

dietary ingredients

Discretionary for 

other food

Postmarket for foods

Premarket for new 

dietary ingredients in 

dietary supplements
Appendix III

Chemical Risk Assessment at the Food and 

Drug Administration

Page 161 GAO-01-810 Chemical Risk Assessment

Source: Compiled from information provided by FDA.

CFSAN − Cancer 

Assessment 

Committee and 

Quantitative Risk 

Assessment 

Committee

Cancer Direct and indirect 

food additives, food 

contact substances, 

color additives, and 

impurities

For additives, 

Delaney clause 

applies (carcinogens 

prohibited)

For others, 

reasonable certainty 

of no harm standard 

applies

Assessment for 

carcinogenicity is 

mandatory as part of 

the premarket 

approval process, 

but a risk 

assessment is 

discretionary

Primarily premarket, 

but can (and has 

been) used for 

postmarket issues

CVM Various noncancer 

toxicological 

endpoints

Residues of new 

animal drugs and 

feed additives

Reasonable 

certainty of no harm

Mandatory Primarily premarket, 

but can (and has 

been) used for 

postmarket issues

CVM Cancer Residues of new 

animal drugs, feed 

additives, or their 

impurities

Reasonable 

certainty of no harm 

with inclusion of 

Delaney clause and 

DES proviso

Mandatory Primarily premarket, 

but can (and has 

been) used for 

postmarket issues

CDRH Cancer and 

noncancer endpoints

Chemical 

compounds released 

(leaching) from 

medical devices

Reasonable 

assurance that the 

device is safe under 

the conditions of use 

prescribed, 

recommended, or 

suggested in the 

labeling thereof

In addition, regarding 

Class III premarket 

approval, 

unreasonable risk of 

illness or injury

Mandatory for 

certain types of 

devices (Class III), 

discretionary for 

others

Primarily premarket, 

but also could occur 

per postmarket 

surveillance

Nature of chemical 

health risk Statutory/regulatory requirements

Stage of product 

review

Product center

(Endpoint of 

concern)

Substances being 

regulated Safety standard

Risk assessment 

mandated?

(Premarket/

Postmarket review)
Appendix III

Chemical Risk Assessment at the Food and 

Drug Administration

Page 162 GAO-01-810 Chemical Risk Assessment

CFSAN Risk Assessment 

Procedures 

CFSAN’s procedures for hazard identification and dose-response 

assessment vary depending on whether noncancer or cancer risks are at 

issue. For noncancer effects, CFSAN starts with the largest dose in a 

chronic animal study that did not appear to lead to an increase in toxic 

effects above the level measured in unexposed control animals— the “no 

observed adverse effect level” or NOAEL.15 CFSAN then divides this 

NOAEL by one or more safety factors to arrive at an “acceptable daily 

intake” (ADI) intended to be an amount that can be ingested daily for a 

lifetime without harm. For example, CFSAN typically divides the NOAEL 

by 10 to allow for the possibility that humans might be more sensitive to a 

chemical than the experimental animals and then by another 10 to account 

for the possibility that some individuals might have greater sensitivity than 

others might. Therefore, for ADIs derived from long-term animal studies, 

CFSAN commonly uses a combined safety factor of 100. Additional safety 

factors may also be applied to account for long-term effects versus shortterm experiments, inadequacies of the experimental data, or other 

factors.16

For cancer effects, CFSAN uses two different hazard assessment/doseresponse approaches, depending on the nature of the products being 

regulated.

15FDA often determines a no observed effects level (NOEL) rather than a NOAEL because 

many significantly altered, standard toxicological endpoints are assumed to be adverse to 

animals and/or humans even in the absence of data affirming that assumption.

16For example, Lorenz Rhomberg noted that, for developmental toxicity, the Center for Food 

Safety and Applied Nutrition may use a combined safety factor of 1,000 for severe, 

irreversible health effects.
Appendix III

Chemical Risk Assessment at the Food and 

Drug Administration

Page 163 GAO-01-810 Chemical Risk Assessment

• For food and color additives that are themselves known carcinogens, 

the Delaney provisions in FFDCA make risk assessment rather 

straightforward. If a petition to market a food ingredient contains an 

adequately conducted animal cancer study, and if results of that study 

indicate that the food ingredient produces cancer in animals, CFSAN 

identifies the substance as a carcinogen under the conditions of the 

study. No further corroboration or weight-of-evidence analysis is 

required, and there is no need for a detailed dose-response assessment, 

exposure assessment, or risk characterization for the purpose of 

determining a specific level of the carcinogenic substance in food that 

may be considered to be safe.17

• CFSAN uses more elaborate procedures for known or suspected 

carcinogenic impurities in food additives. The center’s method for lowdose cancer risk estimation is similar to EPA’s method (presented in 

app. II) on extrapolation for carcinogens (see fig. 3). On the doseresponse curve of tumor incidence versus dose for a chemical, CFSAN 

chooses a point below which the data are no longer considered reliable, 

usually in the range of a tumor incidence of 1 percent to 10 percent. A 

straight line is drawn from the upper-confidence limit on the estimated 

risk at that point to the origin (i.e., zero incremental dose/zero 

incremental response). This provides the slope of the line used to 

provide upper-bound estimates of cancer risk at low doses. CFSAN 

does not specify a particular mathematical form for the dose-response 

relationship in the experimental dose range; the only requirement is an 

adequate fit to the data. 

According to FDA officials, CFSAN risk assessors use one of two different 

methods in animal-to-human scaling when extrapolating this dose-response 

curve to the estimation of upper bounds on human risk. In one of the 

methods, CFSAN assumes that cancer risks are equal in animals and 

humans when doses are similar on a lifetime-averaged 

milligram/kilogram/day basis (i.e., body weight scaling). In the other 

method, CFSAN bases its interspecies dose scaling on body weight to the 3⁄4

power (in the absence of information to the contrary). Although the 

literature suggests that scaling methods can have a significant impact on 

risk assessment results, FDA officials said that using one approach versus 

the other makes relatively little difference. Also, because tumor rates can 

be biased by intercurrent mortality in animal studies (i.e., some animals die 

17 FDA may do a detailed assessment for other purposes, such as helping to determine 

regulatory priorities.
Appendix III

Chemical Risk Assessment at the Food and 

Drug Administration

Page 164 GAO-01-810 Chemical Risk Assessment

during the study from causes other than the tumor type being investigated), 

CFSAN uses a statistical procedure to make adjustments for intercurrent 

mortality in testing and estimating tumor rates.

CFSAN procedures for exposure assessments to food and color additives 

are largely driven by the FFDCA requirement that the safety of a chemical 

compound be assessed in terms of the total amount of the compound in the 

diet. Therefore, to determine exposure, CFSAN risk assessors must 

consider all potential uses of the compound being reviewed. Similarly, in 

defining the allowable limits, the assessors must conclude that the sum 

total of all of these uses is within safe limits. CFSAN generally assumes in 

its exposure assessments that the compound is present at its maximum 

proposed use level in all foods in which it may be used, that any 

contaminants are present at residue levels established through chemical 

analysis, and that consumers are exposed to the additive every day. 

Although most of the agency’s focus is on chronic (long-term) exposures, 

the agency must also sometimes focus on very short-term, or even single, 

exposures, especially for contaminants associated with acute toxic effects.

The first component in CFSAN’s exposure assessment for food safety is the 

determination of the concentrations (i.e., use levels or residue levels, in the 

case of a chemical contaminant) of a chemical in foods. In the premarket 

approval process, the sponsor of the petition or notification provides this 

information. For postmarket assessments, information may come from 

focused field surveys or from established monitoring programs such as the 

Total Diet Study, which has provided data since 1961 on dietary intakes of a 

variety of food contaminants, including pesticides, industrial chemicals, 

toxic and nutritional elements, and vitamins and radionucleides. Analyses 

are performed on foods prepared for consumption in order to provide a 

realistic measure of human intake. 
Appendix III

Chemical Risk Assessment at the Food and 

Drug Administration

Page 165 GAO-01-810 Chemical Risk Assessment

The second component of CFSAN’s exposure assessment is determining 

the extent of consumption of different foods. In this process, CFSAN 

primarily relies on multiple-day national food consumption surveys, and 

focuses on the upper end of the food intake distribution (i.e., the heaviest 

consumers of particular foods). CFSAN assumes that, within demographic 

subgroups, all variation in the survey data represents variation among 

individuals. That is, the average daily consumption of a food during the 

survey period is assumed to apply to that person for his or her whole life, 

and the intakes for different survey participants are assumed to reflect 

differences from one person to the next in each person’s lifetime 

consumption. This default assumption has acknowledged biases that 

result in both overestimating high-end chronic exposures and 

underestimating the proportion of the population ever consuming 

particular foods.18

To complete the exposure assessment, levels of an additive or contaminant 

in each food type are combined with estimates of daily consumption of 

each food type to give a total estimated daily intake. FDA may calculate 

exposures for various demographic groups, attempting to characterize 

both a mean exposure and an exposure for the heavy consumer (typically 

consumers at the 90th percentile of the intake distribution). FDA officials 

also pointed out that the exposure models they use for direct food additives 

are very different from those for food-contact substances (e.g., 

packaging).19 For the latter, they said that the bottom line is usually a mean 

exposure. 

18EPA’s pesticide office uses an alternative assumption—that surveyed variation represents 

day-to-day variation. Using this assumption, the exposure estimate represents average 

chronic consumption, but fails to estimate high-end exposures.

19 See CFSAN’s “Guidance for Industry: Preparation of Premarket Notifications for Food 

Contact Substances: Chemistry Recommendations.”
Appendix III

Chemical Risk Assessment at the Food and 

Drug Administration

Page 166 GAO-01-810 Chemical Risk Assessment

FDA officials said that for risk management purposes they may attempt to 

show the implications of different scenarios used to estimate risk. FDA 

noted that a computer program that employs Monte Carlo techniques has 

been developed to study the effects of variability and uncertainty of 

potency and exposure estimates on estimates of risk.20 Such complex 

analyses have been applied principally to contaminants rather than in the 

premarket evaluations for food and color additives. 

CVM Risk Assessment 

Procedures

CVM uses risk assessment in both the premarket approval process and 

postmarket surveillance. Risk assessments support risk management 

decisions such as the development of safe concentration values and 

residue tolerances for these drugs in foods. The primary human health 

concern in chemical risk assessment for CVM is animal drug residues in 

food. Residue is defined as any compound present in edible tissues 

(including milk and eggs) of the food-producing animal that results from 

the use of the chemical compound, including the compound, its 

metabolites, or other substances formed in or on food because of the use of 

the compound.

Like CFSAN, CVM’s risk assessment procedures vary based on whether 

noncancer or cancer risks are at issue. According to FDA officials, the 

center’s risk assessment procedures for noncarcinogens are similar to 

those used by the rest of FDA, and are based on laboratory animal data, 

estimated daily food consumption, drug and metabolite residue data, and 

appropriate safety factors. CVM’s guidelines for industry note that the 

agency will calculate the ADI from the results of the most sensitive study in 

the most sensitive species. The center will normally use different safety 

factors depending on the type of study supporting the ADI calculation. 

When using the ADI to calculate the “safe concentration” for an animal 

drug product, CVM uses standard values for residues of veterinary drugs in 

edible tissues for the weight of an average adult and the amount and 

proportion of meat products, milk, and eggs consumed per day. CVM 

officials pointed out that the consumption values in their guidelines for 

industry are standard values used by the Joint Expert Committee on Food 

Additives, sponsored by the World Health Organization and Food and 

20Monte Carlo analysis involves a repeated random sampling from the distribution of values 

for each of the parameters in a calculation (such as average daily exposure) to derive a 

distribution of estimates of exposures for a population. According to FDA, because Monte 

Carlo modeling is a probabilistic technique that can use all the available food intake and 

concentration data, it will result in more accurate estimates at upper percentiles of 

exposure than those obtained using point values from consumer surveys. 
Appendix III

Chemical Risk Assessment at the Food and 

Drug Administration

Page 167 GAO-01-810 Chemical Risk Assessment

Agriculture Organization, that provides food safety recommendations to 

the Codex Committee on Residues of Veterinary Drugs in Foods.

For carcinogen risk assessments, CVM uses a nonthreshold, conservative, 

linear-at-low-dose extrapolation procedure to estimate an upper limit of 

low-dose risk (as described under CFSAN). Cancer risk estimates are 

generally based on animal bioassays, and upper 95-percent confidence 

limits of carcinogenic potency are used to account for inherent 

experimental variability. FDA officials noted that some elements and 

assumptions of its dose-response analysis procedures are likely to 

overestimate risk by an unknown amount. Similarly, some of its 

assumptions on exposure may also overestimate cancer risks. For 

example, CVM’s risk assessment procedures assume that the concentration 

of residue in the edible product is at the permitted concentration and that 

consumption is equal to that of the 90th percentile consumer. In addition, 

the agency assumes that all marketed animals are treated with the 

carcinogen. While acknowledging that all of these assumptions result in 

multiple conservatisms, FDA also states that they are prudent because of 

the uncertainties involved.

CDRH Risk Assessment 

Procedures

Medical devices, supplies, and implants may contain chemicals that can 

leach out of the devices into surrounding tissues. Risks from these types of 

chemical contaminants are considered during the premarket review of the 

material safety of a device, but concerns may also arise during CDRH’s 

postmarket surveillance activities.21 According to FDA officials, the 

concentrations of such leachants in human tissues are generally small and 

amenable to typical safety risk assessment procedures. 

21As an example of a postmarket quantitative risk assessment, FDA cited its assessment of 

cancer risk posed by patient exposure to 2,4-toluenediamine released from polyurethane 

foam-covered breast implants.
Appendix III

Chemical Risk Assessment at the Food and 

Drug Administration

Page 168 GAO-01-810 Chemical Risk Assessment

CDRH has issued guidance for the preclinical (premarket) biological safety 

evaluation of medical devices.22 In that guidance, CDRH recognizes and 

uses a number of domestic and international consensus standards that 

have been developed to address aspects of medical device safety, including 

risks posed by exposure to compounds released from medical devices. 

However, CDRH officials pointed out that they and medical device 

approval applicants may use approaches other than those described in the 

consensus standards to conduct risk assessments. They said the standard 

that comes closest to describing CDRH’s approach for chemical risk 

assessment is International Organization for Standardization (ISO)/FDIS 

10933-17.23 CDRH officials noted that, although this international standard 

is still in draft and has not been formally recognized by the center, the 

methods that it describes represent the primary procedures used by CDRH 

to assess the risk posed by patient exposure to compounds released from 

medical devices. They also pointed out that this standard is unique among 

risk assessment guidelines in that it provides methods to derive healthbased exposure levels for local effects such as irritation, which often 

“drive” the risk assessment for compounds released from implanted 

devices.

According to CDRH, hazards posed by patient exposure to a device are 

typically determined after subjecting the device to a series of tests defined 

by the preclinical evaluation guidance. Evaluation of potential toxicity is 

supposed to cover a number of adverse effects, including local or systemic 

effects, cancer, and reproductive and developmental effects. Unless 

justification is otherwise provided, CDRH assumes that the results 

obtained in animal studies are relevant for humans. One notable exception 

for medical device risk assessment, according to CDRH, is that 

implantation-site sarcomas (malignant tumors) found in rodents are not 

assumed to be relevant for humans.

One option available to applicants is to use a risk assessment approach 

involving: (1) characterization of the chemical constituents released from a 

22The Center for Devices and Radiological Health’s Office of Device Evaluation “Blue Book”

memorandum #G95-1, “Use of International Standard ISO-10993, ‘Biological Evaluation of 

Medical Devices Part-1: Evaluation and Testing.’”

23Biological evaluation of medical device − Part 17: Methods for the establishment of 

allowable limits for leachable substances. The International Organization for 

Standardization is a nongovernmental federation of national standards bodies from about 

140 countries. Its work results in international agreements that are published as 

international standards.
Appendix III

Chemical Risk Assessment at the Food and 

Drug Administration

Page 169 GAO-01-810 Chemical Risk Assessment

device; (2) derivation of a tolerable intake (TI) value for the compound; and 

(3) comparing the dose of each constituent received by a patient to its 

respective TI value. A TI value is a dose of a compound that is not 

expected to produce adverse effects in patients following exposure to the 

compound for a defined period. According to CDRH, it is conceptually 

similar to EPA’s reference dose, but different TI values can be derived for a 

compound depending on the route and duration of exposure to the medical 

device.

