Researching Health Risks

January 1993

OTA-BBS-570

NTIS order #PB94-134749

GPO stock #052-003-01360-6
Recommended Citation:

U.S. Congress, Office of Technology Assessment, Researching Health Risks,

OTA-BBS-570 (Washington, DC: U.S. Government Printing Office, November

1993).

For \Jlc h) [IN [ ‘.S (ioi crnmcn[ PI 11)[111: 011 ILe

SIIIICI lll[ClldCfl( oi [) OL’llf)lCfll\, M,III sl~)p’ SSOP, \$ <ldllll#{m. [>(’ ?(k$()~-() l?~

ISBN 0-16 -043021-6
—.

Foreword

I

n everyday life, we evaluate the risks associated with various activities and make

choices, considering such things as benefits, costs, convenience, and past

experience. As a society, we must make similar choices. The process of health risk

assessment can help guide the decisions necessary for living in a world full of

chemicals, radiation, and fibers, both natural and manufactured.

Risk assessment illuminates the hazards that result from exposure to a substance

and the magnitude of the risk associated with different levels of exposure. Results of

health risk assessments are used as one of the inputs in formulating regulatory decisions.

Those decisions affect expenditures for regulatory compliance or treating exposurerelated diseases that can total billions of dollars.

Because of the public health and economic implications of risk assessments,

Congress has grown increasingly interested in the accuracy and scientific underpinning

of risk assessment. An indication of this interest was the request by the House Energy

and Commerce Committee and the House Science, Space, and Technology Committee

to the Office of Technology Assessment (OTA) to analyze the nature, organization, and

management of federally supported research on health risk assessment. This focus is

important because such research provides the scientific foundation for health risk

assessments.

In this report, OTA describes the Federal Government’s research activities that are

intended to improve health risk assessments. One of the findings of this Report is that

the attention and resources allotted to health risk assessment research are not

commensurate with its national impact, A particular problem is that research is

fragmented within and across the Federal agencies, greatly complicating setting research

priorities. Consequently, the agencies are not focusing on areas of research likely to have

the most far-reaching effect on policy+ specially risk assessment methodology-and

they are unable to harness fully the rapid advances in the basic biological and biomedical

sciences.

Many individuals and institutions contributed their time and expertise to this

project. Experts from government, industry and academia served on the project’s

advisory panel and workshop on research structure and organization and reviewed drafts

of chapters and the full report. OTA gratefully acknowledges their contributions and

assistance. As with all OTA analysis, however, responsibility for the content is OTA’s

alone.

Roger C. Herdman, Director . . .

Ill
Advisory Panel

Ronald W. Estabrook, Panel Chair

The University of Texas Southwestern Medical Center

Dallas, Texas

Eula Bingham

University of Cincinnati

Cincinnati, OH

Thomas A. Burke

The Johns Hopkins University

Baltimore, MD

Adam M. Finkel

Resources for the Future

Washington, DC

Joseph H. Guth

Natural Resources Defense Council, Inc.

New York, NY

Oliver Hankinson

University of California, Los Angeles

Los Angeles, CA

David Lilienfeld

Potomac, MD

Gilbert S. Omenn

University of Washington

Seattle, WA

Colin N. Park

The Dow Chemical Co.

Midland, MI

David P. Rail

Washington, DC

Joseph V. Rodricks

ENVIRON Corp.

Arlington, VA

Curtis C. Travis

Oak Ridge National Laboratory

Oak Ridge, TN

James D. Wilson

Monsanto Co.

St. Louis, MO

Lauren Zeise

California Environmental Protection Agency

Berkeley, CA

Rae Zimmerman

New York University

New York, NY

NOTE: OTA appreciates andisgratejldfor the valuable assistance andthoughfilcn”tique sprovided by the advisory panel members. Thepanel

does not, however, necessarily approve, disapprove, or endorse this report. 0’24 assumesjidl responsibility for the report and the accuracy

of its contents.

i v
Clyde J. Behney

Assistant Director

Health, Life Sciences,

and the Environment

Michael Gough

Program Manager

Biological and Behavioral Sciences

CONTRACTORS

Leah Mazade

Editor

Washington,DC

Miriam Davis

Washington,DC

George Gray

Harvard University

Boston, MA

William Pease

University of California

Berkeley, CA

Sandy Weiner

Massachusetts Institute

for Technology

Cambridge, MA

PRINCIPAL STAFF

DALTON PAXMAN

Project Director

Margaret McLaughlin

project Directorl

Margaret Chu

Senior Science Fellow (EPA)

Project Staff

Ginger Roehrig

Research Assistant2

Kerry Conroy

Intern3

John Hall

Intern4

Terri Smith

Intern

CONTRIBUTORS

Hugh L. Spitzer

International Life Sciences

Institute

Risk Sciences Institute

Jill S. Litt

International Life Sciences

Institute

Risk Sciences Institute

ADMINISTRATIVE STAFF

Cecile Parker

Office Administrator

Linda Journiette-Rayford

PC Specialist

Jene Lewis

Administrative Secretary

PUBLISHING STAFF

Mary Lou Higgs

Manager, Publishing Services

Denise Felix

Production Editor

Cheryl Davis

Typographer

Susan Hoffmeyer

Graphic Designer

Through May 1992.

Wbrough May 1993.

%rough August 1993.

tillgh March 1993.
workshop Participants

Thomas Burke, Workshop Co-chair

Department of Health Policy and Management

The Johns Hopkins University

Baltimore, MD

Rae Zimmerman, Workshop Co-chair

Robert F. Wagner Graduate School of Public Service

New York University

New York, NY

Marvin Cassman

National Institute of General Medical Sciences

National Institutes of Health

Bethesda, MD

Irwin Feller

Graduate School of Public Policy and Adminstration

The Pennsylvania State University

University Park, PA

Carolyn Fulco

National Academy of Sciences

Washington, DC

Bryan Hard in

National Institute for Occupational Safety and Health

U.S. Department of Health and Human Services

Washington, DC

Ira Raskin

Center for Medical Effectiveness Research

U.S. Department of Health and Human Services

Rockville, MD

John Vandenberg

Health Effects Research Laboratory

U.S. Environmental Protection Agency

Research Triangle Park NC

Dan Vandermeer

National Institute of Environmental Health Sciences

U.S. Department of Health and Human Services

Research Triangle Park NC

Jeanette Wiltse

Office of Health Effects Assessment

U.S. Environmental Protection Agency

Washington, DC

Frank E. Young

U.S. Department of Health and Human Services

Washington, DC

NOTE: OTA appreciates and is gratejid for the valuable assistance and thoughqld critiques provided by the workshop pm”cipants. The

participants do not, however, necessarily approve, disapprove, or endorse this report. OTA assumesjidl responsibility for the report and the

accuracy of its contents.

vi
contents

1 Summary, Issues and Options I

Health Risk Assessment Research at Federal Agencies 3

Linking Health Risk Research to Decisionmaking 12

Prospects for the Future 19

Introduction to Issues and Options 20

Issues in Health Risk Research, Structure and Funding 22

Issues in Linking Research to Decisionmaking

(Radon as a Case Study) 36

2 An Introduction to Health Risk Assessment and

Its Research Base 45

Research Data for Health Risk Assessment 48

The Health Risk Assessment Process 50

Issues in Health Risk Assessment 54

Why Conduct Risk Assessment Research? 60

Summary 63

Chapter 2 References 63

3 Federal Research in Health Risk Assessment 67

Research at the Federal Agencies 67

Trends and Gaps 81

Summary 83

Chapter 3 References 83

4 Setting Priorities for Risk Assessment Research 87

Categorizing Health Risk Assessment Research 88

Federal Resources for Health Risk Assessment Research 93

National Research Priorities 98

Agency Priorities 102

Programmatic priorities and Program Management 108

Administrative Tools for Priority-Setting 109

Findings and Conclusions 112

Chapter 4 References 115

vii
5 Research and Decisionmaking 119

Impact of Research on Risk Assessment Guidelines and

Decisionmaking 120

The Interdependency of Research and Decisionmaking 130

The Limits of Science in Social Decisions 133

Linking Health Risk Research to Decisionmaking 137

summary 140

Chapter 5 References 141

6 Indoor Radon: A Case Study in Decisionmaking 145

How Large Is the Waterborne Radon Problem? 146

Radon, Mining, and Indoor Exposures 146

Epidemiologic Studies of Radon-Related Lung Cancer 149

Policy 154

The Future 165

Chapter 6 References 167

7 Structuring the Future of Health Risk

Assessment Research 171

Structuring a High-Quality Research Program 172

Prospects for Research 174

Fostering Research Linkages 181

Surnmary and Conclusions 183

Chapter 7 References 184

APPENDIXES

A International Risk Assessment 187

B Department of Health and Human Services

Organization Chart 211

C Federal Obligations for Health R&D by Source

or Performer 212

D FY 1992 Estimates of Funding Support by

DHHS Agencies 214

E List of Abbreviations 216

F Acknowledgments 220

INDEX 225

Vill
—.

H

ealth risk assessment provides a systematic approach to

evaluating and estimating risks to human life and

well-being. Risk, as it pertains to the health effects of

toxic substances, is the probability of injury, disease, or

death for individuals or populations who undertake certain

activities or are exposed to hazardous agents. It is sometimes

expressed numerically (e.g., one excess cancer death in 1 million

exposed people is termed a 10-6 risk of cancer). If quantification

is not possible or necessary, risk may be expressed in qualitative

terms such as low, medium, or high risk. Health risk assessment

is a synthesis of the following four steps: hazard identification,

dose-response analysis, exposure assessment, and risk characterization (figure l-l).

The primary sources of data for assessing risks to human

health are from epidemiologic, toxicological, structure-activity

relationship, and exposure studies. But those data are usually

incomplete, failing to describe the risk from the exposure being

considered. The incompleteness of the data requires the use of

extrapolations to make predictions. Common extrapolations are

from measured effects in people exposed to high concentrations

of substance to the effects expected at lower exposures, from the

results of animal tests to predictions of effects in humans, and

from observations of effects from one route of exposure to

estimates of effects from another route.

To perform those extrapolations, Federal agencies use assumptions or science policy choices to bridge gaps in data or

knowledge. Because assumptions and policy positions contain

value judgments and a substantial measure of scientific uncertainty, they are the main areas of controversy in risk assessment.

Issues

and

Options 1
2 Researching Health Risks

Figure l-l—Elements of Risk Assessment and Risk Management

RESEARCH RISK ASSESSMENT RISK MANAGEMENT

Laboratory and field

observations of adverse

health effects and

exposures to

particular agents

-___i

Information on

methods to extrapolate

from high to low doses -

and from animals

to humans

I

Field measurements,

estimated exposures,

and characterization

of populations

1

Hazard identification

(Does the agent cause

the adverse effect?)

-_----l Dose-response

assessment

(What is the relationship

between dose and

incidence in humans?)

Exposure assessment

(What exposures are

1

currently experienced or –

anticipated under

different conditions?)

I

Development of

regulatory options

if

Risk characterization

(What is the estimated

incidence of the adverse

effect in a given

population?)

1

I Evaluation of public I

health, economic,

social, and political

consequences of

regulatory options

,

1 T

*

Agency decisions

and actions

, J

SOURCE: National Research Counal, Rkk Assessment in the faded Government: Managing the FYoc41ss, 1993.

But, however uncertain the results of health risk

assessments may be, they provide the foundation

for health risk-based decisions (e.g., emission

standards for incinerators). Those decisions affect

expenditures for complying with regulations and

medical expenses for exposure-related diseases

that can total billions of dollars.

With so much at stake, it seems fitting to seize

opportunities to use scientific research to narrow

the scope of uncertainty in health risk assessment.

In its landmark 1983 report, the National Research Council (NRC) concluded that improving

the quality and comprehensiveness of knowledge

is by far the most effective way to improve risk

assessment. The decade following the publication

of the NRC report saw impressive advances in the

biological and biomedical sciences and provided

regulatory agencies with considerable experience

in conducting risk assessments and applying risk

assessment methods. This report reviews Federal

research efforts to harness those advances and

experiences and develop abetter knowledge base

for health risk assessment.

In this study, the Office of Technology Assessment (OTA) analyzed the nature and organization

of federally supported research on health risk

assessment and examined whether such research

was adequately supported and managed. The first

section of the report summmizes the results of the

survey OTA conducted of Federal programs and

identifies the resources, research priorities,

trends, and gaps of current research in this area

Subsequent sections describe the linkage of

research to decisionmaking and the limits of

research-based information in making social decisions, using management of the risks associated

with radon exposure as a case study. A final

section describes prospects for the future, including promising areas of research on risk assessment and factors to enhance the chances of

success in the endeavor.
Chapter 1: Summary, Issues and Options 3

Table l-l-Categories of Health Risk Research

Methods Development

Method and model development-Developing tests and structure-activity analysis for identifying toxicants; developing models

for predicting human exposures; developing methods for extrapolating effects, dose, and dose-response from laboratory study

results to humans. Activities for method and model development include:

. Toxic effects identification and extrapolation

● Exposure extrapolations

● Dose-response extrapolations

. Uncertainty analysis

Methods evacuation and validation--The iterative process for validating new methods by comparisons to methods of known and

established veracity. When validated, methods can be applied to risk assessments.

Basic Research

Toxicity mechanisms--Research to determine the nature, sequence, and combinations of events that result from exposure of

test animals or humans to toxicants. This includes the study of the concentration of the toxicant or its metabolize that reaches the

site of action, the rates and nature of the reactions with target organs or tissue that are causally linked to disease or the

development of toxic effects, and an understanding of how the toxic effect comes about.

Biological and biomedical--Research on the structure and function of molecules, ceils, organs, physiological systems, and

organisms. The resulting knowledge of comparative genetics, biochemistry, and physiology can be used to guide studies on

toxicity mechanisms or reduce uncertainty in effects, dose, and dose-response extrapolations.

Chemical and physical sciences--Research on physical and chemical properties that govern absorption, distribution, fate,

transport, and transformation in the environment and in biological systems.

Chemical-Specific Data Development

Toxic effects--Research designed to identify the toxic effects of agents and the nature of dose-response relationships under

defined conditions of exposure. Activities include:

. Human studies

. Whole-animal studies

● Mammalian tissue, organ, and cellular studies

● Microorganism and other studies

Human exposure data--Measuring toxicant levels in different media or commodities and biological materials to test predictive

models and to validate measurement methods.

SOURCE: Office of Technology Assessment, 1993.

HEALTH RISK ASSESSMENT RESEARCH

AT FEDERAL AGENCIES

OTA surveyed Federal programs that conduct

research on the toxicity of environmental pollutants, occupational toxicants, and toxic contaminants in food. It collected information through

written requests for data, following up those

requests with interviews of agency representatives and visits to agency laboratories.

 Survey of Federal Research Activities

To narrow its range of inquiry, OTA restricts

risk assessment research to two types of activities: 1) generalizable research to improve

methods for assessing the risks of adverse

health effects from food contaminants and

environmental and workplace exposures, and

2) research to improve estimates of risks from

exposure to specific agents. Because of the

controversies that surround the methods for

evaluating and estimating risks from exposure to

agents suspected of causing cancer, this report

frequently uses research to improve the assessment of risk from potential carcinogens to illustrate the directions and needs of research on

health risk assessment in general.

Given that framework, OTA divided health

risk assessment research into three key areas

(table l-l). Two of the areas encompass more

general research, and the third encompasses

chemical-specific research. Methodological research, the first area, is specifically aimed at
4 Researching Health Risks

improving the approaches and methods used for

assessing risks. The second, basic research,

contributes to an understanding of how environmental agents perturb normal biological functioning. The third category involves research that

expands the database about specific chemicals

for use in risk assessments. The results of all

three types of research are crucial; inadequate

development in any one area could impede

progress toward the overarching objective of

making risk assessment more credible and its

results more widely accepted. For instance, the

models developed in methodological research

depend on the results of basic research and

chemical-specific data development.

RESEARCH TO IMPROVE HEALTH

RISK ASSESSMENT METHODS

OTA sees the goal of research on health risk

methodology as development of better methods

for extrapolating results: from animal models to

humans, from high to low exposures, and from

emission data to predictions of population or

individual exposure. It also encompasses efforts

to estimate uncertainty and develop new methods

for toxicity testing. An important and often

overlooked part of methods research is evaluating

and validating the methods with experimental

data.

Many scientists argue that methodological

research holds the most immediate promise for

substantive improvement of risk assessments.

To begin with, generic methodology research, in

contrast to chemical-specific studies, can have

considerable impact on assessing the risks from

exposure to many different chemicals and radiation. Moreover, when the methods are directed at

the most uncertain aspects of risk assessments

(extrapolations from high to low doses and from

animal models to human populations and predicting the risk of chemicals for which few or no

toxicity data exist), they can reduce the range

of uncertainties in current risk assessment approaches. Because of a number of characteristics,

methodological research falls in between basic

and chemical-specific research, making it a

bridge between basic and applied efforts. In other

respects, however, this research is sufficiently

unique that its practitioners refer to it as “risk

science.

BASIC RESEARCH TO SUPPORT

RISK ASSESSMENT

For the purposes of this report, basic research

is separated into two types: basic health risk

research and basic sciences research. Basic

health risk research investigates the mechanisms of disease associated with exposure to

toxic agents. These studies examine the fate and

transport of chemicals and physical agents, the

avenues of exposure, and interactions with living

systems and biological tissues, all of which feed

into health risk assessment research. The focus of

basic health risk research on the application of

results to risk assessment problems and opportunities sets it apart from the basic sciences.

Basic sciences research encompasses the basic

biological and biomedical, chemical and physical

sciences. Although some research in the basic

sciences contributes to risk assessment research,

basic sciences research is a very broad endeavor,

and it is not included in OTA’s analysis of

relevant research. These studies examine the

structure and function of molecules, cells, organs,

and physiological systems and their relationship

to the functioning organism, as well as the

properties of chemicals and physical agents.

Of the three types of health risk assessment

research, findings from basic research usually

require the most time to be incorporated into

decisionmaking. The research has also been

generally characterized as having the lowest

probability of success. Nevertheless, it can serve

as the foundation for developing new methods in

generating or applying primary data for health

risk assessment and affect risk assessment in a

far-reaching way, as it does other applications of

science. Recently, techniques and findings from

basic research have been rapidly incorporated

into health risk research. Within the past several
Chapter 1: Summary, Issues and Options 5

years, for example, many molecular biological

principles and techniques have proliferated throughout the field of toxicology.

CHEMICAL-SPECIFIC DATA DEVELOPMENT

Chemical-specific data development identifies

the toxic effects of agents and characterizes

dose-response relationships under defined conditions of exposure. Efforts to identify toxicants

probably constitute the broadest and most diverse

type of data development. Usually, they involve

testing agents in laboratory animals, sometimes

complemented by results from epidemiologic

studies. This type of research also includes

collecting data on exposure of humans to environmental agents. Some scientists dismiss the idea

that collecting or gathering data using “routine”

tests or monitoring methods is research. In

contrast, the majority of scientists who advised

OTA in the study and who reviewed drafts of this

report voiced the opinion that such activities are

properly classified as research. In OTA’s evaluation of research funding, only two Federal agencies reported collection of exposure data as a

research activity, but many included toxicity

testing in research activities. The programs that

carry out toxicity tests do more than provide the

basic information for risk assessments, they also

do research that leads to better tests and basic

research on mechanisms of disease causation.

 Resources and Priorities for Research

The Federal Government’s support of research

on health risk assessment extends from basic

studies in the biological and biomedical sciences

to toxicity testing and methods for extrapolating

observations from one setting to another. That

breadth was evident during OTA’s attempts to

evaluate the funding devoted to improving health

risk assessments. Under the broadest definition of

research that affects health risk assessment, a

significant portion of the Federal Government’s

obligations in health research and development

(R&D) generally can be considered as contributing to the effort.

OTA used the research objectives and the three

categories of risk assessment research discussed

above, which parallel the categories used by the

executive branch,l as the framework for the

analysis of the research funding. OTA’s call for

information from the various Federal agencies

resulted in estimates of resources that were highly

dependent on how the responder classified agency

research activities. OTA concluded that reliable

estimates of expenditures for health risk assessment research had not been obtained; nonetheless, OTA was able to discern some general trends

and directions.

using Summary data issued between 1981 and

1991 from the National Toxicology Program

(NTP) review of research related to toxicology as

a surrogate for health risk R&D,3 OTA determined that total support of health risk assessment

research increased from $336 to $520 million, a

55 percent increase before adjusting for inflation.

During the same period, Federal obligations for

health R&D, as reported in the National Institutes

of Health data book, increased from $5.0 to $10.7

billion, a 123 percent increase before adjusting for

inflation (figure 1-2).

Using the above data, OTA estimated health

risk R&D’s share of total Federal health R&D

dropped from 6.8 percent in 1981 to 4.9 percent

in 1991. Moreover, this relative decline in health

risk R&D took place during a period of expanding

Federal legislation and responsibilities to protect

~ The NTP Reviews of DI-IHS, DOE, and EPA Research Related to ‘hicology COL@CS &h 011 W~CY p~xh~~kgda of Buic

Toxicology Researc~ Toxicology Testing, and Toxicology Methods Development.

2 me NTP review also includes hIUXMII studies as research related to toxicology.

3 OTA’s mvey in 1993 indicates health risk research is also carried out by the Department of Defense, Department of Agriculture, the

c onsumer Product Safety Commission and Nuclear Regulatory Cornmis sion. NTP data did not cover resources for those agencies. However,

their contributions are small relative to the agencies covered in the review.
6 I Researching Health Risks

Figure 1-2-Funding fo Federal Health Research and

Development, Fiscal Years 1982-1991

12 ~-_...

o “

I I I I I I I I I I I I 1 I I I 1 I 1<

19821983198419851986 19871988198919901991

SOURCES: National Institute of Health Data Book, 1992; Review of

Current DHHS, DOE and EPA Research Related to Toxicology, F“ml

Years 1982 through 1991, National Toxicology Program, U.S. Department of Health and Human Services.

human health from environmental pollutants.

During that period, the number of environmental

legislative mandates increased with each successive Congress-horn 4 in the 97th Congress

(1981 and 1982) to 26 in the 101st Congress

(1989 and 1990) (figure 1-3).

In addition the NTP data also illuminated

trends in how the various agencies apportioned

support and resources for methods development,

basic toxicology, and testing (data development)

(figure 1-4). In general, over the 1980-92 period,

research agencies such as the National Institute of

Environmental Health Sciences (NIEHS) and the

National Cancer Institute increased the percentage of basic toxicological research that they

conducted. In contrast, regulatory agencies such

as EPA and the Food and Drug Administration

(FDA) devoted a larger proportion of their health

R&D to methods research than did the research

institutes.

Figure l-3-Environmental Legislative Mandates

30 ~—-–----—-

 - — ‘- -

2 5

97 98 99 100

SOURCE: Office of Technology Assessment, 1993.

The personnel figures, in full-time equivalents

(FTEs), devoted to this research reflect the size of

the intramural program. In general, the regulatory

agencies have sizeable intramural programs compared to their R&D budgets, while the research

agencies support relatively larger extramural

programs. For example, these data show that

NIEHS devotes the most resources, in both

dollars and FTEs, to health risk research. EPA,

in contrast, has FTEs nearly equivalent to NIEHS,

but only about one-third of the R&D budget.

Based on fiscal year 1993 estimates in the OTA

survey of research (table 1-2), less than 11 percent

($65 million) of the total R&D budget of $600

million for environmental and occupational

health and food safety is devoted to research on

methods. It is possible only to estimate roughly

the total amount that was actually spent on

methods research during the period, because of

the difficulties in categorizing the research. Nevertheless, the small size of the risk research

analysis programs at the National Center for

Toxicological Research of FDA and the National

Institute of Environmental Health Sciences, and

the reported part-time participation of researchers

at the regulatory agencies, support a conclusion

that methodological research is underfunded.
Chapter 1: Summary, Issues and Options 7

Table 1-2—Health Risk Research and Development Estimates, 1993 (In millions of dollars)

Health risk research* Agency total: health

Agency Total Methods or biomedical research**

National Institute of Environmental Health Sciences. . . . . .

Department of Energy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Department of Defense . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

U.S. Department of Agriculture . . . . . . . . . . . . . . . . . . . . . .,

Agency for Toxic Substances and Disease Registry . . . . .

Environmental Protection Agency . . . . . . . . . . . . . . . . . . . .

Food and Drug Administration (other than NCTR) . . . . . . .

National Center for Toxicological Research . . . . . . . . . . . .

National Institute for Occupational Safety and Health. . . . .

National Cancer Institute ., . . . . . . . . . . . . . . . . . . . . . . . . .

Other NIH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Alcohol, Drug Abuse, and Mental Health Administration . .

Total . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

129.0

I0.0a

19.6

11.5

16.9

32.0

13.0a

33.6

49.0

82.08

140.oa

64.0a

600.6

14,0

3.Oa

2 . 5

b

0.5

0.0

21.3d

3.5a

7.6

6.1

4.4a

2.2a

O.Oa

65.1

251.2

90.0”

300,0’

11 .5nd

16.9nd

49.0e

1 3 .

n d

38.9*

49.0*

1,981.4

6,929.9

1,164.1

10,894.5

a Estimate based on agency’s 1992 fund~ng for research on toxicology as reported in the National Toxicology Program Review of current DHHS,

DOE, and EPA Research Related to Toxicology, Fiscal Year 1992.

b ca~ulat~ as 13 percent of agency R&D for health.

C ~einb~rg, 19930 Journa/ ~f~//.f ~egearc~ 5:3!5, Data on biomedkal regearch, which excjudes $210 million for breast cancer research.

d R=ear& t. Improve Health Risk ~~e~ment program ~ti~at~ to be $5 million; $21.3 millioniS sum of funding for human exposure, health

effects, and risk assessment methods.

e Figure represen~ Health Effects Research Laboratory total budget: EPA-wkfe data are not available.

nd No data (research related to toxkok)gy WS.S used).

● Based on data from the OTA survey of agency resources.

● “U.S. Congress, CRS, 1993. Research and development funding; fiscal year 1993; issue brief (IB2062).

SOURCE: Office of Technology Assessment, 1993.

As would be expected for activities as broad as

risk assessment research, some fields of inquiry

have received more funds, some fewer. However,

environmental health research funding has neither kept up with the increase in health research

nor increases in environmental mandates that

depends on that research for decisionmaking.

Methodological research, in particular, seems

inadequately supported, despite the most immediate promise that OTA sees for this research to

improve risk assessment.

 Setting Priorities for Research

Charting a course for improving risk assessment research requires Federal agencies to work

at several organizational levels. OTA examined

the priority-setting process for such research at

three different levels: national, agency, and program. Each level uses different processes and

methods. OTA’s analysis indicated that prioritysetting at the program level uses the most

formalized, systematic processes; the national

level, the least. In addition, OTA identified

various factors that influenced the choice of one

type of research over another.

National priorities for research, based on national needs and goals, are influenced by prevailing economic, social, and political conditions.

Federal research to improve risk assessment is

largely decentralized and uncoordinated. The

work of Federal researchers is almost entirely in

support of the agencies and departments that

sponsor the research. Except for the NTP, which

sets priorities for toxicity testing, OTA observed

few national priority setting efforts. One of those

is the Federal Coordinating Council on Science,

Engineering, and Technology (FCCSET), an

interagency body within the Executive Office of

the President (EOP). However, participants and

nonparticipants alike displayed little enthusiasm

for or optimism about the recent FCCSET process

as it relates to risk assessment or risk assessment
8 I Researching Health Risks

Figure 1-4--Federal Research Related to Chemical Toxicology, 1980-1992

(In millions of dollars and full-time equivalents)

160 140 120 100 80 60 40 20 0 20 40 60 80 100 120 140 160

(S mllllons) (FTE)

6 5 4 3 2 1 0 10 20 30 40 50 60 70

($ millions) (FTE)

1989- [

1990-

1991-

1992- :::,:::, .. :,., . . ::

1 1

12 10 8 6 4 2 0 50 100 150 200

($ millions) (FTE)
Chapter 1: Summary, Issues and Options 9

1989 - C=EXXSSnx::=::-”’--’:::.

1 m.=

..—

1990- ~XS::_=:::::::::: ‘-~2.ZZZZZZZZA -. —..

. . . . . . . . . . . . . . . . . . . . . . .

1991- .—.————. . . .—. . ::–L—VZZZZZZZ

1992- 1992::T_:::”:”’ ““”’”:

— -

—7–- --- -- –- -. ---— ~

~

160 140 120 100 80 60 40 20. 0

($ millions)

Environmental ProtectIon Agency

:r--;-.58~:i

1986

1987

1988

1989

1990

1991

1992

60 50 40 30 20 10] 0

($ millions)

National Center for Toxlcologlcal Research

100 200 300 400

(FTE)

1980- [ Exl ““ . .Y% ‘--–---’–- ’

1981- [ ~\’+j:

1982- 1

~NN.... ..:... :.:

1983 - k\RSI” ”’ ““’’”””””

1984- [ ‘ NXXXW:..:.A:

1985- N\NNw: ‘:::. :: :

~ 1

1986 - “r - ‘Eh\YY..l:!’&:.A:

1987- L-. . . .kTI:......::.:::..::

1988- :- -- : kN:_.-::::..::

1989 - ~:. -ky:---’” -

. . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

.— . . . . . . . . . . . .

1990- . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1991-

~-.

h=:::::”::-”--::

1992 -

~=== --- ~:::=-:. . . . . . . . . . . . . . . .

I -- -—— .-.* —-T–. --

40 30 20 10 0 50 100 150 200 250

($ millions) (FTE)

Dollars FTE

= Basic &~\~ Testing Method , I m Basic I ] Testing ~ Method

SQURCE: Review of Current DHHS, DOE and EPA Research ;l~!.?td t

Tox/m/ogy, FISCal Years 1980 through 1992, National Toxicology

Program, U.S. Department of Health and Human Services.
10 I Researching Health Risks

research. In any case, the Clinton Administration

plans on eliminating FCCSET and creating a

National Science and Technology Council.

The priorities for risk assessment research vary

with the mission and function of an agency—

especially whether or not the agency’s responsibilities include risk management. The research

conducted by the regulatory agencies, and the

Departments of Defense and Energy, is mostly

chemical-specific data development; the research

agencies, by and large, conduct basic research.

Setting priorities at the program level is generalIy a more developed—that is, both a more

systematic and a more formal-process than

priority-setting at the agency or national levels.

One of two distinct types of management methods

is used to determine priorities for individual

research projects. The style termed ‘‘bottom up’

depends on researchers to develop research ideas

and priorities and to communicate those ideas and

requests for research support to their superiors or

to grant managers. In contrast, ‘ ‘top-down’

management has the most senior decisionmakers

in an agency deciding the priorities for research.

OTA observed both styles of management used

separately or in combination in its survey of risk

assessment research. In general, research priorities for programs at the regulatory agencies are

more frequently decided by top-down management, whereas program priorities at the research

agencies are determined through a bottom-up

process. EPA and DOE have used a combination

of these styles in managing their research programs.

 Trends and Gaps

Over the course of this study, OTA observed

several major trends in Federal research activities

that support health risk assessment. To begin

with, agencies are expanding their research

horizons to include not only cancer but other

adverse effects on health. Many scientists interviewed by OTA expressed the belief that research

on health effects other than cancer has the

potential to influence regulatory policy significantly. But they also believe that the current

science base is not sufficient for adequate assessments of noncarcinogenic health effects. One

reason that such research may have a great impact

on policy is that health risk issues about noncarcinogens do not usually lead to the acrimonious policy debates associated with carcinogens.

Many agency research programs, along with

expanding the breadth of their research, have been

restructuring. In most of those cases, the restructuring reflects a greater emphasis on

social relevance. As agencies link their research

activities more closely to social needs, their

research becomes, by necessity, increasingly

multidisciplinary. No one field of academic

training or research encompasses all aspects of

health risk research, which ranges from basic

biomedical research to computer modeling. The

increasing complexities of the science involved

and the need to incorporate more science into

rulemaking have made it clear that multidisciplinary research is required to provide the requisite

scientific underpinning for future risk assessments.

Yet overall, few incentives exist for longterm multiagency, multidisciplinary research

on health risks, and very few resources are

allocated to this work. Scientists from all of the

environmental health disciplines, such as toxicology, epidemiology, biostatistics, environmental

chemistry, and clinical studies, make contributions to health risk assessments and are the

mainstay of agency research to improve the risk

assessment process. Nonetheless, those fields

remain disparate, and collaborative studies remain the exception rather than the rule.

Without more incentive to collaborate, disciplinary myopia may continue and grow more

pronounced and entrenched. Compartmentalization by agency or discipline can only hinder

progress and retard the infusion into risk assessment research of newly developed techniques and

knowledge arising out of the rapid advances now

occurring in the biomedical sciences. Ironically,
Chapter 1: Summary, Issues and Options I 11

dwindling agency resources may actually be

spurring some collaboration: evidence indicates

that decreasing budgets have catalyzed some

interaction as the need for cooperation becomes

apparent. Setting aside turf battles, Federal agencies are beginning piecemeal approaches to promoting multiagency, multidisciplinary research.

Today, Federal Government risk assessment

research support is spread out across at least 12

different agencies. That dispersion has both

positive and negative consequences. On the one

hand, agencies can monitor their agency-specific

research without having to overcome additional

hurdles, and they can target their activities to the

areas they consider of highest priority. On the

other hand, work is fragmented and diffuse. Those

characteristics may hinder progress with risk

assessment problems that are common to several

agencies.

OTA finds a particular lack of emphasis on

collaborative research to evaluate and validate

new methods and models, especially in the

important area of corroborating experimental

results from animal studies with studies in humans. Admittedly, this is a most difficult undertaking, but it is critical to elevating the level of

confidence to be accorded to risk assessment

results. OTA also found little research under way

to examine or attempt to validate extrapolation

models for general use or for use with specific

chemicals.

The basic building block for much of the

critical research-chemical-specific toxic effects

data—is generally obtainable, although the Federal Government supports fewer toxicology tests

than in years past. The number of tests carried out

by industry is uncertain. Regardless of the number of tests, what is missing is funding for studies

to use those data in combination with expanding

knowledge in toxicity mechanisms and biomedical sciences to examine various extrapolation

models in order to learn which models are more

predictive. With additional resources, Federal

agencies could conduct those bridging studies.

For instance, the Federal Government has

collected toxicity information in response to

mandates for registering or approving drugs

and pesticides. Both animal and human data

have been collected in those efforts, and they

could be used in attempts to evaluate and

validate existing models as well as develop new

ones. However, such research requires better

collaboration between and among agencies

and research disciplines. Although it remains to

be seen how much such analyses would cost,

gathering of data is typically the largest cost, and

that has already been accomplished.

The past decade has witnessed nearly revolutionary developments in the biological sciences.

Researchers are poised to use those advances to

improve health risk assessments. Yet despite the

potential for progress, the present Federal risk

assessment R&D infrastructure maybe an impediment to moving forward. Many scientists interviewed by OTA claim that the research system is

“broke.” Resources, they argue, are squandered

on a system that is incapable of setting priorities.

Consequently, the perception exists that the areas

of research of highest priority-those most likely

to improve risk assessment approaches—are not

being funded or studied, to the benefit of lower

priority or even irrelevant research. Even the $65

million spent on methods research may not be

targeted correctly. Instead, according to some

scientists, there is a tendency to fund projects that

may yield improvements on current methods but

that are unlikely to open new avenues of research

or application.

The absence of an identified central leader in

risk assessment research contributes to the pessimistic viewpoint and to the current level of

funding and disciplinary and agency fragmentation in the effort to improve health risk assessments. A nationally recognized leader could

provide leadership and assurances about political

support for research, promote multiagency collaborations, and provide incentives for overcoming bureaucratic hurdles and turf battles. A

national leader in the White House in a position

equivalent to the “Drug Czar” or “AIDS Czar,”
12 I Researching Health Risks

could bring national visibility and unify and

coordinate research activities across agencies, in

addition to articulating the needs of the field to

Congress and the President. Furthermore, this central figure could instill a sense of common

purpose among researchers and program managers.

LINKING HEALTH RISK RESEARCH TO

DECISIONMAKING

The complex relationship between research

and decisionmaking demonstrated in figure 1-5

deviates from the conventional representation of

a unidirectional flow of information from risk

assessment to risk management. It is, however, a

reasonable evolution of the conventional model

put forward in a 1983 report by the National

Research Council. Part of the reason for the

unidirectional information flow was the desirability of the compartmentalization of the risk assessment process from risk management. In the 10

years since the publication of the report, the

importance of information sharing to increase the

efficiency of research for decisionmaking has

become apparent. Thus, OTA’s figure highlights

the bidirectional flow of information as well as

the integration of the various disciplines and

types of research. In addition, it shows that

evaluating and validating methods can be the

focal point for integrating different lines of health

risk research, since anew model or method should

be examined and compared with methods of

known and established veracity. The figure also

indicates OTA’s stress on the interdependency of

research activities, the risk assessment process,

and policymaking.

Moreover, the interdependence of health risk

research and decisionmaking limits the capacity

of agencies to structure long-term solutions to

problems posed by toxic substances. As research

identifies potentially adverse health effects of an

agent, the public conveys its concern to Congress,

and Congress considers and passes laws to

address those concerns. By necessity, agencies’

addressing those more immediate concerns restricts their opportunities to continue research to

decrease the reliance on science policy assumptions in risk assessments.

 The Impact of Research

Science and policymaking are uneasy partners.

Nevertheless, the primary criterion for health

risk assessment research is that it be useful for

decisionmaking. OTA examined three questions

about the relationship of research to decisionmaking:

1.

2.

3.

How has research influenced Federal risk

assessment guidelines and risk assessment

practices?

What impact has research had on decisionmaking?

How can research be designed to make risk

assessment more useful in decisionmaking?

To answer those questions, OTA reviewed the

evolution of Federal risk assessment guidelines

and risk assessment practices and some of the

comments and criticisms made about them.

Research findings from many scientific fields

provide the basic data for health risk assessment.

But those data are never extensive enough for

answering questions about exposure, effect, and

the people who are likely to be affected. Agencies

frequently confront questions that science cannot

answer, and in order to make decisions they have

adopted so-called science policy assumptions to

bridge the gaps in the available information. The

assumptions have some grounding in sciencethey don’t contradict accepted scientific conclusions and opinions at the time they are adopted—

but they necessarily incorporate other ideas that

are based on policy rather than science. For

instance, choosing the risks of the maximallyexposed individuals as a basis for regulatory

decision is a policy decision, as is the decision to

include 24-hours/day exposure for 70 years in

calculating maximum exposure. Those decisions
Chapter 1: Summary, Issues and Options I 13

, -, Y.

E ‘,,

,1 ;’ +0 1 (+ i

\ E “ .

,/ 1- /

I

A

v

I

-. ——--

A

I

v

- -.. ,,

m

‘ \

.

(n’

al

u,

\

ii ,’ .—c)

u) ,’

/

/ I

1 I

‘ \ ,

. — -

—
14 I Researching Health Risks

can be set aside, but as matters of policy, not

science.

The assumptions that are used in health risk

assessments can be divided into two general

types: those that bridge gaps in scientific

knowledge and those that compensate for a

lack of agent-specific data.

After reviewing the evolution of EPA’s risk

assessment guidelines, OTA concluded that research has had only a modest effect on the

agency’s efforts to revise the science policy

assumptions adopted in its risk assessment guidelines. The controversary generated by EPA’s current efforts to revise its 1986 cancer risk assessment guidelines underlines the importance of

policy-based decisions. Research has, however,

had a substantial impact on chemical-specific risk

assessments and consequently on regulatory actions,

Three interacting factors account for the

limited impact of new scientific research on

EPA’s science policy assumptions: the nature

of the assumptions, the importance of the

assumptions to regulatory approaches, and the

policy reverberation from changing specific

default assumptions.

 The Limits of Science

Whatever is expected of risk assessment in any

given circumstance, it is only one of the elements

in formulating regulatory actions. Legislative

mandates, social values, technical feasibility, and

economic factors may take a more prominent role

than expert assessments of risk (figure 1-6).

The limits of science are manifest at different

levels. Uncertainty in measurements and observations constrains science at the most fundamental

level, and the scientific underpinnings of risk

assessment are more subject to those limitations

than the experimental sciences. At a higher level

of complexity, the interpretation of data and

observations to predict outcomes introduces other

unknowns. And risk management actions can

themselves produce uncertainty. Solving the

F gure 1-6-Research as an Element

of Decisionmaking

“

I Legislatlve/ ‘\

:-’’”-%

\

--- I

‘\ political

~ factors ,’ ‘\ , Research I - ---

i ‘--- ‘ ~::y:;::~

1 ,

Ris k

I

‘! I assessment 1‘-’-

,/

~ Technical

‘I feasibility

.:’:-’L--”-’ —-

SOURCE: Off Ice of Technology Assessment, 1993.

problems in health risk assessment goes beyond more and better science; it also requires

building trust among government, industry,

and citizens.

 Radon as a Case Study of

Research and Decisionmaking

The controversy developed around EPA’s proposed regulation of radon in drinking water

illustrates some of the interplay between science

and decisionmaking. When radon gas, which

originates in the Earth’s crust, is emitted into an

open space such as outdoor air, it is rapidly

diluted to the low “background” or “outside”

levels found around the world. But when it is

emitted into a home, a school, or another type of

building, dilution is slower. As a result, the

concentrations of radon inside structures are

usually higher than the concentrations outside.