CDRH’s procedures recommend establishing TI values for noncancer 

adverse effects using standard uncertainty factors in order to account for 

interspecies and inter-individual differences in sensitivity. However, CDRH 

permits flexibility in the event that data are available to characterize these 

uncertainties more accurately. CDRH also uses a lumped uncertainty factor 

to adjust for limitations in data quality such as (1) the use of short-term 

studies in the absence of long-term studies, (2) the absence of supporting 

studies, and (3) use of studies involving different routes or rates of 

exposure. According to CDRH, this lumped uncertainty value typically 

does not exceed 100, but can exceed 100 when acute (short-term) toxicity 

data are the only basis of the calculation of a TI value for permanent 

exposure. CDRH considers this provision especially important for medical 

device risk assessment because of the paucity of long-term toxicity data for 

many of the compounds released from medical devices. 

For carcinogenic leachants, FDA often uses low-dose linear extrapolation 

techniques. For a device-released compound that has been determined to 

be a carcinogen, CDRH uses a weight-of-the-evidence approach to 

determine the likelihood that it exerts its carcinogenic effect via a 

genotoxic mechanism.24 If the evidence suggests that the compound is 

genotoxic, then CDRH uses quantitative risk assessment to estimate a TI 

consistent with a risk level of 1 per 10,000. No specific quantitative risk 

assessment approaches have been identified as better than others for 

conducting the cancer risk assessment. If, however, the weight-of-theevidence test suggests that the compound is a nongenotoxic carcinogen, 

the uncertainty factor approach described above should be employed to 

derive the TI.

24A genotoxic carcinogen is one that initiates cancer through a direct effect on genetic 

material. It is capable of causing heritable changes or damage leading to heritable changes 

in genetic material.
Appendix III

Chemical Risk Assessment at the Food and 

Drug Administration

Page 170 GAO-01-810 Chemical Risk Assessment

Once the TI is derived for each compound released from a device, it is then 

converted to a tolerable exposure value by taking into account the body 

weight of the patient and the usage patterns of the device that releases the 

compound. Overall, the agency noted that one of the most challenging 

problems in risk assessments for devices is determining the level of 

exposure to leached chemicals.

Risk Assessment 

Assumptions and 

Methodological 

Choices

As previously noted, FDA does not require the use of a specific risk 

assessment protocol or of specific default assumptions. However, the 

summary of FDA procedures also demonstrated that assumptions and 

methodological choices are an integral part of a risk assessment. FDA 

officials noted that they employ many default assumptions or choices by 

precedent. In particular, FDA officials and several reference documents on 

FDA risk assessment procedures pointed out that the agency routinely 

incorporates conservative assumptions into its assessments in the face of 

uncertainty. The report on the U.S. food safety system emphasized that 

precaution is embedded in the underlying statutes and the actions of 

regulatory agencies to ensure acceptable levels of consumer protection.25 

Therefore, precautionary approaches are very much a part of the agency’s 

risk analysis policies and procedures. 

Although not intended to be comprehensive, the following table illustrates 

in detail some of the specific assumptions or methodological choices that 

are used in FDA as a whole and within particular FDA product centers. 

The information in the table was taken primarily from FDA documents, but 

also reflects additional comments provided by FDA officials. (GAO notes 

and comments appear in parentheses.)

25Precaution in U.S. Food Safety Decisionmaking.
Appendix III

Chemical Risk Assessment at the Food and 

Drug Administration

Page 171 GAO-01-810 Chemical Risk Assessment

Table 7: FDA Risk Assessment Assumptions and Methodological Choices

Assumption or 

methodological choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 

(Methodological assumptions 

and choices in general.)

According to FDA officials, 

“reasons” always include the 

following three general items:

• information essential to a risk 

assessment is not known;

• the assumption, selected by 

FDA to substitute for that 

information, is scientifically 

plausible; and

• the effect of using the 

assumption is consistent with 

agency regulations or policy 

(e.g., for CFSAN, an 

assumption is expected to be 

reasonably protective of human 

health).

According to FDA officials, the 

circumstances under which 

these assumptions would be 

used always include that data 

indicating the assumption may 

be invalid for a particular 

circumstance are not available.

(Not applicable to this generic 

information.)

1. CFSAN general procedures regarding food safety

1.1

Animal studies are useful for 

human risk assessment, with 

appropriate uncertainty factors 

(i.e., you can extrapolate human 

effects from animal data).

This is a fundamental 

assumption of quantitative risk 

assessment, accepted as a 

basic precedent according to 

FDA officials. They noted that, in 

general, adequate information 

from human studies is preferred 

to adequate data from animal 

studies. However, when human 

data are not available, or when 

such data are judged to be 

relatively insensitive to 

moderate- or low-level risks and 

difficult to quantify, FDA makes 

the assumption that animal 

studies can be used for human 

risk assessment. FDA officials 

also said that the application of 

appropriate uncertainty factors 

to data from animal studies 

makes this assumption 

reasonably protective of human 

health.

When there are no data or 

inadequate data on human 

outcomes.

For chemicals that are human 

carcinogens, animal data may 

underestimate human risk by up 

to one order of magnitude and 

overestimate risk by up to three 

orders of magnitude [citations 

provided].
Appendix III

Chemical Risk Assessment at the Food and 

Drug Administration

Page 172 GAO-01-810 Chemical Risk Assessment

1.2

Use the most sensitive animal 

species, unless you have 

information to the contrary.

(Not identified in the FDA 

documents that we reviewed 

describing risk assessment 

procedures. However, FDA 

officials explained that 

comparative absorption, 

metabolism, distribution, and 

elimination data could identify 

the most appropriate animal 

model for extrapolating results 

from animals to humans. They 

also stated that FDA has 

determined that use of this 

assumption is reasonably 

protective of human health.)

When choosing which animal 

study data to use for hazard 

identification and dose-response 

estimation, when the most 

appropriate animal model for 

humans is not known.

(Not specifically identified, but 

FDA officials commented that 

risk assessment literature 

identifies the “usual” range of 

toxicological responses among 

animal models for this 

assumption.)

1.3

You can extrapolate low-dose 

effects from high-dose effects.

FDA officials identified this 

assumption as another 

fundamental assumption, similar 

to 1.1 above, noting that, in 

general, low-dose effects cannot 

be directly measured in human 

epidemiology studies or in 

animal toxicity and 

carcinogenicity studies. They 

said that, in such circumstances, 

the mechanism of action at low 

doses is assumed to be the 

same as that operating at higher 

doses, which makes the related 

assumption that one can 

extrapolate effects at low doses 

from effects at high doses 

scientifically plausible. FDA has 

determined that such an 

assumption is reasonably 

protective of human health.

When doing low-dose 

extrapolation because low-dose 

effects were not directly 

measured in available human or 

animal studies and the 

mechanism of action at low 

doses is not known to be 

different than the mechanism at 

higher doses. 

(Not explicitly identified. FDA 

officials explained that the 

literature on this subject shows 

“very large” variability among 

predictions of low-dose effects 

using different modeling 

assumptions. They also stated 

that, because they do not know 

the correct relationship between 

high-and low-dose effects for a 

substance, they do not know 

how much conservatism is 

associated with the use of this 

assumption.)

Assumption or 

methodological choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix III

Chemical Risk Assessment at the Food and 

Drug Administration

Page 173 GAO-01-810 Chemical Risk Assessment

1.4

Low-dose cancer risk estimation 

is done using a linear, nothreshold approach.

The point of departure for this 

linear extrapolation is the upperconfidence limit on risk at a point 

on the dose-response curve 

below which the data no longer 

appear to be reliable. However, 

the agency does not specify any 

particular mathematical form for 

the dose-response relationship 

in the experimental dose range, 

just that there is an adequate fit 

to the data.

A more specific, but related, 

string of assumptions is that 

genotoxic carcinogens do not 

have thresholds, and the 

appropriate low-dose 

extrapolation is linear.

Not specifically identified, but 

FDA noted in general that, 

because it is not possible to 

determine the accuracy and 

precision of low-dose cancer 

estimates, the agency employs 

conservative risk assessment 

procedures to compensate for 

weaknesses in scientific rigor.

The agency did provide specific 

citations for various low-dose 

extrapolation procedures.

When doing low-dose 

extrapolation for carcinogens.

This linear extrapolation provides 

upper-bound estimates of cancer 

risk at low doses.

1.5

Dose scaling across species is 

based on body weight to the 3⁄4

power (an adjustment factor for 

calculating the dose at which 

cancer risks are equal in rodents 

and humans)

(In meetings with CFSAN 

officials, we were informed that 

the agency’s risk assessors may 

also use the default that cancer 

risks are presumed equal when 

daily amounts of a chemical 

agent are scaled in proportion to 

a species’ body weight.)

The 3⁄4 power approach was 

recommended in a 1992 

proposed rule by an interagency 

committee [citation provided].

When extrapolating equivalent 

doses of a carcinogen from 

animals to humans, in the 

absence of information to the 

contrary.

(Not addressed in FDA 

materials, but other sources 

indicated that the “body weight 3⁄4

power” approach is considered 

to produce the midpoint of 

plausible values from among the 

common alternative approaches 

for interspecies dose scaling, 

while “body weight” scaling is 

considered to produce the least 

conservative values. A CFSAN 

official stated that this choice 

makes little difference in the 

results.)

Assumption or 

methodological choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix III

Chemical Risk Assessment at the Food and 

Drug Administration

Page 174 GAO-01-810 Chemical Risk Assessment

1.6

FDA/CFSAN uses a basic no 

observed effect level (NOEL) 

safety factor approach for 

noncancer effects. The agency 

generally uses standard safety 

factors to account for 

uncertainty:

a. A safety factor of 10 is used 

to account for the possible 

increased sensitivity of 

humans compared to test 

animals.

b. Another safety factor of 10 is 

used to account for the 

increased sensitivity of 

some humans.

c. Additional safety factors are 

often employed to account 

for long-term effects based 

on short-term experiments, 

use of a LOAEL instead of a 

NOEL/NOAEL, and other 

inadequacies of the 

experimental data.

(Note that the underlying statute 

specifically directs the use of 

safety factors.)

Risk assessments for noncancer 

endpoints − estimating an ADI 

from the results of animal 

experiments.

The resulting ADI is an estimate 

with uncertainty spanning 

perhaps an order of magnitude 

of a daily exposure that is likely 

to be without appreciable risk of 

deleterious effects during a 

lifetime.

Assumption or 

methodological choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix III

Chemical Risk Assessment at the Food and 

Drug Administration

Page 175 GAO-01-810 Chemical Risk Assessment

1.7

CFSAN uses a series of 

assumptions about food 

consumption:

a. The agency assumes that 

the average total diet of a 

60-kg adult generally 

consists of 1500 grams (g) 

of solid food and 1500 g of 

liquid per day.

b. For calculating exposure to 

additives or contaminants, 

CFSAN frequently uses the 

90th percentile of 

consumption to represent 

intake of heavy consumers.

c. In the absence of the 

distribution of intakes 

among individuals in a 

population and a direct 

measure of the 90th

percentile, the 90th

percentile is estimated to be 

two to three times the 

average intake.

a. Empirical: based on food 

consumption survey data.

b. Concern that the mean 

exposure is not sufficiently 

public-health conservative.

c. The method for estimating 

the 90th percentile in the 

absence of other data is 

based on observations from 

dietary survey distribution 

data for a variety of 

products.

Assumptions about consumption 

used when estimating human 

exposure to chemical 

substances (i.e., additives, 

residues) in foods.

FDA officials told us that these 

assumptions provide a publichealth conservative estimate of 

exposure for comparison with 

the ADI.

1.8

The agency usually assumes 

that, within demographic groups, 

food intake survey variation 

represents differences in chronic 

consumption among individuals. 

The average daily consumption 

by an individual of a food during 

the survey period is assumed to 

apply to that person for his or her 

whole life.

FDA officials said they use this 

assumption because only shortterm food intake surveys are 

available.

When basing exposure 

estimates on food intake 

surveys.

According to the Rhomberg 

report, the effect of this 

assumption is an acknowledged 

overestimation of high-end 

chronic exposures and an 

underestimation of the 

proportion of the population ever 

consuming particular foods.

Assumption or 

methodological choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix III

Chemical Risk Assessment at the Food and 

Drug Administration

Page 176 GAO-01-810 Chemical Risk Assessment

1.9

The agency generally assumes 

that all foods in which a chemical 

additive is proposed or permitted 

for use will bear it at the 

maximum proposed or 

permissible use level.

The agency also assumes that 

consumers are exposed to an 

additive every day for a lifetime.

FDA officials said that they use 

these public-health conservative 

assumptions because of the lack 

of scientifically sound 

information that would permit 

their relaxation.

When doing exposure 

assessments.

FDA officials said these 

assumptions were public-health 

conservative.

1.10

When dealing with mixtures of 

carcinogens, the agency usually 

considers that interactions are 

not likely and uses some 

standard assumptions:

a. It is assumed that 

carcinogens are acting 

independently. Therefore, 

the risk of cancer from a 

mixture may be obtained by 

summing the individual risk.

b. It is generally assumed that 

all carcinogenic 

components are at their 

tolerance concentrations.

The agency noted that its intent 

is to be conservative, and it cited 

research on the estimation of 

upper-confidence limits on 

estimates of risk for mixtures.

When doing risk assessments 

involving mixtures of chemicals 

(with dose levels for each 

component below those having 

measurable effects for that 

compound).

The intent is to be conservative.

Assumption or 

methodological choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix III

Chemical Risk Assessment at the Food and 

Drug Administration

Page 177 GAO-01-810 Chemical Risk Assessment

2. CVM procedures regarding animal drug residues in food

2.1

As a matter of policy regarding 

potential risks from residues of 

carcinogenic animal drugs in 

foods consumed by humans (per 

the DES Proviso to the Delaney 

Clause), FDA accepts a lifetime 

risk below one per million as an 

insignificant level.

In general, FDA noted that all of 

the assumptions identified in this 

section on the DES Proviso (see 

following rows 2.2 through 2.5), 

“result in multiple conservatisms, 

but are prudent because of the 

uncertainties.”

“Thus, adoption of a [residue] 

concentration associated with a 

cancer risk of one per million is 

likely to be well below that level 

of risk and to satisfy the FDA’s 

responsibility under the statute 

[FFDCA] to ensure to a 

reasonable certainty that the 

public will not be harmed.”

When conducting cancer risk 

assessments.

This set of assumptions was 

identified generically as 

“resulting in multiple 

conservatisms.”

2.2

Regulation is based on the target 

tissue site exhibiting the highest 

potential for cancer risk for each 

carcinogenic compound.

If tumors are produced at more 

than one tissue site, the 

minimum concentration that 

produced a tumor is used.

(No additional information 

provided, but see row 2.1 for 

general rationale.)

Choosing data sets to use for 

cancer risk assessments.

(See previous row.)

Assumption or 

methodological choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix III

Chemical Risk Assessment at the Food and 

Drug Administration

Page 178 GAO-01-810 Chemical Risk Assessment

2.3

Cancer risk estimates are 

generally based on animal 

bioassays, using upper 95-

percent confidence limits of 

carcinogenic potency.

Low-dose extrapolation is done 

using a nonthreshold, 

conservative, linear-at-low-dose 

procedure (modified GaylorKodell).

Upper 95-percent confidence 

limits are used to account for 

inherent experimental variability.

The low-dose extrapolation 

procedure estimates an upper 

limit on low-dose risk.

In its general principles for 

industry (guideline #3), CVM 

notes that none of the 

mathematical procedures for 

extrapolation has a fully 

adequate biological rationale, 

because the mechanism of 

carcinogenesis is not sufficiently 

understood.

When doing low-dose 

extrapolation from animal 

bioassay data in the absence of 

information establishing the 

mechanism of carcinogenesis of 

a compound.

The process of linearly 

extrapolating from the high 

doses used in animal bioassays 

to concentrations of residues is 

likely to overestimate risk by an 

unknown amount.

2.4

It is assumed that the 

carcinogenic potency in humans 

is the same as that in animals.

(No additional information 

provided, but see row 2.1 for 

general rationale.)

In cancer risk assessments 

when doing low-dose 

extrapolation from animal 

bioassay data.

From rather limited data 

comparing human and animal 

cancer potencies of compounds, 

animal results are likely to 

overestimate human cancer risk 

but could underestimate risk by 

an order of magnitude (citations 

provided).