These higher levels raise concerns about health

because studies have revealed higher rates of lung

cancer among miners and other workers exposed

to radon on the job than are found in the general

public. (All estimates of risk from indoor radon

are based on extrapolations from the results of

studies of miners.)
Chapter 1: Summary, Issues and Options I 15

Responding to those concerns, Congress and

EPA have considered ways to reduce the risks

posed by indoor radon. Most indoor radon enters

buildings directly from the soil, and efforts to

lessen those exposures have included EPA programs to inform homeowners about the risks from

radon and about methods to reduce radon inflow

into buildings. The private sector has also acted

on the problem by imposing requirements for

measuring and, if it is deemed necessary, reducing indoor radon as a condition in real estate

contracts in some localities.

EPA cannot, of course, regulate radon from the

soil because radon from that source enters homes

directly, without passing through any entity that

can be regulated. Some radon, however, enters

buildings through the water supply, and the

agency can regulate radon in water just as it

regulates other contaminants under the Safe

Drinking Water Act (P.L. 93-523 and P.L. 99-

339).

Some Members of Congress, including the

Chairman of the House Committee on Science,

Space, and Technology, asked OTA to examine

an ‘‘inconsistency ‘‘ in EPA’s approach to radon.

That request arrived at OTA after this study to

examine health risk assessment research was in

progress. OTA officials decided to include the

office’s response to the request as a case study in

this report.

REGULATORY APPROACHES

EPA divides its regulatory programs along

media lines: air, water, industrial wastes, and so

forth. It has approached the issue of indoor radon

as a media problem, and has different policies

toward radon entering buildings directly from the

soil and through water. The agency has not

proposed regulating radon emitted directly from

the soil, but it has proposed regulating water

suppliers. Some scientists, Members of Congress,

and other policymakers have recognized that

indoor radon is only a single part of the larger

issue of indoor air pollution. The question of risks

to health from indoor exposures presents assessFigure 1-7—Estimates of Deaths From Lung Cancer

at Different Levels of Radon Exposure

1 4 ,000

r

—.

#

 1 2

’

000 

~–- ‘- -

4

%

-6 10,000

:

:

‘

c

 8,000 r

73

? 6,000

c

a

ug 4,000

2—

fi 2,00 0

~ I

o l—

0

——- ~–— ,— — . J

4 8 12 16 20 24

Maximum exposure level (pCi/L)

SOURCES: Office of Technology Assessment, 1993, based on

Environmental Protection Agency, 1992. Technical Support Document

for the 1992 Citizen’s Guide to Radon. M. Reimer, U.S. Geological

Survey.

ment, remediation, and regulatory difficulties that

differ from those associated with pollutants in

outside air.

Air—Based on its National Residential Radon

Survey, EPA estimates that about 5.8 million

homes (6 percent of all U.S. homes) have

concentrations of radon in air above 4 pico curies

per liter (pCi/L), the level at which EPA would

recommend remedial action. The agency estimates that the average home has a concentration

of around 1.25 pCi/L.

As figure 1-7 shows, the bulk of cancers that

are associated with exposures to radon occur in

the population exposed to low levels, below 2

pCi/L. The primary reason is that many more

people are exposed to those levels than to higher

levels, Given EPA’s conclusion that it is impossible to reduce levels below 2 pCi/L in some

houses, the practical lower limit on the number of

deaths associated with radon may be as high as

10,500. That estimate is based on extrapolations

from studies of miners who were exposed to

radon. Refining those extrapolations might re-
16 I Researching Health Risks

Figure 1-8-Cost-Effectiveness of Different

Action Levels for Reducing Indoor

Radon Exposures

o 4 8 12 16 20 24

Maximum exposure level (pCi/L)

SOURCE: Office of Technology Assessment, 1993.

duce or increase the estimate of the number of

cancers.

Because radon is present in all air, both inside

and outside, it is impossible to have zero exposure

to radon. Thus, some risk of death from radonassociated lung cancer is always present, if one

assumes that there is no threshold for radonassociated lung cancer deaths. Exposures to radon

in outside air is estimated to be associated with

about 500 deaths from lung cancer annually.

EPA’s Technical Support Document for the

1992 Citizen’s Guide to Radon provides the

agency’s reasoning behind choosing 4 pCi/L as

the level at which homeowners should obtain

more information about exposure and take steps

to bring the level of radon in their homes below

that concentration. But because EPA does not

regulate radon in air, the Federal Government is

not required to provide an administrative forum to

debate whether the projected benefits of reaching

4 pCi/L of radon justified the associated costs.

Figure 1-8 summarizes EPA’s cost-effectiveness

analysis for reducing concentrations of indoor

radon to various levels. Reducing exposures to 8

pCi/L is expected to save lives at a cost of less

than $0.5 million per life; the cost per life saved

just about doubles (to a little less than $1.0

million) at 4 pCi/L and increases further at lower

action levels.

Water—The Safe Drinking Water Act (SDWA)

Amendments of 1986 require EPA to develop

regulations for toxic chemicals in water. The

agency has decided to regulate radon like any

other waterborne carcinogen; it calculates that

radon in water is associated with 30 to 600 cancer

deaths a year. That single radioactive element

accounts for most of the total risk from radiation

in water, and the upper bound on its risk exceeds

the total risk from all chemicals in water (table

1-3). The regulatory process can be considered in

two time periods. Before the summer of 1992,

EPA was developing the regulation under its

usual procedures, but at that time Congress

intervened in the process and mandated that EPA

reassess its estimates of risks and costs in relation

to radon in water and imposed a one-year

moratorium on any regulation of radon in water.

The SDWA imposes a goal of zero for concentrations of carcinogens in water, which is unattainable for radon. Extensive aeration of radonbearing water would discharge the radon into the

air, but there would always be radon at least at the

concentration found in outside air. EPA determined that the lowest “practical quantification

level” for radon in water was 150 pCi/L, and in

1991 it set the regulatory maximum contaminant

level at that value in its proposed rule. Because of

the decay of radon over time, the “quantification

level” translates to a concentration of 300 pCi/L.

Differences in the procedures for measuring

radon in air and water account for the fact that

measurements of 2 pCi/L or less of radon in air are

routinely obtained, whereas EPA contends that

measurements below 150 pCi/L in water are not

practical.

Scientists generally agree that 10,000 pCi/L of

radon in groundwater results in 1 pCi/L of radon

in air from volatilization. Therefore, if the 300

pCi/L limit on radon in water were imposed, it

would mean that no more than 0.03 pCi/L of

radon in indoor air would result from the waterborne radon. That concentration is 10 percent or

less of the radon in outdoor air, and it would

contribute about 5 percent to total indoor expo-
—

Table 1-3-Cancer Risks From Water

Estimated annual

Source of risk cancer mortality

Radiation in drinking water . . . . . . . . . . 37 to 730’

All chemicals in drinking water. . . . . . . . 215 to 430

a her EpA estimates vary within this range.

SOURCES: Office of Technology Assessment, 1993, based on M.

Gough, 1989. Estimating canoer mortality. Enviromnenta/Sciencemd

Technology 23 S25-930, based on USEPA. 1987. Unfinished Business. Washington, DC: USEPA.

sures. EPA has carefully examined such things as

how much radon is released into the air from

water during showering, laundering, and flushing

the toilet in order to estimate the contribution of

radon from water to indoor air.

 “Inconsistency” in EPA’s

Approach to Radon

The letter that requested this OTA examination

of indoor radon cited the concerns expressed in

1992 by EPA’s Science Advisory Board about

inconsistencies in the agency’s approach to reducing risks from radon. It contrasted the goals of

the Indoor Radon Abatement Act (IRAA) with

EPA's action level for indoor radon and its

proposed level for regulating radon in water under

SDWA. The IRAA goal is to bring indoor radon

levels down to those commonly found outdoors

(0.1 to 0.5 pCi/L). EPA, however, urges that

remediation be undertaken to reduce concentrations of radon in homes to 4 pCi/L or less and

acknowledges that it is infeasible to reduce

concentrations below 2 pCi/L in some homes. In

contrast, EPA’s proposed regulation under SDWA

would set 300 pCi/L radon in drinking water as

the highest permitted level, limiting radon in

indoor air to 0.03 pCi/L from this source. Clearly,

the goal, the action level, and the proposed

regulation set different exposures as acceptable

levels of risk (box l-A).

These inconsistencies are not surprising, given

the way that the goal, the action level, and the

regulation were derived. Congress in the IRAA

acknowledged that the level of radon in outdoor

Chapter 1: Summary, Issues and Options 17

air is unavoidable and that concentrations cannot

be reduced below it. At the same time, it maintained that reducing concentrations indoors to

that level would be as protective of health as

possible.

EPA, in setting the 4 pCi/L action level for

indoor radon, accepted a risk of cancer from radon

that is far higher than the 1 X 10-6 (one excess

cancer per million people) that the agency routinely uses as a goal in regulating exposure to

toxic chemicals. A 10-6 cancer risk is equivalent

to about three excess cancer deaths annually;

thus, the risk of 7,900 excess cancer deaths at

exposures of 1.25 pCi/L, which is the national

average for indoor exposures, is about 2,600 x

10-6 or 3 X 10-3

. The Citizen’s Guide to Radon, a

publication issued jointly by EPA and DHHS,

provides some examples of comparative risk; for

instance, the risk that a nonsmoker bears from

constant exposure to radon at 4 pCi/L is roughly

the same as that person’s risk of drowning,

The level of 300 pCi/L of radon in water, set at

what EPA had determined was the practical limit

on quantification, was projected to reduce risks to

about 2 X 10-4. In its preamble to the proposed

rule, EPA raised the question of the significance

of waterborne radon to total exposure to radon:

“In evaluating the various alternatives for proposing a radon MCL [maximum contaminant

level, which is the regulatory standard], EPA

considered the critical policy questions of whether

radon in water should be regulated like other

drinking water contaminants, or whether it should

be regulated more in accord with its importance

compared to overall radon exposure. EPA

decided to regulate radon as it does other waterborne contaminants, but its Science Advisory

Board in 1992 criticized that action because of the

small contribution that waterborne radon makes

to overall exposure to radon.

As a result of Congress’s mandating the

multimedia risk assessment in 1992, EPA’s risk

and cost assessment changed slightly, but whether

it will make a difference in regulation remains to

be seen. The risk estimate of about 200 cancer
18 I Researching Health Risks

Box l-A–Reducing Exposures to Radon: A Goal, an Action Level, and

a Regulatory Standard

Nazaroff and Teichman (1990)1 calculate that current exposures to radon are associated with about 15,700

lung cancerdeaths annually. They estimate that 97 percentof those deaths are expected in smokers with 3 percent

in nonsmokers. Concentrations of indoor radon are higher than those outdoors, and the Federal Government has

directed several initiatives at reducing indoor exposures. As a result, there is a goal for the reduction of indoor

concentrations of radon, an action level to guide voluntary reductions, and a proposed regulation to reduce

concentrations of radon in water.

A Goal

The indoor Radon Abatement Act sets the goal of reducing indoor concentrations of radon to the

concentrations found outdoors-that is, 0.4 pCi/L. Currently, the average indoor concentration is about 1.5 pCi/L,

with about 6 percent of all houses having concentrations greater than 4 pCi/L. EPA states that it is difficult to reduce

indoor levels below 2 pCi/L (apparently for houses with current levels greater than 4 pCi/L). if, however, the goal

of 0.4 pCi/L could be reached, it would reduce EPA’s estimated annual number of radon-associated lung cancer

deaths to about 3,100 (a reduction of about 80 percent).

An Action Level

EPA recommends that indoor radon concentrations be reduced to 4 pCi/L or below, a level considered

technologically feasible for all houses. Reducing ail indoor radon concentrations that are now greater than 4 to

2.7 pCi/L is expected to eliminate about 3,500 deaths (a reduction of about 17 percent). (The 2.7 pCi/L figure is

the mean between the national average of 1.5 and the action level of 4 pCi/L.)

A Regulatory Standard

Under the provisions of the Safe Drinking Water Act, EPA proposes regulating radon in drinking water so that

the concentration of radon in air that is the result of the volatilization of radon from drinking water is no more than

0.03 pCi/L. According to EPA, reducing all higher concentrations of radon in water to this level would eliminate

80 radon-associated lung cancer deaths annually (a reduction of about 0.5 percent).

1 W.W, Nuroff and K. Tekhrnan, Indoor radon. Erw/romnenta/Science and 7WVIO10gY34:774-782, 1990.

SOURCE: Office of Technology Assessment, 1993.

deaths expected from waterborne radon changed

hardly at all, and radon in water remains associated with a risk greater than 10-4, which is the

usual upper limit on the risk that EPA finds

tolerable.

Despite EPA’s revisiting its risk assessment

and making only small changes, there is little

consensus about the certainty of the estimate of

risks or the costs of addressing them. As the

Science Advisory Board of the EPA pointed out

in its review of the multimedia risk assessment,

substantial questions remain about the validity of

EPA’s estimate of the risk from ingested radon,

about the number of water suppliers that will

exceed the regulatory limit, and the costs of

regulation. As of October 1993, EPA’s multimedia risk assessment had not been released, pending the agency’s development of responses to the

Science Advisory Board critiques. Congress in

1993 again intervened in the regulatory process

and imposed an additional one year moratorium

on any regulation of radon in water.

The specific questions raised by radon maybe

answered by congressional or EPA decisions that

impose new regulations or leave the current

approaches intact. New epidemiologic results

may inform those decisions by revealing more

certain evidence of the level of risk posed by
Chapter 1: Summary, Issues and Options 119

indoor radon. And it is possible that research into

mechanisms of carcinogenesis may shed some

light on such risks. More generally, however,

radon is a case that illustrates the difficulties

posed by an environmental risk of uncertain size

that reaches human beings through different

media.

PROSPECTS FOR THE FUTURE

In its study, OTA noted several qualities that

characterize common to high-quality research

programs that should be considered in structuring

the future of health risk assessment research.

These include leadership, well-defined objectives, investigator initiation of projects, competitive awards and peer review, planning and criteria

for evaluating success, collaboration and coordination, training, and advisory input.

OTA also identified several areas of research

that promise to advance health risk assessment:

new methods for toxicity studies, biomedical and

molecular epidemiology, mechanistically bawd

dose-response extrapolation methods, improved

methods for measuring or estimating human

exposures, mechanistic studies, data development

and management to support toxicity evaluation

and methods evaluation and validation.

The exploration of the many promising

areas for research requires establishing linkages not only among various scientific disciplines but also with decisionmakers. No one

category of research can be classified as the most

useful for decisionmaking. Instead, risk assessments will increasingly require multidisciplinary

approaches and analyses of available information.

The nature of the health risk being addressed, the

nature of the information already at hand, and the

other factors that affect decisionmaking should all

be considered when structuring a research program for health risk assessment.

Research linkages and collaborations offer

enduring benefits to all participants. They bring

together researchers with different strengths and

expertise, foster the dissemination of knowledge,

Figure 1-9--Linking Scientific Disciplines in Health

Risk Research

I

, It ‘ ~ ‘+ !

t +,

, !

,, i, .’ , .
20 I Researching Health Risks

health risks can transfer knowledge to the private

sector to foster economic growth, now a vital part

of the mission of many research agencies. Revenue raised in technology transfer could be used to

bolster research in this area. Such a contribution

would be an important source of funds since, as

this report describes, few resources are allotted

for long-term funding of research to improve risk

assessments despite the amounts of money involved in decisions that depend on risk assessment.

Risk assessment involves the analysis and

synthesis of the entire knowledge base on the risk

at hand, such as a specific chemical or class of

chemicals. A substantial amount of reasoning and

judgment is required in determiningg whether the

composite data on toxic effects, exposure, and

dose-response characteristics as a whole make the

hypotheses of risk tenable. This line of questioning and reasoning weighed against scientific

principles and data is an iterative process, not

unlike conducting experiments. It is a process

different from the frequent practice of summing

up the data that indicate risk and downplaying or

ignoring contradictory information. When applied, questioning and reasoning can reveal the

strengths and weaknesses of the evidence for risk

and identify additional research needs.

Health risk assessments, by their very nature,

require extrapolations from current information

to estimates of effects under different circumstances. Scientists contribute to those extrapolations, but the science policy decisions that guide

the choices of models include assumptions with

embedded value judgments. The process of

selecting the science policy assumptions (e.g.,

extrapolation models) may benefit from involving practitioners of disciplines other than

the biological, chemical, or physical sciences.

In this, OTA agrees with analyst Sheila Jasanoff,

who argues for ‘‘bridging the two cultures of risk

analysis’ —the “hard” quantitative sciences and

the soft’ nonquantitative disciplines such as the

behavioral and political sciences.

The objectives of this OTA report are more

limited. They are to describe current research,

how research contributes to decisionmaking, and

the limits of research and science in decisionmaking. Accepting those limits, it remains clear that

improvements in scientific understanding from

research will produce better risk assessments,

which are mighty contributors to decisions about

how much society will pay to cleanup pollution,

how many resources will be expended on pollution prevention, and judgments about the extent

of environmentally related illnesses.

INTRODUCTION TO ISSUES AND OPTIONS

This OTA study finds that health risk assessment research is itself ‘‘at risk:

●

●

●

●

The attention and resources allotted to health

risk assessment research are not commensurate with its impact on public health and the

economy. Moreover, the proportion of funds

devoted to environmental health R&D relative to health R&D declined from 6.8 to 4.9

percent in the decade from 1982 to 1991,

despite expanded congressional mandates

for Federal environmental responsibilities.

The research being conducted is fragmented

within and across at least 12 Federal agencies, resulting in the inefficient and ineffective use of resources.

Inadequate resources are devoted to research

on risk assessment methodology, the area

likely to have the most far-reaching effect on

policy. Methodological research receives

about $65 million in 1993-only about 11

percent of the $600 million of Federal

spending on risk assessment research.

Not enough attention is given to linking

research to decisionmaking.

Opportunities to link government, university, and industry research are not being

exploited.

OTA raises six issues related to health risk

assessment research (box l-B). Four interrelated
Chapter 1: Summary, Issues and Options 21

Box l-B-Summary of Issues and Options

HEALTH RISK RESEARCH, STRUCTURE AND FUNDING

ISSUE 1: Given what is at stake, inappropriate attention being paid to health risk assessment research?

. Option A-Continue with present policies.

. Option B-Create a national initiative for health risk assessment research.

. Option &Expand resources for health risk assessment research by redirecting funds, raising tax

revenues, collecting user fees, or increasing funds.

ISSUE 2: How can Congress foster research on risk assessment methodology?

● Option A--Continue with present policies.

● Option B--Promote or mandate more interagency coordination of methodological research.

. Option C-Establish a risk assessment research agency.

ISSUE 3: Should Congress mandate more targeted research to improve risk assessment?

. Option A-Continue with present policies.

. Option B-Mandate programs of targeted research at some Federal agencies.

● Option C-Provide incentives for programs of targeted research.

* Option D--Support research priority-setting based on level of risk.

ISSUE 4: How can Congress promote research linkages and technology transfer among the Federal

Government, universities, and Industry?

. Option A--Continue with present policies.

● Option B-Establish more academic centers for health risk assessment research.

. Option &Promote technology transfer from health risk assessment research.

. Option D-Encourage industry support of health risk assessment research.

● Option E—Provide incentives for collaborative research.

LINKING RESEARCH TO DECIS1ONMAK1NG (RADON AS A CASE STUDY)

ISSUE 5: Can epidemiologic studies confirm, reject, or sharpen estimates of the risk posed by indoor

radon?

. Option A--Accept the results of a meta-analysis as sufficient to answer questions about the level of risk

posed by exposure to indoor radon.

. Option B-Convene a planning group to consider a study to answer questions about risks from exposure

to indoor radon.

ISSUE 6: Can there be a consistent approach to reducing radon exposures?

. Option A—Accept the inconsistency and let the Environmental Protection Agency (EPA) deal with

exposures to radon under existing laws.

. Option B-Use the reauthorization of the Indoor Radon Abatement Act to direct EPA to integrate all routes

of exposure in considering activities to reduce exposure to indoor radon,

. Option C-include radon in a comprehensive law for regulating indoor air.

issues address the Federal research infrastructure: fer among and between Government, universities,

1) deciding on the appropriate level of health risk and industry.

assessment research; 2) fostering research on Two issues are related to understanding risks

health risk assessment methodology; 3) targeting from exposures to radon and controlling them.

research to improve health risk assessment; and 4) They involve research, risk assessment, and

promoting research linkages and technology trans- regulatory decisionmaking. This example typifies
22 I Researching Health Risks

the issues relating to the limitations of science for

resolving policy questions. The issues for radon

are: 1) using epidemiologic studies to confirm,

reject, or sharpen the estimates of risk posed by

indoor radon, and 2) developing a consistent

approach to reducing radon exposures.

OTA has provided options for congressional

consideration for each of the issues raised in the

OTA report. The options are not mutually exclusive; in many cases, they are complementary and

can be integrated to improve health risk assessment research.

ISSUES IN HEALTH RISK RESEARCH,

STRUCTURE AND FUNDING

ISSUE 1: Given what is at stake, is appropriate

attention being paid to health risk

assessment research?

Health risk assessment research provides the

scientific foundation for health risk-based regulatory decisions (e.g., emission standards for incineration). Those decisions affect expenditures for

complying with regulations, cleaning up contaminated sites, and treating exposure-related diseases

that can run into the billions of dollars.

EPA estimates that complying with its regulations costs more than $150 billion annually.

Compliance with FDA and Consumer Products

Safety Commission regulation of food and product safety adds to the above estimate as does

compliance with Occupational Safety and Health

Administration regulations. Moreover, although

estimates of the total health costs from environmental exposures are not available, a number of

studies suggest that the costs of some environmentally related illnesses-such as lead poisoning and pollution-related respiratory conditions

-could reach well into the billions of dollars.

Yet OTA finds that health risk assessment

research is not high on the national research

agenda. To elevate this research to a priority level

consistent with its impact on health and the

economy, requires leadership from higher reaches

of government, strategic initiatives that incorporate and respond to the needs of many Federal

agencies, and funding commensurate with the

magnitude of the problem. Currently, health risk

assessment research, according to this OTA

study, has none of those hallmarks. Only about

$600 million-less than one-half of 1 percent of

the costs of complying with EPA regulations

alone-is spent annually on health risk assessment research.

With adequate support, research can develop

informative, cost-effective toxicity testing, better

evaluations of human exposure, and health risks.

The results will improve health risk-based decisionmakin- g and strengthen public confidence in

environmental decisionmaking.

The expected health, environmental, and economic benefits from health risk assessment research warrants the consideration of raising it to

a higher level of research priority. OTA explored

several options for improving leadership and

providing additional funding.

Option A: Continue with present policies.

If Congress takes no action, the present piecemeal approach will probably yield slow, incremental progress in health risk assessment research. In the absence of congressional action,

Federal health risk assessment research is likely

to remain focused on carrying out individual

agency priorities, responding to specific legislative mandates, or being based on the culture and

talents of agency researchers. This is not a

completely undesirable outcome, Research by its

very nature is a foray into the unknown, making

progress difficult to predict.

However, continuing with present policies

means that advances in research on health risk

assessment are left very much to chance. In

particular, little research is devoted to finding

solutions to problems with overarching impact or

tailoring solutions to meet risk assessment needs

that cut across the boundaries of discipline,

agency, or risk assessment issue.

Risk assessment research has not kept abreast

of the needs of our modern society. It is estimated
Chapter 1: Summary, Issues and Options 123

that more than 1,500 new chemicals are introduced into U.S. commerce each year, adding to

the more than 62,000 chemicals already in use.

Studies suggest that only 10 percent of chemicals

existing worldwide have adequate toxicity data.

New insights from research can produce better

tools to decide which chemicals require more

investigation and which require regulation. But

without better tools, Government agencies and

private companies will never eliminate the

backlog of chemicals needing testing or unanswered questions about their risk to human

health.

Regulatory agencies attempt to protect the

public’s health by counterbalancing uncertainty

and incomplete information with conservative

assumptions. From the standpoint of those that

must comply with Federal regulations (e.g.,

industry and government entities and utilities),

that orientation leads to unnecessary costs that

must be passed on to consumers and citizens.

Although their points of view may differ in some

respects, representatives from both regulatory

agencies and the regulated entities would agree

that resources are misspent if risks of greater

magnitude are not handled earlier and with more

resources than risks of lesser magnitude. Both

would argue for adequate resources for health risk

research to take advantage of progress made in

science (e.g., cellular and molecular biology) to

reduce uncertainty in health risk assessments.

Finally, without national leadership and a

commitment to health risk assessment research,

the public’s support for environmental protection

may erode.

Option B: Create a national initiative for health

risk assessment research.

If the decision is reached that current activities

in the area of health risk assessment are too

fragmented, Congress can consider methods to

centralize the planning and evaluation of

Federal health risk assessment research. Some

areas of health risk assessment research would

benefit from a multiagency approach. A national

initiative would focus attention on such research

and make it more responsive to national needs. It

would provide a forum to debate, develop, and

plan research. In particular, it would identify

problems in risk assessment that cut across the

agencies and distinguish which of those problems

are addressable by research and which remain

essentially policy choices. It would also provide

guidance of Federal policy that is open to scrutiny

by the public and Congress, and its plans and

operation would reflect the overall needs of the

Nation. It can be accomplished by:

●

●

●

setting up crossagency strategic planning,

providing leadership from the White House,

or

directing the Department of Environmental

Protection (should it be established) to develop a program.

CROSSAGENCY STRATEGIC PLANNING

Crossagency strategic planning can be designed to bring agencies together to establish

common research goals-for the short, medium,

and long terms. On paper, the benefits of crossagency strategic planning appear within reach,

but formidable obstacles lie in the way of securing

them. Most agencies have a deeply rooted commitment to their own priorities, based on historical or legislative imperatives. Their resistance to

change can thwart the setting of national goals.

The most typical forms of resistance are to set

objectives that are so broad as to be meaningless

or to repackage existing programS to make them

appear to be meeting objectives for which they

were not actually intended. The nature of health

risk assessment research and the breadth of

disciplines that support it lends itself to those

kinds of deception.

One way to enlist agency cooperation in

strategic planning is to offer financial incentives

for participation, such as additional research

resources that are earmarked for research tailored

to meeting government-wide objectives. The

Bush Administration used such a mechanism,
24 I Researching Health Risks

called a ‘ ‘ crosscut,’ ‘ to augment funding in

priority areas of research under the auspices of the

Office of Science and Technology Policy’s Federal Coordinating Council on Science, Engineering, and Technology. Given the currently tight

Federal budgets, providing additional funding

will be difficult. However, another way to enlist

agency cooperation is through strong and wellrespected leadership.

LEADERSHIP FROM THE WHITE HOUSE

Leadership at the pinnacle of the executive

branch can provide accountability, authority, and

responsibility for risk assessment research. Furthermore, a nationally recognized leader can

elevate the stature of programs for health risk

assessment research, instill a sense of common

purpose, and persuade agencies to cooperate in

attaining national objectives. Such a person

within the Executive Office of the President

(EOP), similar to the “Drug Czar” or the “AIDS

czar, ” would provide a focus for discussing

research needs across agencies. The President’s

Science Adviser might fill this role; he or she

could certainly spearhead the important function

of cross-agency strategic planning. Similarly, the

Carnegie Commission recently proposed that the

EOP become the focal point for developing

environmental and risk-related policy and coordinating the activities of the Federal agencies. One

potential pitfall, however, in assigning this responsibility to a political appointee in the White

House is that it will engender fears, warranted or

unwarranted, about the politicization of science.

In contrast to a designated leader, a Center for

Research Policy could serve within the EOP,

most likely in the Office of Science and Technology Policy, as a neutral forum for linking research

to decisionmaking. Such a forum could assist

Federal agencies in identifying important gaps in

research, setting crosscutting research objectives,

and monitoring whether those objectives are

being met. Another of the center’s functions could

be to distinguish issues of policy from issues of

science. Those distinctions are necessary because

the high stakes and commercial interests involved

in health risk assessment research virtually guarantee controversies about the scope, interpretation, or application of research. The center could

help to educate policymakers and the public about

the nature and limitations of research; it could

also help identify which areas of controversy

involve unverifiable assumptions and which are

amenable to resolutions by further research.

The center may well be unnecessary, however,

because it would be performing the same functions that existing agencies could perform by

working together.4 However, as the center would

evaluate the potential impact of research on

policy, it would require an analysis of cultural and

social factors as well as scientific merit. Commingling science and policy may be viewed unfavorably by some communities: keeping policy separate from research has been seen as essential to

maintaining the credibility of scientific research.

It may also be problematic to assign the job of

developing and monitoring objectives to a center

without also giving it the responsibility or the

capacity to implement those objectives. All of

these issues require a discussion of the scope and

scale of the center and the source of its resources,

which is not attempted here.

PROGRAM IN THE DEPARTMENT

OF ENVIRONMENTAL PROTECTION

(SHOULD IT BE ESTABLISHED)

As part of the responsibilities for a new

department, the much discussed Department of

Environmental Protection could be instructed to

establish a high-level program in health risk

assessment research. Such a program could be

made to provide a collaborative atmosphere for

Federal research and to include private sector

initiatives.

4 A worki.ngparty under the auspices of FCCSET had been attmlpting to Identify government-wide gaps in health risk assessment researeh

However, the effort apparently has been abandoned before [he release of its results.
Chapter 1: Summary, Issues and Options 25

Option C: Expand resources for health risk

assessment research by redirecting funds,

collecting user fees, raising tax revenues, or

increasing appropriations.

Congress could increase the level of support for

health risk assessment research through several

mechanisms. For example, it could use any of the

following approaches:

. redirecting funds to risk assessment research,

● collecting user fees,

● raising tax revenues, or

● increasing appropriations.

New legislation could channel special taxes or

user fees to finance health risk assessment research. Unlike many areas of science, health risk

assessment research is so closely linked to

regulatory action that a strong argument can be

made for the appropriateness of finding such

research through charnels related to regulation.

REDIRECTING AGENCY FUNDS TO RISK

ASSESSMENT RESEARCH

Congress could redirect existing Federal resources toward research programs with potentially high dividends for health risk assessment.

The funds could be secured from Federal agencies

that support health risk assessment research or

from agencies whose programs depend critically

on the results of such research. DOE, for example,

relies on the results of research in its vast program

of environmental cleanup, which is larger in

scope than EPA’s Superfund program. Yet DOE

lacks a targeted, coordinated research program

that could help it set priorities among cleanup

sites on the basis of the risk to human health.

Redirecting a portion of the funds appropriated

for remediation of its sites would provide a

substantial increase in research funding. Even a

comparatively small 2 percent redirection of the

$5.4 billion allocated to DOE’s cleanup activities

would expand risk assessment research by more

than $100 million. That figure is substantially

larger than the estimated $65 million this country

spends on health risk assessment methodological

research and is more than double the entire health

effects research budget at EPA. Based on its

research, OTA agrees with those who point out

that DOE’s own national laboratories have the

expertise and laboratory capacity necessary to

absorb an infusion of funds for methodological

research. Given EPA’s experience with the types

of research necessary to improve policy decisions, Congress may want to consider joint

EPA/DOE projects.

Redirected funds could be used either to bolster

existing programs in health risk assessment

research or to create a new program. They could

be channeled within the agency or to another

agency that is already supporting health risk

assessment research. In any case, this approach is

viable only if the redirected funds are sufficient to

support a meaningful level of research.

RAISING TAX REVENUES

The Superfund law is an example of Federal

legislation that provides funds for research from

directed tax revenues—in this case, from a tax on

the petrochemical industry.s The tax revenues are

deposited in the Superfund trust fund, which

finances cleanup, compliance, and research.6

Research receives the smallest share of the funds,

and the exact amount is not a fixed proportion or

set-aside. Of the 1992 Superfund appropriation of

$1.6 billion, Congress appropriated about $116

million for research, of which only a small portion

was devoted to health risk research. In fiscal year

1994, Superfund research programs are being cut

13 percent.

At the State level, California has enacted a

cigarette tax of 25 cents per pack that specifically

s The Comprehensive Environmental Response, Compensation and Liability Act of 1980.

s Superfund appropriations also come from general revenues. In 1992, for example, $250 million of the Superfund’s appropriation of $1.6

billion came from general revenues.
26 I Researching Health Risks

sets aside a flat percentage of tax revenues for

research. Proposition 99, passed in 1988, earmarks 5 percent of collected revenues for research. As a result of this legislation, $30 million

was set aside in 1989 for a competitively awarded

grants program of research on tobacco at the

University of California.

There are many arguments, pro and con, over

the use of such ‘sin’ taxes. On the one hand, they

can raise substantial revenues for desired programs and can promote socially desirable behavior, such as reducing pollution and reducing

smoking. On the other hand, these taxes are often

levied on those individuals who can least afford

them. Moreover, the earmarking of tax revenues

can be seen as a license for agencies to raise

money for their own ends. Many in Congress

adamantly oppose earmarking of tax revenues,

insisting that collected money go into the general

revenue.

COLLECTING USER FEES

To augment the resources available for research, Congress could enact legislation authorizing user fees for regulatory review of industry

products. The money collected in fees could be

earmarked for research on health risk assessment.

The concept behind a user fee is that the

Government is entitled to charge for a service that

directly benefits private individuals or entities.

The idea of charging user fees for the regulatory

review of drugs has been debated for many years

on the grounds that industry is not the only direct

beneficiary of a premarketing review; the public

also stands to benefit from drugs being introduced

into the market. In 1992, Congress passed groundbreaking legislation, the Prescription Drug User

Fee Act (P.L. 102-57), requiring drug manufacturers to pay user fees for FDA’s review of their

product applications. Under the provisions of the

act, FDA uses a portion of the funds it collects to

improve the drug approval process.

Similarly, Congress could enact new legislation to allow EPA to collect user fees from

individual manufacturers for reviewing industrysubmitted information about pesticides and toxic

substances. Although a sizable portion of EPA’s

regulatory activities involves industry-wide standardsetting, the agency also reviews the applications

of individual manufacturers. Manufacturers or

importers of new pesticides and new chemicals,

in general, are required to obtain premarketing

registration or submit premanufacturing notices,

respectively. Fee levels would have to be set to

approximate the costs of such reviews. Whether

the fees would be sufficient to warrant creating

and administering a user fee program would need

analysis.

INCREASING FEDERAL APPROPRIATIONS

As another approach, Congress could appropriate more money for health risk research. Research

is the source of new methods for improving the

accuracy of risk assessment and new ways of

preventing, treating, or remediating risks that

have already been identified. The desired outcome of this area of research is to enable society

to make informed decisions about which risks to

reduce and which to tolerate.

Yet despite the advantages of increased resources, nondirected increases in funding can

present problems. Chief among them is that little

evidence exists to suggest that Federal agencies,

if given more money, would direct the funds

toward research of the highest national priority. In

fact, existing priority-setting mechanisms may

allocate resources ineffectively and inefficiently

to agency programs. As a result, enhanced resources alone may not provide a commensurate

improvement in the process of risk assessment

because the most critical areas of research maybe

neglected. In any case, substantial increases in

appropriations are not likely.

ISSUE 2: How can Congress foster research on

risk assessment methodology?

As defined in this report, methodological

research is aimed at improving the methods for

assessing risks to human health. Specific examples of such research include efforts to improve
Chapter 1: Summary, Issues and Options 27

the extrapolations from laboratory results to

predictions of human effects; to explore new

approaches to extrapolating results obtained at

high doses in animals and at high exposure levels

in workers to estimates of effects at low ‘ ‘environmental’ exposures; and to improve estimates

of risks and methods for analyzing uncertainties.

OTA’s emphasis on methodological research

does not imply that other research is not important

to risk assessment. Rather, it recognizes that other

kinds of risk assessment research have already

benefited from substantial attention and support.

For instance, research in chemical-specific data

development for identifying toxicants has long

been emphasized in Federal programs and undoubtedly that emphasis will continue. Today,

however, methodological research seems to

offer the best opportunity to move the field of

risk assessment-forward. Yet it receives little

attention and funding.

Optimism about methodological research

springs from several sources, but two are especially important. The rapid advances in basic

biological and biomedical research provide a

wealth of information that further research may

incorporate into health risk assessments and tools

for toxicological research. In addition, generic

methodological research provides results that can

be applied to large numbers of chemicals. That

kind of broad scope is particularly attractive given

the enormous backlog of chemicals for which

little or no information about risk is available and

for which resolving questions about toxicity

through traditional testing methods are impractical. Furthermore, new chemicals are being developed, many to replace older chemicals. Methodological research offers the possibility of developing methods for screening to prevent introducing

new risks.

Option A: Continue with present policies.

A major conclusion of this study is that

relatively meager resources are devoted to

such research. In particular, of the $600 million

that OTA estimates the Federal Government

spent on health risk assessment research in fiscal

year 1993, only $65 million (11 percent of the

total) went toward improving risk assessment

methodology. Some progress is likely under

present policies, but the pace will be slow.

While methodological research holds the

prospects for improving the accuracy of risk

assessments, the controversies on health-risk

based decisions are not entirely about the

accuracy of risk assessments. They are about

different viewpoints. There is not now and

there may never be a consensus among those

who hold the two major conflicting views in

this area: the one, that human health is

paramount and that costs and forgone benefits

should not be weighed against it, and the other,

that some threats to health are sufficiently

small that they can be tolerated and that

controlling them costs too much. The general

conflict between the two perspectives may be

intractable, but conflicting interpretations of toxicity data from scientists supporting either view

help to fuel the discord. Research into specific

areas of uncertainty can help to reduce some of

this conflict.

Moreover, under present policies, any augmenting of the resources allocated to methodological research will involve shifting funds from

other programs, a move that could cause new

controversy. For instance, if the shift were made

at the expense of toxicity testing in support of the

identification of toxicants, it could be viewed as

reducing research in an area of historical Federal

emphasis and promoting research that is perceived by some as being the industry’s responsibility.

Still, there are arguments for such shifts.

Continuing with present research policies will

exacerbate problems in setting standards and

undercut the confidence of the public in the

standards (and government) because of questions

raised about risk assessment results. While industry and taxpayers pay billions of dollars in

control and cleanup costs, everyone is left

uncertain about how much safety has been
28 I Researching Health Risks

purchased or how much risk has been left

unaddressed.

Option B: Promote or mandate more

interagency coordination of methodological

research.

It is all too frequent a complaint that Federal

research programs need to be better coordinated.

But some areas of research labor under a greater

disadvantage than others when coordination is

lacking. Health risk assessment research and

especially methodological research, which draws

from diverse scientific disciplines, are such areas.

The linkage to regulatory decisions is a distinctive feature of health risk assessment research and

a further reason for coordination. Many of these

decisions pose problems common across agencies

that can be addressed by targeted research. Such

targeted research could be potentially better

handled in a coordinated manner.

Improving the coordination of research efforts,

both within and across agencies, has been seen as

important to improving risk assessment for more

than a decade. And some efforts have been

undertaken. At the national level, the National

Toxicology Program was created in 1978 to

coordinate Federal programs in toxicological

testing. At the program level, EPA’s Research to

Improve Health Risk Assessment program coordinates research by providing funds to offices

within EPA’s Office of Research and Development to address problems that cut across research

disciplines and issues in improving health risk

assessments.

Yet despite those and other efforts, research

programs are separated by more than the barriers

of organization and location existing among and

between agencies, programs, and disciplines.

Power struggles over budgetary and bureaucratic

turf are common, according to many agency

scientists and managers interviewed by OTA. In

addition, fragmentation within and across agencies has impeded effective communication, created unnecessary duplication, and stymied research progress toward overarching goals.

Some coordination can occur as a result of

leadership at different levels of management—

within, between, and among agencies and within

programs and laboratories. Perhaps perversely,

dwindling resources may provide momentum to

these voluntary efforts as program and laboratory

managers have no choice but to enter into

collaborative efforts to complete research that

previously they might have accomplished alone.

A major drawback to taking no action to

promote or mandate more interagency coordination is the opportunities that may be lost for

large-scale integration of programs. More comprehensive efforts at coordination can lead to

synergistic advances in research and more efficient uses of resources-provided that strong

leadership is exercised to prevent agencies from

transforming coordination efforts into mere paper

exercises.

To coordinate research on health risk assessment methodology research, Congress could

promote central coordination or establish a lead

agency.

PROMOTING CENTRAL COORDINATION

Congress could mandate that research on risk

assessment methodology be coordinated centrally

through the Executive Office of the President

(EOP) to enhance its visibility and promote better

communication. Because Federal agencies spend

only about $65 million for research on health risk

assessment methodology, coordinating such a

program would require only modest resources. In

fact, the Federal Government’s investment in this

type of research is so small that some might argue

that coordination is unnecessary. The other side

of that argument holds that scarce resources

deserve the greatest of care.

One possible mechanism has been established:

the Federal Coordinating Council on Science,

Engineering, and Technology (FCCSET), which

is chaired by the President’s Science Adviser, is

a cabinet-level interagency group charged with

coordinating the Federal Government’s activities

in science and technology.
Chapter 1: Summary, Issues and Options 29

FCCSET in 1991 and 1992 had some focus on

health risk assessment research: its Subcommittee on Risk Assessment of the Committee on Life

Sciences began effort to identify future health risk

assessment research needs. Although this activity

was not aimed at coordinating research projects,

the activities of the subcommittee were a first step

in creating an inventory of ongoing research

activities, which could be useful in future coordinating efforts. A research inventory would have

allowed FCCSET members to identify redundant

research, areas of little or no activity, and research

efforts that could be usefully integrated across

agencies. However, this project apparently has

been put quietly to rest with the transition to the

Clinton Administration.

Even with an active effort, there are limits to

the effectiveness of FCCSET or an organization

like it. First, FCCSET members were typically

policymakers so highly placed in each Federal

agency that they were unfamiliar with the technical aspects of research, which impaired their

credibility among researchers. Second, the

FCCSET staff was quite small; often one staff

member was assigned to more than one committee, leaving the bulk of the staff work to agency

personnel. Unless FCCSET (or a like organization) were given more staff, it will lack the

capacity to coordinate government-wide research

efforts. Third, any FCCSET-like activity, however worthy the cause, will inevitably raise the

specter among researchers of political tampering,

because of the committee’s proximity to the

President.

ESTABLISHING A LEAD AGENCY

A lead agency could be assigned responsibility

for developing and maintaining g an inventory of

ongoing projects; spearheading cross-agency planning of research to meet the most pressing needs

of risk assessors; encouraging collaborative research across Federal agencies and possibly with

industry and academia; and offering centralized

resources, technical assistance, and public information.

A lead agency to coordinate research offers

several advantages. It can draw on its own

experience, staff, and resources—although additional resources would be needed for its

increased responsibilities. No legislative changes

would be necessary if it were located in an

existing department or an agency. Also, the

creation of a Department of Environmental Protection could provide an administrative location

for a lead agency. A lead agency also has an

operational investment in the success of efforts at

coordination because of its own responsibilities

for research or risk management (or both). In

addition, using a lead agency instead of the EOP

for coordination can ameliorate concerns about

the politicization of research.

Yet such an undertaking as coordinating all

research on health risk assessment methods may

drain the resources of a lead agency. A further

problem is the resentment such a designation—

and the additional resources to be provided-may

foster among other agencies. That outcome could

conceivably undermine the very purpose of the

action.

Were Congress to proceed with this option, a

key factor in selecting a lead research agency

would be whether to choose a research or a

regulatory body. A regulatory agency would help

to ensure greater relevance in selecting research

directions aimed at meeting the immediate needs

of regulation. A research agency, in contrast,

would help to ensure proximity to scientific

advances, but its link to regulation would be more

remote.

Option C: Establish a risk assessment research

agency.

Congress could establish a small agency to

administer funds for health risk assessment methodology research. A small but highly visible

source of funding for research on health risk

assessment methods could focus Federal efforts,

draw attention to the promise of the research,

attract qualified investigators, provide a forum for

review and guidance of the research from all
30 I Researching Health Risks

interested parties, and, if it were structured

appropriately, include built-in mechanisms for

judging its success. Such a Risk Assessment

Research Agency (RARA) could review applications for research funds from inside and outside

the Federal Government, evaluating them in the

light of whether they would improve risk assessment. Funding for RARA could be secured by

tapping the resources of Federal research agencies, which would raise problems, or by new

appropriations, also problematic.

Any tap on a Federal agency, however, is likely

to encounter stiff resistance. It is to be expected

that each of the agencies that currently funds risk

assessment research will be reluctant to part with

its funds. Somewhat counterbalancing that tendency will be the knowledge that money spent by

RARA will be directed at risk assessment methodology. Managers in other agencies who

support such research may favor its being

performed by the new agency, since, as this

report documents, it is currently being done on

the margins at the agencies. By contributing

agency funds and individual guidance, they

will earn credit for successes and dilute responsibility for approaches or programs that

do not work.

To ensure that each agency currently involved

in risk assessment is treated fairly, RARA could

be governed by aboard of directors consisting of

the head of each agency that contributes to it. The

board could designate an executive officer to

oversee the day-to-day operation of RARA and

later decide between a permanent executive (the

model for most grants and contracts officers at the

National Institutes of Health and EPA) and a

rotating executive who would serve a fixed 1- or

2-year term (as is done in some programs at the

National Science Foundation). RARA would also

benefit from a board of nonfederal expert advisers

on the direction of its research and panels of

experts to review proposals that it is considering

funding.

RARA could be located administratively in

any Federal organization that supports health risk

assessment research, but at least two reasons can

be advanced for placing it within the National

Institute of Environmental Health Sciences (NIEHS).

NIEHS has more than a decade of experience

hosting the National Toxicology Program, which

pools the resources of a number of agencies to

address cooperatively government-wide needs

for toxicological research and testing. Moreover,

NIEHS has mechanisms in place to administer

grants, and it would need few additional resources

to administer the RARA programs. An argument

can also be developed to support EPA’s housing

such a program based on that agencys experience

in its Research to Improve Health Risk Assessment program and its administration and funding

of competitive cooperative agreements. Establishing RARA within a new organization, such as

the proposed Department of Environmental Protection or the National Institute of the Environment, would allow the program to develop in an

environment without pre-established barriers.

Regardless of where RARA is placed, it may be

criticized as duplicating or being unresponsive to

the functions of existing agencies. An active

board of directors, with an interest in the coordination of research as well as the concerns of their

own agencies, could dampen such criticisms.

One of the most significant aspects of RARA

is that it would provide a mechanism for evaluation if it commanded all (or a major part) of the

funds allocated for risk assessment methodology

research. The agency could be established with a

sunset provision that required a thorough review

of its activities at the end of some set period. Eight

years might be appropriate. Two years could be

used to establish RARA, solicit proposals, and

make the first funding decisions. Most grants

would be made for 3 years, provided that the

agency’s funding pattern parallels other Federal

research activities. With 3-year grants, the scientists who received the earliest grants would be

able to apply for continuation grants during the

8-year period.

During those years, the board of directors, in

consultation with researchers, policymakers, and
Chapter 1: Summary, Issues and Options 31

users of risk assessment results, could be required

to set forth the objectives of the methodological

research supported by RARA. The primary criterion for success might be whether RARAsupported research had made a perceptible difference in risk assessment policies. At the end of the

8 years, RARA’s board of directors, along with

other agency managers and appropriate congressional committees, would evaluate the agency’s

success. Its future would depend on the outcome

of the evaluation.

ISSUE 3: Should Congress mandate more

targeted research to improve risk

assessment ?

In broad terms, targeted research is designed

to solve a specific problem or meet an objective

set in advance by an agency or by congressional imperative. In the context of this report,

research can be targeted to areas likely to have the

greatest impact on policy and decisionmaking.

Targeted research is a tool that can be used to link

research to the decisionmaking process,

Targeted research on health risks is especially

appropriate for regulatory agencies that use risk

assessment to develop standards, guidelines, and

regulations. It is also appropriate for agencies like

DOD and DOE that have research capability as

well as an operational investment in the outcome

of research-in the form of cleanup programs

designed to reduce risk.

Targeted research is especially useful for

filling gaps in the data required for specific risk

assessments and, more generically, for developing new methods of performing risk assessment.

It should not be confused with “mandated” or

‘‘manager-directed’ research, in which the scope

and methods of a research project are dictated in

advance by the managers of an agency. Such

projects are less likely to undergo peer review and

be awarded competitively. Pertinent examples of

targeted research programs are EPA’s Research to

Improve Health Risk Assessment program and

methodological programs at FDA’s National

Center for Toxicological Research (NCTR).

Frequently people think of targeted research as

synonymous with applied research, but targeted

research can be either basic or applied, as long as

its goal is to meet an agency’s established

objective. The Human Genome Project of the

National Institutes of Health/Department of Energy is an example of targeted research that is

basic in orientation. As defined by OTA in this

report, targeted research is linked to a specific

goal; thus, terms such as “directed,” “identified,” or “prioritized” research are also appropriate. Any of those terms expands the concept of

targeted research beyond the narrow connotation

of applied research.

The most familiar method for Federal agencies

to target research is Requests for Proposals issued

to the scientific community to solicit research

intended to address a specific problem. Scientists

inside or outside the agency prepare competitive

applications detailing how they would study the

problem. After a process involving peer review

and ranking of the proposals, funds are awarded

to scientists whose applications appear most

likely or best suited to yield an answer.

Option A: Continue with present policies.

More targeted research may not be necessary. Programs at EPA and FDA’s NCTR are

already moving in the direction of more targeted research. In addition, establishing more

targeted research programs may discourage highly

productive researchers, who would rather pursue

projects of their own design and interest. Another

advantage of no congressional action at this time

is that increased targeting may be perceived as

leading to lower-quality science. (One way of

overcoming such a perception is by using a

properly designed procedure for competitive awards.)

A final advantage to inaction is that the efficacy

of programs of targeted research-in health risk

assessment specifically-has not been evaluated.

It may be too soon to assess the achievements of

EPA’s prototype for that kind of research, the

RIHRA program. RIHRA was established in

1988 to support targeted, long-term research to
32 Researching Health Risks

reduce uncertainties in risk assessment. Such

programs take at least 5 years-and usually

longer—to mature.

Option B: Mandate programs of targeted

research at some Federal agencies.

Congress could mandate more programs of

targeted health risk assessment research at Federal agencies with responsibilities for risk management. In its mandate, Congress could stipulate

broad objectives (e.g., ‘‘improve risk assessment

methodology’ yet permit agencies enough flexibility to set and revise their own discrete goals to

meet those objectives.

An example of possible targeted risk research

comes from an OTA study that stated that DOE

cleanup of contaminated nuclear sites is proceeding haphazardly, without an adequate understanding of the risks to human health. A program of

targeted research in health risk assessment at

DOE might improve the process. It could focus on

those substances and combinations of substances

at cleanup sites, such as complex mixtures of

solvents and radioactive materials to which people are likely to be exposed. Furthermore, by

redirecting some resources from remediation to

research, strategies for cleaning up the sites could

be underpinned by research results based on the

conditions for a particular site, such as soil,

geography, climate, and the number and types of

exposure conditions. These efforts could direct

DOE’s remediation efforts to those areas of

highest priority and set levels for remediation that

are appropriate for that site.

Option C: Support setting research priorities

based on risk.

Congress could support risk-based prioritysetting for health risk assessment research as a

less prescriptive way of encouraging agencies to

establish their own programs of targeted studies.

In the simplest terms, risk-based priorities

constitute a “worst-first” strategy: priorities

for research are established on the basis of the

degree of risk that a substance or situation

represents. The degree of risk, in turn, is determined by risk assessment. In recent years, this

kind of prioritization has received endorsements

from several sources. For example, EPA managers, responding to concerns that EPA’s agenda is

set more by public and political perceptions than

by expert-based judgment about risks, issued a

landmark report in 1987 that ranked and compared environmental problems on the basis of the

managers’ risk estimates. The report’s message

was that EPA should set priorities for its programs-and its resources-according to the ranking of risks. EPA’s Science Advisory Board

reviewed and endorsed the report and in so doing

expanded the concept of risk-based priorities for

research. Two other advisory committees of

nationally recognized scientists have also recommended risk-based research priorities. Such a

priority for research does not dictate priorities for

regulation, which are set inconsideration of many

other factors in addition to the level of risk.

Not everyone endorses setting research priorities on the basis of risk. Those who object cite

several arguments, for example:

●

●

●

●

risk assessment itself is so fraught with

uncertainties that it should not be used to set

directions for research programs;

agencies will use risk-based priorities to

ignore environmental problems that are of

concern to the public or to ignore environmental problems that have few data on

which to base risk assessments;

rankings of environmental problems tend to

be problem-specific and fail to recognize the

need for research that can cut across many

risk assessment issues and affect many

problem-specific needs; and

using risk to set priorities will skew research

in the direction of existing problems rather

than anticipating those that may crop up over

the long term.

Supporters of using risk-based research priorities acknowledge that the approach has problems,
Chapter 1: Summary, Issues and Options 33

but they contend that it ensures a role for science

in a process that historically has been dominated

by political and budgetary concerns. Supporters

also point out that the vast majority of EPA’s

research is driven by legislative mandates and

would not be affected.

Similarly, Congress could support a "valueof-information” approach to resource allocation that bases priorities for research on

whether its results can improve risk management. Most research aims for a greater degree of

scientific certainty. In contrast, a value-ofinformation approach gives higher priority to

research based on utility for risk management,

channeling resources to research that will have

the most impact on decisionmaking. That kind of

decision framework “point[s] decisionmakers

towards the most valuable improvements in

information, enabling them to better evaluate the

ever changing tradeoff between more analysis

and more action. This type of analysis could be

appropriately conducted in the Center for Research Policy discussed in issue 1, option B,

under Central Coordination.

ISSUE 4: How can Congress promote research

linkages and technology transfer among the

Federal Government, universities, and

industry?

In times of limited, even declining Federal

budgets, research linkages among the Federal

Government, industry, and universities are critical for advancing health risk assessment research.

These linkages could be important for at least

three reasons: they infuse more resources into the

field; they bring together researchers with different backgrounds, expertise, and interests; and

they increase the trust between the public and

private sectors. Congress could consider ways to

promote research collaborations. Not all areas of

health risk assessment research lend themselves

to industry linkages because of inherent conflicts

of interest, but many areas would benefit from

Federal collaborations with researchers from

academia and industry.

One way to foster such linkages and provide

incentives for industry involvement is through the

commercialization of products developed by

health risk assessment research. In addition,

product development and commercialization could

provide incentives for the private sector to invest

even more in this research, given the enhanced

prospects for commercial success.

In addition to the growing demands for research in the United States, the other industrialized countries are increasingly interested in using

these risk assessment methods for making their

regulatory decisions. As quantitative risk assessment (QRA) methodologies were being developed by the United States in the 1980s, the

international use of QRA was limited or nonexistent. That pattern, however, may be changing. The

overwhelming need, for example, for environmental cleanup in the former communist countries in Central and Eastern Europe has spurred

interest in U.S. risk assessment methodologies. In

particular, the potential usefulness of QRA in

setting priorities for those massive cleanup efforts

has prompted ever greater demands from those

countries for environmental health information.

As the world leader in health risk assessment

research [see app. A of the full report], the United

States can set the pace in research and product

development:

●

●

●

A

equipment and supplies for toxicological

testing;

equipment and supplies for monitoring exposure, both in the environment and inside

the body; and

computer software for estimating risks and

their associated uncertainties and for providing options for decisionmaking.

Other types of products, which are beyond the

scope of this report, include pollution prevention

devices and technologies for environmental remediation.

Specifically, Congress can act to encourage the

academic foundation of research and set the stage
34 I Researching Health Risks

for commercializing products invented by Federal scientists or university scientists who receive

Federal support. In particular, Congress could

develop programs at the Department of Commerce for transferring technologies that arise

from health risk assessment research. The National Institute for Standards and Technology

could play an important role in such transfers.

Option A: Continue with present policies.

If Congress takes no action, opportunities may

be lost for cultivating U.S. preeminence in health

risk assessment research and assisting in the

commercialization of products. That market is not

limited to the U. S., and it is likely to expand as

Central and Eastern Europe begins to confront

decades of environmental contamination. Those

market pressures will probably lead to commercialization regardless of Federal support of such

efforts.

Domestically, the need for information about

the toxicity of the new chemicals added annually

to U.S. chemical registers increasingly outpaces

the ability of researchers to produce it. Furthermore, new methods are needed to provide decisionmakers with sufficient data on large numbers

of chemicals for regulatory decisions. Those new

methods will come from new investigators entering the field. Congressional support could enhance opportunities for collaboration that might

otherwise be lost as declining resources and

incentives discourage researchers from conducting health risk assessment research.

Option B: Establish academic centers for

health risk assessment research.

Congress could establish academic centers that

support health risk assessment research and

training. It could also supplement the existing

support for center grants funded by the National

Institute of Environmental Health Sciences and

the National Institute for Occupational Safety and

Health. To stimulate support for research by

industry, the grant awards for centers could be

contingent on attracting matching levels of industry support. (The element of matching support is

an essential feature of National Science Foundation center grants to universities in other areas of

scientific and technological research.)

Even though academic centers are more likely

to concentrate on research at the beginning of the

‘‘pipeline’ of commercialization, industry might

well be interested in investing in research at this

early stage, provided that the Federal Government

offers encouragement through such mechanisms

as tax incentives. Industry also has a stake in

ensuring that training of environmental health

professionals continues at academic centers, especially since some analysts predict a shortage of

trained professionals in the field.

Option C: Promote technology transfer of

innovations from health risk assessment

research.

Congress could build on existing legislation

and take steps to encourage the transfer of ideas

and innovative technologies derived from health

risk assessment research-for example, improved

toxicological tests and technologies for exposure

monitoring.

Legislation enacted over the past decade promotes the commercialization of research by

permitting Federal grantee institutions, contractors, and laboratories to retain the rights to

inventions they develop with Federal funding.7

Scientists at those institutions can collect a

portion of the royalties attached to the inventions;

in addition, the legislation authorizes Federal

agencies to enter into research efforts with the

private sector through cooperative research and

development agreements (CRADAs). Such agreements can be in place early in the research

process—well before an invention has been

developed.

The United States is currently the world leader

in the kind of research discussed in this report, but

7 The Bayh-Dole Act of 1980 (P.L. %517) and the Federal Tdmology Transfer Ax of 1986 (P.L. 99-502) set out these principles.
Chapter 1: Summary, Issues and Options 35

it may be flittering away opportunities to transfer

the technology to the private sector. The burgeoning national and international demand for these

products offers a promising prospect for commercial ventures. But even more relevant to this

report are the research opportunities that might be

created if more resources were infused into the

field. Some of the steps Congress could take to

expand Federal efforts to transfer technology

from health risk assessment research to the

private sector include the following:

●

●

●

Educational efforts----Congress could encourage Federal agencies to be more vigorous in educating their scientists about the

personal financial advantages of patenting

inventions. Agencies can also be encouraged

to market their scientists’ inventions more

aggressively to private investors. The National Institutes of Health, for example,

maintains an online database, available to

the private sector at no charge, that lists by

research topic inventions developed by Federal scientists. Similar initiatives could be

fostered in other agencies.

Grants or contracts to universities--Research grants and contracts to universities

can be targeted toward the development of

health risk assessment technology. They

could also be structured to require matching

industry funds for commercializing research

products.

Government programs for technology transfer----congress could create or strengthen

programs at EPA and the Department of

Commerce to promote the transfer of technology developed by health risk assessment

research to industry. EPA’s Office of Science, Planning and Regulatory Support administers the agency’s responsibilities for the

Federal Technology Transfer Act of 1986

and tries to find additional users for the

agency’s research products. The primary

role of the Commerce Department is to

develop and promote new inventions and

technologies, and it could be directed to

establish a program to promote the products

of health risk research. The internal research

programs of the department are conducted

within the National Institute for Standards

and Technology, which would appear to be

the logical location for such a program.

Option D: Encourage industry support of

health risk assessment research.

Chemical industry organizations, like the American Industrial Health Council, have long called

for increasing the use of research results in

decisionmaking. Their rationale is that these

results would support enlightened regulatory

policies. With such a tangible investment in the

outcome of research, industry is ripe for encouragement to expand its commitment to health risk

assessment research. Congress could seek ways to

increase industry’s investment in research

through tax credits, joint sponsorship of projects,

or regulatory incentives.

INCENTIVES FOR RESEARCH INVESTMENT OR

PUBLIC-PRIVATE PARTNERSHIPS

There are two existing models of partnerships

in industry-sponsored research in health risk

assessment: industry consortia and private-public

partnerships. The Chemical Industry Institute of

Toxicology represents a consortium of industries

that sponsors toxicological research. In contrast,

a model of public-private partnership is the

Health Effects Institute, a nonprofit research

organization created by Congress in 1980. Its

$6-million budget, which is jointly supported by

EPA and automobile manufacturers, is directed

toward determining the effects of auto emissions

on health. In both cases, the designers of these

programs devoted extensive efforts to ensuring

high-quality, unbiased research and avoiding

possible conflicts of interest. Such efforts are vital

considering that even the perception of a conflict

of interest can doom research results to obscurity.

Conflict of interest in public-private collaborations can be averted by judiciously selecting the
36 I Researching Health Risks

research projects to be conducted and by carefully

reviewing the results of the research, perhaps by

using an external review board. At least two areas

of research are less likely to provoke controversy

because public and private interests converge:

research to prevent or reduce risks, and research

on methods of toxicological testing aimed at

developing cheaper, more cost-effective means of

hazard identification.

REGULATORY INCENTIVES

Regulation can also encourage industrysponsored research. Existing regulations can be

revised and new regulations formulated to include

incentives-rather than requirements-for scientific innovation. FDA, for example, responded to

the plight of patients with acquired immunodeficiency syndrome (AIDS) by developing regulations that urged manufacturers to establish a

drug’s efficacy by faster means through new,

clinical ‘‘surrogate endpoints. ’ Those endpoints

replaced the standard clinical endpoint-mortality-and are used to predict more quickly

whether a drug is actually working. This kind of

regulation is purposefully intended to encourage

innovation in clinical research.

Congress could foster industry-sponsored research by mandating or encouraging Federal

regulatory agencies to review existing regulations

more frequently than they now do and to update

them with the latest scientific and technological

advances. But health advocates may argue that

because that approach merely sets forth a process

and does not require regulatory changes, and

because most regulations are oriented toward

protecting health, a review of that kind could

create a climate favoring less protection, which

would force the advocates to defend the status

quo. In contrast, industry may favor more frequent reviews and updating, given its opinion

that, in general, most risk-related regulations are

too burdensome and often obsolete scientifically.

Another difficulty with this approach is that

experts usually disagree about whether and when

the science is ready to be incorporated into

regulations. Debates over the strength of the

science, however, can sometimes be a smoke

screen for insoluble differences in regulatory

philosophy.

A further obstacle to government-industry

partnerships has been the protection of industry’s

proprietary information. Industry-government collaborations are unlikely unless industry is guaranteed that there will be no punitive reprisals or loss

of control over proprietary material.

Option E: Provide incentives for collaborative

research.

Congress could provide or designate discretionary funds to agencies to promote multidisciplinary collaborative research. The agencies could

award the funds competitively, through a process

of peer review, to investigators who are collaborating within or across agencies, with academia,

or with industry. Funding could be administered

through existing mechanisms; however, criteria

would have to be developed for what constitutes

collaborative research, because the intent of this

option is to stimulate new collaborations that

might not have otherwise occurred. Its advantages

are that health risk assessment research would

become broader and more responsive to diverse

needs. Its disadvantage is the length of time

required for establishing interdisciplinary communication.

ISSUES IN LINKING RESEARCH

TO DECISIONMAKING

(RADON AS A CASE STUDY)

The original request for this analysis asked for

an examination of risk assessment research and

not for a study of any particular issue in risk

assessment. A subsequent request, however, specifically asked OTA to analyze an ‘ ‘inconsistency’ in EPA’s approaches to reducing exposures to “indoor’ radon, under the provisions of

the Indoor Radon Abatement Act and the Safe

. . Drinking Water Act. The request also asked OTA

to provide policy options for developing a con-
Chapter 1: Summary, Issues and Options 37

sistent approach to reducing risks from indoor

radon.

Radon is a radioactive gas. It originates from

minerals in the Earth, and it has increased cancer

rates in miners exposed to high levels. Typically,

concentrations of radon are higher inside buildings than they are outdoors because the building

partially “traps” the gas, making indoor radon

the greater risk.

Radon in water poses a risk, in part because a

fraction of waterborne radon volatilizes into

indoor air, and, in part, because of ingestion of

waterborne radon. EPA has proposed regulating

radon in water based on its responsibilities under

the Safe Drinking Water Act and the risks it

associates with inhalation of airborne radon that

comes from water and risks from ingesting water

that contains radon. The proposed regulation is

opposed by many utilities that provide drinking

water. They claim that EPA has overestimated the

number of cases of cancer that can be expected

from radon in water and that the regulation will

cost more than EPA estimates. The resulting

controversy over the expected benefits and costs

of the regulation resulted in Congress’s directing

EPA to revisit its estimates of benefits and costs

and to submit the revised estimates to EPA’s

Science Advisory Board for review. That review

concluded that the estimate of neither benefits nor

costs is certain, and EPA has not yet released its

report (November, 1993).

The indoor radon issue is a case study of the

interplay between risk assessment and risk management. It is discussed here in two parts. The

first part examines the opportunities to derive a

more certain estimate of the risks from indoor

radon; the second presents options for addressing

the inconsistency in Federal approaches to reducing exposures to indoor radon.

RADON EPIDEMIOLOGY AND

RISK FROM RADON IN WATER

Extrapolating from the results of animal tests to

estimate the risks to humans complicates most

risk assessments. It does not complicate the issue

of risk from radon, however, because information

about radon comes from studies of exposed

humans. Nevertheless, no direct information exists to associate exposure to indoor radon with the

risk of cancer. Instead, information has been

culled from studies of miners. Miners in the past

were exposed to radiation levels well above those

experienced in most dwellings and, indeed, well

above the levels experienced in today’s regulated

mines and other nuclear workplaces. Moreover,

the miners were exposed to other toxic substances

in the workplace, and almost all of them smoked.

(Smokers are much more likely than nonsmokers

to develop lung cancer as a result of radon

exposure.)

Estimating the risk posed by radon in homes,

therefore, involves an extrapolation from the

effects seen at high levels of exposure and under

mining conditions to estimates of the cancer rates

that may be associated with the lower levels of

radiation encountered in homes. Although some

of the specifics differ, radon is typical of all

assessments that depend on using risk data from

high exposures in the workplace as the basis for

estimating environmental risks. The options that

follow focus on epidemiologic studies that might

better inform estimates of risk from radon. In

addition to those, it is possible that laboratory

studies of the mechanisms of carcinogenesis and

of the chemistry and molecular biology of repairing radiation-caused damage will be instrumental

in Confirming or altering risk estimates.

There is no requirement for direct evidence

of risk to justify environmental regulations. In

fact, for many regulated chemicals, the evidence of cancer risks comes from animal

toxicity testings. The projected risks for some of

these chemicals are so small (risks of 10-6 to 10-5,

which are equivalent to between 3 and 30 excess

cancer deaths per year in the United States), that

no epidemiologic study can detect them. The risks

of lung cancer deaths from indoor radon, however, are sufficiently large-EPA calculates them

as between 7,000 and 30,000 deaths annually,

with upwards of 90 percent of those deaths
38 I Researching Health Risks

occurring among smokers—that they might be

verified, falsified, or sharpened by epidemiologic

study. Studies to date do not answer the question

of whether the risk estimate is correct, but

ongoing or future studies may provide an answer.

Such information could improve public health

decisions regarding exposures to radon and provide researchers with invaluable experience

through an investigation designed to test the

accuracy of a risk assessment.

ISSUE 5: Can epidemiologic studies confirm,

reject, or sharpen the estimates of the risk

posed by indoor radon?

According to EPA and DOE, scientists around

the world are conducting some 18 epidemiologic

studies to determine quantitative relationships

between exposure to different levels of indoor

radon and rates of cancer. The studies share

certain characteristics: all involve locating people

with lung cancer or the records of people who

have died from lung cancer and comparing their

exposures to radon and other risk factors with the

exposures of people who do not and have not had

lung cancer. The frost group of people are called

“cases,” the second, “controls”; the studies are

called ‘‘case-control studies. ’ Ideally, exposures

to indoor radon are determined by measuring the

levels of radon in all of the houses in which each

case and control lived. (In practice, houses

sometimes have been torn down or are no longer

available for such measurements.)

The studies can differ from one another in a

number of ways. Some studies question both

cases and controls (or their surviving next of kin)

about diet. All of them include questions about

smoking, and some may obtain more complete

information than others about radon exposure.

Such differences complicate the interpretation of

all of the studies taken together. For example,

studies that do not ask about diet cannot supply

information about that issue, and the rigor with

which questions about smoking habits are asked

provides more or less certain information about

that risk factor. Such difficulties in comparison

and interpretation can be at least partly overcome

by the technique of meta-analysis.

Option A: Accept the results of a meta-analysis

as sufficient to answer questions about the

level or risk posed by exposures to indoor

radon.

Some of the 18 epidemiologic studies of

indoor radon noted above have been completed, and the results are mixed. Some show

no association between levels of indoor radon

and rates of cancer, and some show a trend in

increasing rates with increasing exposure. All

of the studies are hampered by their small

size-a few hundred or fewer cases and controls—and all of them have limited power to

detect increases in cancer that would be expected if the currently accepted method of

extrapolating from the results of the miner

studies is accurate. Combining the results of all

studies in a meta-analysis will increase the

statistical power of the analyses and may be able

to inform scientists and policyrnakers about the

level of risk posed by exposure to radon in homes.

Both DOE and EPA are considering metaanalyses that will begin when the ongoing studies

have been completed and published. DOE has

designated two university researchers as coordinators for the review, one in the United States for

analysis of North American studies and one in

England for analysis of European studies. The

ongoing studies are expected to be completed in

1994; allowing 12 months for the analyses would

mean that results from the meta-analysis should

be available in 1995. (It may be more realistic,

given how schedules slip, to expect the results of

the meta-analysis in 1996.) Completion of the

meta-analysis will not mark the end of the flow of

new information about radon, however, and new

information will be factored into other metaanalyses as it becomes available. For instance,

two case-control studies, one in Iowa and one

in Missouri, are expected to be quite informative but will not be completed before the end of

1997.
Chapter 1: Summary, Issues and Options 39

When the DOE or EPA meta-analysis is

complete, the scientists involved will probably

have satisfied themselves that the evidence supports one of three conclusions about the risks

from indoor radon: 1) the studies of indoor radon

and cancer justify no change in the estimates of

the range of risks and the best estimate of risk

based on the miner studies; 2) the studies justify

changes in the estimates; or 3) the studies, for

whatever reasons, do not provide sufficient information to decide between conclusions 1 and 2.

Reaching conclusion 1 or 3 would support

EPA’s continuing use of the current risk estimate,

based on the miner data, in risk management

decisions. Conclusion 2 would probably lead to

consideration of a new risk estimate, and risk

management decisions are certain to be influenced by such a change. Whatever conclusion is

reached, Congress or a department or agency in

the executive branch might consider an additional

study to examine the question of how much lung

cancer is associated with exposure to indoor

radon.

Option B: Convene a planning group to

consider a study to answer questions about

risks from exposure to indoor radon.

Based on extrapolations from the studies of

miners, EPA’s best estimate is that residential

exposure to radon is associated with about 14,000

deaths (with a range of between 7,000 and 30,000

deaths) from lung cancer annually. These estimates are sufficiently large that the risks, if they

are realized, might be detectable in an epidemiologic study. One scientific justification for a

large-scale study of the effects of exposure to

indoor radon is that it offers the chance to test a

risk assessment estimate-in this case, the estimate of risk from indoor radon that is based on the

miner studies.

In 1981, OTA proposed a large-scale study

of lung cancer to provide definitive answers

about quantitative relationships between smoking patterns and lung cancer, as well as

information about occupational and other

exposures and lung cancer. To those still-valid

justifications can be added the opportunity to

learn about quantitative relationships between

indoor radon and lung cancer.

Lung cancer is the most frequent cause of death

from cancer in the United States. Congress could

directly mandate that a committee be established

to plan a large-scale study of lung cancer in the

United States, or it could direct a department or

agency of the executive branch, to establish such

a committee. The committee could be housed in

an executive branch organization, at the National

Academy of Sciences, in a university or consortium of universities, or at OTA. Its functions

would be to decide whether any study can provide

a definitive answer to the question of how much

risk is associated with indoor radon and, if it is

possible, to design such a study. If an organization

such as the Risk Assessment Research Agency

(described in issue 2) or the Center of Research

Policy (described in issue 1) were established, it

would be appropriate to assign it the task of

deciding whether a large-scale study of indoor

radon should be undertaken.

A committee such as that just described offers

several advantages. Its deliberations would be

highly visible. It would call attention to the

process of designing the study and invite the

participation of everyone with a stake in its

design; that inclusiveness would promote efforts

to make the study as comprehensive as possible.

If the study were comprehensive, it might provide

substantial data not only about radon but also

about smoking, occupational exposures, dietary

habits, and perhaps other risk and protective

factors. The committee could decide whether to

collect and store lung tissue from subjects in the

study to provide material for biochemical and

molecular analysis, both with current techniques

and with techniques yet to be developed.

Yet the chances of agreeing that such a study is

possible and that it could provide definitive

answers are probably rather small. Obtaining

accurate measures of past exposure to radon is

fundamental to the success of such a study, as is
40 I Researching Health Risks

obtaining accurate information about past or

present smoking, exposure to environmental tobacco smoke, workplace exposures, and eating

habits. The planners may well conclude that no

study can obtain that information with sufficient accuracy to provide definitive answers.

That decision would not be without value: the

evaluation methods used by the committee would

find further employment in the Government’s

consideration of requests for epidemiologic studies to investigate other environmental hazards.

If the planning committee decides that no

feasible study could be designed to answer

questions about indoor radon, Congress and the

country might have to accept that radon reduction

activities would continue to be based on risks

estimated from the studies of miners. It is also

possible that the costs of a study like the one

described above or the time necessary to complete

it would make the effortless than worthwhile, and

Congress could decide not to fund it.

Finally, Congress could decide that the

study was feasible and worthwhile and could

allocate funding for its conduct. If that decision were made, policy makers would have to

decide on a regulatory course for the time

necessary to conduct the study. In particular, a

decision would have to be made about whether to

impose a moratorium on regulating radon until

the study was finished.

Planning such a study could involve one or two

staff members for perhaps 2 years and the cost of

three meetings of the committee. It would also

include evaluation and review of all documents

and their publication. The total cost of the

planning phase would be between $250,000 and

$750,000.

Whatever the results of the epidemiologic

effort, any result that does not support the

current risk estimate is likely to cause few

difficulties for scientists but substantial problems for regulatory agencies. Although scientists may have to modify their conclusions as

new results are produced, the nature of their

data-dependent work makes such revisions

relatively commonplace. In contrast, EPA might

have to adjust its regulations, which is a more

difficult task. If the new studies show that the

risk estimate on which the regulations are based

is low, tighter regulations can be drafted in

keeping with the new information. If the current

risk estimate is found to be high, the regulations

could be relaxed, but relaxing regulations has

proved to be difficult in the past. Moreover, the

expenses borne under the prior regulation would

not be recoverable.

ISSUE 6: Can there be a consistent approach

to reducing radon exposures?

The request that OTA examine questions

relating to indoor radon was prompted by EPA’s

proposal to regulate the level of radon in water to

300 pCi/L under provisions of the Safe Drinking

Water Act. According to EPA, that concentration

in water will contribute 0.03 pCi/L radon to air

because of the volatilization of radon from water.

(The ratio of radon in water to radon in air that

originates from the water source is about 10,000

to 1.) The request to OTA noted that the

regulatory goal, 0.03 pCi/L, is lower than the

concentration of radon in outdoor air, which

varies between 0.1 and 0.5 pCi/L; in addition, it

is more than a hundred times lower than EPA’s

‘‘action level” for indoor radon, which is currently 4 pCi/L. The request asked OTA to

examine the inconsistency’ between and among

the levels and provide options for a more consistent approach to reducing risks from radon (see

box l-A).

The apparent inconsistency arises because

different laws apply to radon in different

media. Under the SDWA, EPA sets goals for the

maximum contaminant levels of toxic substances

in water. For carcinogens, those goals are zero

because of the policy position that exposure to

any level of a carcinogen poses some risk. When

zero is not attainable, EPA generally sets the

maximum contaminant level (MCL) to allow the

cancer risk from the substance in drinking water

to range between 10-4 and 10-4. Although EPA’s
proposed MCL for radon in water, 300 pCi/L, was

established because EPA concluded that the

technology was available to achieve this standard,

it is nevertheless associated with a risk of 2 X

10-4, which is near the desired range.

The goal of the Indoor Radon Abatement Act

(IRAA) is to reduce exposures to indoor radon to

the same levels seen in outdoor air. Currently,

EPA’s action level of 4 pCi/L radon in air is

greater than that goal, and it is based, at least in

part, on practical considerations, As former EPA

Assistant Administrator L.S. Wilcher noted:

While the 4 pCi/L target risk for radon in

indoor air represents a higher level of risk [than

the risk associated with the proposed MCL for

radon in water], it is the lowest risk level which

the Agency considers to be technologically feasible for all homes.

The inconsistency takes on practical significance when the observer considers the contribution that radon in water makes to total exposure to

radon. The proposed regulation of radon in water

would reduce the concentration of radon in air

that comes from water to 0.03 pCi/L and leave

most of the exposure to indoor radon unaddressed. Indeed, EPA’s Science Advisory Board

said in 1992, ‘‘Frankly, radon in drinking water is

a very small contributor to radon risk except in

rare cases, and the Committee suggests that the

Agency focus its efforts on primary rather than

secondary sources of risk. ’

Formally, three approaches are available to

address the inconsistency: 1) reduce exposure to

radon from air that enters the house to the level of

radon expected from the volatilization of radon

from water under the EPA’s proposed regulation;

2) relax the proposed regulation on exposures

from waterborne radon so that exposures from

water and air are reduced to some comparable

level; or 3) work toward a politically acceptable

compromise between reductions in waterborne

and airborne radon.

The first approach is impossible. EPA’s proposed regulation would reduce the concentration

Chapter 1: Summary, Issues and Options 41

of radon in air that comes from water to 0.03

pCi/L. The ‘background’ concentration of radon

in outdoor air is approximately 10 times higher

than EPA’s regulatory limit for radon in water.

Therefore, the infiltration of outdoor air into a

house produces a 10-fold higher concentration

than EPA would allow from water. As is recognized by IRAA, it is impossible to reduce indoor

concentrations below outdoor concentrations.

Under the second approach, the proposed

regulation of waterborne radon could be put aside

and new regulations brought forward so that the

contribution from waterborne radon to inside

radon is no greater than the contribution from

outside air or no greater than some fraction of the

contribution from outside air. This second approach is discussed in the options below. Its

advantages include eliminating the inconsistency

and reducing the costs of the water regulation; its

primary disadvantage is that it would lessen the

reduction in exposure to radon that would be

achieved under SDWA regulation.

Acknowledging the tradeoff in the second

approach leads to the third. Resolution of the

inconsistency, should it be reached, would surely

be a political act, perhaps involving Congress,

EPA, other agencies, both Federal and nonFederal, and private sector organizations.

OTA offers the following three options that

address the inconsistency identified in the request.

Option A: Accept the inconsistency and let the

Environmental Protection Agency deal with

exposures to radon under existing laws.

The inconsistency does not prevent actions

to reduce exposure to radon. In responding to

congressional inquiries, EPA points out that its

approach to regulating radon parallels its approach to other waterborne carcinogens. In addition, the agency actively encourages citizens to

test houses and other buildings for radon gas and

to take action if the levels of radon in air are

greater than 4 pCi/L. Should Congress do nothing
42 I Researching Health Risks

further about regulating radon, EPA will probably

continue along this course.

Under its responsibilities for the SDWA, EPA

estimates that about 41,000 water suppliers now

produce and distribute water that would exceed

the proposed regulatory standard. EPA specifies

aeration as the best available technology to reduce

concentrations of radon in those systems to the

proposed regulatory limit, and it has estimated the

benefits and costs of that course of action.

As a result of the so-called Chafee-Lautenberg

Amendment (Section 591 of the Housing and

Urban Development, Veterans Administration,

and Independent Agencies Appropriations Bill of

1992), EPA completed a multimedia risk assessment for radon in July 1993. The same amendment imposed a moratorium, which expired on

October 1, 1993, on EPA’s proposed regulation.

[Congress has extended the moratorium to October 1, 1994.] The amendment was prompted by

the inconsistency of approaches to reducing

exposure to radon and the costs of the proposed

regulation. As Senator Chaffee said during consideration of the amendment:

The dispute here is about the relative risk of

radon in drinking water. And since the Federal

Government does not require that any steps be

taken to correct the principal source of the risk,

namely the gas that comes from the soil, the

. . drinking water suppliers, quite rightfully, wonder

why they should be required to clean up drinking

water at a great expense.

The results from the congressionally mandated

1993 multimedia risk assessment were very

nearly the same as those that EPA presented in its

proposed regulation in 1991. According to EPA,

the regulation will save about 80 lives annually.

Some organizations, such as the Natural Resources Defense Council (NRDC) and Friends of

the Earth (FOE) have stated that an MCL of 300

pCi/L is too high and that it (and the attendant

risk) can be reduced further. Some water suppliers, pointing to the costs of the measure, also

object to the proposed MCL. In its draft regulation, EPA estimated that each averted cancer

death would cost about $2.3 million. On one side

of the argument, some water utilities estimate

costs of between $65 million to $89 million for

each averted cancer death and between $443

million and $592 million for each averted cancer

death in nonsmokers. Arguing on the other side,

NRDC and FOE assert that a lower MCL would

require regulation of more water suppliers with

further reductions in radon exposures and in

cancer risks at little additional cost.

The costs of regulating radon in water can be

compared with the costs of childhood immunizations, a public health measure that has greatly

increased in cost in recent years and produced

calls for reducing the profits of pharmaceutical

companies. The costs of childhood immunizations have increased from between $7 and $23 in

1982 to between $129 and $244 in 1992. The

annual cost of regulating radon in water—

estimated by EPA to be about $50 per family

served by average-sized water supply systems

and $120 per family served by small systemsranges between a fifth to a little less than half the

one-time cost of immunization. The estimate by

the Association of California’s Water Agencies of

$340 per family per year for the radon-in-water

regulation exceeds the one-time cost of immunization.

The continuing annual family cost—between

$50 and $340-of the radon-in-water regulation

(which will affect about 1 percent of the total

exposure to radon) can also be compared with

EPA’s estimate of the cost of actions to reduce the

amount of radon entering homes directly from the

soil. Direct entry of radon from soil contributes,

on average, 99 percent of the radon in indoor air.

The one-time cost of bringing indoor radon

concentrations down to 4 pCi/L or lower ranges

from $500 to $2,500 per house, with an average

of $1,200 and average operating expenses of $68.

Whatever the actual costs would be, it is likely

that NRDC and FOE are correct in stating that

reducing concentrations to levels below the MCL

is possible and could be realized if the regulation
Chapter 1: Summary, Issues and Options 143

were made final. Given the capital and operating

costs of reaching the proposed MCL and the

possibility that the MCL would be changed as

technology improves, many water suppliers will

probably design their systems to reduce concentrations to a level well below the currently

proposed MCL. Moreover, NRDC and FOE cite

experts who state that the only additional cost,

after aeration systems are installed, of lowering

radon concentrations in water is the cost of

electricity. The review by EPA’s Science Advisory Board of the agency’s 1993 multimedia risk

assessment suggested that EPA should consider

using granulated activated charcoal as an alternative for radon removal in some water systems.