Assumption or 

methodological choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix III

Chemical Risk Assessment at the Food and 

Drug Administration

Page 179 GAO-01-810 Chemical Risk Assessment

2.5

Multiple assumptions are used in 

carcinogen exposure 

assessments:

a. The concentration of 

residue in the edible product 

is at the permitted 

concentration.

b. Consumption is equal to that 

of the 90th percentile 

consumer.

c. All marketed animals are 

treated with the carcinogen.

d. In the absence of 

information about the 

composition of the total 

residue in edible tissue, 

assume that the entire 

residue is of carcinogenic 

concern.

(See row 2.1 for general 

rationale. Note that item d is 

taken from CVM’s guidance for 

industry.) 

Used for exposure assessments 

for cancer risks.

These assumptions on 

exposures also overestimate the 

risk.

2.6

For noncancer toxicological 

endpoints, the agency will 

calculate the ADI from the NOEL 

of the most sensitive effect in an 

animal study of the most 

sensitive sex and species.

FDA officials said this 

assumption was used because 

of historical precedent back to at 

least 1954, because, in the 

absence of data (e.g., 

physiologically based 

pharmacokinetic or other data) 

suggesting that another species 

is more appropriate to use for 

extrapolating to humans, using 

the most sensitive endpoint in 

the most sensitive species and 

sex is still considered to be 

protective of public health.

In noncancer risk assessment, 

when calculating the ADI based 

upon animal studies and in the 

absence of data suggesting that 

an alternative approach is 

scientifically justified.

(Not identified, but the intent of 

this calculation is to provide 

protective, public-health 

conservative estimates.)

Assumption or 

methodological choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix III

Chemical Risk Assessment at the Food and 

Drug Administration

Page 180 GAO-01-810 Chemical Risk Assessment

2.7

The agency will normally use the 

following safety factors, 

depending on the type of study 

supporting the ADI estimate:

a. chronic study (factor of 100),

b. reproduction/teratology 

study (100 for a clear 

indication of maternal 

toxicity; 1000 for other 

effects), and

c. 90-day study (1000).

These are identified as 

“appropriate” safety factors.

In noncancer risk assessment 

when calculating the ADI by 

dividing the NOEL from an 

animal study by safety factors.

(Not identified, but the intent of 

such factors is usually to provide 

protective, public-health 

conservative estimates.)

2.8

The agency uses a series of 

standard values and 

assumptions to estimate an 

individual’s daily food 

consumption:

a. edible muscle (300 grams);

b. liver (100 g);

c. kidney (50 g);

d. fat (50 g);

e. assume that when an 

individual consumes a full 

portion of a meat product 

from one species, he or she 

will not consume a full 

portion of a meat product 

from another species;

f. assume a person consumes 

a full portion of milk (1.5 

liters) in addition to the full 

portion of edible muscle or 

organ tissue; and

g. assume that a person 

consumes a full portion of 

eggs (100 g) in addition to 

the consumption of muscle 

or organ tissue.

CVM officials noted that the 

standard consumption factors 

(e.g., 300 grams of muscle) were 

established by the Joint Expert 

Committee on Food Additives 

(sponsored by the World Health 

Organization and the Food and 

Agriculture Organization of the 

United Nations).

Exposure analysis for noncancer 

risk assessments. Consumption 

values applied to determine the 

safe concentration for most new 

animal drug products, unless an 

appropriate scientific justification 

supports alternative 

consumption values.

(Not identified, but the intent of 

such factors is usually to provide 

protective, public-health 

conservative estimates.)

Assumption or 

methodological choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix III

Chemical Risk Assessment at the Food and 

Drug Administration

Page 181 GAO-01-810 Chemical Risk Assessment

2.9

The agency assumes the weight 

of an average adult is 60 kg 

when calculating the safe 

concentration of a compound in 

edible tissue of a food-producing 

animal.

CVM officials said this 

assumption is used because of 

historical precedent and 

because the 60-kg person is 

likely to cover the exposure of 

women, growing adolescents, 

and the elderly. 

CVM officials said that this 

assumption is applied in all 

circumstances.

CVM officials said the 

assumption should protect 

women, growing adolescents, 

and the elderly.

3. CDRH procedures regarding medical devices (For purposes of this report, limited to chemical leachants. Does not include 

engineering or radiation risk assessments.)

3.1

CDRH assumes that the results 

obtained in animal studies are 

relevant for humans, but with one 

notable exception for medical 

device risk assessment −

implantation-site malignant 

tumors found in rodents are not 

assumed to be relevant for 

humans.

(Not specifically addressed in 

the material provided by CDRH, 

although the first part is a 

standard assumption of 

quantitative risk assessment.)

During hazard identification. (Not mentioned.)

3.2

Extractions of medical devices 

(to test for adverse effects) are 

typically carried out using 

rigorous but not exhaustive 

conditions to provide a “safety 

factor” for the hazard 

identification phase.

To provide a safety factor. During hazard identification. (Not specifically identified, but 

the intent of such factors is 

usually to provide protective, 

public-health conservative 

estimates.)

Assumption or 

methodological choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix III

Chemical Risk Assessment at the Food and 

Drug Administration

Page 182 GAO-01-810 Chemical Risk Assessment

Source: Compiled from GAO review of FDA risk assessment guidelines and related documents and 

from additional comments provided by agency officials.

Risk Characterization Unlike EPA, FDA does not have an official policy on how the results of the 

agency’s risk assessments should be characterized to decision makers and 

the public. However, FDA officials said that, in practice, the agency uses a 

standard approach for risk characterization that is similar to EPA’s official 

policy. They said that FDA’s general policy is to reveal the risk assessment 

assumptions that have the greatest impact on the results of the analysis, 

and to state whether the assumptions used in the assessment were 

conservative. FDA officials also said that their risk assessors attempt to 

show the implications of different distributions and choices (e.g., the 

results expected at different levels of regulatory intervention). As noted 

earlier, FDA may employ methods such as Monte Carlo techniques to 

provide additional information on the effects of variability and uncertainty 

on estimates of risk.

3.3

The following uncertainty factors 

are typically used for adverse 

effects other than cancer:

a. a factor to adjust for 

interspecies differences in 

sensitivity to toxic 

compounds;

b. a factor to adjust for 

interindividual differences in 

sensitivity to toxic 

compounds; and

c. a “lumped” factor to adjust 

for limitations in data quality.

The first two factors are standard 

uncertainty factors 

recommended in the scientific 

literature.

The lumped uncertainty factor 

takes into account:

1. use of short-term studies in 

the absence of long-term 

studies;

2. having only a LOAEL 

instead of a NOAEL;

3. absence of supporting 

studies;

4. route-to-route extrapolation 

of dose, when needed;

5. rate of exposure; and

6. confidence in the data base.

CDRH noted that the lumped 

factor typically does not exceed 

100, but can exceed this value 

when acute toxicity data are the 

only basis for the calculation of a 

TI value for permanent exposure.

Used when calculating TI values 

for noncancer effects of chemical 

compounds, unless case data 

are available to characterize 

these uncertainties more 

accurately.

(Not specifically identified, but 

the intent of such factors is 

usually to provide protective, 

public-health conservative 

estimates.)

Assumption or 

methodological choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix III

Chemical Risk Assessment at the Food and 

Drug Administration

Page 183 GAO-01-810 Chemical Risk Assessment

There are some differences in FDA risk characterization procedures 

depending on the products being regulated and the nature of the risks 

involved. For food ingredients (direct and indirect food additives, color 

additives used in food, and substances generally recognized as safe) and 

animal drug residues that are not carcinogenic, risk characterization under 

the FFDCA focuses on whether the mandate of reasonable certainty of no 

harm will be achieved given the proposed limits on use and permissible 

residues. The main issue is whether the higher end (the 90th percentile) of 

the distribution of estimated daily intakes is below the ADI calculated from 

toxicity data. The statutory mandate is interpreted as requiring that, for a 

food additive to be declared safe, heavy consumers of particular foods 

should be reasonably assured of protection even if residues were at the 

maximum level allowed. For carcinogenic impurities, FDA’s focus is also 

on characterizing whether there is reasonable certainty of no harm. 

However, because of the Delaney clause, risk characterization is not 

needed for carcinogenic food ingredients. Residues of carcinogenic animal 

drugs are also evaluated separately under the DES proviso.

CDRH officials pointed out that the draft ISO/FDIS 10933-17 international 

standard explicitly addresses one risk characterization issue—how 

sensitive subpopulations should be taken into account when setting 

allowable limits for compounds released from devices. Although it states 

that “idiosyncratic hypersusceptibility” should not normally be the basis of 

the tolerable exposure or allowable limit, the ISO standard does not 

preclude setting standards in this manner. Furthermore, the standard says 

that limits should be based on the use of the device by the broadest 

segment of the anticipated user population. Therefore, if a device is 

intended for a specific population, such as pregnant women, estimates 

should be based on that population.
Page 184 GAO-01-810 Chemical Risk Assessment

Appendix IV

Chemical Risk Assessment at the 

Occupational Safety and Health 

Administration ApendxiIV

Although the Occupational Safety and Health Administration (OSHA) 

generally follows the standard four-step National Academy of Sciences’

(NAS) paradigm for risk assessment, there are several distinguishing 

characteristics of its assessments. Under its statutory mandate, OSHA has 

a specific and narrow focus on the potential risks to workers in an 

occupational setting. Further, the underlying statute and court decisions 

interpreting the statute have required the agency to focus on 

demonstrating, with substantial evidence, that significant risks to workers

exist before it can regulate. In addition to presenting its own best 

estimates of risk, OSHA may present estimates based on alternative 

methods and assumptions.

Context for OSHA 

Chemical Risk 

Assessment

Much of what is distinct about risk assessment at OSHA can be traced to 

statutory provisions, court decisions, and the nature of workplace 

exposures to chemicals. OSHA, an agency within the Department of Labor, 

was created by the Occupational Safety and Health Act of 1970 (the OSH 

Act).1

 The central purpose of the act is to ensure safe and healthful 

working conditions. As one of the primary means of achieving this goal, 

the act authorizes the Secretary of Labor to promulgate and enforce 

mandatory occupational safety and health standards.2

 Certain provisions 

in the act stipulate both the nature and the manner in which these 

standards should be established. For example:

• Under section 3(8) of the OSH Act, a safety or health standard is defined 

as a standard that requires conditions, or the adoption or use of one or 

more practices, means, methods, operations, or processes, reasonably 

necessary or appropriate to provide safe or healthful employment or 

places of employment.

• According to OSHA, a standard is reasonably necessary or appropriate 

within the meaning of section 3(8) if it eliminates or substantially 

reduces significant risk and is economically feasible, technologically 

feasible, cost effective, consistent with prior OSHA action or supported 

by a reasoned justification for departing from prior OSHA actions, 

supported by substantial evidence on the record as a whole, and is 

1

 29 U.S.C. 651 et seq.

2

 Safety standards are generally designed to reduce on-the-job injuries. Health standards are 

usually directed at limiting the risk of workers developing occupational diseases from 

exposure to hazardous chemical or physical agents.
Appendix IV

Chemical Risk Assessment at the 

Occupational Safety and Health 

Administration

Page 185 GAO-01-810 Chemical Risk Assessment

better able to effectuate the act’s purposes than any national consensus 

standard it supersedes.

• Section 6(b)(5) of the act states that “The Secretary, in promulgating 

standards dealing with toxic materials or harmful physical agents... 

shall set the standard which most adequately assures, to the extent 

feasible, on the basis of the best available evidence, that no employee 

will suffer material impairment of health or functional capacity even if 

such employee has regular exposure to the hazard dealt with by such 

standard for the period of his working life.”

A significant factor influencing the interpretation of the OSH Act provisions 

and OSHA’s approach to risk assessment is the Supreme Court ruling in its 

1980 “Benzene” decision that, before issuing a standard, OSHA must 

demonstrate that the chemical involved poses a “significant risk” under 

workplace conditions permitted by current regulations and that the new 

limit OSHA proposes will substantially reduce that risk.3

 This decision

effectively requires OSHA to evaluate the risks associated with exposure to 

a chemical and to determine that these risks are “significant” before issuing 

a standard. However, the court provided only general guidance on what 

level of risk should be considered significant. The court noted that a 

reasonable person might consider a fatality risk of 1 in 1000 (10-3) to be a 

significant risk and a risk of one in one billion (10-9) to be insignificant. 

Thus, OSHA considers a lifetime risk of 1 death per 1,000 workers to 

represent a level of risk that is clearly significant. The court also stated 

that “while the Agency must support its findings that a certain level of risk 

exists with substantial evidence, we recognize that its determination that a 

particular level of risk is significant will be based largely on policy 

considerations.”

4

Later Court of Appeals decisions have interpreted the Supreme Court’s 

“Benzene” decision to mean that OSHA must quantify or explain the risk for 

each substance that it seeks to regulate unless it can demonstrate that a 

group of substances share common properties and pose similar risks.5

 

Although this decision does not require OSHA to quantitatively estimate the 

risk to workers in every case, it does preclude OSHA from setting new 

3 Industrial Union Dept. v. American Petroleum Inst., 448 U.S. 607, 642 (1980).

4

 448 U.S. at 655-56 n.62.

5 AFL-CIO v. OSHA, 965 F.2d 962 (11th Cir. 1992), International Union, UAW v. Pendergrass, 

878 F.2d 389 (D.C. Cir. 1989).
Appendix IV

Chemical Risk Assessment at the 

Occupational Safety and Health 

Administration

Page 186 GAO-01-810 Chemical Risk Assessment

standards without explaining how it arrives at a determination that the 

standard will substantially reduce a significant risk.

According to OSHA officials, the other important contextual influence on 

OSHA risk assessment is the very nature of workplace exposures to 

chemicals. Generally, workplace exposures to chemicals are at higher 

levels than most environmental exposures to chemicals experienced by the 

general public. Workers are often exposed to many chemical agents at 

levels not much lower than those used in experimental animal studies. 

According to agency officials, this is one of the unique features of OSHA’s 

chemical risk assessments. Also, OSHA frequently has relevant human 

data available on current exposures, in contrast to most other agencies 

regulating toxic substances.

Risk Assessment 

Procedures

General Approach OSHA currently has no formal internal risk assessment guidance. Instead, 

OSHA has primarily described its general risk assessment methods, as well 

as the rationale for specific models and assumptions selected, in the record 

of each risk assessment and regulatory action. One reason for this, 

according to agency officials, is that OSHA performs risk assessments only 

for its standards. Overall, they said the agency only publishes two or three 

proposed or final rules per year, and not all of these rules involve a 

chemical risk assessment. The officials also emphasized the incremental 

nature of advances in risk assessment methods and science, with 

successive assessments establishing precedents for methods that may be 

used for succeeding analyses.

Like EPA and FDA, OSHA uses the basic NAS four-step process for risk 

assessment. Another fundamental source for OSHA’s (and EPA’s and 

FDA’s) methods was the 1985 document on chemical carcinogens produced 

by the Office of Science and Technology Policy.6

 OSHA often refers to the 

reference sources of other entities, including other federal agencies, in 

6

 Office of Science and Technology Policy, Executive Office of the President, “Chemical 

Carcinogens: A Review of the Science and Its Associated Principles, February 1985,” 50 FR 

10372 (Mar. 14, 1985).
Appendix IV

Chemical Risk Assessment at the 

Occupational Safety and Health 

Administration

Page 187 GAO-01-810 Chemical Risk Assessment

both specific rulemakings and as general technical links to its on-line 

information on occupational risks. 

Despite these common elements and procedures, several features of 

OSHA’s approach differ from those of other federal agencies. Because 

OSHA does not currently have written internal guidance on its risk 

assessment procedures, the information in the following sections is derived 

primarily from an examination of OSHA’s chemical risk assessments.7

 We 

also relied on secondary sources, such as Lorenz Rhomberg’s report on 

federal agencies’ risk assessment methods.8

 

Hazard Identification In OSHA’s risk assessments, the hazard identification step results in a 

determination that an exposure to a toxic substance causes, is likely to 

cause, or is unlikely or unable to cause, one or more specific adverse health 

effects in workers. According to OSHA, this step also shows which studies 

have data that would allow a quantitative estimation of risk. OSHA defines 

hazardous and toxic substances as those chemicals present in the 

workplace that are capable of causing harm. In this definition, the term 

chemicals includes dusts, mixtures, and common materials such as paints, 

fuels, and solvents. OSHA currently regulates exposure to approximately 

400 such substances. In the workplace environment, chemicals pose a 

wide range of health hazards (e.g., irritation, sensitization, carcinogenicity, 

and noncancer acute and chronic toxic effects) and physical hazards (e.g., 

ionizing and nonionizing radiation, noise, and vibration). 