The costs of that course of action have not been

estimated.

The option discussed here, allowing EPA to

continue along the course it has plotted, will not

address the inconsistency in the legislation, but it

could nevertheless be presented to the public as

the chosen option. The inconsistency is built into

the current system; it does not make the system

unworkable.

Option B: Use the reauthorization of the Indoor

Radon Abatement Act to direct EPA to

integrate all routes of exposure in

considering acctivities to reduce exposure to

radon.

The multimedia risk assessment demonstrates

again that only a small part of the risk posed by

radon comes from waterborne radon. It does not

offer guidance for what is to be done as a result of

that demonstration.

If Congress decides that the multimedia risk

assessment or other considerations suggest a new

approach to reducing radon exposures, it can use

the reauthorization of the IRAA as a vehicle.

However, while Congress is working out the

details of an integrated approach to reducing

exposures to radon, it would probably have to

advise EPA about regulating radon in water.

If Congress anticipates that an integrated approach to reducing exposure to radon would

produce a different level for radon in water than

the level proposed under the Safe Drinking Water

Act, it could direct EPA to continue the moratorium on the proposed regulation. Or, as an

alternative to having no regulation of radon in

water while EPA works out an integrated program

of exposure reduction under the IRAA, Congress

could require EPA to set a standard for water,

taking into consideration other radon exposures.

For instance, radon in water could be regulated so

that it contributes no more radon to indoor air than

is present in outdoor air. (As an approximation,

the Science Advisory Board suggests that the

regulatory level for radon in water under this

approach be set between 1,000 and 3,000 pCi/L

rather than at 300 pCi/L as in the current

proposal.) Such an approach would serve at least

three purposes: it would reduce the greatest risks

from radon in water; it would provide valuable

experience to EPA, utilities, and engineering and

consulting firms in designing mechanisms to

reduce concentrations of radon in water; and it

would allow for adjusting those levels after the

integrated exposure reduction program is completed under the IRAA. Moreover, results from

ongoing or future epidemiologic studies may alter

EPA’s risk estimates. The period allowed for EPA

to develop an integrated radon exposure program

under the IRAA would permit the incorporation

of new scientific information.

A congressional decision to delay the proposed

regulation of radon in water has drawbacks as

well. It will allow more exposure than would be

permitted if regulation proceeded under the SDWA.

As a result, some of the exposures that would

have been averted under the SDWA would

remain. A decision to delay the regulation would

also insinuate Congress into EPA’s regulatory

program and interfere with the functioning and

autonomy of that agency.

Option C: Include radon in a comprehensive

law for regulating indoor air.

Some indoor air pollutants, such as radon, arise

from soil and water. Others come from utilities, as
44 Researching Health Risks

when natural gas is used for cooking and heating;

from cooking itself; from building materials such

as asbestos; from formaldehyde in carpeting;

from commercial chemicals; and from biological

sources-animal dander, insect parts, molds, and

mildews. Over the years, legislators have considered enacting an indoor air pollution law to

address these complicated exposures. Such

legislation, combined with Congress’s directing

EPA not to regulate radon in water under the

SDWA, could resolve the inconsistency in current approaches and give EPA the authority to

approach indoor radon in a unified, multimedia

way. Treating the risks presented by indoor air

in a concerted fashion would probably lead to

greater reductions in overall exposures than

would be achieved under current laws. In

general, the solutions to indoor air problems

caused by different substances are all likely to

follow similar paths, such as improving ventilation and filtration, among others. A single

piece of legislation might facilitate considering

the risks as a whole rather than piecemeal.

Given the time it takes to enact legislation,

implement new programs, and draft regulations,

a few years might pass before radon in water is

regulated under a new, comprehensive law. To

deal with that possibility, Congress could direct

EPA to formulate interim regulations, as in option

B, to limit radon in water to levels that contribute

no more to total exposure than does outdoor air.

EPA administers 12 laws. That multitude of

mandates and responsibilities reflects the twists

and turns of increased concern about the environment over the years and Congress’s intense

interest in the agency’s functioning. The suggestion of a new law directed at indoor pollutants

does not mean that the number of laws would be

increased by one. Rather, it could lead to subsuming the IRAA under the new law and keeping the

number of laws constant.
An Introduction

to Health Risk

Assessment

and Its

Research Base

T

his chapter presents a brief introduction to the process of

health risk assessment, the kinds of research and data

that support it, and the controversies that have arisen in

some areas of research and assessment. It is intended for

the lay reader with little or no technical background. Because of

its brevity, it cannot provide details about specific differences in

the use of health risk assessment among the Federal agencies or

a thorough review of the scientific literature. Readers interested

in pursuing those topics are advised to look at recent, accessible

reviews (Paustenbach, 1989a, 1989c; Rosenthal et al., 1992;

Silbergeld, 1993; Zimmerman, 1990). The chapter does include

a brief discussion of the costs of regulatory compliance and of

treating environmentally related diseases.

Health risk assessment is most developed for estimating the

risk to humans from exposure to carcinogens (box 2-A).

Therefore, this chapter and, indeed, this report tend to focus on

carcinogens, not because substances causing other risks to health

are less important but because Federal agencies have more

experience in assessing the risk of cancer. The report also

emphasizes risk assessment associated with low levels of

exposure to harmful substances in the environment, probably the

area of greatest scientific controversy.

We estimate risks every day, every time we cross the street,

every time we drive. Before making a left turn, we examine the

hazard (the oncoming traffic), we consider the consequences of

exposure to the hazard (dents, injuries, death), and we estimate

the probability of occurrence (the likelihood of being hit). When

we overestimate that probability, we hesitate and waste time.

Usually, we assess the risks reasonably well, turn when the

2

I

45
46 I Researching Health Risks

Box 2-A—The Growth of Health Risk Assessment in the Federal Government

Although the connection between the environment and human health was recognized in ancient times,

attempts to quantify that relationship are of more recent origins. Scientific papers published in the early 20th

century described unusual diseases observed in workplaces, and by the 1930s, researchers were able to estimate

quantitative relationships between occupational exposure to potentially hazardous substances and their effects

on human health. One observer refers to the early use of these relationships to establish no-observed-effect levels

(NOELs) for humans as “a primitive quantitative risk assessment methodology” (Friess, 1987). By the 1950s,

research on safety factors (later known as uncertainty factors) was developing as well.

But using NOELs and uncertainty factors for quantifying the risks associated with carcinogens became

increasingly problematic. Studies showed that even very low levels of ionizing radiation or certain chemicals

seemed to cause corresponding low levels of disease, but thresholds could not be established. Researchers thus

began to develop dose-response extrapolation models starting in the 1960s to estimate the effects on humans

of low doses of carcinogens.

The Nuclear Regulatory Commission was probably the first government agency to use such models to

estimate the risks to humans associated with ionizing radiation. The Food and Drug Administration (FDA),

however, was the first Federal agency to employ those quantitative methods in a regulatory context. In 1973, FDA

proposed using an extrapolation model to determine the level of sensitivity necessary for methods to detect

residues in foods from drugs given to animals. Since then, the use of health risk assessment has spread to other

agencies within the Department of Health and Human Services, such as the Centers for Disease Control and

Prevention and the Agency for Toxic Substances and Disease Registry.

In the early 1970s, the Environmental Protection Agency (EPA) sought to suspend the registrations of

pesticides that had been shown to be carcinogenic in animal tests. After being criticized for taking what some

viewed as a zero-risk approach, EPA responded by developing comprehensive guidelines for assessing the risks

associated with health effects other than cancer. Today, programs throughout EPA use health risk assessment.

The Occupational Safety and Health Administration (OSHA) proposed its generic cancer policy in 1977 and

formally adopted it in 1980, despite intense criticism from the regulated community. But a 1980 U.S. Supreme Court

decision on OSHA’s benzene regulation forced the agency to make significant changes in its policy. Today, OSHA

can use studies by the National Institute for Occupational Safety and Health to meet the Court’s requirement of

showing that an exposure poses a significant risk that would be reduced by imposing a regulation. The Consumer

Product Safety Commission (CPSC) also turned to the use of health risk assessment in the 1970s, publishing its

guidelines in 1978. Still other agencies, such as the Departments of Defense and Energy, use risk assessment

to help protect workers and the public from the risks associated with their activities. These agencies, however, do

not use risk assessment in a regulatory context.

Attempts to coordinate policy across the Federal agencies also began in the 1970s, particularly through the

efforts of the Interagency Regulatory Liaison Group, formed in 1977 by agreement of the four main regulatory

agencies: CPSC, EPA, FDA, and OSHA. The groups published a draft of a report on cancer policy in 1979. in the

same year, the White House Office of Science and Technology Policy (OSTP) published another set of cancer

guidelines. OSTP has continued its efforts to coordinate the use of health risk assessment across Federal

agencies, publishing further cancer principles in 1985,

In short, health risk assessment is a relatively young method of analyzing data on toxic substances. As its

use has grown since it was introduced into regulatory programs in the 1970s, it has been adapted to suit the needs

of many agencies and programs. Since the late 1970s, efforts have been made that continue to this day to

coordinate the use of health risk assessment across agencies.

SOURCES: S. Friees, “HkNory of Risk Assessmen~” Pharmaco/dnetlcsin Risk Assessment: Drinking 144ter and Hea/th, vol. 8

(Washington, DC: National Academy Press, 1987); P.B. Hutt, “Use of Quantitative Risk Assessment in Regulatory Decislonmaking Under

Federal Health and Safety Statutes,” Risk@antitation andRegu/atoryPo/icy, Banbury Report 19, D.G. Heel, R.A. Merrill, and F.P. Perera

(eds.) (Cold Spring Harbor, NY: Cold Spring Harbor Laboratory, 1985); D.J. Paustenbach, “A Survey of Health Risk Assessment,” Ths

R/sk of Entirorrnwnta/andHuman Hea/th Hazard%, DJ. Paustenbach (cd.) (New York: John Wiley & Sons, Inc., 1989); M.E. Rushefeky,

Making Carrcw Po/lcy(Albany, NY: State University of New York Press, 1986).
Chapter 2: An Introduction to Health Risk Assessment and its Research Base 47

probability of an accident is small, and make it

safely through the intersection. Occasionally,

however, we underestimate the probability of

being hit and sometimes suffer the consequences.

Risk assessment uses similar thinking to determine the probability of harm or disasters—both

natural ones, like fires and floods, and those

resulting from engineering problems, like engine

failure in aircraft, or from exposures to toxicants.

This information is useful for those who work to

prevent disasters-for example, the engineers

who design safety features-and for those who

insure potential disaster victims. It is also useful

for governments, which seek to protect the health

and safety of their citizens, and, ultimately, for

citizens themselves, who participate in decisions

about acceptable or tolerable and unacceptable or

intolerable levels of risk.

Health risk assessment deals with the risks

people face when they are exposed to harmful

substances. It is generally used for agents whose

health effects are hard to measure directly, such as

low levels of exposure to chemicals and ionizing

radiation. Time factors may also increase the

difficulties involved in measurements. Diseases

resulting from exposure to some harmful substances, like asbestos, may not develop for 20 or

30 years. And some substances, like lead, have no

obvious acute effects at low levels but can cause

subtle and significant effects after chronic lowlevel exposure.

In such situations, questions arise not only

about the probability of occurrence but also about

the relationships between the duration and intensity of the exposure to the hazard and the type and

severity of the adverse health effect. Researchers

have directed most of their efforts in developing

health risk assessment toward answering the

following questions: What health effects are

associated with exposure to a particular substance? How large a dose—and at what frequency

and over how long a period of time-does it take

to cause those effects? How much of a substance

are people likely to be exposed to? Given some

Table 2-l—Estimated Risk of Death From Various

Human-Caused and Natural Accidents

Accident Risk

Automobile . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 in 4,000

Drowning . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 in 30,000

Air travel , . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 in 100,000

Lightning , , . . . . . . . . . . . . , . . . . . . . . . . . . . 1 in 2 million

SOURCE: C.D. Klassen, “Principles of Toxicology,” Cmarett and

DouW.s Tox~o/ogy, C.D. Klassen, M.O. Amdur, and J. Doull (eds.) (New

York, NY: Macmillan, 1986).

level of exposure, how many people may be

affected?

Health risk assessment provides a systematic

approach to evaluating and quantifying risk. As it

pertains to the health effects of toxic substances,

risk is the probability of injury, disease, or death

for individuals or populations who undertake

certain activities or are exposed to hazardous

substances. It is sometimes expressed numerically (e.g., 1 excess cancer death in 1 million

exposed people). A risk of 1 in 10,000 may be

described as 10-4, a risk of 1 in 1 million as 10-6

,

and a risk of 1 in 100 million as 10-8. Risks

smaller than 10-6 are rarely regulated (Rosenthal

et al., 1992; Travis et al., 1987). If quantification

is not possible or necessary, risk may be expressed in qualitative terms (e.g., low, medium, or

high risk).

Experts have quantified the risk of death from

some familiar hazards (table 2-l). Traveling in an

automobile, for example, involves a risk of

accidental death of 1 in 4,000 (i.e., people on the

road), which is relatively high. As might be

expected, the risk of being killed by lightning is

much lower (1 in 2 million). But the public’s

perception of risk does not always agree with the

risk calculated by experts. Some people, for

example, avoid air travel even though the risk

associated with automobile travel is 25 times

greater. In particular, people tend to overestimate

the risk or number of deaths from rare, dramatic

events and underestimate the risk from common,

undramatic causes. Public perception of the

annual rates of death from floods or tornadoes are
48 I Researching Health Risks

A

1 in 4,000 die

of accident

ahead

TJ. /‘“ ?

,. ““i

/“-’”

typically overestimated, whereas the risks from

smoking and “drinking alcoholic beverages are

typically underestimated.

In everyday life, we evaluate the risks associated with various activities and make choices,

considering such factors as benefits, costs, convenience, and past experience. As a society, we

must make similar choices. Health risk assessment can help clarify those decisions by illuminating the kinds of hazards that result from

exposure to a substance, by identifying those

people who have been exposed, and by estimating

the magnitude of the risk associated with different

levels of exposure. But health risk assessments

are only one of the factors on which such

decisions are based. Decisionmakers may also

need to consider the technical and economic

feasibility of various control technologies, social

values and political forces, the missions of their

agencies, and their legal responsibilities.

The results of a health risk assessment are

usually intended for use by “risk managers,’

decisionmakers who determine what, if anything,

should be done to reduce or eliminate a risk

(Zimmerman, 1990). Health risk assessment is

used not only by agencies of the Federal Government, the main focus of this report, but also by

other organizations with an interest in the health

effects of exposure to chemicals. Those groups

may include State and local authorities, environmentalists, manufacturers, representatives of consumer organizations, and, increasingly, local

citizens.

Health risk assessment is used for many

different purposes as well. People may be exposed to many types of potentially harmful

substances through the air they breathe, the water

they drink, and the food they eat. They may be

exposed in the workplace, outdoors, or at home.

Those exposures may be regulated under a variety

of Federal and State laws. Consequently, the

details of the health risk assessment process may

vary, depending on those circumstances.

RESEARCH DATA FOR HEALTH

RISK ASSESSMENT

The primary source of data for assessing

human health risks is epidemiologic, toxicological, structure-activity relationship, and exposure

studies. Other research data on metabolism,

pharmacokinetics, and mechanisms of toxicity

are used to determine the relevance of those

primary data for predicting adverse health effects

in humans. The primary sources of data are

described briefly below.

 Epidemiologic Studies

Epidemiologic studies examine patterns of

disease in human populations and the factors that

influence those patterns. The greatest advantage

of such studies is their direct relevance to human

populations because they are based on the experiences of human subjects. Epidemiologic studies

are especially informative when levels of exposure are well documented, the exposed population

is well defined, and the adverse effect associated

with the substance is known. Those conditions,

however, are seldom met.

The essence of epidemiology is the observation

of a natural experiment-the release of an agent

into an environment, resulting in exposure of a

population. Sometimes, however, relationships
Chapter 2: An Introduction to Health Risk Assessment and its Research Base 149

between exposure and health effects may be

obscured because of a lack of precise information

about the amount and frequency of exposure or

the presence of confounding factors, such as

exposure to other substances. Factors such as

genetic variability and population mobility are

difficult to take into account. In addition, most

epidemiologic studies are not sensitive enough to

detect small increases in risk. Still when enough

information is available and epidemiologic studies can be undertaken, they can provide valuable

information about the relationships between exposure to hazardous substances and human

health.

Epidemiologic studies may be descriptive,

observational, or experimental (Lilienfeld and

Lilienfeld, 1980). Descriptive epidemiologic studies provide clues to the causes of disease by

examining the distribution and extent of disease

in different groups of people defined by age, race,

gender, or other parameters. In observational

studies, scientists examine statistical associations

between exposure to a hazard and disease in

individuals or relatively small groups. In experimental epidemiology, scientists control the population groups in the study, determining in advance

the groups to be exposed, often in occupational or

clinical settings.

 Toxicological Studies

Most often, the information needed to predict

adverse health outcomes from exposure to potentially hazardous chemicals comes from testing

substances in animals or through in vitro tests,

that is, in cells or tissues isolated from animals

and humans. Such toxicological studies allow

scientists to test chemicals and control the amount

and conditions of exposure and the genetic

variability of the subjects, factors that cannot be

controlled in most epidemiologic studies. Toxicological studies are the only means available to

evaluate the risks of new chemicals.

Biologically, animals, even the rats and mice

typically used in toxicity testing, resemble humans in many ways. A substantial body of

evidence indicates that results from animal studies can be used to infer hazards to human health

(Huff, 1993; Huff and Rail, 1992; NRC, 1991a).

There are exceptions to this generalization, but

each must be proved before setting aside the

assumption that animal tests are predictive. The

proof can be data on human toxicity that convincingly contradict a specific finding in animals, or

mechanistic or physiological reasons that support

the idea that the animal data are irrelevant to

humans. Otherwise, the assumption is generally

made that toxicity data from animals can be used

to identify potential human hazards (NRC, 1991a;

Perera and Boffetta, 1988; Silbergeld, 1993; U.S.

EPA, 1986a). Much of toxicological research

focuses on developing and employing various

animal ‘‘models’ to predict adverse health effects in humans, understand mechanisms of

toxicity, and verify that metabolic pathways and

toxic effects are similar in test animals and

humans.

Toxicological disciplines can be distinguished

by the “endpoint” being studied, that is, the

resulting disease or the organ affected by exposure to a toxic substance. Increasingly, researchers are studying subtle endpoints other than

cancer, such as immunotoxicity (U.S. Congress,

OTA, 1991a), lung toxicity (U.S. Congress, OTA,

1991b), neurotoxicity (U.S. Congress, OTA, 1991c),

reproductive and developmental toxicity, and

liver and kidney toxicity. Scientists are also

devoting more attention to studying the effects of

long-term (’ ‘chronic’ exposures, rather than the

effects of large, short-term (’‘acute’ exposures.1

Toxicological studies, however, have limitations. Cost considerations limit most animal

1 For excellent reviews and research papers on the various types of toxicological studies being conducted on health effects other than cancer,

see volume 100 of Environmental Health Per.rpectives (1993), in particular, see Luster and Rosenthal (1993), Schwetz and Harris (1993), and

Fowler (1993).
50 I Researching Health Risks

studies to a few hundred test animals, and in most

instances, researchers use high levels of exposure

to increase the likelihood of observing a statistically significant effect in a relatively small group

of animals. It can also be very difficult to verify

any quantitative extrapolation of the results of

animal studies to human effects.

 Structure-Activity Relationships

Structure-activity relationships refer to studies

that compare the chemical structures of substances in order to make inferences about toxicity

and identify candidates for further testing. The

accuracy of prediction from this method of

assessment has grown over time, but it is clear

that there are no simple relationships between

structure and toxicity (Friess et al., 1986; Klopman and Rosenkranz, 1991; Rosenkranz and

Klopman, 1989).

 Exposure Data or Models

Data for assessing human exposure come from

measuring the presence of an agent in air, water,

soil, or food. Frequently, such data are not

available for a specific kind or level of exposure.

In those situations, mathematically derived computer models are used to simulate the exposure

conditions and predict the level of possible

exposures.

Personal monitoring measures the actual concentrations of a hazardous substance to which

people are exposed by using devices that individuals wear or by sampling the food, air, and water

they eat, breathe, and drink. Biological monitoring measures the toxicant or its metabolize in

biological samples such as blood or urine. Ambient monitoring measures hazardous substances in

air, water, or soil at freed locations. That method

is often used to provide some information about

the exposure of large populations, such as people

exposed to air pollution in a region.

THE HEALTH RISK ASSESSMENT

PROCESS

Health risk assessment uses tools derived from

many scientific fields in a systematic way to

organize and evaluate the available scientific

information about a potentially harmful substance. The goal of health risk assessment is to

identify the kinds of adverse health effects that

may be associated with exposure to a harmful

substance and to quantify the magnitude of the

risk of experiencing those effects according to

levels of exposure. As conducted by Federal

agencies, health risk assessment consists of some

or all of the following four steps: hazard identifi

cation, dose-response evaluation, exposure assessment, and risk characterization (NRC, 1983;

U.S. Congress, OTA, 1981; U.S. EPA, 1986a;

U.S. OSTP, 1985). Originating in a 1983 National

Research Council report, figure 2-1 is the most

commonly used graphic representation of the risk

assessment process.

 Hazard Identification

Hazard identification evaluates the available

data on the types of injury or disease that maybe

associated with exposure to a substance and on

the conditions of exposure under which the

disease or injury maybe produced. For example,

does a substance cause cancer or birth defects?

Does it harm the nervous system or the immune

system? Three types of scientific studies are used

to identify adverse effects associated with exposure to chemicals: epidemiologic studies, toxicological studies, and structure-activity relationships (Cohrssen and Covello, 1989; Lave and

Omenn, 1986; U.S. Congress, OTA, 1981; U.S.

EPA, 1986a; U.S. OSTP, 1985).

Hazard identification involves judgments about

the quality, relevance, and limitations of the

available data. It typically includes an evaluation

of all available toxicological data (much less

frequently, an evaluation of all epidemiologic

data) to identify those adverse effects that are best

documented and those that are most relevant to
. . .

Chapter 2: An Introduction to Health Risk Assessment and its Research Base 51

Figure 2-l—Relationship of Research, Risk Assessment, and Risk Management

RESEARCH RISK ASSESSMENT RISK MANAGEMENT

Laboratory and field

observations of adverse

health effects and >

exposures to

particular agents I

Field measurements,

estimated exposures,

‘ >

and characterization

of populations

Risk characterization

(What IS the estimated

Incidence of the adverse

effect in a given

population?) ~

————-— ——. ——

I

Development of

regulatory options

-----

v

Evaluation of public

health, economic,

social, and political

consequences of

regulatory options

.

.J r

I

Agency decisions

and actions

, .— --

SOURCE: National Research Council, FtIsk ,ls.;assP~wIt In the Federal Government: Managing the Process (Washington, DC: National Academy

Press, 1983).

human health. Generally, the toxic effects causing

the greatest concern are those that are the most

severe, occur at the lowest levels, and persist after

exposure ceases.

dose, it is necessary to estimate biological effects

at the doses that people typically encounter, based

on dose-response relationships. Currently, there

are two main methods of using the high experimental doses to predict effects at the low doses of

interest: one method for noncarcinogens and

another for carcinogens. Such predictions of

effects at low doses from the observed effects at

high levels are termed extrapolations.

For noncarcinogens, biological effects are assumed to occur only when a certain level of

exposure has been exceeded. That level is known

as the threshold. Researchers usually derive an

approximate threshold from identifying a‘ ‘no-observed-effect level’ (NOEL) or a “no-observedadverse-effect level’ (NOAEL) in exposed people or experimental animals. The NOEL is that

dose at or below which no biological effects of

any type are detected; the NOAEL is that dose at

or below which no harmful effects are detected. If

scientists observe more than one effect in animal
52 I Researching Health Risks

tests, they generally use the effect occurring at the

lowest dose in the most sensitive animal species

and sex as the basis for estimating a NOEL or

NOAEL. Safety factors or uncertainty factors

(which are discussed further in the section on risk

characterization) are used to account for uncertainties in the use of NOELs or NOAELs for

determining g levels of acceptable exposure.

For carcinogens, researchers generally assume

that there are no thresholds, that is, that carcinogens pose some risk at even the lowest levels of

exposure. For those substances, extrapolations

from high to low doses are done using mathematical models, and a number of those models fit data

derived from toxicity tests fairly well; because

such data are available only for high doses, the

extrapolation models make quantitative predictions of risks at lower doses using different

models, which can result in widely divergent

predictions of risk. Because data are seldom

available at those doses, those predictions can

seldom be verified or falsified.

The most commonly used model among Federal agencies is the linearized, multistage model.

It is based on the hypothesis that cancer develops

in stages and that a carcinogen can have an effect

at each stage (U.S. OSTP, 1985). Agencies use

the model to estimate an upper limit to the

increase in probability of cancer resulting from a

given exposure, rather than a “most likely” or

“best” estimate (U.S. EPA, 1986a).

When the dose-response relationship is based

on animal data, yet another extrapolation is

necessary. Researchers use species extrapolation

factors, also called scaling factors, to account for

differences between test animals and humans that

may affect the response to exposure to harmful

substances. Such factors can include considerations of lifespan, body size, genetic variability or

population homogeneity, metabolic rate, and

excretion patterns (Travis and White, 1988; U.S.

OSTP, 1985).

 Exposure Assessment

Exposure assessment determines or calculates

the number and kinds of people exposed to a

substance, the amount of the substance to which

individuals or populations are exposed, and the

distribution, sources, routes, frequency, and duration of exposures. Assessors then use this information to estimate the dose, that is, the amount of

a substance that reaches the cells, tissues, or

organs of people who have been exposed. In

general, less information is available about actual

human exposure than about other aspects of

health risk assessment (Cohrssen and Covello,

1989; Paustenbach, 1989b). Paustenbach (1989b)

states that “it is likely that the major improvements in risk assessment that will be achieved in

the near future will be due to improvements in our

ability to estimate the uptake the chemicals

caused by specific exposure scenarios.

Exposure assessments vary widely because of

the kinds of information that maybe available or

that are possible to obtain. The most accurate

information about exposure is based on monitoring, or actual measurement, of the amounts of a

substance to which people are exposed (NRC,

1991 b).

Often, however, monitoring data are not available. As a result, assessors often estimate exposures to emissions from a distant source like a

factory by using exposure models (NRC, 1991 b).

Exposure models simulate the dispersion of

substances in the environment. Many of the

hundreds of published models are quite specific

for classes of substances or for the types of

environments the substances travel through, such

as the atmosphere, ground or surface water, or the

food chain. Other models are multimedia in

nature and assess the combined impact of many

routes of exposure.

Exposure assessments may also account for the

movement and activities of people. Over the

course of a day, people spend time in their homes,

their cars, and their workplaces. Their activities,

as well as their locations, can have an effect on
Chapter 2: An Introduction to Health Risk Assessment and its Research Base 153

their exposure to different substances. Exercise or

work, for example, affects the rate of breathing

and increases the amount of airborne substances

that people inhale. Assessors can combine information on activity patterns with information on

environmental concentrations to estimate exposure (Lioy, 1990; NRC, 1991a).

 Risk Characterization

This final step in a risk assessment summarizes

and combines the main points in the hazard

identification and the dose-response and exposure

assessments to provide an integrated picture of

the data. It describes the conclusions reached

concerning the kinds of hazards associated with

exposure, whether particular subpopulations are

at special risk, the assumptions that were made in

arriving at the conclusions, the strengths and

weaknesses of the data, and the uncertainty

surrounding the conclusions. Finally, it may

provide a quantitative estimate of risk or a range

of possible values.

Historically, risk characterization has received

much less attention than the other components of

risk assessment, but that state of neglect appears

to be changing (Habicht, 1992). Gray (1993)

discusses recent developments in this area.

Risk characterization for noncancer effects

evaluate risks against an estimated threshold level

of toxicity. The Environmental Protection Agency

(EPA) calls the exposure level at which risk

becomes a problem the reference dose (RfD), or

the acceptable daily intake (ADI). However this

level is identified, it is a ballpark value. If human

exposure is consistently below the RfD, risk

assessors assume that there is little or no health

risk. If exposures exceed the RfD significantly,

they assume that a risk exists.

To determine the RfD, assessors divide the

NOEL or NOAEL (determined in the doseresponse evaluation) by a series of uncertainty

factors or safety factors, which attempt to account

for areas of uncertainty or gaps in the data

(Dourson and Stara, 1983), For example, if the

NOEL or NOAEL is based on data from studies

in animals, it may be divided by a factor of 10 to

account for the possibility that humans may be

more sensitive to the chemical than the test

animals. Another uncertainty factor of 10 accounts for differences in susceptibility in human

populations. Usually, a NOAEL for animal studies is divided by 100 (10X 10) to develop an RfD

(or ADI). When assessors are faced with the

problem of developing a long-term RfD but only

short-term test data are available, they may divide

the NOEL or NOAEL by yet another uncertainty

factor. In addition, a factor is sometimes used to

account for an incomplete database. The magnitude of the uncertainty factor may vary from

chemical to chemical.

When a NOEL or NOAEL is not available,

assessors may use the lowest-observed-effect

level (LOEL) or the lowest-observed-adverseeffect level (LOAEL) in deriving an RfD. When

the LOEL or LOAEL is used, it maybe divided

by an additional uncertainty factor of 10.

A variation on the uncertainty factor approach

is the margin of safety (MOS), which divides the

NOEL or NOAEL by the current, desired, or most

feasible level of human exposure. To judge the

adequacy of the MOS, it may be compared with

criteria of tolerable or acceptable safety margins,

which vary according to the setting (e.g., environmental or occupational) (Tardiff and Rodricks,

1987). Risk assessors generally use this approach

to make judgments about the safety of existing or

proposed levels of exposure.

Risk characterization differs for carcinogens.

Although the extrapolation model assessors actually use may involve a number of subtle factors,

all models incorporate the idea that risk varies

with exposure. Therefore, by knowing the relationship between dose and risk as well as exposure, as determined in the earlier steps of the risk

assessment process, it is possible to estimate the

number of people who may be expected to

develop cancer as a result of exposure to a

chemical. But those estimates should not be

considered predictions of the future incidence of
54 Researching Health Risks

disease. The many uncertainties in each part of

the assessment, the difficulties of extrapolating

from the results of scientific studies to predictions

of human exposure at environmental levels, and

the fact that the dose-response extrapolation

models are used to generate an upper bound on

risk preclude precise predictions. More appropriately, these figures should be considered estimates of risk with varying ranges of uncertainty.

As other areas of risk assessment mature, signs

of interest in and dissatisfaction with the current

process of risk characterization are becoming

apparent. Most criticism is aimed at the generation of a single numerical risk estimate that does

not provide information on how it was generated

or the information used in that task. Recent

reports and agency communications have called

on risk assessors to ‘‘convey what is known and

what is not known about a particular risk in away

that accurately reflects the current state of scientific knowledge and is useful to decision makers’

(AIHC, 1989); they have also defined key aspects

of good risk characterization (AIHC, 1989, 1991).

Former EPA Deputy Administrator F. Henry

Habicht released a memo that provided guidance

for agency risk assessors and risk managers on

risk characterization (Habicht, 1992). The

Habicht memo emphasizes that risk managers

must be made aware of the strengths and limitations of a risk assessment to allow them to make

“informed evaluation and use of [it].”

Several common themes are present in the

reports and in the Habicht memo. Specifically,

they all stress that risk characterization must

characterize more completely all uncertainties,

assumptions, analytical alternatives, and the full

range of plausible risk estimates.

ISSUES IN HEALTH RISK ASSESSMENT

Health risk assessment has several strengths: it

provides a structure for collecting, organizing,

and evaluating data; it gives agencies the capacity

to base decisions on estimates of risk to people;

and it provides information for ranking hazards,

enabling agencies to focus their resources on the

most significant risks to health (U.S. EPA, 1987,

1990b). This last point has become increasingly

important because the ubiquity of carcinogens

and other toxic substances in the environment

make it impossible to prevent all human exposure

(Ames and Gold, 1990; Loehr, 1991). Aspects of

health risk assessment have prompted heated

debate in recent years among scientists, regulators, the regulated community, and interested

citizens. The issues being debated are more

numerous than can possibly be introduced here.

The National Research Council, in its groundbreaking 1983 report Risk Assessment in the

Federal Government: Managing the Process,

identified 50 points in the risk assessment process

at which scientific uncertainty is encountered and

inferential bridges are needed in order to continue

(box 2-B). A consensus has developed on some of

these issues since the council’s report was published. For example, Federal agencies have proposed using a common scaling factor for interspecies extrapolation (U.S. EPA, 1992a). Most of the

issues, however, are still being discussed a decade

after they were frost listed.

The section that follows describes some of the

issues that arise frequently in discussions of the

use of health risk assessment by Federal agencies.

Further research will clarify questions that stem

from missing or ambiguous data or gaps in

scientific theory. (For past examples, see ch. 5.)

Other issues arise, however, not because of a lack

of scientific consensus but because people hold

different views about how much risk is acceptable

and when it is appropriate to err on the side of

caution. Further research may help to refine those

policy debates, but it cannot and will not end

them.

 Conservative Assumptions

Agencies typically deal with the kinds of issues

identified by the National Research Council by

choosing a standard, or default, assumption and

using it consistently. In the absence of data to the
Chapter 2: An Introduction to Health Risk Assessment and its Research Base 155

contrary, agencies have tended to choose defaults

that are said to be conservative; that is, they have

erred on the side of caution.

During the Bush Administration, economists

from the Office of Management and Budget

(OMB) as well as others (Gori and Flamm, 1991,

for instance) criticized Federal regulatory agencies for using default assumptions that were, in

their opinion, overly cautious and unnecessarily

expensive. OMB pointed to such common practices as the use of test data from the most sensitive

animal species, the choice of an extrapolation

model (the linearized, multistage model) that

tended to yield the highest estimates of risk, and

the use of exposure models that assumed that

people lived close to hazardous waste sites or

other sources of exposure continuously for 70

years (Belzer, 1991; U.S. OMB, 1990-1991).

According to those arguments, risks are being

overestimated, leading to burdensome, unnecessary regulatory costs and a disordering of agency

priorities (Barnard, 1986, 1991; Belzer, 1991;

Gori and Flamm, 1991; U.S. OMB, 1990-1991),

Regulatory agencies and many analysts defend

those choices as being within their mission of

protecting human health, and they point out why,

despite the conservatism, risks may yet be underestimated (Finkel, 1989; Huff et al., 1991; Perera

and Boffetta, 1988; Rail, 1991; Silbergeld, 1993).

For example, test animals are not exposed at the

beginning of their lives, during fetal development, when they are more susceptible to certain

agents. In addition, agencies do not consider the

cumulative effect of exposure to agents from all

possible routes.

 Animal Bioassays

Currently, tests in rats and mice are the main

tool for assessing chemicals for carcinogenicity.

In the absence of data from humans, information

on animals is clearly the next best basis for

decisionmaking. Its supporters defend the use of

the rodent bioassay as science’s most important

method for identifying potential human carcinogens (Cogliano et al., 1991; Huff and Rail, 1992;

Perera and Boffetta, 1988; Silbergeld, 1993).

Huff (1993) examined the results from 2-year

carcinogenesis experiments, in both sexes of at

least two animal species, on 450 chemicals and

concluded that ‘‘carcinogenicity findings from

experiments in laboratory animals are scientifically reasonable for identifying and predicting

potential carcinogenic effects to humans. ” Indeed, all known human carcinogens have been

found to be carcinogenic in at least one other

animal, although that fact does not necessarily

mean that the converse is true, that is, that all

animal carcinogens are carcinogenic in humans

(U.S. OSTP, 1985).

Critics, however, have pointed out a number of

problems with current testing methods. The

traditional long-term carcinogen bioassay is quite

expensive and time-consuming, so the number of

animals it uses must be limited. To increase the

likelihood of identifying carcinogens, researchers

administer high doses of the test chemical. The

highest dose used, the maximum tolerated dose

(MTD), is that quantity of the substance that is

just large enough to elicit signs of minimal

toxicity without significantly altering the animal’s lifespan as a result of effects other than

carcinogenicity (NRC, 1993; U.S. OSTP, 1985).

Lower doses, such as one-half the MTD, are also

given. Unlike test animals, humans are rarely

exposed to such high levels, aside from accidents

and some workplace exposures, and never over

their entire lifespan. Researchers assume, however, that if a chemical causes an increase in the

incidence of cancer at a high dose, it will also

cause cancer, albeit at lower frequencies at lower

doses.

For agents like ionizing radiation and some

chemicals, substantial scientific evidence supports that assumption (Huff et al., 1991). But

others argue that at such high doses, many

chemicals tested are carcinogenic (Ames and

Gold, 1990), They suggest that this result may be

due to secondary effects that do not occur at lower

doses. They further suggest that doses at the MTD
56 I Researching Health Risks

Box 2-B-issues in Health Risk Assessment

HAZARD IDENTIFICATION

Epidemiologic Data

What relative weights should be given to studies with differing results? For example, should positive results

outweigh negative results if the studies that yield them are comparable? Should a study be weighted in

accord with its statistical power?

What relative weights should be given to results of different types of epidemiologic studies? For example,

should the findings of a prospective study supersede those of a case-control study, or those of a

case-control study those of an ecologic study?

What statistical significance should be required for results to be considered positive?

Does a study have special characteristics (such as the questionable appropriateness of the control group)

that lead one to question the validity of its results?

What is the significance of a positive finding in a study in which the route of exposure is different from that

of a population at potential risk?

Should evidence on different types of responses be weighted or combined (e.g., data on different tumor

sites and data on benign versus malignant tumors)?

Animal-Bioassay Data

●

●

●

●

●

●

*

●

●

●

●

●

What degree of confirmation of positive results should be necessary? Isa positive result from a single

animal study sufficient or should positive results from two or more animal studies be required? Should

negative results be disregarded or given less weight?

Should a study be weighted according to its quality and statistical power?

How should evidence of different metabolic pathways or vastlydifferent metabolic rates between animals

and humans be factored into a risk assessment?

How should the occurrence of rare tumors be treated? Should the appearance of rare tumors in a treated

group be considered evidence of carcinogenicity even if the finding is not statistically significant?

How should experimental-animal data be used when the exposure routes in experimental animals and

humans are different?

Should a dose-related increase in tumors be discounted when the tumors in question have high or

extremely variable spontaneous rates?

What statistical significance should be required for results to be considered positive?

Does an experiment have special characteristics (e.g., the presence of carcinogenic contaminants in the

test substance) that lead one to question the validity of its results?

How should findings of tissue damage or other toxic effects be used in the interpretation of tumor data?

Should evidence that tumors may have resulted from these effects be taken to mean that they would not

be expected to occur at lower doses?

Should benign and malignant lesions be counted equally?

Into what categories should tumors be grouped for statistical purposes?

Should only increases in the numbers of tumors be considered, or should a decrease in the latent period

for tumor occurrence also be used as evidence of carcinogenicity?

Short-Term Test Data

. How much weight should be placed on the results of various short-term tests?

● What degree of confidence do short-term tests add to the results of animal bioassays in the evaluation of

carcinogenic risks for humans?

● Should in vitro transformation tests be accorded more weight than bacterial mutagenicity tests in seeking

evidence of a possible carcinogenic effect?
Chapter 2: An Introduction to Health Risk Assessment and its Research Base 57

● What statistical significance should be required for results to be considered positive?

● How should different results of comparable tests be weighted? Should positive results be accorded greater

weight than negative results?

Structural Similarity to Known Carcinogens

. What additional weight does structural similarity add to the results of animal bioassays in the evaluation

of carcinogenic risks for humans?

General

● What is the overall weight of the evidence of carcinogenicity? (This determination must include a judgment

of the quality of the data presented in the preceding sections.)

DOSE-RESPONSE ASSESSMENT’

Epidemiologic Data

●

●

●

●

●

●

●

What dose-response models should be used to extrapolate from observed doses to relevant doses?

Should dose-response relations be extrapolated according to best estimates or according to upper

confidence limits?

How should risk estimates be adjusted to account for a comparatively short followup period in an

epidemiologic study?

For what range of health effects should responses be tabulated? For example, should risk estimates be

made only for specific types of cancer that are unequivocality related to exposure, or should they apply to

all types of cancer?

t-low should exposures to other caranogens, such as cigarette smoke, be taken into consideration?

How should one deal with different temporal exposure patterns in the study population and in the population

for which risk estimates are required? For example, should one assume that lifetime risk is only a function

of total dose, irrespective of whether the dose was received in early childhood or in old age? Should recent

doses be weighted less than earlier doses?

How should physiologic characteristics be factored into the dose-response relation? For example, is there

something about the study group that distinguishes its response from that of the general population?

Animal-Bioassay Data

●

●

●

●

●

●

What mathematical models should be used to extrapolate from experimental doses to human exposures?

Should dose-response relations be extrapolated according to best estimates or according to upper

confidence limits? If the latter, what confidence limits should be used?

What factor should be used for interspecies conversion of dose from animals to humans?

How should information on comparative metabolic processes and rates in experimental animals and

humans be used?

If data are available on more than one nonhuman species or genetic strain, how should they be used?

Should only data on the most sensitive species or strain be used to derive a dose-response function, or

should the data be combined? If data on different species and strains are to be combined, how should this

be accomplished?

How should data on different types of tumors in a single study be combined? Should the assessment be

based on the tumor type that was affected the most@ some sense) by the exposure? Should data on all

tumor types that exhibit a statistically significant dose-related increase be used? If so, how? What

interpretation should be given to statistically significant decreases in tumor incidence at specific Sites?

(continued on next page)
58 I Researching Health Risks

Box 2-B-issues in Health Risk Assessment-Continued

EXPOSURE ASSESSMENT

*

●

●

●

●

●

●

●

How should one extrapolate exposure measurements from a small segment of a population to the entire

population?

How should one predict dispersion of air pollution into the atmosphere due to convection, wind currents,

etc., or predict seepage rates of toxic chemicals into soils and groundwater?

How should dieter habits and other variations in lifestyle, hobbies, and other human activity patterns be

taken into account?

Should point estimates or a distribution be used?

How should differences in timing, duration, and age at first exposure be estimated?

What is the proper unit of dose?

How should one estimate the size and nature of the populations likely to be exposed?

How should exposures of special risk groups, such as pregnant women and young children, be estimated?

Risk Characterization

●

●

●

What are the statistical uncertainties in estimating the extent of health effects? How are these uncertainties

to be computed and presented?

What are the biologic uncertainties in estimating the extent of health effects? What is their origin? How will

they be estimated? What effect do they have on quantitative estimates? How wil the uncertainties be

described to agency decisionmakers?

Which population groups should be the primary targets for protection, and which provide the most

meaningful expression of the health risk?

1 Current methods and approaches to exposure assessment appear to be medium- orroute-specific. In contrast

with hazard identification and dose-response assessment, exposure assessment has very few components that could be

applicable to all media.

SOURCE: National Research Council, IWsk Asssssmsnt In the Federa/ Government: Managing ths Process (Washington, DC: National

Academy Press, 19S3).

may cause chronic cell killing and consequent

increased cell division, which in turn causes

increased rates of mutagenesis and carcinogenesis (Ames and Gold, 1990; Cohen and Ellwein,

1990, 1991a, 1992).

The use of the MTD was the focus of a recent

report by the National Academy of Sciences. In an

unusual occurrence for an academy committee,

the participants failed to reach a consensus.

Two-thirds of the 17-member panel favored

continuing the use of the MTD, and one-third

favored the use of more moderate doses (NRC,

1993; Science, 1993). Clearly, this issue remains

unresolved.

Some carcinogenic mechanisms and pathways

that occur in animals may not occur in humans.

For example, unleaded gasoline, d-limonene, and

1,4-dichlorobenzene cause kidney tumors in male

rats but not in mice or female rats. These substances appear to induce accumulation of a

protein found only in adult male rats, which

appears to be responsible for increased cell death

and concomitant cell regeneration (U.S. EPA,

1991a). Because that protein does not occur in

humans, substances that cause tumors in the kidneys of male rats through this mechanism may not

be human carcinogens. Better understanding of

the basic mechanisms of chemical carcinogenesis

should help to resolve these and similar issues.
Chapter 2: An Introduction to Health Risk Assessment and its Research Base 59

 Models for Dose Extrapolation

Research has developed a number of different

statistical “models for extrapolating from high to

low doses, and all of them generally fit the data in

the range of doses used in animal tests. (The

White House Office of Science and Technology

Policy offers a good description of various

models; see U.S. OSTP, 1985.) However, the

models can differ significantly in the low-dose

region, the area of primary interest to risk

assessment (Paustenbach, 1989a). In general, the

one-hit model and the linearized, multistage

model (LMS,) predict the highest risk (Munro and

Krewski, 1981). EPA prefers the LMS model “in

the absence of adequate information to the

contrary’ (U.S. EPA, 1986a).

All of the models now in use are based on the

current scientific understanding of carcinogenesis

induced by ionizing radiation or by one particular

class of chemical carcinogens known as genotoxins, which interact with DNA. There is growing

evidence, however, that these models may be

inappropriate for other kinds of chemical carcinogens, some of which may even have thresholds.

EPA has stated that it recognizes that the LMS

model should not be used for certain chemicals;

however, it prefers this model for chemicals

whose mechanisms of action are unknown. Some

observers have suggested that a better approach

might be to report results using more than one

model, citing the lack of evidence that the LMS

model predicts the low-dose response better than

other models (Paustenbach, 1989a).

Critics have charged that current models are

‘‘overly simplistic. probabilistic representations

of highly complex biological phenomena’ (Sielken,

1987). They contend that the models do not take

into account current knowledge of the mechanisms of carcinogenesis or the impact of other

biological processes such as rates of cell turnover,

repair processes, immune system responses, and

physiological and pharmacokinetic models of the

absorption, delivery, metabolism, and elimination of chemicals. Such critics suggest that

methods be developed to permit consideration of

more biological information in quantifying the

dose-response relationship (Barnard, 1991; Cohen

and Ellwein, 1991b; Sielken, 1987).

 Weight of the Evidence

Scientific studies vary in their quality, but

regulatory agencies tend to place heavy emphasis

on any study suggesting that a chemical might be

hazardous, regardless of the quality of the research. Increasingly, however, agencies are responding to criticisms of this practice by adopting

a weight-of-the-evidence approach (U.S. EPA,

1986a, 1992b). That approach takes into consideration the quality and adequacy of the available

data and the kinds and consistency of responses

induced by a suspected toxic substance (U.S.

EPA, 1986a; U.S. OSTP, 1985).

 Evaluating Mixtures of Chemicals

People are exposed to multiple substances

simultaneously, but with few exceptions, chemicals are studied and regulated individually. Little

is known about the effects of most chemicals

when encountered in mixtures. In fact, many

components of common mixtures may be unknown. It is usually assumed, for the purposes of

risk assessment, that each substance exerts its

effect independently and that the effects are

simply additive. Researchers have found examples, however, of substances whose toxic effects

are not additive. For example, exposure to either

tobacco smoke or radon is associated with an

increased risk of lung cancer. Exposure to both

poses an even greater risk than would be predicted

by an additive model (see ch. 6). Such an effect is

said to be synergistic. Although fewer cases are

known, examples also exist of substances that

show antagonistic effects; that is, when the substances are administered together, the toxic effects

are less than the sum of the effects when each is

administered individually. For example, administering dioxin before administering another carcin-
60 I Researching Health Risks

ogen reduces the rate of cancer. For most chemicals, however, such data are unavailable.

Chemical mixtures may be regulated as such

(e.g., coke oven emissions or diesel exhaust) if

data on the mixture itself are available. If they are

not, assessments may be based on the data

collected about a similar mixture or on some of

the components of the mixture. EPA’s guidelines

for the health risk assessment of chemical mixtures (U.S. EPA, 1986b) recommend that assessors assume that effects are additive, that interactions decrease significantly with decreasing doses,

and that they seldom play a role at the usual, low

levels of human exposure.

 Characterizing Uncertainties

and Assumptions

Acceptance is growing for the need to move

beyond simple numerical estimates of risk and to

give risk managers a broader picture of the

uncertainties associated with risk estimates (Habicht, 1992). When health risk assessments discuss

uncertainties, they tend to take the form of lists of

uncertain assumptions. It is unclear whether that

practice improves the decisionmaking process.

Some analysts have proposed a more complete

picture of risk by replacing point estimates with

uncertainty distributions that would show all the

possible values of the risk and their associated

probabilities of occurrence (Finkel, 1990).

Few in the risk assessment field would argue

with the notion that the estimates provided by risk

assessment are highly uncertain. In hazard identification, the exact relationship of animal tests to

human risk and the predictive value of highexposure occupational epidemiology to environmental exposures are quite unclear. There is

generally no way to determine the most appropriate mathematical model for extrapolating from

high to low doses in dose-response evaluation.

And methods of exposure assessment, especially

when exposure may be from many pathways, are

rudimentary. All of these factors contribute to the

great uncertainty present in estimates of risk

(Rosenthal et al., 1992).

According to Gray (1993) and others (AIHC,

1989, 1991), making that uncertainty known to all

of the users of a risk assessment is of paramount

importance. As Habicht (1992) states, ‘ ‘uncertainty should be acknowledged and expressed

both qualitatively and quantitatively.’ His memo

directed EPA personnel to develop a statement of

confidence in a given risk assessment and emphasized that identifying uncertainties is a key

component of such a statement. In addition,

Habicht emphasized that numerical risk estimates

must not be allowed to stand alone, separated

from the various assumptions and uncertainties

on which they are based.

Current and future scientific research will help

reduce the uncertainties in many aspects of risk

assessment. Today, however, in the absence of

definitive science, a number of default assumptions are made. For example, current practices in

hazard identification assume that any animal

carcinogen has the potential to be a human

carcinogen even though exceptions to this rule are

thought to exist; current dose-response evaluation

assumes that the dose-response function for

carcinogens has no threshold; and exposure

assessments assume that maximally exposed

individuals spend their entire 70-year lifetime at

the point of maximum exposure. Some of the

assumptions used in risk assessment are generally

accepted, but others are matters of contention.

Furthermore, a distinction can be made between

science-based issues that can be answered experimentally and policy issues that are based on

values and cannot be addressed by research.

WHY CONDUCT RISK ASSESSMENT

RESEARCH?

Risk assessment—through its incorporation

into dozens of Federal, State, and local laws and

regulations—influences the expenditure of hundreds of billions of dollars in the domain of health

and environmental protection. Accurate risk as-
Chapter 2: An introduction to Health Risk Assessment and its Research Base I 61

sessment demands extensive knowledge that only

research can generate. The approaches used in

risk assessment depend on research findings. It is

typically the lack of data and knowledge that

limits the accuracy of, and confidence in, a given

assessment.

Policymakers depend on health risk assessment

and research in making regulatory decisions

about which risks to tolerate and which to reduce

or prevent. They also have to weigh the costs and

benefits associated with those decisions. Overly

cautious decisions to reduce the risks posed by

contaminants in the environment, for example,

may mean inappropriate expenditures of limited

national resources for environmental cleanup

operations. Complacent decisions to tolerate risks

may result in increases in environmentally related

illness.

The costs of complying with environmental

regulations and the costs of environmentally

related illnesses are discussed here as an illustration. The purpose of this discussion is not to argue

the merits or costs and benefits of individual

regulatory decisions but rather to capture the

general magnitude of the public health, environmental, and economic interests at stake.

Hahn and Hird (1991) determined that the

annual costs of environmental regulation alone in

1988 were between $55 and $135 billion, and the

benefits were between $16 and $135 billion.

These estimates do not include the costs and

benefits of regulations covering the occupational

workplace, consumer product, and food safety,

Senator Daniel P. Moynihan’s “Environmental

Risk Reduction Act of 1993” (S. 110) states that

the annual cost of protecting the Nation’s environment is more than $115 billion. Moynihan said

on introducing the bill that although ‘‘this may

not be too much money to spend on environmental protection, it is too much to spend

unwisely. With so much riding on regulatory

decisions, the Office of Technology Assessment

(OTA) concludes that the time is ripe for attention

to the foundation of those choices: research and

its contribution to risk assessment.

 The Costs of Compliance

What level, if any, of exposure to a chemical is

‘‘safe’ or tolerable? How clean must a waste site

be to be considered cleaned up? Risk assessment

cannot answer those questions because concepts

of equity as well as laws and regulations play a

role. It can, however, provide estimates of the

harm that may result from inaction or from

various actions. Those estimates can guide and

inform regulators, influencing how billions of

dollars may be spent on regulatory decisions to

reduce cur-rent or prevent future exposure to

potentially hazardous chemicals. That type of

cost, which is incurred by complying with a law

or regulation, is generally referred to as a compliance cost. The costs of handling, treating, and

disposing of solid and hazardous wastes are

examples of compliance costs.

In fiscal 1993, Congress appropriated more

than $9 billion for environmental cleanup at

Federal facilities of the Departments of Energy

and Defense, an amount much larger than the $1.6

billion appropriated for cleaning abandoned hazardous waste sites under the Superfund legislation. (That effort is financed partly by a tax on the

chemical industry and partly from general revenues.) As a direct result of such cleanup activities

focused on military and nuclear waste, EPA has

projected that Federal cleanup expenditures will

increase by 140 percent over the 1987-2000

period (U.S. EPA, 1990a). In other words, the

costs of compliance increasingly fall directly on

the Federal Government.

The cost of complying with EPA regulations is

not the only type of compliance cost, but it is the

best documented. Compliance with Food and

Drug Administration (FDA) regulations also

consumes substantial resources, but a formal

estimate is not available, The Pharmaceutical

Manufacturers Association, however, states that

its members spent $9.2 billion for research and

development in 1991, some portion of which

represented toxicity and safety testing to satisfy

FDA regulatory requirements (PMA, 1991). Sim-
62 I Researching Health Risks

ilarly, compliance costs are incurred by complying with the rules and regulations promulgated by

the Occupational Safety and Health Administration and the Consumer Product Safety Commission.

 Costs of Environmentally

Related Illnesses

Besides compliance costs, there are other

risk-related costs. For example, what are the costs

of existing environmentally related illnesses, and

how would future costs be affected by regulatory

decisions? 2

The answers to those questions can only be

estimated. Estimating the costs of some environmentally related illnesses is easier than assessing

how regulatory decisions are likely to affect their

costs. Regulatory decisions have a bearing on the

costs of environmentally related illnesses, but the

relationship is not as straightforward as that

between regulation and the cost of compliance.

The costs of some environmentally related

illnesses have been estimated to reach well into

the billions of dollars, although no comprehensive estimates are available. The Institute of

Medicine, for example, attempted to quantify

such costs in 1981 in response to a congressional

mandate (P.L. 95-623). The institute determined,

however, that it was not possible at that time to

document the costs of environmental pollution

(the main focus of the study). Instead, it offered an

extensive plan of study that would fulfill the goal

envisioned by Congress (IOM, 1981).

Studies that attempt to assess the economic

burden of illnesses generally rely on epidemiologic estimates of the number of people afflicted

(i.e., the prevalence of disease), national surveys

of health care expenditures, and studies that

assign monetary values to disability and premature death. Because cost-of-illness studies are

difficult to perform and depend heavily on the

definitions of direct and indirect medical costs

that researchers use, those who employ and

interpret them must exercise caution. Direct costs

usually include inpatient and outpatient expenditures; indirect costs may include costs related to

loss of work, years of productive life lost, quality

of life, and premature death.

One example of the costs associated with

environmentally related illnesses comes from

lead poisoning, a preventable environmental hazard that may affect the cognition, behavior,

endocrinology, and growth of children in the

United States (U.S. DHHS, 1991a). It is estimated

that 250,000 children have lead levels greater

than 25 micrograms per deciliter (ug/dl) of blood

and require medical treatment and special education averaging about $4,600 per child (U.S.

DHHS, 1991 b).

Although EPA has not performed a comprehensive study of the costs of lead exposure from

all sources, it has analyzed the costs associated

with exposure to some sources of lead. For

. . drmkmg water, EPA’s Regulatory Impact Analysis assigned a range of monetary values to the

projected health benefits for children and adults

of reducing exposure to lead from that source. The

direct and indirect medical benefits (quantified as

savings) that are expected to occur annually when

States eventually meet EPA’s new drinking water

standards were estimated at between $2.8 and

$4.3 billion (U.S. EPA, 1991 b). (The estimate is

based on lead’s adverse effects on adult male

blood pressure and children’s intelligence.)

It should be noted that overall mean blood lead

levels declined by 37 percent during the 1976-80

period (Farfel, 1985), when lead in gasoline was

reduced as a result of the passage of the Clean Air

Act. In 1985, EPA estimated that its further

phase-downs of the lead content of gasoline

ordered in that year would produce health benefits

for children and adults valued at approximately

2 This question addresses the current economic burden of environmentally related illness. It might also be posed as, what are the savings

or benefits of preventing environmentally related illnesses? It h a matter of convention regarding whether to cast the question in terms of costs

or benefits, because economists typically define costs and benefits in opposition to one another.
Chapter 2: An Introduction to Health Risk Assessment and its Research Base 63

$5 billion in 1992, based on 1983 dollars (U.S.

EPA, 1985).

Analysts can also estimate the health costs that

arise from other environmentally related diseases,

which cannot be sufficiently discussed here.

Relevant examples include respiratory problems

from air pollution and environmental tobacco

smoke, and occupational diseases such as mesothelioma from exposure to asbestos.

 The Role of Research

Controversies or conservative assumptions in

risk assessment stem from the lack of data or

scientific knowledge about the risks being assessed. With so much at stake, it seems fitting to

seize the opportunity of using scientific research

to narrow the scope of uncertainty in health risk

assessment.

In 1983, the National Research Council (NRC)

concluded that improving the quality and comprehensiveness of the knowledge used in risk assessment is by far the most effective way to improve

the process (NRC, 1983). The decade following

publication of the NRC report saw impressive

advances in the biological and biomedical sciences. Is an appropriate investment being made in

research to harness those advances in developing

a better knowledge base for health risk assessment?

In this report, OTA analyzes the resources

devoted to such development. It also examines

the nature, organization, and management of

federally supported research on health risk assessment and whether this area of research is adequately supported. Subsequent chapters discuss

how priorities are set for health risk assessment

research and the relationship of this area of

research to regulatory decisionmaking.

SUMMARY

Health risk assessment offers a systematic

approach to evaluating data and formulating

judgments about risk. It consists of some or all of

the following four steps: hazard identification,

dose-response analysis, exposure assessment, and

risk characterization.

The primary source of data for assessing risks

to human health is epidemiologic, toxicological,

structure-activity relationship, and exposure studies. However, the data such studies provide are

usually incomplete for evaluating the risk from

the exposures being considered. Researchers

therefore use various extrapolations (e.g., from

high to low doses, animals to humans, and

ingestion to inhalation) to predict the possible

outcomes from the available data.

To perform those extrapolations, Federal agencies use assumptions or policy positions to bridge

gaps in the data or knowledge. Because assumptions and policy positions contain value judgments and a large measure of scientific uncertainty, they are the main areas of controversy in

risk assessment.

However uncertain the results of health risk

assessment may be, they provide the scientific

foundation for decisions about how to mitigate

health risks (e.g., emission standards for incinerators). Those decisions, and the standards that are

their frequent consequence, can lead to expenditures for compliance with regulations and medical

expenses for exposure-related diseases that may

run into billions of dollars.

With so much at stake and given the opportunity presented by advances in the biological and

biomedical sciences, research is capable of narrowing the uncertainties in health risk assessment. This report reviews the Federal Government’s research efforts to determine whether

appropriate attention is being given to this field.

CHAPTER 2 REFERENCES

AIHC (American Industrial Health Council). 1989.

Presentation of risk assessment of carcinogens. Report

of an ad hoc study group on risk assessment presentation. (AHIC, Washington, DC).

AIHC. 1991. Improving risk characterization. Summary of a workshop, Washington, DC, Sept. 26 and 27

(AHIC, Washington, DC).
64 I Researching Health Risks

Ames, B.N,, and Gold, L.S. 1990. Chemical carcinogenesis: too many rodent carcinogens. Proceedings of

the National Academy of Sciences (USA) 87:7772-

7776.

Barnard, R.C. 1986. Critical discussion of carcinogenic risk policy. Regulatory Tom”cology and PharmaCOIOgy 9:225-229.

Barnard, R.C. 1991. Major issues raised by the OMB

report from the perspective of the Federal regulatory

agencies. Regulatory Toxicology and Pharmacology

14:223-228.

Belzer, R.B. 1991. The peril and promise of risk

assessment. Regulation Fall:40-49.

Cogliano, V. J., Farland, W.H., and Preuss, P.W. 1991.

Carcinogens and human health: part 3. Science 251:606-

608.

Cohen, S. M., and Ellwein, L.B. 1990. Cell proliferation in carcinogenesis. Science 249:1007-1011.

Cohen, S. M., and Ellwein, L.B. 1991a. Genetic errors,

cell proliferation, and carcinogenesis. Cancer Research 51:6493-6505, Dec. 15.

Cohen, S. M., and Ellwein, L.B. 1991b. btters:

carcinogenesis mechanisms: the debate continues.

Science 252:902-903, May 17.

Cohen, S. M., and Ellwein, L.B. 1992, Risk assessment

based on high-dose animal exposure experiments.

Chemical Research in Toxicology 5(6):742-748.

Cohrssen, J. J., and Covello, V.T, 1989. Risk Analysis:

A Guide to Principles and Methods for Analyzing

Health and Environmental Risks. Council on Environmental Quality (Washington, DC: Executive Office of

the President).

Dourson, M. and Stara, J. 1983. “Regulatory history

and experimental support of uncertainty (safety) factors. Regulatory Toxicology and Pharmacology.

3:224-238.

Farfel, M. 1985, Reducing lead exposure in children.

Annual Review of Public Health 6:333-360,

Firdwl, A.M. 1989. Is risk assessment really too

conservative? Revising the revisionists. Columbia

Journal of Environmental Luw 14:427467,

Finkel, A.M. 1990. Confronting Uncertainty in Risk

Management: A Guide for Decisionrnakers (Washington, DC: Resources for the Future).

Fowler, B.A. 1993. Mechanisms of kidney cell injury

fknn metals. Environmental Health Perspectives 100:57-

64.

Friess, M. R., Klopman, G., and Rosenkranz, H.S.

1986. Structure-activity relationships (SARS) among

mutagens and carcinogens: a review. Environmental

Mutagenesis, pp. 283-327.

Gori, B. G., and Flarnm, W.G. 1991. How sick a

patient? Report of a workshop on cancer risk assessment. Regulatory Tom”cology and Pharrnacolo~ 14:215-

222.

Gray, G. 1993. The Challenge of Risk Characterization (Washington, DC: U.S. Government Printing

Office). NTIS# PB93-218857.

Habicht, F.H. 1992. Guidance on risk characterization

for risk managers and risk assessors (U.S. Environmental Protection Agency, Washington, DC) Feb. 26.

Hahn, R. W., and Hird, J.A. 1991. The costs and

benefits of regulation: review and synthesis. YaZe

Journal on Regulation 8:233-278, winter.

Huff, J.E. 1993. Chemicals andcancerin humans: first

evidence in experimental animals. Environmental

Health Perspectives 100:201-210.

Huff, J. E., and Rail, D. 1992. Relevance to humans of

carcinogenesis results fkom laboratory animal toxicology studies. iWaxcy-Rosenau-Last Public Health and

Preventive Medicine. J.M. Last and R.B. Wallace

(eds.). (Connecticut: Appleton Century Crofts).

Huff, J. E., Haseman, J., and Rail, D. 1991. Scientific

concepts, value, and signi.flcance of scientific studies.

Annual Review of Pharmacology and Toxicology

31:621-652.

IOM(Instituteof Medicine). 1981. CostofEnvironrnentRelated Health eflects: A Plan for Continuing Study.

Report of a study done by the Committee for a

Planning Study for an Ongoing Study of EnvironmentRelated Health Effects (Washington, DC: National

Academy Press).

Klopman, G., and Rosenkrantz, H. 1991. Structureactivity relations: maximizing the usefulness of mutagenicity and carcinogenicity databases. Environmental Health Perspectives 96:67-75.

Lave, L. B., and Omenn, G.S. 1986, Cost-effectiveness

of short-term tests for carcinogenicity. Nature 324:29-

34, NOV. 6.
Chapter 2: An Introduction to Health Risk Assessment and its Research Base I 65

Lilienfeld, A. M., and Lilienfeld, D.E. 1980. Founaiztions of Epidemiology. (New York and Oxford: Oxford

University Press).

Lioy, P. 1990. Assessing total human exposure to

contaminants: a multidisciplinary approach. Erzvironmental Science and Technology 24:933-945.

behr, R. 1991. What raised the issue? EPA Journal

17:6-12, March/April.

Luster, M. I., and Rosenthal, G.J. 1993. Chemical

agents and the immune response. Environmental

Health Perspectives 100:219-226,

Munro, I. C., and Krewski, D.R. 1981. Risk assessment

and regulatory decisionmaking. Food and Cosmefic

Toxicology 19:549.

NRC (National Research Council). 1983. Risk Assessment in the Federal Government: Managing the

Process (Washington, DC: National Academy Press).

NRC. 1991a. Animals as Sentinels of Environmental

Health Hazards (Washington, DC: National Academy

preSS),pp. 1-160.

NRC. 1991b. Human Exposure Assessment for Airborne Pollutants: Advances and Opportunities (Washington, DC: National Academy of Sciences).

NRC. 1993. Issues in Risk Assessment. Committee on

Risk Assessment Methodology (Washington, DC:

National Academy Press).

Paustenbach, D.J. 1989a. Health risk assessments:

opportunities and pitfalls. Columbia Journal of Environmental Luw 14(2):379-410.

Paustenbach, D.J. 1989b, Important rczent advances in

the practice of health risk assessment: implications for

the 1990s. Regulatory Toxicology and Pharmacology

10:204-243.

Paustenbach, D.J. (cd.) 1989c. A survey of health risk

assessment. The Risk of Environmental and Human

Health Hazarak (New York: John Wiley& Sons, Inc.).

Perera, F, P., and Boffetta, P. 1988. Perspectives on

comparing risks of environmental carcinogens. Journal of the National Cancer Institute 80:1282-1293.

PMA (Pharmaceutical Manufacturers Association).

1991. Facts at a Glance (Washington, DC).

Rail, D.P. 1991. Carcinogens and human health: part

2, Science 251 :10-13.

Rosenkranz, H. S., and Klopman, G. 1989. Identification of rodent carcinogens by an expert system. Fzfth

International Conference on Environmental Mutagens, M.L. Mendelssohn (cd) (New York: Liss).

Rosenthal, A., Gray, G. M., and Graham, J.D. 1992.

Legislating acceptable cancer risk from exposure to

toxic chemicals. Ecology Lzw Quarterly 19(2):269-

362.

Schwetz, B. A., and Harris, M.W. 1993. Developmental toxicology: status of the field and contribution of

the National Toxicology Program. Environmental

Health Perspectives 100:269-282.

Science. 1993. Academy splits on risk. vol. 259, p. 759.

Sielken, R.J. 1987. Cancer dose-response extrapolations. EnvironrnentalScience and Technology 21:1033-

1039, November.

Silbergeld, E.K. 1993. Risk assessment: the perspective and experience of U.S. environmentalists. Environmental Health Perspectives 101(2):100-104.

Tardiff, R. G., and Rodricks, J.V. 1987. Toxic Substances and Human Risk: Principles of Data interpretation (New York and Lxmdon: Plenum Press.)

Travis, C. C,, and White, R. 1988. Interspecies scaling

of toxicity data. Risk Analysis 8:119-125.

Travis, C. C., Richter, S.A., Crouch, E.A.C. et al. 1987.

Cancer risk management. Environmental Science and

Technology 21:415420.

U.S. Congress, OTA (Office of Technology Assessment). 1981. Assessment of Technologies for Determining Cancer Risks From the Environment. OTA-H138.

U.S. Congress, OTA. 1991a. I&ntifying and Controlling Immurwtoxic Substances. OTA-BP-BA-75.

U.S. Congress, OTA. 1991b. Identifying and Controlling Pulmonury Toxicants. OTA-BP-BA-91.

U.S. Congress, OTA. 1991c. Neurotom”city: Identi~-

ing and Controlling Poisons of the Nervous System.

OTA-BA436.

U.S. DHHS (Department of Health and Human

Semices). 1991a. Preventing Lead Poisoning in Young

Children. U.S. Public Health Service, Centers for

Disease Control.

U.S. DHHS. 1991b. Strategic Plan for the Elimiruztion

of Childhood bad Poisoning. U.S. Public Health

Service, Centers for Disease Control.

U.S. EPA (Environmental Protection Agency). 1985.

Costs and Benefits of Reducing LQad in Gasoline.
66 I Researching Health Risks

U.S. EPA (Environmental Protection Agency).

1985. Costs and Benefits of Reducing Lead in

GasoZine. Final Regulatory Impact Analysis,

Office of Policy Analysis.

U.S. EPA. 1986a. Guidelines for carcinogen

risk assessment. Federal Register 51 :33992-

34003.

U.S. EPA. 1986b. Guidelines for the health risk

assessment of chemical mixtures. FederaZ Register 51:34014-34025.

U.S. EPA. 1987. Unfinished Business: A Com -

parative Assessment of Environmental Problems.

Office of Policy Analysis, Office of Policy,

Planning, and Evaluation.

U.S. EPA. 1990a. Environmental Issues: The

Cost of a Clean Environment. EPA-230-12-90-

084.

U.S. EPA. 1990b. Reducing Risk: Setting

Priorities and Strategies for Environmental Protection. Report of the Science Advisory Board,

Committee on Relative Risk Reduction Strategies, William K. Reilly, Administrator.

U.S. EPA. 1991a. Alpha -2u-Globulin: Association With Chemically Induced Renal Toxicity

and Neoplasia in the Male Rat. EPA 625/3-91/

O19F.

U.S. EPA. 1991b. Maximum contaminant level

goals and national primary drinking water regulations for lead and copper: final rule. FederaZ

Register, pp. 26460-26564.

U.S. EPA. 1992a. Draft report: a cross-species

scaling factor for carcinogen risk assessment

based on equivalence of mg/kg3/A/day. Federa2

Register 57:24152-24174.

U.S. EPA. 1992b. Working paper for considering draft revisions to the U.S. EPA guidelines for

cancer risk assessment. EPA 600/AP-92/003.

U.S. OMB (Office of Management and Budget).

1990-1991. Regulatory Program of the United

States Government. Executive Office of the

President, pp. 4-26.

U.S. OSTP (Office of Science and Technology

Policy). 1985. Chemical ca.rcinogenesis: a review

of the science and its associated principles.

Federal Register 50:10372-10400.

Zimmerman, R. 1990. Governmental A4anagement of Chemical Risk: Regulatory Processes for

Environmental Health (Chelsea, MIT: Lewis

Publishers).
T

Federal

Research

in Health

Risk

Assessment 3

his chapter describes the research that the Federal

Government is now conducting to improve health risk

assessments. It summarizes the results of the Office of

Technology Assessment’s (OTA) survey of such Federal

research efforts and identifies their strengths, weaknesses, and

trends.

To analyze the activities of the various agencies, OTA defined

health risk assessment research as research to improve existing

methods and develop new ones to reduce reliance on the

assumptions and policy options that are currently necessary. We

focus on research related to assessing adverse effects on the

health of human populations, and exclude research to improve

ecological risk assessments. The substances addressed in the

research survey are chemical and physical agents present in

environmental and occupational settings or as food additives or

contaminants.

RESEARCH AT THE FEDERAL AGENCIES

OTA surveyed Federal programs that conduct research on the

toxicity of environmental pollutants, occupational toxicants, and

toxic contaminants in food. We collected information through

written requests for data, which were followed up by interviews

with agency representatives and visits to agency laboratories.

Because of the controversies surrounding and the Federal

experience with the methods for evaluating and estimating risks

from exposure to carcinogens, we frequently use research to

improve the assessment of carcinogens in order to illustrate the

directions and needs of research on health risk assessment in

general.

(!!!!)

\“-’._//

67
68 I Researching Health Risks

 Environmental Protection Agency

The mission of the Environmental Protection

Agency (EPA) is to protect the environment and

the health of the public. In support of its

regulatory functions, the agency conducts missionoriented research, mostly within its Office of

Research and Development (ORD), on a broad

range of environmental contaminants. EPA conducts research in three general areas to support the

agency’s assessments of health risks: the health

effects of environmental toxicants; the nature,

patterns, pathways, and magnitudes of human

exposures; and the relationships between exposure and toxicity.

A large research facility in Research Triangle

Park, North Carolina, the Health Effects Research

Laboratory (HERL), houses most of the agency’s

in-house research on the health effects of environmental pollutants. The research at HERL includes

various approaches and emphases.

One area of interest is in developing and

applying validated test methods for screening and

characterizing the toxicity of new and existing

chemicals.l A second area of study is the health

effects of specific environmental agents in humans. A third area of activity focuses on developing methods to evaluate relationships between

chemical structure and biological effects (structureactivity relationships). Last, research is being

conducted to investigate the mechanisms of

toxicity. HERL scientists also conduct research in

comparative physiology and biochemistry as the

foundation for improved methods to extrapolate

from observations in animals to predictions of

effects in humans.

Research to determine the nature of environmental pollutants and the extent to which humans

are exposed to them is spread across a number of

EPA laboratories. The goal of that research is to

provide a foundation for answering questions

about exposure assessment and risk management.

For example, what are the magnitude, duration,

and frequency of exposure to a particular pollutant for both the general population and for groups

exposed to high levels of the pollutant? By what

pathways are humans exposed, and which are the

most important? What emission sources, activity

patterns, lifestyles, or other factors are important

determinants of human exposure? How many

people are exposed within a given exposure

scenario? Are people’s actual or anticipated

exposures expected to result in adverse health

effects? The kinds of research activities conducted to answer those questions include developing cost-effective methods for collecting and

analyzing samples; monitoring pollutants of interest in various media, materials, and biological

samples and designing monitoring devices; integrating ingestion, dermal contact, and inhalation

studies with other research to determine doseresponse effects; and developing predictive models for estimating past, present, and future exposures.

EPA’s research of the relationships between

exposures to a substance and the effects of those

exposures on health uses animal models to

determine the effects of changing doses of a

substance on response. In investigating exposure,

researchers employ biochemical and physiological methods to estimate the dose received by

selected organs or tissues of an organism. EPA is

also working to corroborate and extend observations in animal models through clinical studies of

humans exposed to air pollutants (box 3-A).

In recent years, more and more calls have come

from a variety of sources for increased attention

to health risk assessment research. In response,

Congress in 1988 recommended that ORD establish an integrated, systematic program that would

target research to improve risk assessments.

Legislators earmarked $10 million for the effort

but made no appropriation. ORD initially funded

the Research to Improve Health Risk Assessment

(RIHRA) program at $7 million by redirecting

2 A total of $3 million was redirected to study ecological effects of environmental pollution.
Chapter 3: Federal Research in Health Risk Assessment 69

Box 3-A-Agency-University Collaborations: Human Exposure Studies at EPA and UNC

The Human Studies Division (HSD) of the

Laboratory has done much of its work under a Coo

the University of North Carolina Medical School

at Chapel Hill (UNC), forming the Center for

Environmental and Molecular Biology of the Lung

(CEMBL). Physically locating HSD’S offices on

the medical school campus has greatly facilitated

this relationship.

The human clinical studies that HSD conducts require highly specialized facilities and

expertise not readily available in EPA’s own labs.

By its UNC relationship, HSD gains access to a

human inhalation chamber, a magnetic resonance imaging scanner, and an electron microscope. Furthermore, CEMBL currently has eight

divisions that house more than 30 doctors and

researchers on the medical school’s faculty in

various medical specialties. It also has joint

programs for postdoctoral fellows and research

assistants.

Given the facilities within CEMBL, humans

can be exposed to air pollutants under controlled

conditions in t he exposure chambers, and scientists can determine the resulting clinical health

effects. Volunteers are exposed to concentrations of pollutants reflecting those generally

found in the environment. Ozone is a prototypical

Environmental Protection Agency’s Health Effects Research

perative agreement with the Pulmonary Medicine Division of

pollutant for these exposure studies because it can be used with humans; it is a noncarcinogen, and its effects

are reversible. The results obtained wit h ozone-exposed humans can be compared with the results of analogous

studies using laboratory animals. The HSD-UNC collaboration therefore allows EPA scientists to address a major

criticism of the risk assessment process: t he use of animal studies to predict effects on human health. The result

has been a series of joint papers about the actual effects on humans of air pollutants such as ozone and sulfur

dioxide.

SOURCE: U.S. Congress, Office of Technology Assessment, 1993.

funds from other programs.2 The current level of collaborative ventures and grants. The program is

funding for the program is $5.1 million (Vanden- meant to complement EPA’s core research activiberg, 1993). ties, which place more emphasis on the near-term

RIHRA both supports and coordinates re- needs of EPA’s regulatory program offices. Now

search. Approximately half of its resources go to in its 4th year, RIHRA addresses research issues

researchers outside EPA through its funding of that cut across the various EPA regulatory pro3 Because of the complex structure and relationship of the various agencies and centers, OTA includes the organizational chart for the U.S.

Public Health Service in appendix B.
70 I Researching Health Risks

At this time, the program’s success is difficult

to assess. Some scientists interviewed by OTA

criticized RIHRA for not doing enough methodological research to improve risk assessments but,

instead, allowing funds to be used for ongoing

activities in fulfillment of regulatory needs. Other

observers argue, however, that the RIHRA program, in meeting its congressional mandate, has

provided resources and support for methodological risk assessment research that the agency might

not have conducted otherwise.

Because of EPA’s diverse regulatory needs,

until 1992 environmental program and mediaspecific research committees guided its health

research agenda. (In 1993, EPA moved to a

risk-based priority approach, as described below.)

The committees consisted of ORD and program

office staff who deliberated on and set priorities

for research. Even today, funding for research is

allocated on a program-specific basis all the way

down to the labs. By maintaining the separation

of research funds along program lines, this system

constrains the ability of HERL’s management, for

example, to establish overall research priorities

(Reiter, 1992) and also hinders their ability to

anticipate new problems.

The agency is now reviewing its system of

medium- and program-specific plannin g. The

1987 internal EPA report Unfinished Business

(U.S. EPA, 1987) concluded that the greatest risks

to the environment and the health of the public, as

determined by senior agency officials, were not

high on the agency’s list of priorities. Instead, the

report concluded that the agency’s priorities

reflected public perceptions of risk and legislative

mandates. Subsequent reports by EPA’s Science

Advisory Board (U.S. EPA, 1990, 1992a) examined ways to use risk assessment and expert

judgment in setting EPA’s priorities. Those

reports provided the cornerstone for EPA’s shift

to risk- and issues-based research planning to

address ‘‘environmental problems in the next

decade and beyond” (Foley, 1993).

To set priorities for the agency in all areas

including research, EPA is converting to “riskbased planning.” Under this approach, the agency

attempts to set priorities for action and research

based on rankings of risks, as determined by

senior agency officials and experts (U.S. EPA,

1992c). Officials in ORD are currently developing a strategic plan and a research planning

document for each of 39 ‘research issues. ’ Three

of those issues contain most of the efforts to

improve health risk assessment: no. 28, human

exposure; no. 29, health effects research; and no.

30, health risk assessment. Both RIHRA and

non-RIHRA projects are included in issue no. 30.

EPA has the largest formal health risk assessment program of any government agency. Even

though each medium-specific program in EPA

performs risk assessments, the Office of Health

and Environmental Assessment (OHEA) in ORD

is the focal point for such efforts. OHEA has three

functions: it conducts risk assessments, coordinates agency and interagency activities in risk

assessment, and conducts research to develop and

improve methods of risk assessment. To promote

consensus within the agency, EPA established the

Risk Assessment Forum to address precedentsetting or controversial risk assessment issues,

such as the association of chemically induced

renal toxicity and neoplasia in the male rat (U.S.

EPA, 1991).

 Department of Health and

Human Services

The Department of Health and Human Services

(DHHS) includes protection from risks posed by

environmental hazards in its widespread programs. Within the vast DHHS organization, the

Public Health Service (PHS) is the organizational

home of the National Institutes of Health (NIH),

the Food and Drug Administration (FDA), the

Centers for Disease Control and Prevention
Chapter 3: Federal Research in Health Risk Assessment I 71

(CDC), and the Agency for Toxic Substances and

Disease Registry (among other agencies).3

Those PHS agencies conduct and support

research on environmental, occupational, and

food-borne health risks. For many of those

activities, DHHS also serves as the focal point for

interagency activities. Furthermore, Congress requires DHHS to publish annual reports concerning environmental health, including the Annual

Review of Carcinogens (U.S. DHHS, 1991d) and

a review of the toxicological research being

conducted in DHHS, EPA, and the Department of

Energy. DHHS has delegated those responsibilities to the director of the National Toxicology

Program (U.S. DHHS, 1991a).

NATIONAL TOXICOLOGY PROGRAM

DHHS established the National Toxicology

Program (NTP) in 1978 to coordinate activities

related to the testing of potentially toxic chemicals. Specifically, it established the program to

test selected chemicals for toxicity, develop and

validate tests and protocols, set priorities for

testing needs, and communicate results to government agencies, the scientific community, and the

public. Administered by the director of the

National Institute for Environmental Health Sciences (NIEHS), NTP coordinates toxicologyrelated programs within NIEHS, the National

Institute for Occupational Safety and Health

(NIOSH), and the FDA’s National Center for

Toxicological Research (NCTR).

Although NTP serves Federal health and regulatory agencies outside of DHHS as well as other

groups and organizations concerned with public

health, most of its resources come from NIEHS,

which contributed $79 million of its $84 million

budget in 1991. At the same time, NCTR contributed $0.06 million and NIOSH $4.5 million (U.S.

DHHS, 1991c).

An executive committee made up of senior

administrators of Federal health research and

regulatory agencies oversees NTP activities. To

ensure high-quality research, an independent

board of scientific counselors, composed largely

of nonfederal researchers, monitors the quality of

the agency’s technical research programs.

NTP selects chemicals for testing based on

nominations from participating Federal agencies

and other public and private organizations. It then

contracts with outside organizations to perform

the trots or arranges for testing onsite at the

NIEHS campus (U.S. DHHS, 1991c). NTP interacts with the scientific community through plenary reports, interagency discussions of regulatory problems, workshops, and symposia; it uses

information gathered in this way to identify and

characterize relevant research issues and encourage research collaborations.

The number of chemicals tested annually by

NTP has been declining because of the rising

costs of conducting bioassays (U.S. DHHS,

1992). The impression of many that the bioassay

program is the state of the art in this country and

abroad is reinforced by the judgments of scientists

and analysts that no other government or industry

program is subject to equivalent levels of quality

control and peer review (Huff et al., 1991;

Ringen, 1992). Yet NTP program administrators

are currently rethinking the program’s primary

functions. They are weighing the relative worth of

toxicity testing against the value of basic science

research in understanding the underlying biological responses to chemical and radiation exposures

(Griesemer, 1992; Schwetz, 1992; Tennant 1992).