7

 Because OSHA’s methylene chloride standard is the most recent hazardous chemical 

rulemaking, most of the specific examples cited come from OSHA’s methylene chloride 

rulemaking: “Occupational Exposure to Methylene Chloride,” 62 FR 1494 (Jan. 10, 1997).

8

 Lorenz R. Rhomberg, A Survey of Methods for Chemical Health Risk Assessment Among 

Federal Regulatory Agencies, a report prepared for the National Commission on Risk 

Assessment and Risk Management (1996).
Appendix IV

Chemical Risk Assessment at the 

Occupational Safety and Health 

Administration

Page 188 GAO-01-810 Chemical Risk Assessment

Most of OSHA’s chemical risk assessments have addressed occupational 

carcinogens. In assessing potential carcinogens, OSHA may consider the 

formal hazard classification or ranking schemes of other entities as part of 

the available evidence on a particular chemical. Ultimately, though, OSHA 

makes its own determinations on the risk posed by particular compounds 

and their classification as potential occupational carcinogens. OSHA’s 

chemical risk assessments may also discuss noncancer hazards. For 

example, in the final rule on methylene chloride the agency discussed the 

evidence regarding central nervous system, cardiac, hepatic (liver), and 

reproductive toxicity, as well as carcinogenicity. Similarly, the agency’s 

rulemaking on 1,3-butadiene addressed adverse health effects such as 

developmental and reproductive toxicity and bone marrow effects in 

addition to the evidence on carcinogenicity.9

 OSHA quantifies the risks of 

noncancer effects if it determines that there are adequate data on exposure 

and response for the substance of interest.

OSHA officials also noted that OSHA has a hazard communication 

standard, which requires manufacturers, shippers, importers, and 

employees to inform their employees of any potential health hazard when 

handling these chemicals. This is usually done through container labeling 

and material safety data sheets. Although this standard does not address 

specific risks posed by individual chemicals, it is a comprehensive hazard 

information standard for nearly all chemicals in commerce.

Dose-Response Assessment

Carcinogens OSHA’s general procedures for dose-response assessment are similar to 

those of EPA and FDA, especially in the choice of data sets to use for 

quantitative assessments. However, OSHA probably uses a linear low-dose 

extrapolation model less often than is the case for other agencies. OSHA 

differs from the other federal regulatory agencies also in being less 

conservative in setting its target risk levels when conducting low-dose 

extrapolation. As previously noted, the main points of OSHA’s risk 

assessments for regulatory purposes are to determine whether significant 

risks exist and to demonstrate in a broad sense the degree to which the 

standard would reduce significant risk. The specific choice of where to set 

9 “Occupational Exposure to 1,3-Butadiene” 61 FR 56746 (Nov. 4, 1996).
Appendix IV

Chemical Risk Assessment at the 

Occupational Safety and Health 

Administration

Page 189 GAO-01-810 Chemical Risk Assessment

the standard is tempered by the statutory mandate that standards must be 

technologically and economically feasible.

Like other agencies, OSHA states that, all things being equal, 

epidemiological data are preferred over data from animal studies whenever 

good data on human cancer risks exist. More often than some other 

agencies regulating exposures to toxic substances, OSHA may have 

relevant human data on adverse health effects available for consideration 

in its risk assessments. However, the rulemaking examples we reviewed 

also illustrate that these epidemiological data may be considered 

inadequate for quantitative dose-response assessment, while animal data 

may provide more precise and useful dose-response information. In both 

the methylene chloride and 1,3-butadiene dose-response assessments, for 

example, OSHA had both epidemiological and animal data available, but 

based its quantitative estimates on data from rodent models. However, 

OSHA did use its analysis of the epidemiological data when examining the 

consistency of the results derived from animal studies. 

When faced with the choice of several animal data sets, OSHA tends not to 

combine tumor sites but to choose the data set showing the highest 

sensitivity (i.e., most sensitive sex, species, and tumor site). The agency 

will, however, frequently present information from alternative data sets and 

analyses. The agency is likely to include benign tumors with the potential 

to progress to malignancy along with malignant tumors in the data set used 

for its quantitative assessments. OSHA cited the Office of Science and 

Technology Policy’s views on chemical carcinogens in support of this 

practice, as well as noting that other federal agencies, including EPA and 

FDA, have also included benign responses in their assessments.

Because occupational exposures tend to be closer to the range of 

experimentally tested doses in animal studies, extrapolation may pose less 

of a challenge for OSHA than for other regulatory agencies. OSHA’s 

preferred model for quantitative analysis of animal cancer dose-response 

data and for extrapolation of these data to low doses is the “multistage 

model,” which is based on the biological assumption that carcinogens 

induce cancer through a series of independent ordered viable mutations, 

and that cancer develops through stages. Unlike EPA and FDA, however, 

OSHA tends to focus on the maximum likelihood estimate (MLE) of the 

fitted dose-response curve rather than on an upper bound, although the 

agency also provides estimates for the 95-percent upper confidence limit 

(UCL) of the dose-response function. This procedure generally leads to a 

less conservative risk estimate than the procedures used by EPA or FDA. 
Appendix IV

Chemical Risk Assessment at the 

Occupational Safety and Health 

Administration

Page 190 GAO-01-810 Chemical Risk Assessment

Like EPA and FDA, OSHA generally assumes no threshold for 

carcinogenesis. In contrast to the other agencies, OSHA’s default dosemetric for interspecies extrapolation is body weight scaling (mg/kg/day −

i.e., risks equivalent at equivalent body weights). According to OSHA, this 

default is used to be consistent with prior chemical risk assessments, but it 

also reflects a conscious policy decision that its methodology should not be 

overly conservative. OSHA says it may in the future move to 3⁄4 -power 

scaling, as agreed to by EPA, FDA, and the Consumer Product Safety 

Commission some years ago. OSHA also says it is currently considering 

developing a different form of the multistage model, which will provide 

more stable MLE estimates than does the current form.

OSHA also considered data from physiologically based pharmacokinetic 

(PBPK) models in the risk assessment examples we reviewed.10 PBPK 

models provide information on target organ dose by estimating the time 

distribution of a chemical or its metabolites through an exposed subject’s 

system.11 OSHA noted that PBPK modeling can be a useful tool for 

describing the distribution, metabolism, and elimination of a compound of 

interest under conditions of actual exposure and, if data are adequate, can 

allow extrapolation across dose levels, routes of exposure, and species. In 

particular, pharmacokinetic information is useful in modeling the 

relationship between administered doses and effective doses as a function 

of the exposure level.12 However, PBPK models are complicated and 

require substantial data, which may not be available for most chemicals. 

OSHA pointed out in the methylene chloride rule that differences in the risk 

estimates from alternative assessments (including those submitted by 

outside parties) were not generally due to the dose-response model used, 

but to whether the risk assessor used pharmacokinetic modeling to 

10 Pharmacokinetics is the study of the absorption, distribution, metabolism, and elimination 

of chemicals in humans and animals. It is the basis for developing more realistic and 

accurate models of the movement and interactions of a chemical with blood, tissues, and 

organs once it enters the body, including consideration of the body’s ability to repair damage 

caused by a chemical. PBPK models are based on the physiology of the exposed subjects, in 

contrast to more general compartmental pharmacokinetic models that do not necessarily 

represent effects on real anatomic regions/compartments of the body. 

11 Once in the body, a chemical may be chemically altered to form metabolites. Either the 

chemical itself or its metabolites may produce toxic effects. Therefore, both may need to be 

considered in assessing the potential harm associated with a given chemical.

12 The administered dose is the amount of a substance given to an animal or human (e.g., 

through diet, drinking water, or ambient air). The effective dose is the amount that actually 

reaches a target organ or tissue.
Appendix IV

Chemical Risk Assessment at the 

Occupational Safety and Health 

Administration

Page 191 GAO-01-810 Chemical Risk Assessment

estimate target tissue doses and what assumptions were used in that 

modeling. 

In the methylene chloride standard, OSHA developed a set of 11 criteria to 

judge whether available data are adequate to permit the agency to rely on 

PBPK analysis in place of administered exposure levels when estimating 

human equivalent doses. Although it is beyond the scope of this appendix 

to provide a full technical explanation of the following criteria, they do 

illustrate the complex nature of PBPK analysis and, more generally, the 

types of issues that risk assessors consider in weighing the available data.

1. The predominant as well as all relevant minor metabolic pathways 

must be well described in several species, including humans.

2. The metabolism must be adequately modeled.

3. There must be strong empirical support for the putative mechanism of 

carcinogenesis.

4. The kinetics for the putative carcinogenic metabolic pathway must 

have been measured in test animals in vivo and in vitro and in 

corresponding human tissues at least in vitro.

13

5. The putative carcinogenic metabolic pathway must contain metabolites 

that are plausible proximate carcinogens.

6. The contribution to carcinogenesis via other pathways must be 

adequately modeled or ruled out as a factor.

7. The dose surrogate in target tissues used in PBPK modeling must 

correlate with tumor responses experienced by test animals.

8. All biochemical parameters specific to the compound, such as blood:air 

partition coefficients, must have been experimentally and reproducibly 

measured. This must especially be true for those parameters to which 

the PBPK model is sensitive.

13 The term in vivo refers to tests carried out within living organisms, while in vitro refers 

to tests outside the organism (e.g., using cells taken from an animal or human).
Appendix IV

Chemical Risk Assessment at the 

Occupational Safety and Health 

Administration

Page 192 GAO-01-810 Chemical Risk Assessment

9. The model must adequately describe experimentally measured 

physiological and biochemical phenomena.

10. The PBPK models must have been validated with other data (including 

human data) that were not used to construct the models.

11. There must be sufficient data, especially data from a broadly 

representative sample of humans, to assess uncertainty and variability 

in the PBPK modeling.

In the 1,3-butadiene standard, which came out after the methylene chloride 

standard, OSHA used these same 11 criteria to judge the adequacy of the 

1,3-butadiene PBPK models for dose-response assessment. In the 

butadiene case, the PBPK models did not meet all of these criteria.

For dose-response analyses from human cancer data, OSHA tends to use 

similar methodologies to the other regulatory agencies. Mostly these are 

simple linear models, such as relative risk models, and estimates of risk are 

based on the MLE.

Noncancer Effects No specific approach or procedure for the assessment of noncancer effects 

was evident in the examples of OSHA rulemakings we reviewed. However, 

OSHA clearly considered a range of noncancer toxic effects in its analyses. 

In its rulemakings, OSHA focused on describing and analyzing a variety of 

relevant studies, case reports, and other information found in the scientific 

literature. Rhomberg noted that, in the past, OSHA used methods that were 

comparable to those of other agencies. However, the federal court in the 

AFL-CIO v. OSHA case questioned the use of standard safety factors, 

noting that “application of such factors without explaining the method by 

which they were determined... is clearly not permitted.”

14

OSHA has produced quantitative risk estimates for reproductive and 

developmental effects (glycol ethers, 1993), heart disease and asthma 

(environmental tobacco smoke, 1994), Hepatitis B virus infection 

(bloodborne pathogens, 1992), tuberculosis, and kidney toxicity from 

cadmium exposure. OSHA is currently working on quantitative risk 

assessments for such adverse health effects as cardiovascular disease 

mortality, neural effects, asthma, and respiratory tract irritation for a 

number of substances. OSHA states that new methodology has been used 

14 965 F.2d at 978.
Appendix IV

Chemical Risk Assessment at the 

Occupational Safety and Health 

Administration

Page 193 GAO-01-810 Chemical Risk Assessment

for these assessments, but review drafts were not yet ready and we cannot 

comment further.

Exposure Assessment Under the OSH Act, OSHA has a relatively specific and narrow focus on

exposure assessment. OSHA’s primary focus is estimating the risk to 

workers exposed to an agent for a working lifetime. This risk is calculated 

in terms of a person exposed at a constant daily exposure level for 45 years 

at 5 days per workweek and 8 hours per workday. The goal is to set 

standards, in the form of permissible exposure limits (PELs), so workers 

would suffer no impairment during the course of their lifetime under a 

continuous exposure scenario. Although this is a hypothetical exposure 

scenario, Rhomberg observed that it is not conservative compared with the 

actual distribution of exposures in the workplace. He also noted that, in 

assessing the exposures and risks associated with the new proposed 

standard, OSHA assumes that the standard is applied to newly exposed 

workers who will work under the new standard for their entire working 

lives. No allowance is made for the fact that current workers may already

have had exposures higher than the new standard.

Despite the primary focus on long-term working lifetime exposures, there 

may also be some risks posed by acute, short-term exposures. Therefore, 

although part of OSHA’s risk assessment could focus on longer-term risks 

and deal with 8-hour time-weighted average (TWA) exposure, the agency’s 

analysis may also cover short-term exposure effects. In the methylene 

chloride rule, for example, OSHA set the 8-hour TWA PEL primarily to 

reduce the risk of employees developing cancer, while the 15-minute shortterm exposure limit (STEL) was primarily designed to protect against 

noncancer risks, such as negative effects on the central nervous system.

Finally, Rhomberg pointed out the following distinct features of 

occupational exposure assessments:

Compared to environmental exposures, exposures in the workplace 

tend to be much better defined. The workplace is a confined setting 

within which practices and behaviors tend to be standardized. 

Exposure levels are often high enough to be easily measured, and many 

workplaces have ongoing monitoring of environmental levels of 

compounds.15

15 Rhomberg (1996), p. 36.
Appendix IV

Chemical Risk Assessment at the 

Occupational Safety and Health 

Administration

Page 194 GAO-01-810 Chemical Risk Assessment

Risk Assessment 

Assumptions and 

Methodological 

Choices

As previously noted, OSHA’s risk assessment procedures, including its 

default assumptions and methodological preferences, tend to be 

established through the precedents of prior rulemakings. In contrast to 

EPA and FDA, OSHA also appears to choose somewhat less conservative 

options, even though the agency notes that Congress and the courts have 

permitted and even encouraged it to consider “conservative” responses to 

both uncertainty and human variability. The Supreme Court’s Benzene 

decision, in particular, affirmed that “the Agency is free to use conservative 

assumptions in interpreting the data with respect to carcinogens, risking 

error on the side of over-protection rather than under protection.”

16 On the 

other hand, OSHA explicitly stated in rulemakings that it takes various 

steps to be confident that its risk assessment methodology is not designed 

to be overly conservative (in the sense of erring on the side of 

overprotection). Although not intended to be comprehensive, table 8 

illustrates some of the specific assumptions or methodological choices 

used by OSHA. It also illustrates the overt balancing of more and less 

conservative choices that characterizes OSHA’s approach to risk 

assessment. The information presented in table 8 was taken primarily from 

OSHA risk assessment documents but also reflects additional comments 

provided by OSHA officials. (GAO notes and comments appear in 

parentheses.)

Table 8: OSHA Risk Assessment Assumptions and Methodological Choices

16 448 U.S. at 656.

Assumption or 

methodological choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 

1.

Most things being equal, 

epidemiologic data are preferred 

to data from animal studies 

whenever good data on human 

risks exist.

Avoids the uncertainty of crossspecies extrapolation. Also, 

most human studies on nondrug 

chemicals come from 

occupational exposures.

Choice of data set for 

quantitative cancer risk 

assessment (hazard 

identification and dose-response 

assessment)

(Not identified.)
Appendix IV

Chemical Risk Assessment at the 

Occupational Safety and Health 

Administration

Page 195 GAO-01-810 Chemical Risk Assessment

2.

It is reasonable to suspect that 

substances that cause cancer in 

multiple animal species and at 

multiple target organ sites would 

be carcinogenic to humans. 

Therefore, OSHA relies on wellconducted, high-quality animal 

bioassays as the primary basis 

for cancer hazard identification 

and often for quantitative risk 

assessment.

Virtually all of the toxic 

substances that have been 

demonstrated to be carcinogenic 

in humans are also carcinogenic 

in laboratory animals.

Choice of data set for qualitative 

and quantitative cancer risk 

assessment (hazard 

identification and dose-response 

assessment) − in the absence of 

sufficiently powerful negative 

epidemiological studies or 

mechanistic studies 

demonstrating that the purported 

carcinogenic mechanism of 

action of the substance is 

irrelevant to humans.