One of the forces driving this reconsideration

has been the continuing public debate and controversy over NTP’s testing role. A series of hearings

by NTP’s Scientific Advisory Council as well as

public hearings were held during the fall of 1992

and the spring of 1993 to discuss the future of

NTP. On one side of the argument are advocates

such as Knute Ringen (1992) of the Center to

Protect Workers’ Rights, who argues that NTP’s

3 Bmause of tie complex smc~e and relationship of the various agencies and centers, OTA includes the organti.ational chart for tie U.S.

Public Health Service in appendix B.
72 I Researching Health Risks

hazard identification efforts are unique and

should remain an ‘‘essential part of this Nation’s

prevention arsenal in public health.” In contrast,

some industry spokespersons argue that industry

adequately addresses toxicity testing and that

NTP should ‘intensify efforts to understand basic

mechanisms of action of toxicants’ (Moolenaar,

1992). They contend that enough information

exists to predict the toxicity of untested chemicals

using structure-activity relationships.

In addition to the program’s primary focus on

toxicity testing, NTP administrators have identified three areas of priority for further improving

hazard identification: developing new methods

for chemical testing, selecting experimental animals and chemicals to refine and remodel experimental protocols to fill gaps in the data needed to

address public health concerns, and reviewing

and reorganizing the chemical selection process

(Griesemer, 1992; Schwetz, 1992; Tennant, 1992).

NATIONAL INSTITUTES OF HEALTH

Most of the National Institutes of Health

conduct and fund basic research in toxicology,

some epidemiologic studies, and, occasionally,

testing of toxicants (U.S. DHHS, 1991a). This

section describes two of the institutes, NIEHS and

the National Cancer Institute (NCI). Both are

NTP agencies and active in research related to

risk assessment. Before 1978, NCI conducted the

carcinogenesis bioassay program, a function now

performed by NTP. However, NCI remains active

in NTP program development and review.

National Institute of Environmental Health

Sciences--NIEHS has the broadest responsibility

among the Federal agencies for research to

identify and characterize the adverse effects of

environmental pollutants on human health. With

the goal of informing activities in disease prevention, the agency focuses a considerable portion of

its research resources on adding to fundamental

knowledge of the mechanisms of chemical toxicity, including the mechanisms of environmental

diseases and particularly cellular and molecular

targets for carcinogenesis. It also works toward a

greater understanding of biostatistics and techniques of quantitative risk assessment. Recently,

the institute has been developing biomarkers of

exposure, susceptibility, and effect and investigating noncancer disease endpoints.

Under its first director, NTEHS established a

reputation for conducting state-of-the-art basic

research on environmentally related diseases,

especially cancer (Thigpen, 1993). That focus

continues today as scientists at the institute

investigate specific changes at the organ, cellular,

and molecular level to understand the role environmental agents play in the development of

cancer. Using recently developed tools of molecular and cancer biology, institute researchers are

elucidating the roles of genetic factors, especially

oncogenes and tumor suppressor genes, in carcinogenesis. In particular, this research attempts to

understand the interaction of environmental agents

with genetic determinants in the development of

cancer (Barrett, 1993).

In addition to their expertise in the mechanisms

of carcinogenicity, NIEHS scientists are expanding their research into health effects other than

cancer. The institute has designed a program to

determine the adverse effects on health of exposure to a variety of air pollutants (e.g., ozone,

industrial emissions, and combustion byproducts)

and the relationship of those exposures to the

development and prevalence of respiratory diseases, such as asthma, emphysema, and other

chronic lung disorders. NIEHS is also developing

short-term tests of genetic toxicity-in particular, methods to assess the effects of environmental agents on human germ cells, which can be

passed down to succeeding offsprings and play a

role in heritable disorders.

Recently, the agency established a new set of

research priorities, motivated in part by NIH-wide

strategic planning (Healy, 1992), a new director,

and a review of the environmental health sciences

by the National Advisory Environmental Health

Sciences Council (U.S. DHHS, 1991 b). The

institute now has four areas of emphasis: basic
Chapter 3: Federal Research in Health Risk Assessment 73

mechanisms of environmental disorders, environmental causes of diseases of public health import,

clinical studies and clinical research, and an

enhanced science base for public health policy

decisions and health programs (Olden, 1992).

NIEHS provides support for internal and external investigator-initiated research on the biological mechanisms of response to environmental

stresses. Formal processes within the agency

determine whether NIEHS scientists or scientists

in other institutions or agencies should conduct

specific projects. A variety of advisory boards and

committees determines the internal allocation of

funds for institute programs, and project boards

review the activities and performance of each

program. Activities within the Division of Intramural Research are overseen by a board of

scientific counselors, all of whom are nonfederal

scientists. The board approves or disapproves of

initial concepts, monitors ongoing research, and

reviews research results. For specific environmental health topics, NIEHS also holds workshops and convenes symposia to gauge the

scientific knowledge base and obtain information

for setting research priorities.

NTEHS administrators are considering shifting

some resources and programs into new research

efforts that would promote more multidisciplinary activities. This internal reorganization will

move the institute away from its present programmatic focus to one more oriented toward process

as a way to foster multidisciplinary interactions,

especially for research on health risk assessment

(Lucier, 1993). NIEHS is also supporting collaborative research, not only within the institute but

with other agencies and universities.

Until 1992, an in-house NIEHS program in

biometry and risk assessment developed statistical methodologies for analyzing toxicological

data and conducting risk assessments. In that

year, NIEHS’s new director created the Laboratory of Biochemical Risk Analysis to examine

more cross-cutting issues in risk assessment. The

lab serves as a focal point of risk assessment

research for both basic molecular biologists at the

institute and the toxicologists conducting the .

toxicity testing at NTP (Lucier, 1993; Stone,

1993). In addition to risk assessment methodology, these investigators are also actively studying

carcinogenic chemicals that do not directly interact with DNA but instead bind to receptors and

seem to work by increasing growth rates of

normal or abnormal cells. This research features

centrally in risk assessment policies for so-called

‘‘nongenotoxic chemicals, which include the

animal carcinogen dioxin (Lucier et al., 1993).4

More recently, in May 1993, NIEHS’s director

established the Laboratory of Quantitative and

Computational Biology (LQCB) (Portier, 1993).

It will conduct independent and collaborative

research on mathematical and statistical models

based on biological mechanisms. The lab’s programs are intended to increase understanding of

the use and application of mathematical and

computational models in the primary fields of

research at NIEHS. Plans include developing

novel computing hardware and software and

applying them to problems in environmental

health through computer modeling, artificial intelligence, and related advances in computer

technology. In its strategic planning, LQCB

scientists anticipate exploring the use of virtual

reality technology in conducting risk assessments

and making risk management decisions.

National Cancer Institute-NCI broadly sponsors research on cancer to fulfill its mission to

reduce the incidence, morbidity, and mortality of

cancer in humans (NCI, 1992). NCI’s Division of

Cancer Etiology conducts research related to

assessing the risks of carcinogens. Its activities

include studies of the mechanisms of carcinogenesis, cancer biology and causation, epidemiology and biostatistics, physical and chemical

4 Diofi is the COmmOnly used term to refer to the chemical 2,3,7,8-tetrachlorobenzene-p-dioxin, which is a prototype for a vfiety of

structurally related organohalogens. See discussion on dioxin in chapter 5.
74 Researching Health Risk s

carcinogenesis, biological carcinogenesis, and

nutrition as a modulating factor.

Current toxicological research at NCI investigates the biological fate of chemical carcinogens

and the mechanisms by which they exert their

carcinogenic effects. Those studies include basic

biological research, development and validation

of short-term in vitro assays, development of

methods to use tissues from humans and nonhuman primates, and research on the interaction of

chemical carcinogens with the primary defense

against foreign chemicals, the cytochrome P450

enzyme system.

Epidemiologic studies conducted by the Division of Cancer Etiology in NCI contribute to

many aspects of risk assessment. In fact, NCI

conducts more epidemiologic research than all

other agencies of the Federal Government combined (Adamson, 1992). Some of the epidemiology research is aimed at identifying risk factors

and geographic ‘‘hot spots” for cancer, that is,

locations in which the number of cancer cases is

statistically greater than the national average.

Those results are then linked with the prioritysetting process at NCI, NIEHS, and other agencies. NCI, NIEHS, and EPA scientists, for example, are collaborating on a large prospective

epidemiologic study of farmers (box 3-B).

NCI establishes its research priorities for extramural and intramural research programs on the

basis of the incidence of and mortality from

specific types of cancers. But the institute also

exploits opportunities for pursuing recent scientific developments, such as studies linking cancers to chromosomal abnormalities or the presence of oncogenes (Adamson, 1992). It determines priorities for its research programs through

a budget review process that includes site visits to

its research sites, which occur every 3 to 4 years

for each project (NCI, 1992). The site visit

procedure is a formalized process, with specific

requirements for the reviewers to report back to

NCI management. Their reports provide material

for discussion at the twice-yearly retreats of

directors and associate directors at which priorities are set. NCI also funds extramural research to

stimulate investigations of particularly understudied areas and holds workshops to foster

interest in a topic and gather information on its

significance.

FOOD AND DRUG ADMINISTRATION

Organizationally, FDA consists of six centers,

three of which conduct health research aimed at

improving risk estimates or the risk assessment

process: the Center for Food Safety and Applied

Nutrition, the National Center for Toxicological

Research, and the Center for Devices and Radiological Health. The other three FDA centers-the

Center for Veterinary Medicine, Center for Drugs

and Biologics, and Center for Drug Evaluation

and Research--do not directly conduct related

research.

Center for Food Safety and Applied Nutrition—The Office of Toxicological Sciences

(OTS) is the focus of risk assessment activity

within the Center for Food Safety and Applied

Nutrition. It conducts long-term animal studies on

substances with potentially carcinogenic and

other health effects. The research is chemicalspecific and restricted to analyzing methods,

dose-response outcomes, and the relevance of

mechanisms of action of potentially toxic food

additives and contaminants (Scheuplein, 1992).

OTS is split into a research component and a

regulatory review group, both of which report to

the office manager.5 The office sets priorities

informally, and there is no external review of

research plans or activities. Upper management

establishes priorities for research, which are

based on regulatory needs, and subsequently

communicated to research scientists.

National Center for Toxicological Research

—NCTR was begun in 1971 under the joint

sponsorship of EPA and FDA, but EPA withdrew

5 OTS underwent restructuring in fiscal year 1992, and k new structure was unavailable to O’Ill at the time this report was prepared.
Chapter 3: Federal Research in Health Risk Assessment 75

Box 3-B-Government Interagency Collaboration: Farmworkers Cancer Study

One of the long-standing issues in cancer epidemiology has been the possible role of pesticides as a risk

factor among agricultural workers. Although various studies have reported links between pesticides and

lymphomas, methodological weaknesses have often hindered interpretation of the results. Gauging exposures

accurately and ensuring an unbiased study

cohort have been difficult with the small, retrospective studies that have been conducted. In

turn, assessing the risks posed by pesticides has

been problematic with such highly variable data.

The Environmental Protection Agency, National Cancer Institute, and National Institute of

Environmental Health Sciences have launched a

joint epidemiologic study of farmers and their

families. Known as the Agricultural Health Study,

this investigation will assess factors that may

account for reported excesses of certain cancers

found among farmers, including leukemia, multiple myeloma, non-Hodgkin’s Iymphoma, and

cancers of the brain, prostate, stomach, skin, and

lips. The study will establish a large cohort of

75,000 people that can be followed prospectively

for 10 years or more. The cohort will be composed of men and women who are either farm

owners or operators or commercial pesticide

applicators and their spouses and dependents.

The study will attempt to achieve many

goals. Its objectives include the following: identifying and quantifying cancer risks among men

and women associated with specific agricultural

practices; evaluating cancer risks among women

and children that may arise from indirect (i.e.,

nonoccupational) exposure to agricultural chemicals (e.g., ambient air drifts, handling contaminated clothing,

residues on rugs and children’s toys, residues in drinking water and food); and identifying and quantifying cancer

risks associated with diet, cooking practices, and the chemicals resulting from the cooking process. The study is

also designed to investigate biomarkers of exposure and disease.

The three agencies plan to develop an integrated strategy for predicting exposures. Their general approach

will be to measure agricultural exposure (both occupational and nonoccupational) by periodic interviews,

environmental and biological monitoring, and biomarker techniques. The research will also evaluate the

relationship between agricultural and dietary exposures and biomarkers of exposure, biological effects, and

genetic susceptibility factors relevant to mechanisms of carcinogenesis.

The project will be the largest, most complex study of cancer and other health effects ever undertaken among

workers in agriculture and their dependents, and its organizers expect it to yield definitive information regarding

the association of cancer risk with diet and occupational exposures In the farming industry. The project will also

provide a resource population, among agricultural populations, for research on health outcomes other than cancer

including neurotoxicity, reproductive hazards, and agricultural safety hazards.

SOURCE: Office of Technology Assessment, 1993, based on National Cancer Institute, Board of Scientific Counselors Meeting, March

1992.
76 I Researching Health Risks

its support in 1980. Today, the agency, which is

located in Jefferson, Arkansas, pursues a research

agenda that responds to the needs of FDA. The

major objectives of its seven programs are to

conduct basic research aimed at understanding

the mechanisms of chemical interactions and

develop better methods to assess toxicity. Collectively, its studies seek to define risks to human

health from exposure to toxicants in foods, animal

and human drugs, cosmetics, medical devices,

and biologics. A further goal is to improve the

agency’s ability to predict the risks posed to

humans by toxic agents.

Four programs at NCTR conduct basic research aimed at improving risk assessment (U.S.

DHHS, NCTR, 1992). Three of them investigate

the mechanisms by which environmental agents

can cause adverse health effects, and the fourth

examines the effects of nutrition on toxicity. The

Developmental Toxicology Program attempts to

understand how compounds produce developmental effects such as mental retardation and

other birth defects. Similarly, the Neurotoxicology Program uses a multidisciplinary approach to

integrate information from all avenues of neurotoxicity, in order to understand how chemicals

may produce brain-related and nervous system

toxicity. The Secondary Mechanisms of Toxicology Program investigates the role of normal

biochemical processes in the bioactivation of

compounds-that is, how enzymes found in

normal individuals may transform relatively nontoxic compounds into toxic chemical intermediates.

Unlike the other programs conducting basic

research, the Nutritional Modulators of Risk and

Toxicity Program examines the effects of a

normal diet on the biological responses of animals to toxic substances. In conjunction with the

National Institute on Aging and FDA’s Center for

Food Safety and Applied Nutrition, the program

is in year 6 of a 10-year project to examine the

effects of calorie-restricted diets on responses to

toxic chemicals. The program also conducts

toxicity studies of food contaminants, which

occur in a portion of the products FDA regulates.

Focusing on methodological studies, the Quantitative Risk Assessment and Extrapolation Program conducts studies that focus on improving

the statistical procedures for analyzing data that

identify adverse effects on health. In addition, the

program examines the assumptions used to extrapolate experimental results to different situations, such as extrapolating the results from

animal models to humans or from high doses in

test conditions to the low levels found in the

environment (U.S. DHHS, NCTR, 1992). Adding

to earlier studies on low-dose extrapolation for

carcinogens (Gaylor and Kodell, 1980), NCTR’s

recent work includes developing procedures to

examine the risks of mixtures of carcinogens

(Kodell, 1993), developmental and reproductive

effects (Kodell et al., 1991), and neurotoxic

effects (Gaylor, 1993).

The agency has recently created two new

programs. The major goal of the Biochemical and

Molecular Markers of Cancer Program is to

develop and validate biomarkers of exposure,

susceptibility, and effect. The Transgenics Program exploits current biochemical and molecular

biological methods to incorporate human DNA

into human or rodent cells or whole-rodent

systems to provide scientists with a tool for

studying how chemicals interact with human

DNA.

NCTR’s current structure and emphasis results

from several efforts to link its research activities

more closely to the regulatory activities of FDA.

In 1985, DHHS’s Committee to Coordinate

Environmental and Related Programs, which

oversees the department’s environmental health

activities, prepared a report on risk assessment

and risk management that included a section on

research needs (U.S. DHHS, 1985).6 Based on the

committee’s recommendations, NCTR decided to

direct more of its research funds toward risk

c IU Iggq w Assistant swre~ for Health formed a task force to evaluate the implementation and mdevance of the mpofi (Ho& 1992).
Chapter 3: Federal Research in Health Risk Assessment 77

assessment (Houk, 1992). Thus, by 1990, NCTR

was allocating nearly 70 percent of its research

funds to reducing key uncertainties in risk assessment (Anson, 1993). Its research will continue to

be investigator-initiated but at the same time will

focus more on the regulatory needs of FDA.

Center for Devices and Radiological Health

--CDRH develops and implements national programs to regulate medical devices and radiological health risks, The center’s Office of Science and Technology provides the scientific

foundation for an array of CDRH functions and

leads CDRH activities in risk assessment. Its

research mission includes laboratory and field

research related to the effects on human health of

ionizing and non-ionizing radiation and of medical devices, such as breast implants (Scheineson,

1992).

CENTERS FOR DISEASE CONTROL

AND PREVENTION

The National Center for Environmental Health

(NCEH) and the National Institute for Occupational Safety and Health are the primary participants in risk assessment research at the Centers

for Disease Control and Prevention (CDC). NCEH,

formerly the National Center for Environmental

Health and Injury Control, conducts investigations, epidemiologic studies, and surveillance

programs on environmental hazards as causes of

human diseases. It emphasizes epidemiologic

studies and exposure surveys in its investigations.

Its research to improve risk assessments is a small

subset of its programs, but it includes such public

health concerns as lead and dioxin (Houk, 1992).

National Institute for Occupational Safety

and Health—The National Institute for Occupational Safety and Health, which administratively resides in CDC, conducts research aimed at

protecting the health and safety of U.S. workers.

NIOSH coordinates its research program of lab

investigations, field surveys, and epidemiologic

studies so that appropriate standards and control

measures can be recommended to the appropriate

regulatory offices, the Occupational Safety and

Health Administration (OSHA) and the Mine

Safety and Health Administration (MSHA), within

the Department of Labor (U.S. DHHS, CDC,

1992).

NIOSH’s research programs are divided among

its several divisions. For example, the Division of

Biomedical and Behavioral Science investigates

the neurobehavioral and neurophysiological effects of exposure to chemical and physical agents

in the workplace. The division’s toxicology

program develops assays for biomarkers of exposure, effects, and host susceptibility and seeks to

understand the dose-response effects and mechanisms of action of toxic agents.

The Division of Respiratory Disease Studies

conducts epidemiologic studies at mines, mills,

and other industrial, construction, and agricultural workplaces to assess the risk of respiratory

disease from exposures in the workplace. It also

performs clinical studies to clarify the mechanisms of human responses. The division collects

data on occupational exposure and also develops

animal models for toxicological studies and for

identifying early markers of respiratory disease.

The Division of Surveillance, Hazard Evaluations, and Field Studies monitors the Nation’s

work force and workplaces to assess the magnitude and extent of job-related illnesses, exposures, and hazardous agents. Fulfilling its legislative mandate, this unit conducts evaluations of

worksite health hazards at the request of unions,

employers, or employees; it also performs industrywide epidemiologic and industrial hygiene surveys. For example, the division is currently

managing and conducting analytic epidemiologic

studies of workers at DOE facilities.7

Most of the research at NIOSH involves

toxicological and epidemiologic studies to iden7 This responsibility was transferred from DOE to NIOSH through a memorandum of understanding between the agencies in December

1990.
78 I Researching Health Risks

tify occupational hazards. The agendas of the

regulatory agencies, OSHA and MSHA, largely

drive research priorities at the institute.

In addition to research, NIOSH conducts risk

assessments. These risk assessments are presented in the NIOSH criteria documents on

specific occupational hazards. Scientists in the

newly formed Risk Assessment Program conduct

risk assessments for the institute, and they also

conduct methodological research as part of the

assessments. They are currently expanding risk

assessments to topics of public health concern, in

addition to responding to OSHA-MSHA regulatory rulemaking (Stayner, 1992).

Quite apart from the scientific and risk assessment capacities of NIOSH, its relationship with

OSHA has been and remains problematic. Several

authors have discussed the stresses and strains of

the relationship under different directors and

Presidential priorities (Bingham, 19!

1992; Robinson et al., 1991).

AGENCY FOR TOXIC SUBSTANCES

AND DISEASE REGISTRY

The Comprehensive Environment

2; Hardin,

Response,

Compensation, and Liability Act of 1980 (more

often called ‘Superfund’ established the Agency

for Toxic Substances and Disease Registry

(ATSDR). The agency’s mission is to conduct

applied research on the health effects resulting

from exposure to hazardous substances at hazardous waste sites. Most of the research efforts under

way at ATSDR relate to exposure assessment

(Johnson, 1992b; Johnson and Jones, 1992),

especially at EPA-designated Superfund sites

(Johnson, 1992a), and ATSDR is instituting

several programs devoted to assessing exposures

at hazardous waste sites. The agency is also

planning a Center for Exposure Characterization,

which will develop interdisciplinary research

programs for characterizing complex exposure

scenarios. In collaboration with EPA and NTP,

ATSDR is developing a program of applied

research that will assess the risks posed by

particular hazardous substances at hazardous

waste sites and develop a list of the needed data

for each substance.8

 Department of Energy

DOE’s health research focuses on the study of

effects of exposure to radiation and chemicals

associated with the production of energy. Under

this broad mandate, DOE supports many areas of

research on risk assessment, and its historical

emphasis has been on epidemiology and experimental toxicology. Currently, as DOE moves

from the production of weapons to disarmament,

those two areas of research are being transformed

in different ways: epidemiologic research is

growing, but research in experimental toxicology

(i.e., DOE’s “health effects” research) is contracting as the department’s emphasis shifts to

more basic research, especially research for the

Human Genome Project. In addition, Congress

designated DOE as the lead agency to coordinate

the Federal research efforts that are investigating

the health effects of prolonged exposure to

power-line electromagnetic fields.

The budget for DOE’s health effects research,

which includes agent-specific toxicity studies of

radiation and toxic chemicals, mostly in vitro, is

currently about $30 million, much reduced since

the 1980s. In contrast, DOE’s budget for epidemiologic research has doubled in the past 2 years and

now stands at about $60 million. Compared with

NCI, DOE’s epidemiologic studies are more

narrowly focused, and the agency supports researchers conducting studies at DOE facilities

and at other national and international energy

production sites (Ripple, 1992). About a third of

DOE’s budget for epidemiologic research is

funneled to CDC, which manages DOE’s studies

of worker mortality through NIOSH, overseeing

grants and contracts to researchers at universities

and DOE facilities (U.S. Congress, OTA, 1993).

g The Superfund Amendments and Reauthorization Act of 1986 directs ATSDR to conduct this activity,
Chapter 3: Federal Research in Health Risk Assessment 79

The DOE laboratory system comprises more

than 30 laboratories. Most of those are federally

owned ‘‘national laboratories, ’ which are operated for DOE by universities, university consortia, or industrial contractors. Nine of the largest

are multiprogram national laboratories with multidisciplinary capabilities and extensive research

facilities. OTA identified specific kinds of health

risk assessment research at the following national

laboratory facilities: Argonne, Illinois; Brookhaven,

New York; Lawrence Livermore, California; Oak

Ridge, Tennessee; Pacific Northwest Laboratory,

Washington; the Inhalation Toxicology Research

Institute, New Mexico; and the Laboratory of

Biomedical and Environmental Science, California. Health effects research at the national laboratories includes research at Brookhaven to measure the ability of human cells to repair DNA in

response to DNA damage from exposure to

ionizing radiation and organic solvents. DOE

funds research at Lawrence Livermore Laboratory for research in epidemiology and health

effects. The Pacific Northwest Laboratory is

located at the Hanford, Washington DOE facility

and has some research that can be directly linked

to the cleanup efforts at the Hanford facility.

Two DOE offices, the Office of Health and

Environmental Research and the Office of Epidemiology and Health Surveillance, account for

the bulk of research in health risk assessment

through grants and contracts to university-based

researchers and researchers at the DOE national

laboratories. Although the distribution of funds

among those two types of recipients varies from

year to year, estimates are that about 50 percent of

DOE’s health effects research and 25 percent of

its epidemiologic research are carried out at the

national laboratories (Beall, 1992; Goldsmith,

1992) 0

The Office of Health and Environmental Research manages about a third of all health risk

assessment research at DOE. This office does not

conduct research per se. Rather, it reviews,

oversees, and funds research applications; provides for external peer review; and sets research

priorities in conjunction with DOE-supported

researchers in universities and the DOE national

laboratories.

The Office of Epidemiology and Health Surveillance is in the midst of expansion, reorganization, and renewal following a commitment by

DOE to strengthen its health and safety research.

The vast majority of the research funded by this

office is devoted to human studies, but it also

funds some animal research. The health surveillance program targets DOE workers—including

those engaged in cleanup activities-and communities living near cleanup sites. A new effort is

focusing on the potential effects on health of new

energy technologies.

Until the late 1980s, historical commitments to

Japan, the Marshall Islands, and the U.S. military

dictated multimillion-dollar expenditures for longterm epidemiologic studies. The scale of those

commitments appears to have left little discretion

in establishing priorities. Many of those longterm projects are continuing, but because the

budget for epidemiologic research has increased,

research managers now have an opportunity to

advance other priorities. Indeed, DOE has instituted myriad changes in its priority-setting process, in part as a result of criticism that the

epidemiology program had not developed clear

goals (U.S. DOE, 1990).

DOE is also preparing a milestone planning

document, a research agenda that carefully sets

specific research priorities for the agency’s epidemiologic research over the next several years.

The Office of Epidemiology and Health Surveillance drafted the agenda in consultation with the

National Academy of Sciences, and the document

is now undergoing review. DOE plans to use the

agenda, which should be available to the public in

late 1993, as the blueprint for research project

grants that the office would like to fund.

 Department of Defense

The mission of the Department of Defense

(DOD) is to protect national security and ensure
80 Researching Health Risks

military preparedness, and its priorities for research related to risk assessment are set within

that context. In the area of toxicology, prioritysetting takes into account forces external to the

military that drive research priorities, such as

scientific advances, regulatory requirements, and

public concerns, and the ongoing impetus to

increase cross-service coordination and cooperation, as initiated by Project Reliance and the Base

Relocation and Closure Commission (U.S. DOD,

1993). Research efforts that receive priority are

those to develop improved methodologies for

describing, quantifying, and understanding toxicity (particularly the endpoints of special concern

to the military), and expanding the ability to

predict toxicity from existing data or from limited

data sets.

A primary consideration for toxicity testing at

DOD is preventing adverse health effects from

exposure to defense-related chemicals in the

workplace. Although the research needs of the

three services differ, similarities in their occupational settings result in many overlapping research projects, which provide opportunities to

share resources and information. As part of the

move toward consolidating service activities and

avoiding needless duplication of projects, the

Army is relocating its toxicology program to

Wright-Patterson Air Force Base in Ohio, which

already hosts the “collocated” toxicology programs of the Navy and Air Force.9 The Army’s

decision has fostered further efforts toward joint

planning with the goal of developing a TriServices Center for Toxicology and Risk Assessment at Wright-Patterson. 10 One cross-service

research project, for example, is looking at

alternative methods of evaluating toxicity by

using simpler animal models. A particularly

promising test model is the medaka, a fish that can

be exposed to a variety of service-related substances (Ostermann, 1992).

 Consumer Product Safety Commission

The Consumer Product Safety Commission

(CPSC) is an independent commission of three

members appointed by the President. CPSC both

performs and funds research on chemicals of

regulatory interest (i.e., chemicals in consumer

products to which the public may be exposed).

CPSC staff perform exposure studies that relate

the results of exposure testing to potential human

risk; they supplement those data in most cases

with information from research on marketing and

product use to gain a more complete picture of

consumer exposure.

The three presidentially appointed members of

the Commission decide which projects CPSC will

undertake. They also approve an operating plan

for each fiscal year and conduct a mid-year review

to determine program progress and adequacy of

funding (Cohn, 1992). In some cases, Congress

specifies topics on which resources are to be

spent. CPSC staff usually recommend projects to

the commissioners, who then set priorities. Statutory mandates require that the commissioners

hold public hearings on priorities and announce

the hearing in advance in the Federal Register.

 Department of Agriculture

The Agricultural Marketing Service (AMS) of

the U.S. Department of Agriculture (USDA)

began the pesticide residue testing program in

May 1991 as part of USDA’s Pesticide Data

Program (PDP). This program collects actual

concentration levels of pesticide residues in fresh

fruit and vegetables reaching the consumer. AMS

developed PDP’s policy and operations procedures and residue testing priorities in close

cooperation with EPA and FDA. These data are

used by EPA for pesticide risk assessment and

serve as a database for national residue levels so

that the government can respond more effectively

g The Navy and Air Force have collocated their toxicology programs at Wright-Patterson for 15 years (U.S. DOD, 1993).

10A tri-semicespro~m~ existed intermittently over the course of the past 5 years, but unstablefunding has kept it frommmahiug tile.

Now, however, military administrators are showing renewed interest in the program (Macys, 1993).
Chapter 3: Federal Research in Health Risk Assessment 81

to food safety issues. The residue monitoring

program is being implemented in stages, based on

the data needs expressed by EPA. The data will be

collected in California, Florida, Michigan, New

York, Texas, and Washington.

 Nuclear Regulatory Commission

Activities related to risk assessment at the

Nuclear Regulatory Commission (NRC) cover a

wide range of research, especially that on the

health risks from exposure to radiation. Scientists

in NRC’s Division of Energy and Materials are

studying the potential adverse effects of electromagnetic fields on health, as well as the effects of

radiation. Work is also under way examining the

feasibility of reducing the uncertainties in estimating risks from protracted exposure to low

doses of ionizing radiation. NRC has also funded

research on placental transfer and other factors

affecting the dose of radiation to the developing

embryo.

TRENDS AND GAPS

Over the course of this study, OTA observed

several major trends in the array of Federal

research activities that support health risk assessment. To begin with, agencies are expanding the

scope of their activities, previously focused on

cancer, to include other adverse health effects.

EPA’s RIHRA program, for example, now devotes only 10 to 20 percent of its resources to

cancer-related research (Vandenberg, 1992). NIEHS

is also reorganizing and broadening its research

program to investigate mechanisms of noncancer

toxicity (Olden, 1992).

Many scientists interviewed by OTA expressed

the belief that research on health effects other than

cancer has the potential to influence regulatory

policy significantly. One reason that such research may have a substantial impact on policy is

that noncarcinogenic mechanisms do not give rise

to the often acrimonious policy debates associated with issues related to carcinogenesis, such as

thresholds for carcinogens (see ch. 2). Those

debates have precluded any indication of flexibility in the policy positions of many agencies. The

scientists interviewed also believe, however, that

the current science base is not sufficient for

adequate risk assessments of noncarcinogenic

endpoints.

Along with expanding the focus of their

studies, many agency research programs have

also been undergoing some form of organizational restructuring. In most of those cases, the

restructuring reflects a greater emphasis on social

relevance: EPA is shifting to risk-based planning,

with the intention of directing agency resources to

areas posing the greatest health risks (Reilly,

1991; U.S. EPA, 1992a); NIEHS is expanding its

role in improving the science base for human risk

assessment (Olden, 1993; Stone, 1993); and the

research activities of NCTR scientists are being

more closely aligned with the regulatory needs of

FDA (Norris 1993; U.S. DHHS, FDA, 1991). All

of those restructuring efforts constitute a departure from the traditional notion of allowing

scientists to “follow their noses’ and focus on

investigator-initiated areas of interest (Carnegie

Commission, 1992; Stone, 1993; U.S. Congress,

House Committee on Science, Space, and Technology 1992). OTA was unable, however, to

evaluate the effectiveness of those efforts because

they had not yet been fully implemented.

As agencies link their research activities more

closely to the needs of society, their research

becomes, by necessity, increasingly multidisciplinary. No one field of academic training or

research covers all of the data needed for a

sufficiently comprehensive risk assessment; the

relevant fields range from basic biomedical research to computer models for simulating experimental conditions. The increasing complexities

of the science involved and the need to incorporate more science into regulatory rulemaking

have made it clear that multidisciplinary research

is required to provide the requisite scientific

underpinning for future risk assessments. Dwindling agency resources have also catalyzed these

interactions as the necessity for cooperation is
82 I Researching Health Risks

becoming apparent. Setting aside turf battles,

Federal agencies are beginning piecemeal approaches to promoting these multiagency, multidisciplinary interactions.

Yet overall, few incentives exist for long-term

multiagency, multidisciplinary research on health

risks, and very few resources are allocated to that

work. Scientists from all of the environmental

health disciplines, including toxicology, epidemiology, biostatistics, and clinical studies, make

contributions to health risk assessments and are

the mainstay of agency research efforts to improve the risk assessment process (Paustenbach,

1989). Nonetheless, those fields remain disparate,

and collaborative studies are still the exception

rather than the rule. Without more and better

incentives to collaborate, disciplinary myopia

may continue and grow more pronounced and

entrenched. Compartmentalization by agency or

discipline can only hinder the progress of risk

assessment research and prevent the infusion of

newly developed technologies and knowledge

arising from the rapid advances now occurring in

the biomedical sciences.

Collaborative research is particularly needed to

evaluate and validate new methods and models

with experimental data. Despite the importance to

risk assessment research of systematic efforts in

this area, OTA found little indication of such

work, especially in the important field of corroborating experimental results from animal studies

with studies in humans. A few examples were

observed: EPA employs exposure chambers to

study the clinical effects of air pollutants and uses

the results to examine the predictive success of

test animal models (U.S. Congress, OTA, 1991b;

U.S. EPA, 1992b) (see box 3-A), and NTP and

NOSH collaboratively evaluate and compare

human and animal responses in the areas of

reproductive toxicology and immunotoxicology

(Schwetz, 1992). Researchers from NIEHS initiated a study of carcinogenicity prediction methods by comparing the results of predictions based

on chemical structure and short-term tests against

the results of rodent bioassays for 44 chemicals

tested by NTP (Hileman, 1993). Beyond those

few programs and studies, however, little research appears to be under way to bridge the gap

between data gathering and basic research by

examining or validating whether testing or extrapolation models can be applied to specific

chemicals. In fact, at least one analyst contends

that the government’s public health programs

have been hamstrung by their lack of ability,

funding, or motivation to conduct such “bridging” studies, which would validate risk assessment methodology (Mirer, 1992).

With additional resources, Federal agencies

could conduct bridging studies on existing data

sets that are presently underused (if used at all) for

analysis and methods development. Such data are

available from several sources. The Federal

Government has collected toxicity information in

response to mandates for registering or approving

drugs and chemicals (U.S. Congress, OTA, 1991c).

FDA requires manufacturers to submit clinical

studies on pharmaceuticals but makes little or no

effort to use those data for analysis, such as in

pharmacokinetic studies or for validating the

results of animal assays (Gaylor, 1993). Similarly, EPA has performed little analysis of the

manufacturer-supplied information on pesticides

that it collects (Kozumbo, 1993), nor has NTP

fully analyzed the entire set of data from the

rodent bioassays it conducts (Huff, 1993b).

Although some advances are being made in

those areas (see, for example, Quest et al., 1993;

Huff, 1993a; and Ashby and Tennant, 1993), in

general the agencies provide few incentives or

funding opportunities. Of course, in some cases,

formidable obstacles prevent agencies from using

these data, which are often from tests of proprietary chemicals and drugs, and whose release

could hamper industrial competitiveness. Nevertheless, this information constitutes a repository

of valuable research data that could improve risk

assessments. Both the animal and human data in

conjunction with an improved understanding of

the mechanisms of environmentally induced diseases could be used to evaluate and validate
Chapter 3: Federal Research in Health Risk Assessment 83

existing models as well as develop new ones. But,

such research requires better collaboration between and among agencies and research disciplines.

SUMMARY

Federally supported risk assessment research is

spread out across at least 12 different Federal

agencies, institutes, and centers. That dispersion

has both positive and negative consequences. On

the one hand, agencies can monitor their own

research efforts without having to overcome

bureaucratic hurdles, and they can target their

research to the areas they consider of highest

priority. On the other hand, work is fragmented

and diffuse. Fragmentation generally impedes the

dissemination of information (Klein, 1990; U.S.

Congress, OTA, 1991a), and hampers progress

toward a stated objective—in this case, better risk

assessments. In addition, this diffusion works

against developing multiagency programs that

could produce solutions to common risk assessment problems.

The past decade has witnessed nearly revolutionary developments in the biological sciences.

Researchers are poised to incorporate those advances into the field of environmental health,

especially into improving health risk assessments

(Olden, 1993; U.S. DHHS, 1991 b).

Yet despite the potential for advances, the

present Federal risk assessment research and

development infrastructure remains a source of

controversy. Many scientists interviewed by OTA

claim that this research system is ‘‘broke. ’

Resources, they argue, are squandered on a

system that is incapable of setting priorities.

Consequently, the perception exists that the areas

of research of highest priority-those most likely

to improve risk assessment approaches—are not

being funded or studied, at the expense of

lower-priority or even irrelevant research. The

nature of the ‘‘right’ research, however, remains

an area of active debate. How agencies determine

their research priorities is an important element of

that controversy.

CHAPTER 3 REFERENCES

Adamson, R. 1992. Director. Division of Cancer

Etiology, National Cancer Institute. Personal communication.

Anson, J. 1993. Director. Division of Planning,

National Center for Toxicological Research, U.S.

Department of Health and Human Services. Personal

communication.

Ashby, J., and Temant, R. 1993. Prediction of rodent

carcinogenicity for 44 chemicals: results. Report to a

public meeting held May 23 and 24, 1993 in Research

Triangle Park, NC.

Barrett, C. 1993. Director. Laboratory of Molecular

Carcinogenesis, National Institute of Environmental

Health Sciences. Personal communication.

Baurngarten, M., and Oseasohn, R. 1980. Studies on

Occupational Health: A Critique. Journal of Occupational Medicine 22: 171-176.

Beall, J. 1992. U.S. Department of Energy. Personal

communication.

Bingham, E. 1992. Professor, Environmental Health,

University of Cincinnati. Personal communication.

Carnegie Commission. 1992. Environmental Research

and Development: Strengthening the Federal Infrastructure. Report of the Carnegie Commission on

Science, Technology, and Government.

Cohn, M. 1992. Health Sciences Directorate, U.S.

Consumer Product Safety Commission. Personal communication.

Gaylor, D. 1993. Director. Division of Biometry and

Risk Assessment, National Center for Toxicological

Research, U.S. Food and Drug Administration. Personal communication.

Gaylor, D.W. 1993. Modeling for risk assessments of

neurotoxic effects. Presented at the Conference on the

Risk Assessment Paradigm After Ten Years: Policy

and Practice Then, Now, and in the Future, WrightPatterson Air Force Base, OH. Apr. 5-8.

Gaylor, D. W., and Kodell, R.L. 1980. Linear interpolation algorithm for low dose risk assessment of toxic

substances. Journal of Environmental Pathology and

Toxicology 4:305-3 12.
84 I Researching Health Risks

Goldsmith, R. 1992. U.S. Department of Energy.

Personal communication.

Gnesemer, R. 1992. Deputy Director, NationaJ Institute of Environmental Health Sciences. Personal

communication.

Hardin, B. 1992. Assistant Director. National Institute

for Occupational Safety and Health. Personal communication.

Healy, B. 1992. Is this your father’s NIH? And other

strategic questions. Science 257:312.

Hileman, B. 1993. Expert tuition tops in test of

carcinogenicity prediction. Chemical and Engineering

News June 21, pp. 35-37.

HoulG V.N. 1992. Assistant Surgeon General and

Director of the National Center for Environmental

Health. Centers for Disease Control and Prevention.

U.S. Public Health Services. Personal communication.

Huff, J., Haseman, J., and Rail, D. 1991. Scientific

concepts, value, and significance of chemical carcinogenesis studies. Annual Review of Pharmacology and

Toxicology 31 :621-652.

Huff, J,E. 1993a. Issues and controversies surrounding

qualitative strategies for identifying and forecasting

cancer causing agents in the human environment.

Pharmacology and Toxicology 72(Suppl.1): 12-27.

Huff, J.E. 1993b. Associate Director for Risk Evaluation. National Toxicology Program. U.S. Department

of Health and Human Services. Personal communication.

Johnson, B. 1992a. Director. Agency for Toxic Substances and Disease Registry, U.S. Public Health

Service. Personal communication.

Johnson, B.L. 1992b. A precis on exposure assessments. Journal of Environmental Health 55:6-9.

Johnson, B. L., and Jones, D.E. 1992. ATSDR’S

activities and views on exposure assessment. JournaZ

of Experimental Analysis and Environmental Epidemiology (Suppl. 1): 1-17.

Klein, J.T. 1990. Interdisciplinarity: History, Theory

& Practice. Wayne State University Press. MI.

Kodell, R.L. 1993. Reducing consematism in risk

estimation for mixtures of carcinogens. Presentation at

the Conference on the Risk Assessment Paradigm

After Ten Years: Policy and Practice Then, Now, and

in the Future, Wright-Patterson Air Force Base, OH,

Apr. 5-8.

Kodell, R.L., Howe, R.B., Chen, J.J., and Gaylor, D.W.

1991. Mathematical modeling of reproductive and

developmental toxic effects for quantitative risk assessment. Risk Analysis 11: 583-590.

Kozurnbo, W. 1993. OffIce of Pesticides and Toxic

Substances, U.S. Environmental Protection Agency.

Personal communication.

Lucier, G.W. 1993. Chief. Laborato~ of Biochemical

Risk Analysis, National Institute of Environmental

Health Sciences. Personal communication.

Lucier, G. W., Portier, C.J., and Ga.llo, M.A. 1993.

Receptor mechanisms and dose-response models for

the effects of dioxins. Environmental Health Perspectives 101(1):3644.

Macys, D. 1993. Officer-in-Charge. Naval Medical

Research Institute, U.S. Navy. Personal communication.

Mirer, F.E. 1992. Director. Health and Safety Department, United Automobile, Aerospace & Agricultu.ml

Implement Workers of America-UAW. Personal

communication.

Moolenaar, R.J. 1992. Overhauling carcinogen classification. Issues in Science and Technology 8(4):70-75.

National Cancer Institute. 1992. Scientific foundation

of cancer prevention: molecular epidemiology, diet

and cancer, chemoprevention. 1994 budget estimate.

Norris, F. 1993. Acting Director. National Center for

Toxicology Research, U.S. Department of Health and

Human Services. Personal communication.

Olden, K. 1992. Director, National Institute of Environmental Health Sciences. U.S. Public Health Service. Personal communication.

Olden, K. 1993. Environmental health science research and human risk. Regulator-y Toxicology and

Pharmacology 17(2):230-233.

Ostermann, J. 1992. Deputy Assistant Secretary for

Defense Resewh and Engineering, U.S. Department

of Defense. Personal communication.

Paustenbach, D.J. 1989. Important recent advances in

the practice of health risk assessment: implications for

the 1990s. Regulatory Toxicology Pharmacology 10:204-

243.
Chapter 3: Federal Research in Health Risk Assessment 185

Portier, C. 1993. Acting Chief. Laborato~of Quantitative Computation and Biology. National Institute for

Environmental Health Sciences. Personal communication.

Quest, J.A., Fenner-Cnsp, P. A., Burnarn, W. et al.

1993. Evaluation of the carcinogenic potential of

pesticides. 4. Chloralkylthiodicarboxamide compounds

with fungicidal activity. Regulatory Toxicology and

Pharmacology 17(1):19-34.

Reilly, W.K. 1991. Why propose a national debate on

risk? EPA Journal March/April :2-5,

Reiter, L. 1992. Director. Health Effects Research Lab,

U.S. Environmental Protection Agency. Personal communication.

Ringen, K. 1992. Comments on the National Toxicology Program: final report of the advisory board.

Presented to the Board of Scientific Counselors,

National Toxicology Program, Washington, DC, Sept.

11.

Ripple, S. 1992. The use of retrospective health risk

assessments at nuclear weapons facilities. Erzvironmental Science and Technology 26: 1270-1276,

Robinson, J., Paxman, D,, and Rappaport, S. 1991.

Implications of OSHA’S reliance on TLVS in developing the air contaminants standard. American Journal of

Industrial Medicine 19:3-13.

Scheineson, M.J. 1992. Associate Commissioner for

Legislative Affairs. Food and Drug Administration.

Department of Health and Human Services. Personal

communication.

Scheuplein, R. 1992. Director, Center for Food Safety

and Applied Nutrition, U.S. Food and Drug Administration. Personal communication.

Schwetz, B.A. 1992, Chief, Systems Toxicity Branch,

Division of Toxicology Research and Testing, National Toxicology Program, U.S. Department of

Health and Human Services. Personal communication.

Stayner, L. 1992. Assistant Director for Risk Assessment Program. Division of Standards Development

and Technology Transfer, U.S. Department of Health

and Human Services. Personal communication.

Stone, R. 1993. Ken Olden heals NIEHS’S “split

brain. Science 259: 1398-1399.

Temant, R. 1992. Chief. Experimental Carcinogenesis

and Mutagenesis Branch, National Institute of Environmental Health Sciences, U.S. Department of Health

and Human Services. Personal communication.

Thigpen, K. 1993. Twenty years of environmental

health research: a dedication to D.P. Rail. Introduction.

Environmental Health Perspectives 100:3-7.

U.S. Congress, House Committee on Science, Space,

and Technology. 1992. Report of the Task Force on the

Health of Research.

U.S. Congress, OTA (Office of Technology Assessment). 1989. Catching Our Breath: Next Steps for

Reducing Urban Ozone. OTA-O-413.

U.S. Congress, OTA. 1991a. Federally Funded Research: Decisions for a Decade. OTA-SEI’-49O.

U.S. Congress, OTA. 1991b. Identifying and Controlling Pulmonary Toxicants. OTA-BP-BA-91.

U.S. Congress, OTA. 1991c. Neurotoxicity: Identi~-

ing and Controlling Poisons of the Nervous System.

OTA-BA436.

U.S. Congress, OTA, 1993. Hazara3 Ahead: Managing Cleanup Worker Health and Safety at the Nuclear

Weapons Complex. OTA-BP-O-85.

U.S. DHHS (Department of Health and Human

Services). 1985. Risk assessment and risk rnanugement

of toxic substances. A report to the Secretary from the

Executive Committee, DHHS Committee to Coordinate Environmental and Related Programs.

U.S. DHHS. 1991a. Fiscal year 1991 annual plan.

National Toxicology program, DHHS. U.S. Public

Health Service.

U.S. DHHS. 1991b. Human health and the environment—

some research needs, Draft Report of Task Force IV,

National Advisory Environmental Health Series Council. National Institute of Environmental Health Sciences.

U.S. DHHS. 1991c. Review of Current DHHS, DOE,

and EPA Research Related to Toxicology. National

Toxicology Program, DHHS. U.S. Public Health

Service.

U.S. DHHS. 1991d. Sixth Annual Report on Carcirwgens: Summary, National Toxicology program, U.S.

Public Health Service.

U.S. DHHS. 1992. National Toxicology Program;

draft response of the program to recommendations in

the final report of the advisory review by the NIT
86 I Researching Health Risks

Board of Scientific Counselors: request for comments.

Fe&ral Register 57:61439-61444.

U.S. DHHS. CDC (Centers for Disease Control and

Prevention) 1992. NIOSH FY 1992-1993 Program

Briefing.

U.S. DHHS. NCIll (National Center for Toxicological

Research) 1992. NCTR Research Plan 1992-1993.

U.S. DOD (Department of Defense). 1993. Coordinated response to the Office of Technology Request for

Information. March 24.

U.S. DOE (Department of Energy). 1990. Report to the

Secretary, March 1990. Secretarial Panel for the

Evaluation of Epidemiologic Research for the U.S.

Department of Energy.

U.S. EPA (Environmental Protection Agency). 1987.

Unfinished business: a comparative assessment of

environmental problems. Office of Policy Analysis,

Office of Policy, Planning, and Evaluation.

U.S. EPA. 1990, Reducing risk: setting priorities and

strategies for environmental protection. Report of

Relative Risk Reduction Strategies Committee, Science Advisory Board, to W.K. Reilly, Administrator,

U.S. EPA.

U.S. EPA. 1991. Alpha 2u-globulin: association with

chemically induced and renal toxicity and neoplasia in

the male rat. Risk Assessment Forum (EPA/625/3-91/

019F).

U.S. EPA. 1992a. Issue based plaming at EPA. Drafl

for external review.

U.S. EPA. 1992b. Research and development: looking

to the future (EPN600/R-92/132).

U.S. EPA. 1992c. Safeguarding the Future: Credible

Sciencep Credible Decisions (EPA/600/9-91/050).

Vandenberg, J. 1992. Director. Research to Improve

Health Risk Assessment Program, U.S. Environmental

Protection Agency. Personal communication.

Vandenberg, J. 1993. Director. Research to Improve

Health Risk Assessment Program, U.S. Environmental

Protection Agency, Personal communication.
—

Setting

Priorities

for Risk

Assessment

Research 4

c

ongressional mandates for risk reduction, the public’s

desire for health and safety, and court rulings requiring

justification of health-based regulatory actions have

increased pressure to provide ever greater scientific

underpinnings for health risk assessments. Judged by the rate of

change in risk assessment methodology and the controversies

that surround risk assessment, Federal agencies lack the necessary resources to meet that demand and can only support a

portion of the research that could or would be useful to them. This

chapter examines how Federal agencies determine their priorities

for health risk assessment research, that is, the type or types of

research an agency will support and conduct. For this analysis,

the Office of Technology Assessment (OTA) categorized such

research as methodological, basic, or chemical-specific data

development.

Priority-setting is influenced by factors that operate at the

national, agency, or programmatic levels. The impact of national

goals on individual projects or, conversely, the effect of

individual projects on national goals, is difficult to gauge, but

generally one can expect that effects at one level will reverberate

to another. For example, the acquired immunodeficiency syndrome (AIDS), became a national concern, and more resources

were directed toward understanding the disease, which resulted

in greater participation by scientists from different disciplines in

the research, The influx of talent and resources affected the

nature of the approaches used to combat the disease and also

contributed to research in other fields (U.S. Congress, OTA,

1990).1

L I

] See Joseph (1992) for a discussion of the role of politics in setting the scientific and

public health priorities for AIDS research and treatment.

87
88 I Researching Health Risks

CATEGORIZING HEALTH RISK

ASSESSMENT RESEARCH

The types of research that Federal agencies

conduct to improve health risk assessments can be

categorized using several different approaches.

One approach is the traditional division between

basic and applied scientific research (Merton,

1973). That approach would distinguish research

focused on, expanding knowledge about human

diseases and their relationships to environmental

factors from research more directly linked to

regulatory agendas.

Basic or pure science involves studies “ordered around the expansion of knowledge and

competence without any regard for practical

application’ (Barnes and Edge, 1982). For health

risk assessment, this kind of research usually

occurs within well-defined disciplinary boundariesfor instance, genetics, molecular biology, chemistry—

and involves testing explanatory hypotheses (e.g.,

about the normal and abnormal functions of organ

systems or mechanisms of carcinogenesis) with a

variety of experimental methods.

Applied science, in contrast, focuses on increasing and improving “the stock of existing

practically useful techniques, processes, and artifacts” (Barnes and Edge, 1982). It involves

developing information that may be useful for

resolving outstanding practical questions (Lindblom and Cohen, 1979). For health risk assessment, those questions are usually determined by

the management problems that regulatory agencies confront (e.g., should human exposure to air

pollution be reduced?), and they require interdisciplinary efforts to characterize the pros and cons

of taking action. Applied research in health risk

assessment can involve experimentation that also

contributes to basic scientific understanding, but

its predominant motivation is to provide a basis

for regulatory decisionmaking.

There are two broad subcategories of applied

research in health risk assessment: 1) substancespecific investigations, e.g., conducting toxicity

tests or monitoring exposures; and 2) methodological research that can improve either qualitative or quantitative risk assessment techniques,

e.g., developing new testing methods or new

low-dose extrapolation models.

Although these categories of risk assessment

research are useful for characterizing the activities of Federal agencies, they are not absolute

because the boundaries between basic and applied

research are frequently blurred. Neurotoxicity

testing, for example, can contribute to a basic

understanding of neurobiology even as it produces results that are useful for identifying

neurotoxic agents for regulatory purposes. Similarly, basic scientific findings, such as the discovery of oncogenes, have important implications for

applied research on chemically induced cancers.

Both sociologists of science and regulatory

policy analysts have developed their own approaches to categorizing risk assessment research. If one focuses on why research is undertaken and on the standards used to evaluate its

results, it is possible to distinguish between

normal (Rushefsky, 1986) and mandated (Salter,

1987), or regulatory (Jasanoff, 1990), science.

In normal science, researchers conduct investigations as part of a basic research program

(Lakatos, 1978), and results are evaluated on the

basis of their reproducibility and the contribution

they make to resolving outstanding scientific

questions. The standards of proof for accepting

findings are quite rigorous because scientists are

reluctant to mistakenly assert that relationships

exist—for example, between a chemical exposure

and human cancer—when such relationships

might in fact be due to chance (Cranor, 1993).

In contrast, mandated science is conducted in

response to statutory mandates-instructions to

regulatory agencies to identify potential health

hazards and control exposures to them to prevent

human illness. The results of research conducted

within that kind of institutional environment are

evaluated against a broader set of criteria than is

typical of normal science and frequently involve

standards of proof that can conflict with the

standards of basic research science (Clark and
Chapter 4: Setting Priorities for Risk Assessment Research 89

Majone, 1985; Jasanoff, 1989). Findings that

indicate potential risks to human health, for

example, will be judged not only on the basis of

the standards of normal science but also on the

basis of regulatory standards. If a regulatory

agency concludes that a risk is present and if

opportunities are at hand to prevent a public

health problem, regulatory action may be taken

on the basis of less-than-conclusive scientific

evidence.

Science used in policymaking can be broken

down further into three basic types of activities:

knowledge production, knowledge synthesis, and

prediction (Jasanoff, 1990). Knowledge production takes in research that is conducted to fill gaps

in the information base relevant to regulation; an

example would be toxicity testing. Knowledge

synthesis involves collecting, evaluating, and

characterizing the available scientific information

about potential environmental problems and often

results in comprehensive risk assessment reports.

The most contentious aspect of regulatory science

involves predicting the health risks posed by

exposure to different toxic agents. Prediction

usually depends on a variety of models and

assumptions that bridge the gaps between current

scientific understanding of relationships between

exposure to toxic agents and health outcomes and

a projection of what relationships might exist

under different conditions.

Because all of these activities are oriented

toward resolution of questions on policymaking,

a characteristic feature of mandated science is the

extensive involvement of nonscientific institutions, such as Congress, the courts, and the media,

in the process of producing and certifying knowledge. In that political environment, normal science’s approach to reducing uncertainty (conducting further research) is frequently unsatisfactory, because decisions to wait are often interpreted as decisions not to act to protect public

health.

Although the distinction between normal and

mandated science cannot easily be used to class@ the research activities of Federal agencies, it

nevertheless illuminates a number of current

policy debates about the appropriate focus of

scientific research conducted by regulatory bodies. The results of agency research programs are

sometimes evaluated by using criteria from basic

science; that practice may lead critics to conclude

that the products of agency research are deficient

and that increased attention to basic research is

necessary to produce “credible’ science (U.S.

EPA, 1992). An example is the controversy over

testing priorities at the National Toxicology

Program (NTP). From a normal science perspective, rodent bioassays should be conducted as part

of a research program to discover basic mechanisms of toxicity and to define the relevance of

positive results in animal tests for assessing the

risks to humans. But from the perspective of

mandated science, bioassays are part of a largescale screening effort to identiy potential chemical hazards in the environment. Increased attention to studying mechanisms for determining

human relevance means that fewer chemicals are

screened and that exposure to avoidable causes of

human disease is potentially greater.

Another approach to categorizing risk assessment research is by examining the potential for

new scientific investigations to increase the

knowledge base and decrease policy conflicts. A

simple model developed by policy analysts categorizes the results of research along two dimensions: the extent to which they contribute to

scientific knowledge and the extent to which they

increase or decrease policy conflict (Graham et

al., 1988). This perspective on the contributions

of health risk assessment research is clearly

helpful for establishing priorities and formulating

a national research agenda. Investments in research that contribute to the knowledge base and

reduce policy conflict are clearly optimal. But

because of the way science works, results may

uncover new conflicts that require additional

experimentation well beyond what can be accomplished with available techniques. Case studies of

U.S. regulatory policy regarding carcinogens

have concluded that more research, leading to
90 I Researching Health Risks

more knowledge, does not necessarily result in

less policy conflict. Extensive investigations of

the mechanisms by which formaldehyde causes

cancer in rodents, for example, have raised more

questions about the possibility of low-dose risks

to humans than they have answered. The result is

an increase rather than a reduction in policy

conflict (Graham et al., 1988).

These analytical perspectives on the different

rationales for conducting basic and applied research on risk assessment and on the varied

effects that research can have on the knowledge

base and the policy process are essential for a

balanced assessment of current efforts by Federal

agencies. Scientific optimists, for example, might

look at the tremendous advances being made in

molecular biology, and conclude that support for

that research is more worthwhile than support for

less scientifically interesting programs of toxicity

screening. But the results of basic science research may not be immediately applicable for

regulatory decisions. There is clearly a need for

applied research to provide data for preliminary

determinations about possible hazards before

acquiring a complete understanding of the hazard.

Similarly, there is a need to develop risk assessment methodologies that address the inevitable

gaps in scientific understanding in order to

characterize potentially significant risks to health.

However, to the extent that uncertainties are ever

reduced, the reduction is more likely to come

from an integration of basic and applied research.

To narrow its range of inquiry, OTA restricts

risk assessment research to two types of activities:

1.

2.

Generalizable research to improve methods for assessing the risks of adverse

health effects from food contaminants

and environmental and workplace exposures, and

Research to improve estimates of risks

from exposure to specific agents.

Because of the controversies surrounding the

methods for evaluating and estimating risks from

exposure to agents suspected of causing cancer,

this report frequently uses research to improve the

assessment of risk from potential carcinogens to

illustrate the directions and needs of research on

health risk assessment in general.

Given that framework, OTA divided health

risk assessment research into three key areas

(table 4-l). Two of the areas encompass more

general research, and the third encompasses

chemical-specific research. Methodological research, the first area, is specifically aimed at

improving the approaches and methods used for

assessing risks. The second, basic research,

contributes to an understanding of how environmental agents perturb normal biological functioning. The third category involves research that

expands the database about specific chemicals

for use in risk assessments. The results of all

three types of research are crucial; inadequate

development in any one area could impede

progress toward the overarching objective of

making risk assessment more credible and its

results more widely accepted. For instance, the

models developed in methodological research

depend on the results of basic research and

chemical-specific data development.

OTA used these classifications as a better

representation of research activities than the

process of risk assessment outlined by the National Research Council (NRC) in 1983 (NRC,

1983). As discussed more fully in chapter 2,

NRC’s sequential four-step process begins with

hazard identification, progresses to dose-response

and exposure assessments, and ends in risk

characterization. The NRC “paradigm’ laid out

and formalized the risk assessment process and

made it transparent for decisionmakers and the

public alike, but it does not delineate the different

kinds of research that underpins each step (Paustenbach, 1989; Rosenthal et al., 1992). OTA’s

analysis focuses on three distinct objectives of

health risk research: improving health risk assessment methodologies, understanding how environmental agents produce their adverse effects,

and filling chemical-specific data gaps.
Chapter 4: Setting Priorities for Risk Assessment Research 191

Table 4-l-Categories of Health Risk Research

Methods Development

Method and model development—Developing tests and structure-activity analysis for identifying toxicants; developing

models for predicting human exposures; developing methods for extrapolating effects, dose, and dose-response from laboratory

study results to humans. Activities for method and model development include:

. Toxic effects identification and extrapolation

. Exposure extrapolations

* Dose-response extrapolations

. Uncertainty analysis

Met hods evaluation and validation—The iterative process for validating new methods by comparisons to methods of known

and established veracity. When validated, methods can be applied to risk assessments.

Basic Research

Toxicity mechanisms—Research to determine the nature, sequence, and combinations of events that result from exposure

of test animals or humans to toxicants. This includes the study of the concentration of the toxicant or its metabolize that reaches

the site of action, the rates and nature of the reactions with target organs or tissue that are causally linked to disease or the

development of toxic effects, and an understanding of how the toxic effect comes about.

Biological and biomedical-Research on the structure and function of molecules, cells, organs, physiological systems, and

organisms. The resulting knowledge of comparative genetics, biochemistry, and physiology can be used to guide studies on

toxicity mechanisms or reduce uncertainty in effects, dose, and dose-response extrapolations.

Chemical and physical sciences—Research on physical and chemical properties that govern absorption, distribution, fate,

transport, and transformation in the environment and in biological systems.

Chemical-Specific Data Development

Toxic effects—Research designed to identify the toxic effects of agents and the nature of dose-response relationships under

defined conditions of exposure. Activities include:

. Human studies

● Whole-animal studies

● Mammalian tissue, organ, and cellular studies

. Microorganism and other studies

Human exposure data--Measuring toxicant levels indifferent media or commodities and biological materials to test predictive

models and to validate measurement methods.

SOURCE: Office of Technology Assessment, 1993.

 Research to Improve Health Risk

Assessment Methods

OTA sees the goal of research on health risk

methodology as development of better methods

for extrapolating results: from animal models to

humans, from high to low exposures, and from

emission data to predictions of population or

individual exposure. It also encompasses efforts

to estimate uncertainty and develop new methods

for toxicity testing. An important and often overlooked part of methods research is evaluating and

validating the methods with experimental data.

Many scientists argue that methodological

research holds the most immediate promise for

substantive improvement of risk assessments.

To begin with, generic methodology research, in

contrast to chemical-specific studies, can have

considerable impact on assessing the risks from

exposure to many different chemicals and radiation. Moreover, when the methods are directed at

the most uncertain aspects of risk assessments

(extrapolations from high to low doses and from

animal models to human populations and predicting the risk of chemicals for which few or no

toxicity data exist), they can reduce the range of

uncertainties in current risk assessment approaches.

Because of a number of characteristics, methodological research falls in between basic and chemica.lspecific research, making it a bridge between

basic and applied efforts. In other respects,
92 I Researching Health Risks

however, this research is sufficiently unique that principles and techniques have proliferated throughits practitioners refer to it as ‘‘risk science. ’ out the field of toxicology (Olden, 1993).

 Basic Research To Support

Risk Assessment

For the purposes of this report, basic research

is separated into two types: basic health risk

research and basic sciences research. Basic

health risk research investigates the mechanisms of disease associated with exposure to

toxic agents. These studies examine the fate and

transport of chemicals and physical agents, the

avenues of exposure, and interactions with living

systems and biological tissues, all of which feed

into health risk assessment research. The focus of

basic health risk research on the application of

results to risk assessment problems and opportunities sets it apart from the basic sciences.

Basic sciences research encompasses the basic

biological and biomedical, chemical and physical

sciences. Although some research in the basic

sciences contributes to risk assessment research,

basic sciences research is a very broad endeavor,

and it is not included in OTA’s analysis of

relevant research. These studies examine the

structure and function of molecules, cells, organs,

and physiological systems and their relationship

to the functioning organism, as well as the

properties of chemicals and physical agents.

Of the three types of health risk assessment

research, findings from basic research usually

require the most time to be incorporated into

decisionmaking. The research has also been

generally characterized as having the lowest

probability of success. Nevertheless, it can serve

as the foundation for developing new methods in

generating or applying primary data for health

risk assessment and affect risk assessment in a

far-reaching way, as it does other applications of

science. Recently, techniques and findings from

basic research have been rapidly incorporated

into health risk research. Within the past several

years, for example, many molecular biological

 Chemical-Specific Data Development

Chemical-specific data development identifies the toxic effects of agents and characterizes

dose-response relationships under defined conditions of exposure. Efforts to identify toxicants

probably constitute the broadest and most diverse

type of data development. Usually, they involve

testing agents in laboratory animals, sometimes

complemented by results from epidemiologic

studies. This type of research also includes

collecting data on exposure of humans to environmental agents. Some scientists dismiss the idea

that collecting or gathering data using “routine”

tests or monitoring methods is research. In

contrast, the majority of scientists who advised

OTA in the study and who reviewed drafts of this

report voiced the opinion that such activities are

properly classified as research. In OTA’s evaluation of research funding, only two Federal agencies reported collection of exposure data as a

research activity, but many included toxicity

testing in research activities. The programs that

carry out toxicity tests do more than provide the

basic information for risk assessments, they also

do research that leads to better tests and basic

research on mechanisms of disease causation.

A look at the number of existing chemicals and

the new compounds that appear each year explains the need for further toxicity testing and data

development. Since 1965, more than 12 million

chemicals have been entered into the Chemical

Abstract Service’s registry file (although the

actual number of chemicals to which individuals

might be exposed is considerably smaller). The

reporting provisions of the Toxic Substance

Control Act require an inventory of the chemicals

currently being manufactured in this country; that

list contains more than 61,000 chemicals (Lao,

1993). More than 3,000 chemicals are registered

as pesticides under the Federal Insecticide, Fungicide, and Rodenticide Act, a listing that consists
Chapter 4: Setting Priorities for Risk Assessment Research 93

of 880 active pesticidal ingredients and 2,200

inert ingredients (Colledge, 1993). The number of

food additives is 3,151 (Hudson, 1993).

After reconciling for overlaps, OTA estimates

that 62,512 chemicals are present in commerce in

the United States. A recent gathering of environmental experts estimated that ‘‘good’ data on the

health effects from exposure are available for only

10 percent of chemicals existing worldwide, with

nearly 1,500 being developed each year (Environmental Health Letter, 1993).

FEDERAL RESOURCES FOR HEALTH

RISK ASSESSMENT RESEARCH

The Federal Government’s support for research

on health risk assessment extends from basic

studies in the biological and biomedical sciences

to methods for extrapolating observations from

one setting to another. That breadth was evident

during OTA’s attempts to evaluate the resources

devoted to improving health risk assessment.

Under the broadest definition of research that

affects health risk assessment, a significant portion of the Federal Government’s obligations in

health research and development (R&D) generally can be considered as contributing to the

effort.

OTA used the research objectives and the

categories of risk assessment research discussed

above, which parallel the categories used by the

executive branch,2 as the framework for the

analysis of agency research resources. This analysis used three main sources of information: the

1992 data book of the National Institutes of

Health (see app. C); the annual National Toxicology Program (NTP) review of the research related

to toxicology (U.S. DHHS, in press), which

includes basic toxicology research, epidemiologic and methodologic research being performed

by the Department of Health and Human Services

(DHHS) agencies (see app. D), Department of

Energy (DOE) and Environmental Protection

Agency (EPA); and OTA’s requests to the various

agencies for data on resources. OTA also contacted organizations such as the National Science

Foundation and the American Association for the

Advancement of Science, which have recently

completed reports on Federal environmental research. The best of these sources, for the purposes

of this report, proved to be the NTP review .

OTA’s call for information from the various

Federal agencies resulted in estimates of resources that were highly dependent on how the

responder defined health risk assessment research. For example, with a broad definition of

research related to health risk assessment, about

33 percent of the 1993 budget of the National

Cancer Institute (NCI) or about $600 million,

would be related to this activity (Lee, 1993). But

using data from NTP’s review of current research

(U.S. DHHS, in press) as representative of their

research on health risk assessment, the NCI

support would be estimated at $80 million, or

about 4 percent of the 1993 NCI budget. Consequently, OTA concluded that it had not obtained

wholly reliable estimates of resources; nonetheless, OTA discerned some general trends and

directions.

using Summary data issued between 1982 and

1991 from the NTP review of research related to

toxicology as a surrogate for health risk R&D,4

OTA determined that total support of health risk

assessment research increased from $336 to $520

million, a 55 percent increase before adjusting for

inflation. During the same period, Federal obligations for health R&D, as reported in the National

z The NTP AXUMI Reviews of Rmearch Related to Toxicology compiles data on agency programs in the Categories of Bmic ~xicology

Research, Toxicology Testing, and Toxicology Methods Development (U.S. DHHS, in press).

3 The NTP review incIudes human epidemiology studies as toxicology testing,

4 OTA’s survey in 1993 indicates health risk research is also carried out by the Department of Defense, Department of Agriculture, the

Consumer Product Safety Commis sion and Nuclear Regulatory Commis sion. NTP data did not cover resources for those agencies. However,

their contributions are small relative to the agencies covered in the review.
94 I Researching Health Risks

Figure 4-l—Funding for Federal Health Research

and Development, Fiscal Years 1982-91

m Tota l

m Health risk

J I ! 1 i I I I I I I I I I I I I I 1 L

19821983198419851986 19871988198919901991

SOURCE: Office of Ttinology Assessment, based on National

Institute of Health Data Sook, 1992; and Review of Current DHHS, DOE

and EPA Research Related to Toxicology, Fiscal Years 1982 through

1991, National Toxicology Program, U.S. Department of Health and

Human Setices.

Institutes of Health data book, increased from

$5.0 to $10.7 billion, a 123 percent increase

before inflation (figure 4-l).

With the above data, OTA estimated health risk

R&D’s share of total Federal health R&D

dropped from 6.8 percent in 1982 to 4.9 percent

in 1991. Moreover, this relative decline in health

risk R&D took place during a period of expanding

Federal legislation and responsibilities to protect

human health from environmental pollutants.

During that period, the number of environmental

legislative mandates increased with each successive Congress-horn 4 in the 97th Congress

(1981 and 1982) to 26 in the 101st Congress

(1989 and 1990) (figure 4-2).

The NTP data describe the fuding support for

research related to chemical toxicology in methods development, basic toxicology, and testing

(data development) (figure 4-3). These data

Figure 4-2—Environmental

30

25

$ 20

$

g 15

5

2 10

5

0

Legislative Mandates

97 98 99 100 101

U.S. Congress

SOURCE: Office of Technology Assessment, 1993.

represent the research priorities for the three types

of health risk research. Of the $524.8 million

spent for the total research effort in fiscal year

1992, methodological research received 15.6

percent, basic research 58.3 percent, and testing

26.1 percent.

In addition the NTP data also illuminated

trends in how the various agencies separately

apportioned support and resources for those types

of research (figure 4-4). In general, over the

1980-92 period, research agencies such as the

National Institute of Environmental Health Sciences (NIEHS) and the National Cancer Institute

increased the percentage of basic toxicological

research that they conducted. In contrast, regulatory agencies such as EPA and the Food and Drug

Administration (FDA) devoted a larger proportion of their health R&D to methods research than

did the research institutes.

In this figure, the personnel numbers, in

full-time equivalents (FIEs), devoted to this

research reflect the size of the intramural program. In general, the regulatory agencies have

sizable intramural programs compared to their

R&D budgets, while the research agencies support relatively larger extramural programs. The

number of FTEs at EPA, for example, is nearly
Chapter 4: Setting Priorities for Risk Assessment Research 95

equivalent to NIEHS, but EPA’s R&D budget is

only about one-third the size.

Taken together, the budget and personnel

figures provide a picture of the Federal health risk

R&D effort and the priorities of the agencies. To

begin with, these data show that NIEHS devotes

the most resources, in both dollars and FTEs,

to health risk research. Furthermore, the agencies with substantial extramural programs, NIEHS

and NCI, to a large extent support basic research.

The intramural program at NCI is predominantly

basic in nature, whereas it is more evenly

distributed at NIEHS among the three types of

research. As the graphs in figure 4-4 demonstrate,

NCI transferred its carcinogen testing program to

NIEHS in 1982. The remaining four programs in

this figure operate mostly intramural research

programs. As the agencies reported in the NTP

Review, EPA and NIOSH programs conduct

mostly methodological research, while, at the

FDA, the National Center for Toxicological

Research’s (NCTR) research is mostly basic and

the Center for Food Safety and Applied Nutrition’s (CFSAN) is more evenly distributed.

Based on fiscal year 1993 estimates in the OTA

survey of research (table 4-2A), less than 11

percent ($65 million) of the total R&D budget of

$600 million for environmental and occupational

health and food safety is devoted to research on

methods. It is possible only to estimate roughly

the total amount that was actually spent on

methods research during the period, because of

the difficulties in categorizing the research. Nevertheless, the small size of the risk research

analysis programs at the NCTR and NIEHS, and

the reported part-time participation of researchers

at the regulatory agencies, support a conclusion

that methodological research is underfunded.

To get a broader accounting of the FY 1992

research resources, OTA incorporated data from

the Departments of Defense and Agriculture with

the NTP review data (table 4-2B). In table 4-2B,

OTA estimates that the agencies devote nearly 16

percent ($91.6 million) of the total $589.5 million

spent in FY 1992 to methods research. The

Figure 4-3-FederaI Research Related to

Chemical Toxicology (In millions of dollars)

600

500

400

300

200

100

0

198081 82 83 84 85 86 87 88 89 90 91 92

SOURCE: Office of Technology Assessment, 1993, based on data from

Review of Current DHHS, DOE and EPA Research Related to

Toxicology, Fiscal Years 1980 through 1992, National Toxicology

Program, U.S. Department of Health and Human Services.

discrepancy between the 1992 and 1993 figures

may result from different reporting methods:

OTA based the FY 1993 estimates on the results

of its agency survey, whereas the 1992 estimates

are based on the results of the 1992 NTP review

DHHS, DOE, and EPA research (U.S. DHHS, in

press). The differences between the two tables

illustrate the difficulties in obtaining accurate

resource figures.

A consistently understudied area is human

exposure measurement. Historically, exposurerelated research efforts have concentrated on

identifying the presence or determining the fate

and transport of pollutants in various media.

OTA’s survey did not cover the entire range of

Federal efforts allocated to human exposure

measurements. However, EPA devoted about

$6.7 million to such efforts in 1993, and the U.S.

Department of Agriculture (USDA) allocated

about $11 million for analyzing pesticide residues

on produce.

As would be expected for activities as broad as

risk assessment research, some fields of inquiry

have received more funds, some fewer. However,
96 Researching Health Risks

Figure 4-4-Federal Research Related to Chemical Toxicology, 1980-92

(In millions of dollars and full-time equivalents)

National Cancer Institute

1980{

1981-

1982-

1983-

1984-

1985-

1986-

1987-

1988-

1989-

1990-

1991-

1992-

160 140 120 100 80 60 40 20 0 20 40 60 80 100 120 140 160

($ millions) (FTE)

6 5 4 3 2 1 0 10 20 30 40 50 60 70

($ millions) (FTE)

12 10 8 6 4 2 0 50 100 150 200

($ millions) (FTE)
Chapter 4: Setting Priorities for Risk Assessment Research 97

National Institute of Environmental Health Sciences

1980 ~

— - -

”

~

” &

–

”

y

”

y

’

1

1981

1982 1

160 140 120 100 80 60 40 20 0 100 200 300 400

($ millions) (FTE)

Environmental ProtectIon Agency

:r---:ssa:=

1984-

1985-

1986-

1987-

1988-

1989-

1990-

1991-

1992-

I v///2zl///2zl

Jzz//////////A

40 30 20 10 0 50 100 150 200 250

($ millions) (FTE)

Dollars FTE

m Basic ~ Testing [~ 1 Method _ Basic m Testing ~ Method

SOURCE: Office of Technology Assessment, 1993, based on data from Review of Current DHHS, DOE and EPA Research Related to Toxicology,

F“-] Years 1982 through 1991, National Toxicology Program, U.S. Department of Health and Human Services.
98 I Researching Health Risks

Table 4-2A—Health Risk Research and Development Estimates, 1993

(In millions of dollars)

Health risk research*

Agency total: health or

Agency Total Methods biomedical research**

National institute of Environmental Health Sciences. . . . . . . 129.0 14.0 251.2

Department of Energy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.0’ 3 . 0

a

90.0’

Department of Defense . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19.6 2.5b

300.0’

U.S. Department of Agriculture . . . . . . . . . . . . . . . . . . . . . . . . 11.5d 0.5d

11.5*

Agency for Toxic Substances and Disease Registry . . . . . . . 16.9 0.0 16.9nd

Environmental Protection Agency. . . . . . . . . . . . . . . . . . . . . . 32.0 21.30 49.0f

Food and Drug Administration (other than NCTR). . . . . . . . . 13.oa 3 . 5

a

13.0nd

National Center for Toxicological Research . . . . . . . . . . . . . . 33.6 7.6 38.92*

National institute for Occupational Safety and Health. . . . . . 49.0 6.1 49.0”

National Cancer institute. . . . . . . . . . . . . . . . . . . . . . . . . . , ., 82.0a 4.4a 1,981.4

Other NIH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140.0a 2 . 2

a

6,929.9

Alcohol, Drug Abuse, and Mental Health Administration. . . . 64.0a O.Oa

1,164.1

Total . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 600.6 65.1 10,894.5

a Estimate based on agency’s IW2 funding for research on toxicology, as reported in the National Toxicology Program Review of current DHHS,

DOE, and EPA Research Related to Toxicology, Fiscal Year, 1992.

b Cakulated as IS percent of agency R&D for health.

C Steinbeq. 1993. Journa/ of N//jF/esearch 5:35. Data on Nomedkal research, whidl exdud~ $210 million for breast cancer research.

d Data suppli~ by the U.S. Depafirnent Of Ag~UltUre, b@eted under expenses and not research and development.

e RXear~ t. [reprove l+~alth Risk ~Se=ment program estirnat~ to be $5 million; $21.3 million is sum of funding for human exposure, health

effects, and risk assessment methods.

f Figure represents Health Effects Re~ar& ~boratory total ~dget: EpA-wjde data are not available.

nd NO data (research related to toxicology W= W@.

● Based on data from the OTA survey of agency resources.

● *U.S. Congress, CRS, 1993. Research and development funding: fiscal year 1993; issue brief (iB2062).

SOURCE: Office of Technology Assessment, 1993.

environmental health research funding has

neither kept up with the increase in health

research nor increases in environmental mandates that depend on that research for decisionmaking. Methodological research, in particular, seems inadequately supported, despite

the most immediate promise that OTA sees for

this research to improve risk assessment.

NATIONAL RESEARCH PRIORITIES

A complex interplay among social, economic,

and scientific factors influences national research

priorities. Depending on the political and social

milieu of the Nation, Government research to

protect the health of the public from environmental agents fluctuates between being more

applied or more basic in nature. In response to the

environmental and social activism of the 1960s

and 1970s, policymakers called for the Government to play a larger role in applying the advances

of research and development to achieving societal

goals, including environmental protection and

improved public health (Smith, 1990). In contrast, the Reagan Administration during the 1980s

channeled research resources toward national

security and basic science (Smith, 1990), Judging

from the early budget figures, science policy in

the Clinton Administration will return to emphasizing applied research and development (Long,

1993).

Mission-oriented research, a type of applied

research, is directed toward identifiable ends

related to meeting an agency’s responsibilities.

After World War II, mission-oriented research

became established in agencies, and basic research tended to be located in universities (Smith,

1990; U.S. Congress, OTA, 1991). The role of the

Federal Government in support of research grew

as regulatory decisions became increasingly technical and complex, and more science-based expertise was needed for agency decisionmaking.
Chapter 4: Setting Priorities for Risk Assessment Research 99

Table 4-2 B-Research Related to Toxicology, 1992

(In millions of dollars)

Chemical Toxicology*

Agency total: health or

Agencv Total Methods biomedical research**

National Institute of Environmental Health Sciences. . . . . . .

Department of Energy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Department of Defense . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

U.S. Department of Agriculture . . . . . . . . . . . . . . . . . . . . . . . .

Agency for Toxic Substances and Disease Registry . . . . . . .

Environmental Protection Agency. . . . . . . . . . . . . . . . . . . . . .

Food and Drug Administration (other than NCTR). . . . . . . . .

National Center for Toxicological Research . . . . . . . . . . . . . .

National Institute for Occupational Safety and Health. . . . . .

National Cancer Institute. . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Other NIH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Alcohol, Drug Abuse, and Mental Health Administration . . . .

Total . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

154.6

9.8

15.0b

11 .8e

17.5

47.3

12.5

30.9

4.4

82.0

139.7

64.0

589.5

22.0

2.7

2.&

O.5e

0.0

35.4

3.5

16.2

2.7

4.4

2.2

0.0

91.6

251.6

90.09

300.0d

11 .8f

17.5~

47.3 nd

12.5 nd

30.@

4.4nd

1,947.6

6,729.8

1,131.4

10,574,8

a Estimate is based on personal communication.

b The ~my ~rtion is estimated using 1993 data from Department of Defense.

c Calculated ~s 13 Perwnt of agency resear~ and development for health, based on ~dier all~ations.

d Steinbrg 1993, Journa/ of N//j R~@~~&5:35 Data on biom~i~[ r~eardl, Wflidl excludes $25 million for breast cancer research.

e Data ~up~l~ by U.S. Department of Agriculture, budget~ under expens~ and f’tot research ad development.

f N. data avai[abIe. Health risk R&D usgd, IJSDA FY 1991 health R&Dis$115 million, from NIH databook.

nd No data (research related to toxicology W= us~).

● Review of current DHHS, DOE, and EPA Rasearch Related to Toxicology, Fiscal Year 1992, National Toxicology Program, U.S. Department of

Health and Human Services.

● *U.S. Congress, CRS, 1993. Research and development funding: fiscal year 1993; issue brief (IB2062).

SOURCE: Office of Technology Assessment, 1993.

Under congressional direction, agencies pursued

research to support a ‘‘scientific base for public

policy, ” with EPA emerging as ‘‘the epitome of

the new expert agency” (Jasanoff, 1990).

Many of the researchers surveyed by OTA

claim that Federal funding, divided between

applied and basic research, allows risk assessment research “to slip through the cracks.”

Consequently, most research efforts to improve risk assessment have inadequate support. No study section at the National Institutes of

Health, for example, reviews proposals for health

risk assessment research. At a more general level,

few funding opportunities exist for multidisciplinary collaborations among basic and applied

scientists, despite the acknowledged need for

such endeavors to make risk assessment research

more effective (U.S. DHHS, 1991c).

Below the surface of the debate over the

balance between basic and applied research lie

questions about the objective and nature of the

research on risk assessment that the Government

should be supporting and conducting. The environmental movement of the 1960s, for example,

stimulated intense Federal efforts to identify

pollutants that can affect human health and the

environment. As a result, NTP was established to

set national priorities for toxicity testing (U.S.

DHHS, 1991a), and both supporters and critics of

the program consider it the Nation’s premier

testing program (Moolenaar, 1992; Ringen, 1992).

If tests of a commercially important substance

reveal that hazards exist, manufacturers or users

who want to retain the commercial uses for the

substance may perform additional research to

clarify the nature of the hazard and support

quantitative risk assessment. In efforts to shift

research priorities, some scientists and industry

spokespersons have called for the Government to

conduct more research on the mechanisms of

toxicity (Abelson, 1993; Gori, 1992; Moolenaa,

1992). Such a controversy currently surrounds the
100 I Researching Health Risks

proposed directing of NTP research away from

toxicity testing and rodent bioassays and toward

studies on such mechanisms (U.S. DHHS, 1992).

As the debate is framed, toxicity tests, on the one

hand, can identify potential hazards to public

health, which can trigger intervention strategies

designed to prevent exposures to the agent. On the

other hand, mechanistic studies can determine the

applicability of the results of toxicity tests to

predict human risks from exposure.