(Not specifically identified, but 

OSHA did note that it is possible 

that a substance may be 

carcinogenic in a laboratory 

species but not in humans. 

OSHA officials also pointed out 

that, as part of its risk 

assessment, OSHA examines all 

relevant toxicity data to 

determine the appropriateness 

of relying on extrapolation from 

animal studies.)

3.

If human (epidemiological) data 

are equivocal, or the 

epidemiologic study is not 

sufficiently sensitive to identify 

an increased risk predicted by a 

well-conducted animal bioassay, 

it is necessary to consider the 

animal data to protect workers 

from significant risk.

To protect workers from 

significant risk.

Analysis of epidemiological and 

animal data for quantitative 

cancer risk assessment (hazard 

identification and dose-response 

assessment) − when animal 

studies indicate a positive 

response to a particular 

chemical and epidemiological 

studies of exposures to the same 

chemical fail to exhibit a 

statistically significant increase 

in risk.

(Not identified.)

4.

In the absence of 

pharmacokinetic information 

satisfying OSHA’s criteria for 

acceptance of PBPK models, 

OSHA relies on a default 

mg/kg/day species conversion 

factor. 

(Not identified.) Choice of animal-to-human dose 

equivalence for quantitative risk 

assessment (dose-response 

assessment).

(Not identified, but this is 

generally considered to be a 

conservative approach.)

5.

OSHA uses site-specific tumor 

incidence, rather than pooled 

tumor response, in determining 

the dose-response function for a 

chemical agent. OSHA 

estimates excess risks to 

humans based on the most 

sensitive species-sex-tumor site.

(Not explicitly identified. Per 

comments from OSHA it reflects, 

in part, a policy choice to be 

conservative, but not overly 

conservative.)

Choice of data set for 

quantitative cancer risk 

assessment (dose-response 

assessment).

OSHA cited this as an instance 

where the agency does not use 

the most conservative approach.

(Continued From Previous Page)

Assumption or 

methodological choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix IV

Chemical Risk Assessment at the 

Occupational Safety and Health 

Administration

Page 196 GAO-01-810 Chemical Risk Assessment

6.

OSHA combines benign tumors 

with the potential to progress to 

malignancies with malignant 

tumors occurring in the same 

tissue and the same organ site.

Evidence suggests that such 

tumors should be interpreted as 

representing a potentially 

carcinogenic response.

(In support of this position, 

OSHA cited the views of the 

Office of Science and 

Technology Policy on chemical 

carcinogenesis [citation 

provided]. OSHA also pointed 

out that other federal agencies—

EPA, FDA, the Consumer 

Product Safety Commission, and 

the National Institute for 

Occupational Safety and 

Health—have also included 

benign responses in their 

assessments.)

Choice of data set for 

quantitative cancer risk 

assessment (dose-response 

assessment).

(Not specifically identified in the 

risk assessments we reviewed, 

but according to OSHA officials 

is almost always conservative.)

7.

OSHA relies on low-dose 

extrapolation to estimate risks 

associated with exposure levels 

of interest; however, because 

occupational exposures are 

typically much higher than those 

encountered in the general 

environment, OSHA’s risk 

assessments do not extrapolate 

as far beyond the range of 

observed toxicity as might be 

necessary to characterize 

environmental risks. 

(Not explicitly identified, but the 

assumption that you can 

extrapolate low-dose effects 

from high-dose effects is a 

standard assumption of risk 

assessment.)

Dose-response assessment. (Not identified.)

(Continued From Previous Page)

Assumption or 

methodological choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix IV

Chemical Risk Assessment at the 

Occupational Safety and Health 

Administration

Page 197 GAO-01-810 Chemical Risk Assessment

8.

For low-dose animal-to-human 

cancer risk extrapolation, 

OSHA’s preference is to use the 

maximum likelihood estimate 

(MLE) in the Crump-Howe 

reparameterization of the 

“multistage model.”

This model is based on the 

biological assumption that 

carcinogens induce cancer 

through a series of independent 

viable mutations in a series of 

stages, and that each mutation 

rate is linearly related to dose.

The multistage model used by 

the agency also assumes no 

threshold for carcinogenesis.

OSHA stated that it believes that 

the multistage model conforms 

most closely to what is known 

about the etiology of cancer, 

including the fact that linear-atlow-dose behavior is expected 

for exogenous agents, which 

increase the risk of cancer 

already posed by similar 

"background” processes. OSHA 

noted that there is no evidence 

that the multistage model is 

biologically inappropriate, 

especially for genotoxic 

carcinogens, and that the 

overwhelming scientific 

consensus is that genotoxins 

follow low-dose linear functions. 

However, OSHA officials also 

pointed out that the CrumpHowe algorithm that OSHA uses 

can yield nonlinear models.

OSHA’s preference is consistent 

with the position of the Office of 

Science and Technology Policy, 

which recommended that “when 

data and information are limited, 

models or procedures that 

incorporate low-dose linearity 

are preferred when compatible 

with limited information” [citation 

provided].

Cancer dose-response 

assessment.

The multistage model is 

generally considered to be a 

conservative model because it is 

approximately linear at low 

doses and because it assumes 

no threshold for carcinogenesis, 

although there are other 

plausible models of 

carcinogenesis which are more 

conservative at low doses.

(OSHA officials also pointed out 

that the algorithm that OSHA 

uses to compute MLE estimates 

is less conservative because it 

may lead to models that are 

sublinear at low doses.)

9.

OSHA’s default choice is to 

select the MLE of the 

parameterized dose-response 

function, rather than the upper 

95-percent confidence limit.

In part, this appears to reflect a 

policy choice. OSHA cited this 

choice as one of the steps it has 

taken that make it fairly confident 

its risk assessment methodology 

is not designed to be overly 

“conservative,” in the sense of 

erring on the side of 

overprotection.

Cancer dose-response 

assessment.

OSHA cited this as an instance 

where the agency does not use 

a conservative (or the most 

conservative) approach.

(Continued From Previous Page)

Assumption or 

methodological choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix IV

Chemical Risk Assessment at the 

Occupational Safety and Health 

Administration

Page 198 GAO-01-810 Chemical Risk Assessment

10.

For interspecies dose scaling, 

OSHA assumes that equivalent 

doses in mg/kg/day (body weight 

scaling) would lead to equivalent 

risks.

(OSHA’s Director of Health 

Standards noted that the agency 

might also move to consideration 

of 3⁄4-power scaling, as agreed to 

by EPA, FDA, and the Consumer 

Product Safety Commission, or 

to develop a probability 

distribution for the power.)

In addition, to convert mg/kg/day 

doses to parts per million (ppm), 

OSHA uses a human breathing 

rate of 9.6 m3

/workday and 

human body weight of 70 kg.

In its risk assessments, OSHA 

points out that there are several 

plausible options for 

extrapolating human risks from 

animal data via interspecies 

scaling factors [citations 

provided]. OSHA states that its 

selection of body weight scaling 

is one of the steps it takes that 

make the agency fairly confident 

that its risk assessment 

methodology is not 

“conservative” in the sense of 

erring on the side of 

overprotection.

(No particular basis cited for 

using the specific breathing rate 

and body weight figures, just that 

they are OSHA’s preferred 

values.)

During dose-response 

assessment, when estimating 

the equivalent human dose 

based upon an experimental 

dose in animals.

OSHA notes that the body 

weight extrapolation approach 

that it generally uses tends to be 

significantly less conservative 

than other plausible 

methodologies and most likely is 

less conservative even than the 

central tendency of the plausible 

values.

The agency also notes that, 

across the series of plausible 

values, its body weight 

extrapolation approach is 

generally considered the least 

conservative, (body weight)2/3

[surface area scaling] the most 

conservative, and (body 

weight)3/4 the midpoint value.

11.

OSHA assumes that workers will 

be exposed to a chemical at the 

maximum permissible level for 

45 years.

The standard values used for 

assessing exposures over a 

working lifetime are:

a. 45 years per working 

lifetime,

b. 5 workdays per week, and

c. 8 hours per workday.

The focus on working lifetime 

exposure comes from the 

statutory mandate under the 

OSH Act to protect an employee 

“even if such employee has 

regular exposure to the hazard...

for the period of his working life.”

The choice of 45 years is based 

on a worker beginning work at 

age 20 and retiring at age 65.

Exposure assessment. OSHA notes that this reflects a 

“more conservative” choice.

(Continued From Previous Page)

Assumption or 

methodological choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix IV

Chemical Risk Assessment at the 

Occupational Safety and Health 

Administration

Page 199 GAO-01-810 Chemical Risk Assessment

Source: Compiled from GAO review of OSHA risk assessment documents and from additional 

comments provided by agency officials.

Risk Characterization Although OSHA does not have written risk characterization policies, recent 

OSHA rulemakings showed that the agency emphasized (1) comprehensive 

characterizations of risk assessment results; (2) discussions of 

assumptions, limitations, and uncertainties; and (3) disclosure of the data 

and analytic methodologies on which the agency relied. Rhomberg noted 

that OSHA’s usual practice is to present the results and methodological 

bases of outside parties’ risk assessments for a chemical in addition to 

OSHA’s own assessment, and to feature several possible bases for risk 

calculation in its characterization of risks. In checking examples of recent 

OSHA rulemakings, we also observed this emphasis on showing a range of 

alternative assessments, both those of external parties and OSHA’s own 

sensitivity analyses.

At least three factors help to explain this proclivity to characterize risks 

using different data sets, assumptions, and analytical approaches, all of 

which are rooted in the statutory context for OSHA standards setting. 

First, the agency’s statutory mandate, reinforced by the Supreme Court’s 

Benzene decision, is that it must demonstrate “significant” risk from 

workplace exposure to a chemical with “substantial evidence.” Second, the 

OSH Act directs OSHA to base health standards on the “best available 

12.

The general boundary within 

which acceptable versus 

unacceptable risk falls is 

between an insignificant fatality 

risk of one in one billion (10-9) 

and a significant risk of 1 in one 

thousand (10-3).

More explicitly, OSHA stated in 

one of its rulemakings that risks 

at or above 10-3 (1 per 1000) are 

always significant by any 

empirical, legal, or economic 

argument available.

The general boundary is directly 

attributed to the Supreme 

Court’s 1980 Benzene decision.

Policy for evaluating “significant 

risk.”

(No direct effect on the risk 

estimates, but this general policy 

does serve as an underlying 

focus in conducting risk 

assessments.)

(Continued From Previous Page)

Assumption or 

methodological choice Reason(s) for selection

When the assumption/choice 

would be applied (step in the 

risk assessment process or 

circumstances)

Likely effect on risk 

assessment results 
Appendix IV

Chemical Risk Assessment at the 

Occupational Safety and Health 

Administration

Page 200 GAO-01-810 Chemical Risk Assessment

evidence” and consider the “latest scientific data.” The third factor is that 

the standard selected will be limited by consideration of its technological 

and economic feasibility and cost effectiveness. Together, these provisions 

provide ample incentive to show that a compound presents a significant 

risk even when using a range of alternative estimates and scientific 

evidence. (This does not preclude the agency from focusing on one 

analysis as the most appropriate to support its final estimate of risk at a 

particular level of exposure.) The bottom line is that OSHA uses risk 

assessment to justify a standard by showing, in general, that significant 

risks exist and that reducing exposure as proposed in the agency’s standard 

will reduce those risks.

In recent OSHA rulemakings, the agency devoted considerable effort to 

addressing uncertainty and variability in its risk estimates. Such efforts 

included performing sensitivity analyses, providing the results produced by 

alternative analyses and assumptions, and using techniques such as Monte 

Carlo and Bayesian statistical analyses. In its risk characterizations, OSHA 

provided both estimates of central tendency (such as the mean) and upper 

limits (such as the 95th percentile of a distribution). In the methylene 

chloride rule, OSHA noted that, in its past rulemakings, it had frequently 

estimated carcinogenic potencies via the MLE of the multistage model 

parameters. However, in this particular rule it chose for its final risk 

estimate to couple one measure of central tendency (the MLE of the doseresponse parameters) with a somewhat conservative measure of its PBPK 

output (the 95th percentile of the distribution of human internal dose). 

OSHA concluded that this combination represented “a reasonable attempt 

to account for uncertainty and variability.”
Page 201 GAO-01-810 Chemical Risk Assessment

Appendix V

Chemical Risk Assessment at the Department 

of Transportation’s Research and Special 

Programs Administration ApendxiV

The chemical risk assessments conducted by the Department of 

Transportation’s (DOT) Research and Special Programs Administration 

(RSPA) focus primarily on acute (short-term) risks associated with 

potential accidents involving unintentional releases of hazardous materials 

(HAZMAT) during transportation.1

 As such, they are very different from 

risk assessments that focus on chronic health risks. According to agency 

officials, RSPA’s assessments are done using a flexible, criteria-based 

system. RSPA’s HAZMAT transportation safety program begins with a 

hazard analysis that results in material classification. There are 

international standards on the transportation and labeling of dangerous 

goods that classify the type of hazard associated with a given substance 

(e.g., whether it is flammable, explosive, or toxic) and the appropriate type 

of packaging. Once a hazard is classified, RSPA’s analysis focuses on 

identifying the potential circumstances, probability, and consequences of 

unintentional releases of hazardous material during its transportation. 

DOT has written principles on how the results of its risk or safety 

assessments should be presented. Those principles emphasize 

transparency regarding the methods, data, and assumptions used for risk 

assessments and encourage DOT personnel to not only characterize the 

range and distribution of risk estimates, but also to put the risk estimates 

into a context understandable by the general public.

Context for RSPA 

Chemical Risk 

Assessment

According to DOT officials, chemical risks may be an element of almost 

any departmental risk assessment. For example, they said that one of the 

alternatives they explored regarding air bags involved potential exposure 

to chemicals used in the inflation mechanism. They also noted that Federal 

Aviation Administration (FAA) safety analyses include some elements 

related to potential exposures to the chemicals that are always found in 

aircraft mechanisms. However, DOT’s risk assessment most commonly 

focus on chemical risks when considering the transportation of hazardous 

materials. Unintentional releases of hazardous materials during 

transportation, whether due to packaging leaks or transportation 

accidents, may pose risks to human health and safety, the environment, and 

property. The potential consequences of such incidents include deaths or 

1

 DOT uses the term “risk assessment” narrowly to refer to risk characterization, specifically 

the determination of risk context and acceptability, often by comparison to other similar 

risks. However, to be consistent with the rest of this report, we are using the term in this 

appendix to refer to the entire process of identifying, analyzing, and characterizing risks.
Appendix V

Chemical Risk Assessment at the Department 

of Transportation’s Research and Special 

Programs Administration

Page 202 GAO-01-810 Chemical Risk Assessment

injuries caused by an explosion, fire, or release of gases that are toxic when 

inhaled.

Under the Federal Hazardous Materials Transportation Act, as amended, 

the Secretary of Transportation has the regulatory authority to provide 

adequate protection against risks to life and property inherent in 

transporting hazardous materials in commerce.2

 DOT officials pointed out 

that, because this act tends to be more general than those relevant to other 

agencies’ regulation of risks from chemicals, it gives DOT more flexibility 

to define what is “adequate” to address potential risks. The statute directs 

the DOT Secretary to designate a material or group or class of materials as 

hazardous when he or she decides that transporting the material in 

commerce in a particular amount and form may pose an unreasonable risk 

to health and safety or property. The Secretary is also directed to issue 

regulations for the safe transportation of such materials. The hazardous 

materials regulations apply to interstate, intrastate, and foreign 

transportation in commerce by aircraft, railcars, vessels (except most bulk 

carriage), and motor vehicles.

The Secretary has delegated authority for implementing these hazardous 

materials responsibilities to various components within DOT. In particular, 

RSPA issues the Hazardous Materials Regulations and carries out related 

regulatory functions, such as issuing, renewing, modifying, and terminating 

exemptions from the regulations. The Superfund Amendments and 

Reauthorization Act of 1986 mandated that RSPA also list and regulate 

under the Hazardous Materials Regulations all hazardous substances 

designated by EPA. According to DOT officials, RSPA conducts most of the 

department’s risk assessments regarding the transportation of chemical 

hazardous materials. RSPA and the modal administrations in DOT—FAA, 

the United States Coast Guard, the Federal Motor Carrier Safety 

Administration, and the Federal Railroad Administration—share 

enforcement authority for hazardous materials transportation. 

RSPA’s Office of Hazardous Materials Safety (OHMS) has the primary 

responsibility for managing the risks of hazardous materials transportation 

within the boundaries of the United States, unless such materials are being 

transported via bulk marine mode (in which case the Coast Guard is 

responsible). Overall, OHMS notes that its Hazardous Materials Safety 

Program and resulting regulations (1) are risk based; (2) use data, 

2

 49 U.S.C. 5101 et seq.
Appendix V

Chemical Risk Assessment at the Department 

of Transportation’s Research and Special 

Programs Administration

Page 203 GAO-01-810 Chemical Risk Assessment

information, and experience to define hazardous materials and manage the 

risk hazardous materials present in transportation; and (3) are prevention 

oriented. Therefore, the analysis of risk is an important element of OHMS’

responsibilities. Within OHMS, the Office of Hazardous Materials 

Technology (OHMT) provides scientific, engineering, radiological, and risk 

analysis expertise.

Other entities may also be involved in conducting transportation-related 

chemical risk and safety assessments. For example, OHMS sponsored a 

quantitative threat assessment by the John A. Volpe National 

Transportation Systems Center (the Volpe Center), which is operated by 

RSPA, to determine the probability that a life-threatening incident would 

occur as a result of transporting hazardous materials in aircraft cargo 

compartments.3

 OHMS also sponsored a multiyear research effort by the 

Argonne National Laboratory to characterize the risk associated with 

transportation of selected hazardous materials on a national basis.4

One of the most distinctive aspects regarding the regulation of hazardous 

materials transportation is the role that is played by international 

agreements and definitions. Criteria for classifying and labeling dangerous 

chemicals being transported have been internationally harmonized through 

the United Nations Recommendations on the Transport of Dangerous 

Goods.5

 This UN classification system is internationally recognized, and 

RSPA has essentially adopted the UN recommendations into the domestic 

hazardous materials regulations. (A more detailed description of this 

classification system appears in the following section.)

3 Threat Assessment of Hazardous Materials Transportation in Aircraft Cargo 

Compartments, U.S. Department of Transportation, Research and Special Programs 

Administration, John A. Volpe National Transportation Systems Center, Final Report 

(December 1999).

4 A National Risk Assessment for Selected Hazardous Materials Transportation, Decision 

and Information Sciences Division, Argonne National Laboratory (December 2000). The 

Argonne National Laboratory is operated by the University of Chicago under contract for 

the U.S. Department of Energy.

5

 The United States and other countries are attempting to develop a Globally Harmonized 

System (GHS) for the classification and labeling of chemicals. However, while criteria have 

been internationally harmonized for purposes of transportation, harmonized requirements 

have not yet been established for purposes of environmental, worker, or consumer safety 

regulations. RSPA participates, along with other federal agencies, in these GHS activities.
Appendix V

Chemical Risk Assessment at the Department 

of Transportation’s Research and Special 

Programs Administration

Page 204 GAO-01-810 Chemical Risk Assessment

Risk Assessment 

Procedures

Because of the particular regulatory context in which it operates—in 

particular, its focus on acute (short-term) risks associated with 

transportation accidents—RSPA does not follow the four-step risk 

assessment paradigm identified by NAS and used by EPA, FDA, and OSHA. 

However, RSPA’s procedures do address similar generic questions, such as 

whether a particular material or activity poses a threat and the likelihood 

and consequences of potential accidents. The agency uses a criteria-based 

system to assess the hazards to human health and safety, property, and the 

environment that are associated with potential accidents during hazardous 

materials transportation. Chemicals are identified and classified as 

hazards according to a classification system in the Hazardous Materials 

Regulations that is largely harmonized with internationally recognized 

criteria. The risk analyses by RSPA then focus on assessing the potential 

circumstances under which exposure could occur during transportation, 

their causes, consequences, and probability of occurrence.

Guidance The general risk assessment procedures applicable to RSPA are found 

within DOT-wide policies on conducting regulatory analyses and also in 

descriptive materials about the agency’s Hazardous Materials Safety 

Program. DOT included general guidelines for conducting a risk 

assessment as part of its broader Methods for Economic Assessment of 

Transportation Industry Regulations (Office of the Assistant Secretary for 

Policy and International Affairs, June 1982). The DOT guidelines for risk 

assessment are grouped under three major topics:

• procedural guidelines that recommend formats for presentation of risk 

analyses, formats for conducting risk analyses, and reporting of 

assumptions and limits of analyses;

• methodology guidelines that discuss some of the more frequently used 

risk methods and their applicability; and

• data guidelines that discuss data sources, collection and presentation of 

data, and raw and derived statistics.

The primary focus of the DOT-wide risk assessment methodology and 

guidelines is on estimating the risk reduction attributable to proposed 

transportation safety regulations. DOT’s guidelines are intended to be 

applicable to risk assessment of hazardous material transport by any mode 

as well as assessment of other types of transportation risk. However, DOT 

stated that the guidelines are not intended to be a “cookbook,” or a 

prescriptive methodology, specifying each step in a risk assessment. DOT 
Appendix V

Chemical Risk Assessment at the Department 

of Transportation’s Research and Special 

Programs Administration

Page 205 GAO-01-810 Chemical Risk Assessment

pointed out in the guidelines that such an approach is not desirable, 

because there is no single “correct” set of methods for assessing 

transportation risk.

In addition to the DOT-wide guidelines, RSPA has produced written 

materials specifically on the Hazardous Materials Safety Program. These 

materials describe the role of risk assessment in the management of risks 

associated with transportation of hazardous materials and the general 

process used for analysis of risks, and they define risk assessment and 

management terms for purposes of hazardous materials safety.6

 There also 

are a number of general guidance documents and reports on various 

aspects of hazardous materials transportation safety that provide 

additional insights into the identification and assessment of risks.

Risk Assessment Approach RSPA does not apply the same NAS four-step paradigm for risk assessment 

as generally used by EPA, FDA, and OSHA. According to RSPA officials, 

the main reason for this difference between their risk assessments and 

most of those conducted by the other three agencies is the focus of RSPA’s 

assessments. RSPA’s concerns relative to hazardous materials 

transportation are primarily directed at short-term or acute health risks due 

to relatively high exposures from the unintentional release of hazardous 

materials. The officials said that, in contrast, the four basic steps of the 

NAS paradigm were intended to focus on chronic health risks due to longterm, low-level background chemical exposure.7

 The main exceptions to 

this difference in general risk assessment procedures occur when other 

agencies’ assessments are similarly directed at risks associated with 

unintentional releases of chemicals. In particular, RSPA officials said that 

there are parallels between their risk assessment and management efforts 

and those of EPA and OSHA programs that are directed at chemical 

accidents. (See, for example, the description of the risk assessment 

procedures for EPA’s Chemical Emergency Preparedness and Prevention 

Office in app. II.) 

6

 DOT’s definitions sometimes vary from the definitions of those terms in other risk 

assessment settings. Items in the glossary of this report identify some of these different 

definitions.

7

 Note, however, that the general risk assessment procedures of the other three agencies 

cover both chronic and acute risks. 
Appendix V

Chemical Risk Assessment at the Department 

of Transportation’s Research and Special 

Programs Administration

Page 206 GAO-01-810 Chemical Risk Assessment

In sharp contrast to most of the risk assessment procedures we described 

for EPA, FDA, and OSHA, toxicity is simply one of several potentially 

dangerous properties of a hazardous material of concern to RSPA. Where 

toxicity is a factor, RSPA’s risk assessments tend to center on exposure 

levels that pose an immediate health hazard. This focus is reflected in the 

types of chemical toxicity information that RSPA helps develop. For 

example, RSPA actively participates on a National Advisory Committee 

developing Acute Exposure Guideline Levels for chemicals. In specific 

cases where chronic toxicity or environmental values play a role in RSPA 

analyses, agency officials said that they rely on what EPA, FDA, OSHA, and 

other agencies have developed. 

Despite such differences, RSPA’s risk assessments address similar basic 

issues as the chemical risk assessments of the other three agencies (e.g., 

whether a particular material or activity poses a threat and the severity and 

likelihood of potential exposures). The DOT-wide risk assessment 

guidelines primarily discuss “consequence” and “probability” analyses, but 

also describe a preliminary step for defining scenarios of concern 

(essentially part of a hazard identification step) and a final step to 

summarize results and conclusions from the preceding analyses 

(essentially a risk characterization). The Hazardous Materials Safety 

Program materials outline a similar risk assessment process that 

progresses from the identification of hazards to an evaluation of incident 

causes, frequencies, and consequences. 

Identifying Hazards RSPA begins with a hazard analysis that results in material classification. 

In RSPA risk assessments, hazardous materials are chemical, radioactive, 

or infectious substances or articles containing hazardous materials that can 

pose a threat to public safety or the environment during transport. 

Hazardous materials pose this threat through chemical, physical, nuclear, 

or infectious properties that can make them dangerous to transport 

workers or the public. For example, RSPA is concerned with the potential 

for the unintentional release of hazardous materials to lead to adverse 

outcomes such as explosions, fires, or severely enhanced fires that can 

cause deaths, injuries, or property damage. The agency is also concerned 

with the potential toxic, corrosive, or infectious effects of released 

materials on humans and the environment.

According to DOT officials, their hazard classification approach is a 

criteria-based system that provides them considerable flexibility in their 

analysis and regulation of potential hazards. They noted that their criteria 

are geared more toward the hazard a material may pose in an accident 
Appendix V

Chemical Risk Assessment at the Department 

of Transportation’s Research and Special 

Programs Administration

Page 207 GAO-01-810 Chemical Risk Assessment

scenario than toward a chronic health risk. The Director of the Office of 

Hazardous Materials Technology characterized this hazard classification 

approach as a more open system than used in other agencies (e.g., EPA). 

He explained that, in this system, any new chemical or substance that fits 

within RSPA’s matrix of hazard criteria falls under the hazardous materials 

transportation regulations.

Hazard identification for these assessments is based largely on 

international agreements regarding transportation of dangerous goods. Of 

particular importance, there is an internationally recognized system for the 

classification, identification, and ranking of all types of hazardous 

materials that was created by the UN Committee of Experts on the 

Transport of Dangerous Goods. This system is revised biennially and 

published as the “United Nations Recommendations on the Transport of 

Dangerous Goods.” Under this classification system, all hazardous 

materials are divided into nine general classes according to physical, 

chemical, and nuclear properties. The system also specifies subdivisions 

and packing group designations (that indicate a relative level of hazard) for 

some classes. (See table 9.)

Table 9: UN Classification System for Transport of Dangerous Goods

Source: Research and Special Programs Administration, Department of Transportation.

Hazard class Description Subdivisions specified

Packaging performance 

requirements specified

1 Explosives and pyrotechnics X

2 Compressed and liquefied gases X

3 Flammable liquids X

4 Flammable solids (including self-reactive liquids) X X

5 Oxidizers and peroxides X X

6 Toxic (poisonous) and infectious materials X X

7 Radioactive materials

8 Corrosive materials (acidic or basic) X

9 Miscellaneous dangerous substances and articles

Packing groups

1 Great danger

2 Medium danger

3 Minor danger
Appendix V

Chemical Risk Assessment at the Department 

of Transportation’s Research and Special 

Programs Administration

Page 208 GAO-01-810 Chemical Risk Assessment

These are broad categories that may include large numbers of diverse 

materials. For example, the air cargo threat assessment noted that there 

were 535 different flammable liquid entries in the hazardous materials table 

and more than 700 toxic material entries. Because there are hazardous 

materials with multiple dangerous properties, these classes and 

subdivisions are not mutually exclusive. Compressed or liquefied gases, 

for example, also may be toxic or flammable. The UN Committee of 

Experts created more than 3,400 possible identification numbers, proper 

shipping descriptions, and hazard classes to be assigned to various 

hazardous material compounds, mixtures, solutions, and devices. There 

are also generic “not otherwise specified” identification numbers and 

shipping descriptions that allow the material to be classed by its defined 

properties.

RSPA uses essentially the same framework as the UN recommendations for 

the hazard classes and packing requirements of its Hazardous Materials 

Regulations. Table 10 shows the hazard classification system in the 

regulations.

Table 10: Hazard Classification System of RSPA’s Hazardous Materials Regulations

Class/division number Description

None Forbidden materialsa

None Forbidden explosivesb

Class 1

• Division 1.1

• Division 1.2

• Division 1.3

• Division 1.4

• Division 1.5

• Division 1.6

Explosives

• Explosives with a mass explosion hazard

• Explosives with a projection hazard

• Explosives with predominantly a fire hazard

• Explosives with no significant blast hazard

• Very insensitive explosives; blasting agents

• Extremely insensitive detonating articles

Class 2

• Division 2.1

• Division 2.2

• Division 2.3

Gases

• Flammable gas

• Nonflammable compressed gas

• Poisonous (toxic by inhalation) gas

Class 3 Flammable and combustible liquid

Class 4

• Division 4.1

• Division 4.2

• Division 4.3

Flammable solids; spontaneously combustible materials; 

and dangerous when wet materials

• Flammable solid

• Spontaneously combustible material

• Dangerous when wet material
Appendix V

Chemical Risk Assessment at the Department 

of Transportation’s Research and Special 

Programs Administration

Page 209 GAO-01-810 Chemical Risk Assessment

a

49 CFR Section 173.21 defines the materials that shall not be offered for transportation or 

transported.

b

49 CFR Section 173.54 defines the explosives that shall not be offered for transportation or 

transported.

Source: 49 CFR section 173.2.

The classification system in these regulations can be very detailed for some 

subjects. For example, the regulations specifically identify the types of 

toxicity tests and data that should be used to determine whether something 

would be classified as poisonous material (class 6, division 6.1). The 

regulations define poisonous material as a material, other than a gas, which 

is known to be so toxic to humans as to afford a hazard to health during 

transportation, or which, in the absence of adequate data on human 

toxicity,

• is presumed to be toxic to humans because it falls within one of several 

specified categories for oral, dermal, or inhalation toxicity when tested 

on laboratory animals; or

• is an irritating material, with properties similar to tear gas, which causes 

extreme irritation, especially in confined spaces. 

Class 5

• Division 5.1

• Division 5.2

Oxidizers and organic peroxides

• Oxidizer

• Organic peroxide

Class 6

• Division 6.1

• Division 6.2

Poisonous (toxic) materials and infectious substances

• Poisonous (toxic) materials

• Infectious substance (etiologic agent)

Class 7 Radioactive material

Class 8 Corrosive material

Class 9 Miscellaneous hazardous material

None Other regulated material

(Continued From Previous Page)

Class/division number Description
Appendix V

Chemical Risk Assessment at the Department 

of Transportation’s Research and Special 

Programs Administration

Page 210 GAO-01-810 Chemical Risk Assessment

Of particular relevance to comparisons with chemical risk assessments of 

other agencies, the regulations contain precise definitions of what 

constitutes oral, dermal, or inhalation toxicity for purposes of the 

Hazardous Materials Regulations. For example, one threshold for 

inhalation toxicity is defined as a dust or mist with an LC50 for acute 

toxicity on inhalation of not more than 10 mg per liter of air.8

 (A different 

definition applies to the inhalation toxicity of a vapor.) The regulations 

also address other testing requirements and conversion factors. The 

regulations state that, whenever possible, animal test data that have been 

reported in the chemical literature should be used.

The Hazardous Materials Regulations include an extensive Hazardous 

Material Table with itemized information about specific hazardous 

materials. The number of HAZMAT table entries corresponds closely with 

the number created by the UN. RSPA officials noted that the number of 

specific chemicals covered by the regulations is many multiples of the 

more than 3,400 entries, though, because of the generic nature of the “not 

otherwise specified” descriptions. The table includes, but is not limited to, 

information such as the material’s description, hazard class or division, 

identification number, packing group, label codes, limits to the quantity of 

the material permitted in a single package, and special provisions 

concerning its transportation. Allyl chloride, for example, is identified as a 

class 3 material (flammable and combustible liquid), is in packing group I 

(indicating great danger), is forbidden on passenger aircraft and rail, and 

has two special provisions regarding the tanks used for transporting this 

substance. A material that meets the definition of more than one hazard 

class or division, but is not specifically listed in the table, is to be classed 

according to the highest applicable hazard class or division according to a 

descending order of hazard. For example, the division of poisonous gases 

is ranked as a greater hazard than the division of flammable gases.

According to OHMS, the process of classifying a material in accordance 

with these hazard classes and packing groups is itself a form of hazard 

analysis. Another important feature of this process is that the regulations 

require the shipper to communicate the material’s hazards through the use 

of the hazard class, packing group, and proper shipping name on the 

shipping paper and the use of labels on packages and placards on the 

8

 In this case, LC50 for acute toxicity on inhalation means that concentration of dust or mist 

which, administered by continuous inhalation for 1 hour to both male and female young 

adult albino rats, causes death within 14 days in half of the animals tested.
Appendix V

Chemical Risk Assessment at the Department 

of Transportation’s Research and Special 

Programs Administration

Page 211 GAO-01-810 Chemical Risk Assessment

transport vehicle. Therefore, the shipping paper, labels, and placards 

communicate the most significant findings of the shipper’s hazard analysis 

to other parties. This communication aspect is particularly important in 

emergency response situations if an accident occurs during transport of 

these materials.

The classification system, by itself, is not sufficient for all risk assessment 

purposes. For example, RSPA and OHMS still need to identify potential 

scenarios in which transportation accidents, spills, and leaks could occur. 

As evidenced by the air cargo threat assessment, such scenarios include 

the possibility that hazardous materials might be transported in a manner 

not in compliance with current regulations.9

 Also, as emphasized in a 

November 2000 report for RSPA, the hazardous materials transport system 

is highly heterogeneous and complex.10 The report pointed out that this 

system involves not only many different materials posing a variety of 

hazards (as reflected in the classification system outlined in table 9) but 

also:

• a chain of events involving multiple players having different roles in the 

process of moving hazardous materials (such as shippers, carriers, 

packaging manufacturers, freight forwarders, and receivers of 

shipments) and the possibility of multiple handoffs of a material from 

one party to another during transport;

• several different modes of transport (principally highway, rail, 

waterway, and air), with some shipments that switch from one mode to 

another during transit; and

• multiple possible routes of transit. 

9

 The threat assessment project was, in fact, initiated following the crash of ValuJet Flight 

592 near Miami, FL in May 1996, which had been linked to hazardous material devices 

(chemical oxygen generators) shipped in violation of DOT regulations.

10 “Risk Management Framework for Hazardous Materials Transportation,” prepared by ICF 

Consulting for the U.S. Department of Transportation, Research and Special Programs 

Administration (Nov. 1, 2000). RSPA officials noted that this framework provides a 

structure for their efforts and serves as a tool for all parties involved in hazardous materials 

transportation to consider in fostering continuous safety improvement.
Appendix V

Chemical Risk Assessment at the Department 

of Transportation’s Research and Special 

Programs Administration

Page 212 GAO-01-810 Chemical Risk Assessment

All of these complex features might need to be considered in identifying 

hazard scenarios. However, in identifying (and analyzing) potential hazard 

scenarios, RSPA and OHMS benefit from being able to use data, 

information, and experience on hazardous materials transportation 

incidents. For example, risk assessors can review data from sources such 

as the DOT Hazardous Materials Information System (HMIS) that 

catalogues transportation-related incidents that involve a release of 

hazardous materials. An OHMS official pointed out that the agency also 

uses fairly sophisticated models in analyzing various scenarios. He said 

that such models were used, for example, to provide a scientific basis for 

determining evacuation zones when developing the 2000 Emergency 

Response Guidebook.

11

Analyzing the Consequences and 

Probabilities of Risks

In contrast to the other agencies covered in this report, determining the 

toxicity of a particular chemical (dose-response assessment) is not a 

central focus of risk assessment in RSPA and OHMS. Toxicity is only one 

of many risk factors under consideration (and should already be addressed 

through the hazard classification system). Instead, the primary focus of 

analysis is on the potential for hazardous materials to (1) spill or leak while 

in transit or (2) cause, contribute to, or multiply the consequences of a 

transportation-related accident. Analysis regarding the first item is 

primarily concerned with the packaging and containers used for 

transportation of hazardous materials, while analysis of the second item 

also considers other elements, such as the modes and routes of 

transportation for these materials. As the DOT risk assessment guidelines 

state, “Hazardous materials accidents generally are transportation 

accidents in which hazardous materials happen to be present.”

DOT documents use a variety of terms to describe and refer to the analysis 

of hazards or risks of concern to the department and its component offices 

(e.g., hazard analysis, risk analysis, threat assessment). However, the core 

of the analysis remains the same—an evaluation of the causes, 

11 The 2000 Emergency Response Guidebook was developed jointly by DOT, Transport 

Canada, and the Secretariat of Communications and Transportation of Mexico. It is 

intended primarily to guide firefighters, police, and other emergency personnel who may be 

the first to arrive at the scene of a transportation incident involving a hazardous material in 

(1) quickly identifying the specific or generic classification of the material(s) involved in the 

incident, and (2) protecting themselves and the general public during the initial response 

phase of the incident. According to RSPA, the 2000 revision of this guidebook was based on 

risk principles and analyses, and the technical basis and derivation of the values in the 

guidebook’s Table of Initial Isolation and Protective Action Distances are available on the 

RSPA website.
Appendix V

Chemical Risk Assessment at the Department 

of Transportation’s Research and Special 

Programs Administration

Page 213 GAO-01-810 Chemical Risk Assessment

consequences, and likelihood of transportation incidents involving 

hazardous materials. The general model in DOT’s guidelines for risk 

assessment of transportation activities or operations partitions the analysis 

of risk into two main parts:

• prediction of possible consequences in terms of loss from accidents (or, 

more broadly, incidents) while transporting materials in a specified way; 

and

• estimation of the probabilities or frequencies of occurrence of the 

consequences of such accidents (e.g., the likelihood or expected 

number of accidents occurring that would result in the above loss).

For purposes of estimating the risk reduction attributable to transportation 

safety regulations, the expected loss or “risk” is computed by summing the 

products of each possible loss multiplied by its probability. (In other 

words, risk in this context is the probability-weighted average loss.)

According to DOT definitions, consequence analysis is the evaluation of the 

severity and magnitude of impacts associated with the occurrence of 

postulated accident scenarios. For purposes of analysis, the DOT 

guidelines recommend partitioning this evaluation into three segments: (1) 

initiating events (i.e., causes of an accident that can result in loss), (2) 

effects (i.e., the possible mechanisms by which an initiating event might 

result in injury or damage); and (3) consequences (i.e., the loss of life, 

injuries, property damage, or other losses expected from the effects). The 

evaluation of consequences reflects many factors, including the 

characteristics of the agent involved, the type of packaging or container 

used, the amount of material being transported, and the particular modes 

and routes of transportation (which also affect the extent of potential 

exposure by the public and environment). DOT defines probability 

analysis as the evaluation of the likelihood of individual accident scenarios 

and outcomes of adverse events. The likelihood of a particular hazard 

might be expressed either as a frequency or probability.

The analyses of consequences and probabilities are based on a variety of 

data sources, including, to the extent possible, “experience” data. Among 

the sources of information identified in OHMS materials to address 

consequences and probabilities are:

• data from the Hazardous Materials Information System (HMIS);

• commodity flow surveys;

• chemical substance manufacturing, use, and transportation studies;
Appendix V

Chemical Risk Assessment at the Department 

of Transportation’s Research and Special 

Programs Administration

Page 214 GAO-01-810 Chemical Risk Assessment

• special analyses (such as the National Transportation Risk Analysis and 

Air Cargo reports mentioned earlier in this appendix, as well as 

shipment counts); and

• public comments on rulemakings.

Such sources can provide valuable information for risk assessment in 

general and the statistical analysis of hazardous material transportation 

incidents in particular. The HMIS database provides a good illustration of 

the types of baseline data available. This database provides incident 

counts according to time, transportation phase (i.e., en route from origin to 

destination, loading or unloading, and temporary storage), and 

transportation mode (e.g., air, highway, and rail). For each incident, the 

database includes information on the hazardous materials involved, 

including the name of the chemical shipped, container type and capacity, 

number of containers shipped, number of containers that fail, and the 

amount of material released. The database also contains information 

concerning the occurrence of fire, explosion, water immersion, 

environmental damage, and the numbers of deaths, major and minor 

injuries, and persons evacuated.

However, because DOT’s risk assessments are often used to estimate the 

“risk impact” of proposed regulations, the DOT guidelines caution that lack 

of directly applicable experience data for assessing the impacts is probably 

the rule rather than the exception. This is because the controls provided by 

the proposed regulations constitute changes from present conditions, and 

experience data, by definition, relate to present conditions. The guidelines 

also emphasize that, to evaluate the impact on risk of a proposed regulation 

or its alternatives, it is necessary to perform a “with and without” type of 

assessment, considering the potential effects on any or all of the elements 

of the risk model.
Appendix V

Chemical Risk Assessment at the Department 

of Transportation’s Research and Special 

Programs Administration

Page 215 GAO-01-810 Chemical Risk Assessment

As was the case with the classification of hazardous materials and 

packaging, the agency may employ criteria-based classifications of the 

consequences of potential adverse events and their likelihood of 

occurrence. A 1995 guidance document illustrates how consequence and 

frequency categories were combined into a “risk assessment matrix” to 

assist decision makers in their risk management decisions.12 (See table 11 

below.)

Table 11: Example of a Hazardous Materials Risk Assessment Matrix

Risk index:

U - Unacceptable

C-MDR - Conditional − management decision required

A-MRR - Acceptable − management review required

A - Acceptable

Source: Adapted from “Procedure for Removal of Nonconforming Hazardous Materials Packagings 

from Service, 7-13-95,” Office of Hazardous Materials Safety.

12 In a nonchemical risk assessment context, DOT’s Federal Transit Administration (FTA) 

and the American Public Transit Association recommend the use of very similar matrices for 

analysis of rail systems’ safety. See FTA’s State Safety Oversight, Issue 6 (Fall 1999).

Consequence of occurrence categories

Frequency of occurrence 

categories Catastrophic Critical Marginal Minor Negligible

Frequent U U U C-MDR A-MRR

Probable U U C-MDR A-MRR A-MRR

Occasional U C-MDR A-MRR A-MRR A

Remote C-MDR A-MRR A-MRR A A

Improbable A-MRR A-MRR A A A
Appendix V

Chemical Risk Assessment at the Department 

of Transportation’s Research and Special 

Programs Administration

Page 216 GAO-01-810 Chemical Risk Assessment

As was the case with the three other agencies covered by our review, some 

of the chemical risk assessments produced by or for DOT have begun using 

more sophisticated methods and models. For example, the Director of 

OHMT characterized the National Transportation Risk Assessment study 

prepared for OHMS by the Argonne National Laboratory as using state-ofthe-art risk assessment techniques to characterize risks associated with the 

transportation of selected hazardous materials on a national basis. The 

consequence assessments in this study employed the Chemical Accident 

Statistical Risk Assessment Model that predicts distributions of hazard 

zones (i.e., areas in which a threshold chemical concentration is exceeded) 

resulting from hazardous material release.13 That model, in turn, reflected 

the input of other physical models on subjects such as hazardous material 

release rates of toxic-by-inhalation materials. The Director noted that his 

office believed this study to be the first comprehensive application of these 

techniques in this arena for this purpose.

Risk Assessment 

Assumptions and 

Methodological 

Choices

Although generally very structured and criteria based, RSPA’s risk 

assessments for hazardous materials transportation also use assumptions. 

DOT-wide guidance documents provide a general framework for the use of 

assumptions. In general, DOT guidance recognizes that assumptions may 

be made when data are lacking or uncertain, or when it is necessary to limit 

the scope of an analysis. However, the assumptions, while not empirically 

verifiable, are supposed to be reasonable, logically credible, and 

supportable in comparison with alternative assumptions. The DOT risk 

assessment methodology guidance specifically states that every 

assessment should include a list of the major assumptions, conditions, and 

limitations of the risk analysis, as well as the reasons why the assumptions 

were made.

As noted earlier in this appendix, RSPA has access to a number of sources 

of directly relevant data and statistics on the transportation of hazardous 

materials. However, there are limitations to these systems and data. For 

example, the authors of the national transportation risk assessment for 

selected hazardous materials cautioned that the information in DOT’s data 

systems was not always sufficient or detailed enough to directly support a 

quantitative risk assessment. For example, incidents involving most 

13 Rather than specifying a deterministic measure of risk, this model determines the 

distribution of possible outcomes, allowing the probability of a particular consequence to be 

identified within the limits of the statistical data used.
Appendix V

Chemical Risk Assessment at the Department 

of Transportation’s Research and Special 

Programs Administration

Page 217 GAO-01-810 Chemical Risk Assessment

hazardous materials (other than gasoline-truck accidents) typically occur 

too infrequently to provide statistically reliable data for directly projecting 

future risks. In his introduction to the study, the Director of OHMT also 

stated that the quantitative results of this study should be used with 

caution. Specifically, he noted, “While the model of the hazardous 

materials transportation system employed in this study is sophisticated, the 

accuracy of the data used in the model is often less precise. Estimates, 

assumptions, and aggregate numbers have been used in many cases.”

Some of the topics that might require assumptions or choices during a 

hazardous materials transportation assessment include:

• the probability of the release of a hazardous material, depending on the 

nature of the accident, type of material being transported, and the 

containers used; 

• the amount of material released in an accident, depending again on 

factors such as the severity of the accident, nature of the material, and 

type of container, but also depending on assumptions about the size of 

holes in containers;

• commodity flows of the materials (e.g., modes of transportation used, 

classes of rail tracks, types of highways, routing through urban and rural 

areas and related population density);

• the dispersion of released hazardous material, including assumptions 

about climate and meteorological conditions and the type of surface 

that a liquid might “pool” on if spilled;

• the probability of a fire or explosion being ignited (both as a 

consequence of a release or as a cause of a release); and

• the extent to which humans potentially exposed to released materials 

would be sheltered or protected (both within a given mode of 

transportation, such as an aircraft, or external to the carrier).

In addition to these topics, RSPA sometimes uses a factor to adjust data in 

the HMIS database to address underreporting. However, RSPA officials 

noted that, for certain purposes, it might be inappropriate to extrapolate 

information in the database.

Although assumptions may be needed in RSPA assessments, RSPA officials 

said that they do not have default assumptions for their risk assessments. 

According to the officials, assumptions must be developed and described 

as part of each risk assessment and are specific to the risk assessment. 

RSPA officials also noted that they do not use “safety factors” in risk 

assessments, but rather base their assessments on expected levels or 
Appendix V

Chemical Risk Assessment at the Department 

of Transportation’s Research and Special 

Programs Administration

Page 218 GAO-01-810 Chemical Risk Assessment

ranges of performance. Therefore, unlike in the appendices on EPA, FDA, 

and OSHA, we have not included a table in this DOT appendix to identify 

major default choices, the reasons for their selection, when they would be 

used in the process, and their likely effects on risk assessment results. 

However, with regard to some of the case-specific assumptions or choices 

we identified during our review, we did observe that DOT’s assessments 

typically discussed the reasons for particular choices (as with the other 

agencies, often citing an interpretation of related research studies). In 

some instances, information was also provided on the likely effect (e.g., 

that a particular value represented a conservative estimate or an upper 

limit) or level of uncertainty (e.g., that a particular parameter value might 

be high by a factor of 3 to 10 times the results from another study) 

associated with choices made by the analysts. 

Risk Characterization DOT has explicit, written principles regarding how the results of its risk or 

safety assessments should be presented. The department’s policies 

emphasize the principle of transparency and encourage agency personnel 

to not only characterize the range and distribution of risk assessment 

estimates, but also to put risk estimates into a context understandable by 

the general public. For example, DOT’s “risk assessment principles” state 

that the risk assessment should: 

• make available to the public data and analytic methodology on which 

the agency relied in order to permit interested entities to replicate and 

comment on the agency’s assessment;

• state explicitly the scientific basis for the significant assumptions, 

models, and inferences underlying the risk assessment, and explain the 

rationale for these judgments and their influence on the risk assessment;

• provide the range and distribution of risks for both the full population at 

risk and for highly exposed or sensitive subpopulations, and encompass 

all appropriate risks, such as acute and chronic risks, and cancer and 

noncancer risks, to health, safety, and the environment;

• place the nature and magnitude of risks being analyzed in context, 

including appropriate comparisons with other risks that are regulated 

by the agency as well as risks that are familiar to, and routinely 

encountered by, the general public, taking into account, for example, 

public attitudes with respect to voluntary versus involuntary risks, wellunderstood versus newly discovered risks, and reversible versus 

irreversible risks; and
Appendix V

Chemical Risk Assessment at the Department 

of Transportation’s Research and Special 

Programs Administration

Page 219 GAO-01-810 Chemical Risk Assessment

• use peer review where there are issues with respect to which there is 

significant scientific dispute to ensure that the highest professional 

standards are maintained.

The DOT risk assessment guidelines also state that every risk analysis 

should present information on (1) quantitative estimates of risk (over the 

entire range of plausible values of the developed variables, and with a “base 

case” loss to provide a point of reference); (2) insights gained from 

performing the analysis into the factors that most affect risk assessment 

results; and (3) assumptions, conditions, and limitations of the analysis. 

With regard to the third item, the guidelines specifically state that reasons 

why the assumptions were made, and why the limitations of the analysis do 

not significantly impact the risk estimate, should be provided. The 

guidelines also suggest two methods for treating uncertainty in a risk 

analysis:

• sensitivity analysis (DOT’s preferred method for treating and reporting 

the impact of uncertainty), which should be conducted for each 

scenario in a risk analysis; and

• bounding analysis involving error propagation (requiring that each 

model parameter be expressed as a distribution, or at least a variance, to 

trace the implication of uncertainty for the risk estimate).
Page 220 GAO-01-810 Chemical Risk Assessment

Glossary

Acceptable daily intake 

(ADI)

The maximum dose of a hazardous substance that can be consumed daily 

without causing adverse health effects over a lifetime. 

Acute effect An effect that results from a brief exposure or shortly after an acute 

exposure (possibly at high levels) of duration measured in minutes, hours, 

or days.

Additive dose-response 

model

A dose-response model in which the health effects attributable to exposure 

to particular levels of two or more risk agents are equal to the sum of the 

responses predicted for each agent alone.

Aggregate risk The risk resulting from the combined exposure of an individual or defined 

population to a single agent or stressor via all relevant routes, pathways, 

and sources.

Ambient concentration The average amount of a substance in a particular environmental medium, 

such as air or water.

Ambient water quality 

criteria (AWQC) 

Numeric values limiting the amount of chemicals present in our nation’s 

waters. Developed under section 304(a) of the Clean Water Act (CWA) and 

periodically updated, they are determined by assessing the relationship 

between pollutants and their effect on human health and the environment. 

These recommended criteria provide guidance for states and tribes in 

adopting water quality standards under section 303(c) of the CWA and to 

ultimately provide a basis for controlling discharges or releases of 

pollutants.

Benchmark dose An exposure level that corresponds to a statistical lower bound on a 

standard probability of an effect, such as 10 percent of people affected.

Bioaccumulation factor 

(BAF) 

Bioaccumulation is a process whereby the concentration of certain 

substances in organisms increases as the organisms breathe contaminated 

air, drink contaminated water, or eat contaminated food. The BAF is the 
Glossary

Page 221 GAO-01-810 Chemical Risk Assessment

ratio of a substances' concentration in an organism’s tissue to its 

concentration in the medium where the organism lives. BAFs measure a 

chemical's potential to accumulate in tissue through exposure to both food 

and water.

Bioassay The use of living organisms to measure the effect of a risk agent or 

condition—for example, a test for carcinogenicity in laboratory animals 

that includes near-lifelong exposure to the agent under test. Used 

interchangeably with animal test.

Biologically based dose 

response model

A model that describes biological processes at the cellular and molecular 

level linking the target organ dose to the adverse effect.

Cancer A group of diseases characterized by abnormal, disorderly, and potentially 

unlimited new tissue growth.

Carcinogen Any chemical or physical agent possessing the ability to induce cancer in 

living organisms.

Chronic health effects Diseases occurring as a result of repeated or persistent exposures.

Chronic exposure An exposure (usually of low concentration) of long duration, e.g., months 

or years.

Consequence The direct effect of an event, incident, or accident. It is expressed as a 

health effect (e.g., death, injury, exposure), property loss, environmental 

effect, evacuation, or quantity spilled.

Contaminant(s) Chemicals, microorganisms, or radiation found in air, soil, water, or food 

that are not normally constituents of these environmental media.
Glossary

Page 222 GAO-01-810 Chemical Risk Assessment

Cumulative risk The combined risk from aggregate exposures to multiple agents or 

stressors.

Dose The amount of a substance available for interactions with metabolic 

processes or biologically significant receptors after crossing the outer 

boundary of an organism. A potential dose is the amount ingested, 

inhaled, or applied to the skin. An applied dose is the amount presented 

to an absorption barrier and available for absorption (although not 

necessarily having yet crossed the outer boundary of the organism). An 

absorbed dose is the amount crossing a specific absorption barrier (e.g., 

the exchange boundaries of the skin, lung, and digestive tract) through 

uptake processes. An internal dose denotes the amount absorbed 

without respect to specific absorption barriers or exchange boundaries. A 

delivered or biologically effective dose is the amount of the chemical 

available for interaction by any particular organ or cell.

Dose-response assessment The determination of the relationship between the magnitude of 

administered, applied, or internal dose and a specified biological response.

Dose-response relationship The relationship between exposure level and the incidence of adverse 

effects.

Ecological risk assessment A process used to estimate the likelihood of adverse effects on plants or 

animals from exposure to stressors, such as chemicals or the draining of 

wetlands. The process includes problem formulation, characterization of 

exposure, characterization of ecological effects, and risk characterization.

Effluent Treated or untreated waste material discharged into the environment. 

Generally refers to wastes discharged to surface waters.

Emission Pollution discharged into the atmosphere from smokestacks, other vents, 

and surface areas of commercial or industrial facilities; residential 

chimneys; and motor vehicle, locomotive, or aircraft exhausts.
Glossary

Page 223 GAO-01-810 Chemical Risk Assessment

Environmental fate The distribution and transformation of a chemical from its first release 

until its ultimate removal from or recycling through the environment.

Epidemiology The study of diseases as they affect populations, including the distribution 

of disease, or other health-related states and events in human population; 

the factors (e.g., age, sex, occupation, economic status) that influence this 

distribution; and the application of this study to assess and control health 

risk. It involves investigating the causes and risk factors of disease and 

injury in populations and the potential to reduce such disease burdens.

Exposure Contact of a chemical, physical, or biological agent with the outer 

boundary of an organism. Exposure is quantified as the concentration of 

the agent in the medium over time.

Exposure assessment The process of developing a description of the relevant conditions and 

characteristics of human and other exposures to risk agents produced or 

released by a specified source of risk. This usually involves the 

determination or estimation of the magnitude, frequency, duration, and 

route of exposure.

Exposure pathway(s) The physical course or means by which risk agents are transmitted—e.g., 

the route by which a given population, individual, species, or setting is 

exposed to a toxic substance (e.g., via drinking water, air, or dermal 

contact).

Exposure route The way an environmental agent enters an organism (e.g., ingestion, 

inhalation, or dermal absorption).

Extrapolation Prediction of the value of a variable outside the range of observation. This 

involves making inferences about the unknown by projecting or extending 

known information, using models and assumptions.

Genotoxic Capable of causing heritable changes or damage leading to heritable 

changes in genetic material (i.e., altering the structure of DNA). A 
Glossary

Page 224 GAO-01-810 Chemical Risk Assessment

genotoxic carcinogen is one that initiates cancer through a direct effect on 

genetic material.

Hazard A (potential) source of risk that does not necessarily produce risk. A 

hazard is the inherent characteristic of a material, condition, or activity that 

has the potential to cause harm to people, property, or the environment and 

produces risk only if an exposure pathway exists and if exposures create 

the possibility of adverse consequences.

Hazard analysis The identification of material properties, system elements, or events that 

lead to harm or loss. The term hazard analysis may also include evaluation 

of consequences from an event or incident.

Incidence The rate at which an event occurs. In toxicology, the number of new cases 

of a disease within a specified period of time, often expressed per 100,000 

individuals per year.

Interspecies extrapolation The act of applying a set of data or an individual test result from one 

species, under certain conditions and subject to particular dose levels of a 

toxic substance and application method, to another population of a 

different species under perhaps different conditions, dose levels, and 

application method.

LC50 The concentration of a substance in air that when administered by 

inhalation to all animals in a test (over a specified time period) is lethal to 

50 percent of the animals.

LD50 The dose that when administered to all animals in a test (over a specified 

time period) is lethal to 50 percent of the animals.

Likelihood Expressed as either a frequency or a probability. Frequency is a measure of 

the rate at which events occur over time (e.g., events per year, incidents per 

year, deaths per year). Probability is a measure of the rate of a possible 
Glossary

Page 225 GAO-01-810 Chemical Risk Assessment

event expressed as a fraction of the total number of events (e.g. 

1/1,000,000).

Lowest effective dose (LED) The lowest dose of a chemical that produced a specified level of an adverse 

effect when it was administered to animals in a toxicity study. For 

example, the LED10 is the lowest effective dose that produced an effect in 

10 percent of the exposed animals.

Lowest observed adverse 

effect level (LOAEL)

The lowest exposure at which there is a statistically or biologically 

significant increase in the frequency of an adverse effect when compared 

with a control group.

Margin of exposure A ratio defined by EPA as a dose derived from a tumor bioassay, 

epidemiologic study, or biologic marker study, such as the dose associated 

with a 10-percent response rate, divided by an actual or projected human 

exposure.

Mechanism of action/mode 

of action

The mechanism of action is the complete sequence of biological events 

that must occur to produce the toxic effect. The mode of action is a lessdetailed description of the mechanism of action in which some but not all 

of the sequence of biological events leading to a toxic effect is known.

Monte Carlo analysis The computation of a probability distribution over consequences by means 

of a random sampling method analogous to the game of roulette. 

Combinations of events and outcomes that yield possible consequences are 

randomly selected according to a specified probability distribution. The 

resulting consequences are counted and used to estimate other probability 

distributions.

Multistage models Dose-response models that assume a given number of biological stages 

occur following exposure to a risk agent (e.g., metabolism, covalent 

binding, DNA repair) before manifestation of the effect in question is 

possible.
Glossary

Page 226 GAO-01-810 Chemical Risk Assessment

Mutagen Any substance that can cause a change in genetic material. Mutagens have 

the ability to induce adverse, heritable changes in the genetic material of 

living organisms.

No observed adverse effects 

level (NOAEL) 

The highest dose at which there is no statistically or biologically significant 

increase in the frequency of an adverse effect when compared with a 

control group. 

No observed effects level 

(NOEL) 

The highest dose at which there is no statistically or biologically significant 

increase in the frequency of any effect, adverse or not, compared with a 

control group.

Order of magnitude An expression often used in reference to calculations of environmental 

quantities of risk. Order of magnitude means a factor of 10. For example, 

20 (2 x 10) is 1 order of magnitude greater than 2; 200 (2 x 10 x 10) is 2 

orders of magnitude greater than 2; and so forth.

Permissible exposure limit 

(PEL)

PELs are time-weighted average (TWA) air concentrations that must not be 

exceeded during any 8-hour work shift of a 40-hour workweek as defined 

by OSHA.

Pharmacokinetics Study of the absorption, distribution, metabolism, and excretion of 

chemicals and the genetic, nutritional, behavioral, and environmental 

factors that modify these parameters.

Pharmacokinetic models Dose-response models based on the principle that biological effects are the 

result of biochemical interaction between foreign substances or 

metabolites and parts of the body.

Physiologically based 

pharmacokinetic (PBPK) 

model

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.
Glossary

Page 227 GAO-01-810 Chemical Risk Assessment

Probabilistic approaches Evaluating a range of possible risk estimates and their likelihood, tied to 

various mathematical models of the likely distribution of potential values, 

instead of relying on single numbers or point estimates.

Reference concentration 

(RfC)/reference dose (RfD) 

A reference concentration is an estimate of a continuous inhalation 

exposure to the human population (including sensitive subgroups) that is 

likely to be without an appreciable risk of deleterious noncancer effects 

during a lifetime. EPA uses a reference dose to express a conservative 

threshold value for a dose-response relationship for noncarcinogenic 

effects. It is an estimate of a daily dose to the human population (including 

sensitive subgroups) that is likely to be without an appreciable risk of 

deleterious noncancer effects during a lifetime.

Residual risk The health risk remaining after risk-reduction actions are implemented, 

such as risks associated with sources of air pollution that remain after the 

implementation of maximum achievable control technology.

Risk The probability that a substance or situation will produce harm under 

specified conditions. Risk is a combination of two factors: the probability 

that an adverse event will occur and the consequences of its occurrence 

(e.g., a specific disease or type of injury).

Risk assessment The systematic, scientific description of potential adverse effects of 

exposures to hazardous agents or activities. According to NAS, it involves 

the four steps of hazard identification, dose-response assessment, 

exposure assessment, and risk characterization. The product of the risk 

assessment is a statement regarding the probability that populations, 

individuals, or environmental entities so exposed will be harmed and to 

what degree.

Risk characterization The process of organizing, evaluating, and communicating information 

about the nature, strength of evidence, and the likelihood of adverse health 

or ecological effects from particular exposures.
Glossary

Page 228 GAO-01-810 Chemical Risk Assessment

Risk management The process of analyzing, selecting, implementing, and evaluating actions 

to reduce risk.

Screening risk assessment A risk assessment performed using few data and many assumptions to 

identify exposures that should be evaluated more carefully for their 

potential risks.

Sensitivity analysis A method used to examine the behavior of a model by systematically 

measuring the deviation in its outputs produced as each input, parameter, 

or assumption is varied from its nominal or base-case value.

Synergistic effects A term used to describe when the combined biological effects of two risk 

agents are greater than the sum of the effects of each agent acting alone.

Target organ The specific organ affected by a dose of a toxic substance, which is not 

necessarily the organ receiving the highest concentration.

Threshold The level of exposure above which adverse health effects are thought to 

occur, and below which no adverse effect is thought to occur.

Threshold dose Minimum application of a given risk agent required to produce a 

measurable response.

Threshold effect An effect for which there is some dose below which the probability of an 

individual's responding is zero.

Tiered approach A series of assessments of increasing complexity.

Toxicity A measure of the degree of harm caused by a specified exposure of human, 

animal, or plant life to a chemical substance.
Glossary

Page 229 GAO-01-810 Chemical Risk Assessment

Toxicokinetics The mechanism by which chemical or physical change causes toxic effects.

Toxicology The study of adverse effects of chemicals on living organisms.

Tumor Any abnormal growth of tissue in which growth is uncontrolled and 

progressive.

Uncertainty factor One of several factors used to calculate an exposure level that will not 

cause toxicity from experimental data. Uncertainty factors are used to 

account for the variation in susceptibility among humans, the uncertainty 

in extrapolating from experimental animal data to humans, the uncertainty 

in extrapolating from data from studies in which agents are given for less 

than a lifetime, and other uncertainties such as using LOAEL data instead 

of NOAEL data.

Variability A population's natural heterogeneity or diversity, particularly that which 

contributes to differences in exposure levels or in susceptibility to the 

effects of chemical exposures.

(410543) Letr
Ordering Information The first copy of each GAO report is free. Additional copies of 

reports are $2 each. A check or money order should be made out to 

the Superintendent of Documents. VISA and MasterCard credit 

cards are accepted, also.

Orders for 100 or more copies to be mailed to a single address are 

discounted 25 percent.

Orders by mail:

U.S. General Accounting Office

P.O. Box 37050

Washington, DC 20013

Orders by visiting:

Room 1100

700 4th St. NW (corner of 4th and G Sts. NW)

U.S. General Accounting Office

Washington, DC

Orders by phone:

(202) 512-6000

fax: (202) 512-6061

TDD (202) 512-2537

Each day, GAO issues a list of newly available reports and 

testimony. To receive facsimile copies of the daily list or any list 

from the past 30 days, please call (202) 512-6000 using a touchtone 

phone. A recorded menu will provide information on how to obtain 

these lists.

Orders by Internet:

For information on how to access GAO reports on the Internet, 

send an e-mail message with “info” in the body to:

info@www.gao.gov

or visit GAO’s World Wide Web home page at: 

http://www.gao.gov

To Report Fraud, 

Waste, or Abuse in 

Federal Programs

Contact one:

• Web site: http://www.gao.gov/fraudnet/fraudnet.htm

• e-mail: fraudnet@gao.gov

• 1-800-424-5454 (automated answering system)

United States

General Accounting Office

Washington, D.C. 20548-0001

Official Business

Penalty for Private Use $300

Address Correction Requested

Presorted Standard

Postage & Fees Paid

GAO

Permit No. GI00