The debate suggests that these types of research

—toxicity testing and mechanistic research—

have necessarily mutually exclusive objectives,

that resources can be used for either type of

research but not both. In fact, the NTP Board of

Scientific Counselors concluded that these research activities can be integrated to complement

each other (U.S. DHHS, NTP, 1992). The results

of toxicity studies often illuminate fruitful avenues of mechanistic research. Similarly, data

from mechanistic studies can illuminate the

implications for human health risk of the results

from toxicity testing. In addition, mechanistic

research provides a foundation for identifying

untested chemicals and chemical classes for

toxicity testing.

The debate over the role of Government

research does not end at NTP. Related discussions

are heard concerning the research priorities of

NTEHS, NCTR, and EPA.

 Setting National Priorities

In the past, the United States has embarked on

national multiagency efforts in public health.

Some were strikingly successful; others were not.

As part of a worldwide campaign, this country

aggressively attacked the childhood scourges

smallpox and polio, culminating in the complete

eradication of smallpox and the virtual eradication of polio. The U.S. ‘‘wars’ on cancer in the

1970s (Epstein, 1979) and AIDS in the 1980s

(Joseph, 1992), however, produced less tangible

results, but those consequences may be more a

reflection of the complexities of those diseases

than of the Federal effort. Generally, the scientific

process is difficult to reconcile with a war

mentality. Science proceeds in discreet, incremental, and often publicly imperceptible steps

confounded by missteps and mistaken paths

(Kuhn, 1962). Moreover, the most brilliant technological breakthroughs often are not planned;

recombinant DNA techniques revolutionized cancer biology, but they were not anticipated in the

detailed planning that went into the war on

cancer. Still, although cancer and AIDS are

problems that currently lack solutions, indisputable progress has been made in both cases. Indeed,

the recent advances in the molecular biology of

cancer, for example, offer promise and optimism

unimagined in the “war years” (Barrett, 1993).

Arguably, the President has the most influence

in setting national priorities for research at the

agencies. With a variety of administrative tools,

such as executive orders (Olson, 1984), the

President can emphasize or reemphasize certain

areas of scientific research. The increased research on cancer in the 1970s, for example,

stemmed from presidential efforts (Epstein, 1979;

Rushefsky, 1986).

Related to presidential influence, the degree of

centralized authority at the national level has

implications for implementing a national research

effort. A centralized program, often a multiagency activity coordinated through a central

authority such as the Executive Office of the

President, provides focus and direction, but the

agencies lose a portion of their authority. A

decentralized effort, in contrast, gives the agencies more autonomy but the objectives can be less

defined, the effort more fragmented, and the goals

of the agencies given more importance than goals

of the effort.

In centralizing research efforts, the President

has at his command several administrative processes to set national priorities. The Federal

Coordinating Council on Science, Engineering,

and Technology (FCCSET), which the Bush

Administration greatly strengthened, serves as

the Federal Government’s focal point for setting
Chapter 4: Setting Priorities for Risk Assessment Research I 101

priorities within the executive branch. Overseen

by the White House Office of Science and

Technology Policy, FCCSET policymakers and

scientists from various research agencies operate

in specialized subcommittees and working

groups, directed at specific problems. Under

D. Allan Bromley, President Bush’s science adviser, FCCSET conducted ‘‘crosscuts, ’ in which

an interagency committee inventors Federal

activities and establishes objectives and priorities

for coordinating basic and applied research in

high-impact areas, Some examples include research on global change, high-performance computing and communications, mathematics and

science education, advanced materials and processing, and biotechnology (Bromley, 1992).

FCCSET in 1991 and 1992 had some focus on

health risk assessment research: its Subcommittee on Risk Assessment of the Committee on Life

Sciences began an effort to identify future health

risk assessment research needs. Although this

activity was not aimed at coordinating research

projects, the activities of the subcommittee were

a first step in creating an inventory of ongoing

research, which could be useful in future coordinating efforts. A research inventory would have

allowed FCCSET members to identify redundant

research, areas of little or no activity, and research

efforts that could be usefully integrated across

agencies. However, this project apparently has

been put quietly to rest with the transition to the

Clinton Administration. OTA carried out a similar survey as part of this assessment (see ch. 3).

According to the National Performance Review, the Clinton Administration is planning to

eliminate FCCSET. In its place, the White House

will coordinate agency research programs

through a new National Science and Technology

Council. This new council combines FCCSET

with the National Materials Council and the

National Space Council, but it will remain within

the Office of Science and Technology Policy

(Hanson et al., 1993).

The Office of Management and Budget (OMB)

also influences executive branch decisions concerning science priorities. Through its review

function, OMB can delay research and regulatory

activity (Olson, 1984). For example, OMB currently reviews proposed Federal research involving human subjects. In many cases, the resulting

delay effectively diminished or even halted research in certain areas, such as in the use of

questionnaires in epidemiologic research (Lilienfeld, 1993).

The legislative branch also sets and influences

national research priorities. Congressional members and committees charged with responsibility

for broad areas, such as environmental protection

or public health, may influence the direction of

research in those areas through legislation, appropriations, or reports. Similarly, congressional

research agencies such as the General Accounting

Office or OTA can affect national priorities

through their analyses of related issues. For

example, congressional representatives (Brown,

1993) and congressional reports (e.g., U.S. Congress, OTA, 1991; U.S. Congress, House Committee on Science, Space, and Technology, 1992)

recently suggested changes in U.S. research

policy that would link research more tangibly to

national goals.

When a particular topic is designated a

national research priority, it is accorded leadership at the highest echelons of government,

strategic initiatives that span many Federal

agencies, and resources that are commensurate with the magnitude of the problem. Health

risk assessment research possesses none of

those hallmarks. Moreover, OTA did not find a

systematic, national multiagency process for setting research priorities for improving health risk

assessments. Apparently, the FCCSET subcommittee on risk assessment research needs will not

release the results of its survey of Federal research

efforts. As a result, that effort has had little

impact, if any, on the direction of research. Some

observers and participants remain sanguine about

the FCCSET process, but the predictions that the

research needs study will end without a product

are strong counter arguments, The proposed
102 I Researching Health Risks

National Science and Technology Council is

designed to have more “teeth” than FCCSET

(Hansen et al., 1993).

In examining agency research, OTA found that

Federal research on health risk assessment, as

a whole, is largely decentralized. Agencies have

different priorities because they have different

legislative mandates and missions. Within agencies and departments, risk assessment research

programs conduct research in support of their

parent organizations. This behavior parallels that

seen for environmental research and development

(Schaefer, 1991; Carnegie Commission, 1992)

and for the Federal research and development

effort in general (U.S. Congress, OTA, 1991).

Leadership from the White House or Congress

could improve health risk assessment research by

bringing cohesion and focus to research goals.

As pointed out in chapter 2, more than 50

assumptions have been identified that are used in

risk assessments. Use of those untested assumptions underlines the promise of research to

illuminate some of the areas of current ignorance.

A coordinated effort, for example, could determine the extent to which research can reduce the

dependence on assumptions. More than a decade

has passed since the NRC report, and research

efforts have expanded on some of these, but

priority-setting to increase the impact of research

does not exist. Assumptions that can be replaced

by research need to be distinguished from assumptions that cannot be replaced by research.

AGENCY PRIORITIES

An agency’s risk assessment research depends

on priorities in its mission, its enabling legislation

(table 4-3), and court decisions. In line with their

missions, the agencies that conduct research

related to risk assessment can be separated into

those with responsibilities for risk management

(regulatory agencies) and those without such

responsibilities (research agencies). Risk management, as described in chapter 5, integrates and

synthesizes myriad information (such as economic, political, and technological factors) along

with risk assessments, to set, implement, and

enforce regulatory standards (NRC, 1983).

Research at the regulatory agencies, especially

at EPA, the Occupational Safety and Health

Administration (OSHA), Consumer Product Safety

Commission (CPSC), and FDA, is mostly driven

by regulatory needs, as mandated by congress.

Regulatory agencies need chemical-specific data

to set standards and establish priorities for rulemaking (Rosenthal et al., 1992). EPA’s authority

to conduct environmental health research derives

mainly from the major Federal laws protecting

public health and the environment. The research

programs of its Health Effects Research Laboratory (HERL) are mandated in at least six major

pieces of legislation, and funding is appropriated

on a medium-specific basis.s By requiring EPA to

protect public health, the statutes give the agency

discretionary authority to conduct research on

health effects.6

Although the Occupational Safety and Health

Administration (OSHA) is not required under the

Occupational Safety and Health Act (OSH Act) to

conduct risk assessments, a U.S. Supreme Court

decision on workplace exposure to benzene

requires OSHA to determine whether risks are

“significant” before imposing regulation.7 Risk

5 The research programs are mandated under one of the following: Clean Air A@ Safe Drirdan4 gWater Act; Federal Insecticide, Fungicide,

and Rodenticide ACG Tbxic Substances Control ACC Comprehensive Environmental Response, Compensating and Liability Act; or Resource

Conservation and Recovery Act (U.S. Congress, CRS, 1993).

s The Environmental Research and Development Demonstration Act -DA) of 1976 brought EPA’s research programs under a single

mandate, but authorimtion for it ended in 1981 (U.S. Congress, CRS, 1993). Recently, the Subcommittee on Technology, Environment, and

Aviation of the House Science, Space, and Technology Committee has been developing the Environmental Research Development and

Demonstration Act of 1993 (H.R. 1994).

7 OSHA does not perform risk assessment research (Marton& 1992). The National Institute for Occupational Safety and Hrxd@ the

research arm of OSHA, conducts studies on workplace agents that affect worker safety and health (Mink 1984).
Chapter 4: Setting Priorities for Risk Assessment Research I 103

assessment is the method OSHA uses in making

that determination (Mintz, 1984).8 The OSHAct

stipulates that the National Institute for Occupational Safety and Health (NIOSH) would conduct

heath effects research for OSHA rulemaking (P.L.

91-596).

Among the Federal agencies, DHHS has the

broadest set of research responsibilities for investigating possible health risks. Within DHHS, are

the research agencies of the Public Health Service—specifically, NIEHS, NCI, NCTR, NIOSH,

and the Agency for Toxic Substances and Disease

Registry (ATSDR) (see app. B). The charters of

these agencies mandate a research mission.

The Departments of Defense (DOD) and Energy (DOE) are neither regulatory agencies nor

public health research agencies. However, they

perform and support research on health risks as

part of their risk management responsibilities

(Macys, 1993; U.S. DOE, 1991).

To gain insight into agency research priorities,

OTA examined the funding and FTEs as a

percentage of the total contribution to research in

toxicology by NIEHS, NCI, NCTR, EPA, and

CFSAN, as reported in the NTP review.9 This

additional analysis attempts to get a snapshot of

the trends in resource allocation to the three areas

of toxicological research-methodological, basic,

and chemical-specific data development, by the

agencies most active in this research. As shown in

figure 4-5A, the agency resources are presented as

percentages of the total for the years 1982, 1986,

and 1991. For these agencies in those years,

funding for basic research increased from 41 to 53

percent, toxicology testing declined from 45 to 24

percent, and methodologic research increased

from 14 to 22 percent. Figure 4-5B provides a

snapshot for the intramural researchers at the

agencies and the nature of their research. In 1991,

39 percent of the full-time equivalents (FTEs)

were conducting basic research, 24 percent in

testing, and 34 percent in methods research. The

relative proportions of FTEs to funding in dollars

suggests that most basic toxicological research is

supported by extramural grants, whereas most

methodological research is conducted in intramural research.

OTA estimates that in 1993 the agencies will

spend nearly $600 million on health risk research,

but that only $65 million of that total will be spent

on methodological research. Even considering

that these estimates are based on agency definitions of research, methodological research receives disproportionately less than the other areas

of research. In times of restricted resources and in

the wake of congressional imperatives, the agencies tend to maintain their existing core programs.

Thus, regulatory agencies focus on chemicalspecific data development, and research agencies

perform basic research. Methodological research

remains marginalized in the process.

A variety of reasons can be forwarded to

explain the relative neglect of methods research.

Incorporating the results of research into policy

requires overcoming substantial bureaucratic hurdles and usually necessitates some sort of scientific consensus on an issue. (Chapter 5 discusses

the difficulties in changing agency policy.) Furthermore, agencies-especially regulatory agencies, which are bureaucratic by nature and slow in

responding to changes—must gain the acceptance

of the scientific community before they adopt

new methodologies (Jasanoff, 1990; Rosenthal et

al., 1992). That sort of support is crucial to

providing credibility to new policies. Moreover,

methodological research requires validation with

experimental data, an activity to which agencies

allocate few resources. These obstacles to the use

8 The 1981 U.S. Supreme Court decision on OSHA’S workplace standard for benzene states that ndemaking must protect workers from

‘ ‘significant’ risk. Signitlcance under tbe Occupational Safety and Health Act has since been interpreted by OSHA to be one adverse effec~

such as cancer, in 1,000 workers (Mintz, 1984; Rodericks et al., 1987).

g OTA did not include the resources of NIOSH in this analysk because their support reported to NTP are resources committed to the NTP

program and k not representative of the total NIOSH contribution to this research.
104 I Researching Health Risks

Lzc

.—0

a

z
. . .

Chapter 4: Setting Priorities for Risk Assessment Research I 105

iii-

(

( 1- .-

mN

la

CD

co

iii

2

ii

c

.-o

%

z
Table 4-&Key Features of Federal Laws Regulating Toxic Substances

Regulatory authority Toxic substance or effect

Statute (regulatory agency) of concern

Part I--Licensing Laws

Federal Food, Drug, and Cosmetic Act

Federal Insecticide, Fungicide, and Rodenticide Act

Toxic Substances Control Act

Part l~tandard-setting Laws

Clean Alr Act

Control levels of added substances (FDA)

Control levels of natural components of food

(FDA)

Control levels of environmental contaminants

(FDA)

Set (EPA) and enforce (FDA, USDA) tolerances for

pesticide residues on food and feed crops

Regulate introduction of new drugs and biologics

(FDA)

Report on adverse reactions to drugs (FDA)

Label cosmetics (FDA)

Register pesticides (EPA)

Require testing of existing chemicals where data are

inadequate to assess risk (sec. 4); prohibit

introduction into commerce of chemicals that will

present an unreasonable risk (sec. 5); restrict or

prevent production, use, or disposal of existing

chemicals that present unreasonable risk (sec. 6)

(EPA)

Conduct research on air pollution (EPA)

Set air quality standards; regulate emissions of

hazardous air pollutants; set standards for vehicle

emissions, fuels, and fuel additives (EPA)

“Any poisonous or deleterious substance which may

render it injurious to health”

“Poisonous or deleterious . . . does not ordinarily

render it injurious to health”

“Poisonous or deleterious . . . does not ordinarily

render it injurious to healh”

“Poisonous or deleterious. . . not general

recognized as safe for use . . . to the extent necessary

to protect the public healh”

“Substantial evidence at safe and effective:” no

“imminent hazard to public health”

“Any adverse experience . . . includes any side effect,

injury, toxicity, or sensitivity reaction”

“Poisonous or deleterious . . . may render it

injurious”

Will not generally cause any unreasonable risk to

man or the environment”

Unreasonable risk of injury to human health or the

environment. . . includ[ing] carcinogenesis,

mutagenesis, teratogenesis, behavioral disorders,

cumulative or synergistic effects, and any other effect

"

. . .

“Adverse effects on health, including, but not limited

to, behavioral, physiological, toxicological, and

biochemical effects”

“Endanger public health”
Federal Water Pollution Control Act;

Clean Water Act

Safe Drinking Water Act

Consumer Product Safety Act

Federal Hazardous Substances Act

Federal Mine Safety and Health Act

Occupational Safety and Health Act

Part 111-Control-Oriented Laws

Comprehensive Environmental Response,

Compensation, and Liability Act; Superfund

Amendments and Reauthorization Act

Controlled Substances Act

Lead-Based Paint Poisoning Prevention Act

Marine Protection, Research, and Sanctuaries Act

Poison Prevention Packaging Act

Resource Conservation and Recovery Act

Set effluent standards for water; establish water

quality criteria (EPA)

Set MCLs and MCLGs for public drinking water

supplies (EPA)

Promulgate consumer product safety standards

(CPSC)

Ban hazardous substances for household use

(CPSC)

Set standards for airborne contaminants in mines

(MSHA)

Set standards for airborne contaminants in the

workplace (OSHA)

Fund cleanup of hazardous waste sites; designate

reportable quantities for environmental release;

report on community preparedness and release;

prepare toxicity profiles on contaminants (EPA)

Control drugs that have potential for abuse (USDJ,

FDA)

Determine, if possible, a safe level of lead in paint

(CPSC)

Regulate ocean dumping (EPA)

Promulgate standards for packaging substances that

could produce effects of concern (CPSC)

Regulate the handling of hazardous wastes; list

hazardous wastes on basis of constituents (EPA)

“Identifiable effects on health and welfare”

“May have an adverse effect on the health of

persons”

“An unreasonable risk of injury”

“Toxic . . . may cause substantial personal injury or

substantial illness”

“Protection of life and prevention of injuries. . .

material impairment of health or functional capacity”

“Material impairment of health or functional capacity“

“Substantial danger to the public health or welfare”

“Substantial and detrimental effect”

Poisoning of children by lead-based paint

“Adversely affect human heath, welfare or amenities”

“Serious personal injury or serious illness”

“Protect human health . . . serious irreversible or

incapacitating reversible illness . . . substantial

present or potential hazard”

NOTES: FDA - Food and Drug Administration; EPA. Environmental Protection Agency; USDA. U.S. Department of Agriculture; USDJ. U.S. Department of Justice; CPSC. Consumer

Product Safety Commission; MSHA - Mine Safety and Health Administration; OSHA - Occupational Safety and Health Administration; MCL - maximum contaminant level; MCLG - maximum

contaminant level goal.

SOURCE: mice of Technology Assessment, 1993.
108 I Researching Health Risks

of the results raises important questions about the

usefulness of methodological research and its

likely impact on policy.

Bureaucratic reluctance to accept new methods

provides an especially strong disincentive for

researchers. Why do the work if it is likely to be

ignored. Individual promotions and advancement

in the scientific community are predicated on

research output and visibility. As a result, researchers either conduct chemical-specific research, which responds directly to agency needs,

or basic research, which is held in higher esteem

in the scientific community and is likely to be

published in more prestigious scientific journals.

Taken all together, there are few incentives for a

researcher to conduct methodological research:

the agencies consider it a secondary priority and

allocate fewer resources to it, and the results of the

work face substantial hurdles before being incorporated into agency practice or being accepted by

the scientific community.

In addition to the mission of an agency and its

enabling legislation, each agency has its own

“culture’ as well, which is a powerful determinant of future research directions (Yosie, 1987;

Zimmerman, 1990). The collective knowledge of

agency personnel often governs the ‘‘way things

are done, ” reflecting the style of the agency’s

management (U.S. Congress, OTA, 1991;

Wilson, 1989). Moreover, the composition and

professional interests of an agency’s work force

can influence research priorities. NIEHS affords

an example of the role agency culture can play in

establishing the direction of research. Because

scientists at that institute consider themselves

basic scientists, some of them have a certain

disdain for the more applied research needed for

regulatory decisionmaking (Stone, 1993). Consequently, those scientists rebelled in 1992 during

the agency’s reorganizing and reordering of its

priorities, which required it to conduct more

applied research; the tension from that confrontation resulted in some scientists leaving NIEHS.

Over the long term, the effects of NIEHS’s new

structure and direction remain to be seen.

PROGRAMMATIC PRIORITIES AND

PROGRAM MANAGEMENT

An agency usually divides its research into

programs or divisions of researchers who share a

common discipline or objectives. For risk assessment research, the disciplinary distinctions are

often found in the disciplines of the environmental health sciences—for example, EPA’s

HERL has programs in, among other areas,

neurotoxicology, immunotoxicology, genetic toxicology, and reproductive and developmental

toxicology. Rarely, do Federal programs cut

across disciplines; the exceptions include EPA’s

Research to Improve Health Risk Assessment

program and NTEHS’s Laboratory of Biochemical Risk Analysis.

Setting priorities at the program level is generally a more developed-that is, both a more

systematic and more formal-process than at the

agency or national levels. Generally, one of two

distinct types of management methods is used to

determine program priorities for individual research projects (U.S. Congress, OTA, 1991). One

style, termed ‘bottom-up, ” allows research ideas

and priorities to originate with individual researchers, who communicate those ideas to their

superiors or to grant managers. As ideas rise

through intermediate levels of management to the

upper tier of program decisionmakers, the better

and more important proposals are selected. In

contrast, “top-down” management has the most

senior decisionmakers in an agency deciding the

priorities for research. Those directives are transmitted down the organizational ladder in consultation with managers, eventually reaching researchers.

OTA observed both styles of management in its

survey of risk assessment research, as well as a

mixture of styles, which is consistent with federally funded science in general (U.S. Congress,

OTA, 1991). At DOD, managers at all levels exert

a great deal of influence in selecting and funding

projects. But research agencies such as NIEHS

and NCI employ mostly bottom-up management,
Chapter 4: Setting Priorities for Risk Assessment Research 109

with individual researchers initiating projects and

influencing the directions of research. The styles

of EPA and DOE are a mixture of the two:

priority-setting is responsive to the choices of top

management but also provides an opportunity for

initiative by individual investigators. The management style of an agency mirrors its research

needs and whether it has risk management responsibilities, Agencies that use the results of

research for decisionmaking require data for their

short-term regulatory needs and rely on top-down

approaches to engender those data. In contrast,

agencies seeking to expand the scientific knowledge base support investigator-initiated projects.

ADMINISTRATIVE TOOLS FOR

PRIORITY-SETTING

Changes in leadership often alters an agency’s

objectives and organization. New directors took

over the reins of NIEHS in 1991, and EPA and

National Institutes of Health (NIH) in 1993, and

FDA is completing its search for a new director of

NCTR. Those new leaders are restructuring or

will restructure their agencies along the lines laid

down by the larger Government organization to

which they are responsible. A past example of

such leadership is the former director of the NIH,

who initiated strategic planning for the institutes

(Healy, 1992). All of the institutes within NIH,

including NIEHS, were developing strategic plans

for future priorities, but the future of this initiative

is now very much in doubt. What is clear is that

initiatives launched and policies set by a new

director of NIH will influence NIEHS’S future.

Restructuring occurs under new directors and

under established directors when conditions, needs,

or wants dictate. At the agency level, NIEHS’s

new director has restructured programs following

consultation with advisory panels (Olden, 1992).

A new FDA commissioner restructured the Center for Food Safety and Nutrition and gave NCTR

the mandate to integrate its research activity more

closely with FDA’s regulatory needs.

Yet even though agency directors can influence, shape, and promote research priorities, they

must solicit scientific, technical, and stakeholder

opinions to satisfy procedural rules and maintain

credibility, not only within the agency but also the

scientific community and other agencies in the

Federal Government. Agencies have a variety of

common administrative tools for establishing the

directions their research will take.

 Use of Advisory Committees

To change directions or to set new policy,

agency directors often employ outside experts to

evaluate research programs and recommend policy shifts (Smith, 1992; Zimmerman, 1990).

Internally, the agencies also receive advice from

institutional committees established as science

advisers. Expert committees, which can be set on

a continuing or ad hoc basis, provide scientific

credibility for administrative decisions (Jasanoff,

1990; Smith, 1992). Carrying out the recommendations of these external and internal advisory

panels remains more problematic.

EPA uses a variety of established and ad hoc

advisory committees to assist it in setting priorities for research. The role of EPA’s Science

Advisory Board has expanded from that of an

independent technical reviewer of EPA documents to include advising on science policy

(Jasanoff, 1990; Yosie, 1991; Smith, 1992).

When it was formed in the early 1970s, the board

was meant to function as an external review body

located in the Office of Research and Development. In 1976, however, it was relocated (and

organizationally ‘‘elevated”) to the Office of the

Administrator (Yosie, 1991).10

EPA committees have released documents

recently that have proved influential in agency

actions. Among the 10 committees of the Science

Advisory Board (SAB), the Research Strategies

10 me 1978 fivfio~en~ Re~ch and Developmm4 Demonstration Act codifkd the board’s mission and mUKktCXi tittie Science

Advisory Board report directly to the administrator (42 U.S.C. 4365 (a)(c)(e)).
110 I Researching Health Risks

Advisory Committee examines scientific issues

and problems that cut across the agency’s many

offices and sets research priorities (Barnes, 1992).

In 1988 and 1990, the Committee released two

influential documents, both of which concluded

that EPA should set priorities for its research and

regulatory programs based on magnitudes of risk

(U.S. EPA, SAB, 1988, 1990). (On a much more

defined level, the EPA SAB provides advice

about such discrete problems as indoor and

waterborne radon; see chapter 6.) In addition to

SAB, EPA forms expert panels for specific

purposes, such as the ad hoc ‘blue-ribbon’ panel

of outside experts that is evaluating EPA’s

science base. The panel’s report concluded that

the agency’s science programs should be given

greater visibility and access to agency administrators (U.S. EPA, 1992).

NIEHS also employs outside experts in environmental health on its Boards of Scientific

Counselors to evaluate priorities and research

directions. Three such boards and several subboards retrospectively reviews the science of the

institute and other agency matters (Olden, 1992;

Griesemer, 1992; Schwetz, 1992; Tennant, 1992).

For example, the institute based its recent restructuring on extensive meetings with those permanent and ad hoc advisory councils and boards. In

an attempt to be responsive to the public as well

as the scientific community, NIEHS administrators are also holding meetings with public organizations across the country and are pursuing

discussions with congressional representatives

(Olden, 1993).

To understand the relative importance of a

particular field of study, NIEHS convenes various

consensus conferences and workshops. The 1991

House Appropriations Bill directed the advisory

council for NIEHS to identify those environmental problems threatening public health over

the coming decade. In response to the congressional mandate, the council formed the Fourth

Task Force for Research Planning in the Environmental Health Sciences (U.S. DHHS, 1991c). The

task force identified and characterized the areas of

particular challenge and promise in the environmental health sciences and influenced the ‘‘bigpicture” directions of the agency (Olden, 1992;

U.S. DHHS, 1991c).

Outside experts are important to the workings

of other agencies as well. In addition to the

regular meetings of NCI’s directors and associate

directors, the agency uses the recommendations

of the National Cancer Advisory Board to help set

priorities. (The board’s membership includes

representatives from EPA, NIEHS, NCI, OSHA,

and other agencies.) Moreover, an external advisory board triggered the reorganization at NCTR.

The Edwards Commission report on FDA provided the background for reconciling investigatorinitiated research at NCTR with the regulatory

needs of FDA (U.S. DHHS, 1991 b). The agency

redesigned its Science Policy Committee in 1992

to address the scientific issues arising from its

new priorities (Anson, 1993).

 Funding Mechanisms

Agencies have a number of mechanisms by

which to fund research projects. Resources can

be allocated through intramural or extramural

grants, cooperative agreements, contracts, and

in-house work (Jasanoff, 1990; U.S. Congress,

OTA, 1991).

Grants and contracts are largely used to

fund extramural research done at locations

other than Federal facilities. Agencies often use a

two-tiered process in determining which grant

applications will be funded. They select applications for funding based on the scientific and

technical ‘merits’ of the work, as determined by

peer review. 11 The product of a peer review of

grant proposals is a priority score, by which that

proposal can be ranked with others. By design,

peer review is supposed to be a self-regulatory

11 peer ~viw is a pmUSS by which scientists involved in an area of research judge the Scientilc merit technical COII@eIICe, d

signifkance of proposals by their professional peers. In general, peer-review is conducted by better known and more successful scientists.
Chapter 4: Setting Priorities for Risk Assessment Research I 111

process for scientists that obviates the need for

external controls (Jasanoff, 1990). Although peer

review possesses a variety of positive attributes

that undoubtedly contributes to this country’s

scientific and technological successes, nonetheless, the process has several faults, such as

inconsistency and the inability to guarantee

quality in science (Jasanoff, 1990; US Congress,

OTA, 1991).

Determination of mission relevance is the

second tier of review. It can justify shifting

resources to particular areas of research that may

not earn the highest marks in peer review. Such

alterations are unusual, even rare, in basic research. They do occur, however. NIEHS, for

example, may redirect funds to projects that

receive less favorable priority scores if the areas

of research need further development or appear

particularly promising (Olden, 1992). ultimately,

grant-sponsoring agencies are accountable to

Congress; thus, both scientific and political factors are incorporated into decisions on grants.

Agencies also use contracts to support work of

a specific, technical nature. Contract proposals do

not undergo the type of peer review used for

grants applications. Even though many contract

proposals go through a competitive bid and

selection process, the process can lend itself to

abuse. For example, EPA has been criticized for

its extensive use and mismanagement of the

contracts process (U.S. Congress, GAO, 1992).

Extramural funding by an agency—for example, to individual university investigators—

represents an effort to provide national leadership

in a field of study. Extramural grants are used to

support university research and as seed money to

develop fields of research. In reality, some fields

of research are almost completely dependent on

Federal support. Generally, basic research, which

can have long-term payoffs, is seen as especially

deserving of Federal support. Many investigators

interviewed by OTA commented that extramural funding for risk assessment research is

inadequate because the research is considered

too applied to be supported by basic research

funds and too basic for applied research funds.

Extramural funding for risk assessment research

also tends to be unstable, which may result in

researchers being forced to leave the field and

new researchers being dissuaded from entering

because of the limited resources. The largest

extramural programs in health risk assessment

research are at NIEHS and NCI; to a smaller

extent, EPA’s Research to Improve Health Risk

Assessment program (RIHRA) funds university

researchers (Adamson, 1992; Olden, 1992; Vandenberg, 1992).

The process for funding internal projects differs because the objectives of intramural research

often differ from the objectives of extramural

programs. An agency will support internal projects provided it has the expertise and the

resources. Usually, internal projects are more

closely tied to the agency’s mission and are more

limited in their scope.

A variety of funding mechanisms allow agencies to collaborate with other institutions and

organizations on projects, sharing resources and

avoiding any duplication of efforts. These mechanisms include memoranda of understanding between and among agencies and cooperative

agreements to foster collaborations between the

government and universities or private institutions. NIEHS, for example, has a memorandum of

understanding with NIOSH for collaborative

research in epidemiology and risk assessment of

occupational hazards.

 Targeting Risk Assessment Research

Agencies use targeted research to direct resources to areas of highest priority. In broad

terms, targeted research is designed to solve a

specific problem or meet an objective set in

advance by an agency or by congressional imperative. In the context of this report, research can be

targeted to areas likely to have the greatest impact

on policy and decisionmaking. Targeted research

is a tool that can be used to link research to the

decisionmaking process.
112 I Researching Health Risks

Targeted research on health risks is especially appropriate for regulatory agencies that

use risk assessment to develop standards,

guidelines, and regulations. It is also appropriate for agencies like DOD and DOE that have

research capability as well as an operational

investment in the outcome of research-in the

form of cleanup programs designed to reduce risk.

Targeted research is especially useful for

filling gaps in the data required for specific risk

assessments and, more generically, for developing new methods of performing risk assessment.

It should not be confused with “mandated” or

‘‘manager-directed research, in which the scope

and methods of a research project are dictated in

advance by the managers of an agency. Such

projects are less likely to undergo peer review and

be awarded competitively.

Frequently people think of targeted research as

synonymous with applied research, but targeted

research can be either basic or applied, as long as

its goal is to meet an agency’s established

objective. The Human Genome Project of the

NIH/DOE is an example of targeted research that

is basic in orientation. As defined by OTA in this

report, targeted research is linked to a specific

goal; thus, terms such as “directed,” “identified,” or “prioritized” research are also appropriate. Any of those terms expands the concept of

targeted research beyond the narrow connotation

of applied research.

The most familiar method for Federal agencies

to target research is Requests for Proposals issued

to the scientific community to solicit research

intended to address a specific problem. Scientists

inside or outside the agency prepare competitive

applications detailing how they would study the

problem. After a process involving peer review

and ranking of the proposals, funds are awarded

to scientists whose applications appear most

likely or best suited to yield an answer.

Only a few examples of targeted risk assessment research exist. (See ch. 7 for a discussion of

the features of successful research programs.) A

small-scale model of targeted research is found in

EPA’s RIHRA program (box 4-A). Another

example of a targeted research program is emerging at FDA’s NCTR, where research proposals

are now reviewed not only on the basis of

scientific merit but also on the basis of relevance

to the needs of the regulatory centers of FDA.

(Previously, proposals were funded solely on the

basis of scientific merit.) To ensure that regulatory relevance plays a role in proposal review,

members of the reviewing committees are drawn

from each center in FDA with regulatory responsibility (Norris, 1993).

DOE represents a case in which a targeted

research program in health risk assessment would

be useful to meet the challenge of environmental

cleanup. DOE’s Office of Environmental Restoration and Waste Management is responsible for

over $5 billion in cleanup programs at DOE

facilities in 1993. With the exception of the

epidemiology program (under the Office of Epidemiology and Surveillance), DOE’s experimental toxicology effort is moving toward answering

basic research questions related to molecular

biology and the mechanisms of toxicity. Some

point out that this shift toward basic research will

improve the quality of DOE’s research and

ultimately pay off in the applied arena. But others

contend that valuable opportunities are being lost

because research is not being targeted to the

problems raised by the most costly cleanup effort

ever undertaken by the Federal Government.12

FINDINGS AND CONCLUSIONS

To evaluate Federal research to improve health

risk assessment, OTA used three distinct categories to classify health risk assessment research: 1)

research to improve health risk assessment methodologies; 2) basic science and basic health risk

research to understand how environmental agents

produce their adverse effects and basic biological,
.

Chapter 4: Setting Priorities for Risk Assessment Research I 113

Box 4-A–The Research To Improve Health Risk Assessment Program at EPA

The objective of EPA’s Research to Improve Health Risk Assessments (RIHRA) program is to identify and

conduct systematic, targeted research to improve the scientific basis and methods used in health risk assessment

In 1988, Congress mandated EPA to develop an integrated research program to reduce uncertainties in the risk

assessment process. RIHRA is the agency’s response to the environmental health risks aspects of the mandate.

RIHRA serves to complement other EPA research programs and address risk assessment issues facing the

agency that cut across the regulatory programs. The program includes investigators from the Environmental

Protection Agency’s Health Effects Research Laboratory in its Office of Health Research; Office of Health and

Environmental Assessment; and the Office of Modeling, Monitoring Systems, and Quality Assurance.

Projects are selected using defined criteria and awarded competitively. RIHRA’s four major project areas

include: 1) integrated exposure assessment; 2) physiologically based pharmackinetic models; 3) biologically

based dose-response models; and 4) analyses of uncertainty in risk assessment. Resources other than RIHRA

funding are also used to support those areas of research at the agency.

EPA integrated RIHRA into its new research planning scheme, which is based on specific issues needing

research support This new issue-based planning places RIHRA under the Health Risk Assessment Methods

issue. The major emphasis of this issue is scientific studies in the laboratory to support the development of

predictive models for assessing health risks but also includes some chemical-specific assessments (eg., dioxin).

It is intended to complement the development of biological assays and chemical-specific data that is emphasized

in other issues. Related research issues for RIHRA include the Health Effects issue, which emphasizes

complementary development of data on the way agents produce adverse effects, and the Human Exposure issue,

which provides information on the route, magnitude, frequency, and duration of exposures to environmental

pollutants.

SOURCE: U.S. Environmental Protection Agency, Off”= of Rasaarch and Dawdopmant, “Strategic Issua Plans” (April 1993).

physical, and chemical sciences; and 3) research enter into new programs. Often, methodological

to fill chemical-specific data gaps. OTA believes

that progress must be made in all three areas

to substantially improve the process of risk

assessment and reduce the uncertainty of

estimates of risk.

Taken as a whole, Federal research to improve risk assessment at the national level

appears neither well integrated nor well

planned. In particular, given the promise that

methodological research offers, the resources

allotted to it appear disproportionately small: in

FY 1993, methodological research received approximately 11 percent of the estimated $600

million spent on health risk assessment research.

As a result, methodological research is a secondary priority for both research and regulatory

agencies. In times of restricted resources and in

the wake of congressional imperatives, the agencies tend to maintain their core programs and not

research becomes marginalized as a consequence.

Yet expanding methodological research is not

simply a matter of redirecting funds at the

expense of either basic research or research on

data collection. Instead, methodological research

should be considered complementary to the

other types of research that agencies are

conducting and should be integrated into a

complete research program. The results of basic

research on biological processes and mechanisms

of toxicity provide the biological framework for

many of the methods and models being developed. Dose-response and pharmacokinetic models, for example, are based on information about

physiology and metabolism obtained from basic

research. Similarly, risk assessments benefit from

research on data collection; a complete risk

assessment requires data on toxicity, doseresponse relationships, and exposures. Further-
114 I Researching Health Risks

more, methodological research, especially extrapolation models, and basic research are closely

linked with chemical-specific data.

Charting a course for improving risk assessment research requires that Federal agencies work

at several organizational levels. OTA examined

the priority-setting process for such research at

three different levels: national, agency, and program. Each level employs different processes and

methods. Setting priorities at the program level

involved the most formalized and systematic

processes; the national level involved the least. In

addition, several factors influence the choice of

one type of research over another.

Despite the national implications of decisions

based on risk assessment, Federal research to

improve risk assessment is largely decentralized

and uncoordinated. There is no central coordinating Federal presence. Most Federal research is

done in support of the agencies and departments

that sponsor the research, as is the case for

environmental research and development in general (Carnegie Commission, 1992; Schaefer, 1991).

OTA observed few multiagency efforts. An

example is the FCCSET process, but participants

and nonparticipants alike displayed little optimism about possible outcomes from it.

The absence of an identified central leader in

risk assessment research contributes to the pessimistic viewpoint and to the current level of

funding and disciplinary and agency fragmentation in the effort to improve health risk assessments. A nationally recognized leader could

provide leadership and assurances about political

support for research, promote multiagency collaborations, and provide incentives for overcoming bureaucratic hurdles and turf battles. A

national leader in the White House in a position

equivalent to the “Drug Czar” or “AIDS Czar, ”

could bring national visibility and unify and

coordinate research activities across agencies, in

addition to articulating the needs of the field to

Congress and the President. Furthermore, this

central figure could instill a sense of common

purpose among researchers and program managers.

At the agency level, priorities are based on the

different constituents, legislative mandates, and

missions of the organizations. They are also

influenced by historical factors and the composition of the work force, which gives rise to an

agency culture that is important in determining

how the organization establishes its directions

and priorities. Often, political and public pressure

dictate priorities to a greater extent than does a

formal process within the agency (U.S. EPA,

SAB, 1988).

The priorities for risk assessment research vary

with the mission and function of the agency:

specifically, whether the agency’s responsibilities include risk management. The health regulatory agencies, DOD, and DOE conduct mostly

chemical-specific data development, whereas the

research agencies, by and large, conduct basic

research.

Setting priorities at the program level is generally a more developed process-both more systematic and more formal-than it is at the agency

or national levels. Generally, two distinct types of

management methods are used to determine

programmatic priorities for individual research

projects (U.S. Congress, OTA, 1991). One style,

termed ‘‘bottom-up,” allows research ideas and

priorities to originate with the individual researchers, who communicate those ideas to their

superiors or to grant managers. In contrast,

‘‘top-down’ management assigns prioritysetting to the most senior decisionmakers in an

agency. OTA observed both styles of management in its survey of risk assessment research, as

well as a mixture of styles, which is consistent

with federally funded science in general (U.S.

Congress, OTA, 1991).

Risk assessment research has not kept abreast

of the needs of our modem society. It is estimated

that 1,500 new chemicals are introduced worldwide each year, which joins the more than 62,000

chemicals OTA estimates is already in use in the

U.S. Studies suggest that only a fraction are
—

Chapter 4: Setting Priorities for Risk Assessment Research I 115

adequately, if at all, tested for toxicity. New

insights from research can produce better tools to

decide which chemicals require more investigation and which do not; which require regulation

and which do not. Without better tools, governmental agencies and private companies will never

catch upon the backlog of untested chemicals and

unanswered questions, and the public will never

have the assurance that sufficient research is

being brought to bear on the risks that concern it.

CHAPTER 4 REFERENCES

Abelson, P.H. 1993. Regulatory costs (editorial).

Science 259:159.

Adarnson, R. 1992. U.S. National Cancer Institute.

Personal communication.

Anson, J. 1993. U.S. National Center for Toxicological

Research. Personal communication.

Barnes, D. 1992. Director. Science Advisory Board.

U.S. Environmental Protection Agency. Personal communication.

Barnes, D. G., and Edge, D. 1982. Readings in Sociology of Science (Cambridge, MA: Massachusetts

Institute of Technology Press).

Barrett, J.C. 1993. Mechanisms of muhistep carcinogenesis and carcinogen risk assessment. Environmental Health Perspectives 100:9-20.

Bromley, D.A. 1992. Science, scientists, and the

science budget. issues in Science and Technology, fall,

pp. 41-48.

Brown, G.E. 1993. Science’s real role in policymaking. CM .Vews, May 31, pp. 9-11.

Carnegie Commission. 1992. Environmental research

and development: strengthening the Federal infrastructure. A report of the Carnegie Commission on Science,

Technology and Government.

Clark W., and Majone, G. 1985. The critical appraisal

of scientific inquiries with policy implications. Science, Technology, and Human Values 10:6-19.

Colledge, C. 1993. Data Quality Assurance Officer,

Office of Pesticides, Prevention, and Toxic Substances. U.S. Environmental Protection Agency. Personal communication.

Cranor, C. 1993. Regulating toxic substances: a

philosophy of science and the law (New York Oxford

University Press).

Environmental Health btter. 1993. 32(10): May 1993

(Business Publishers, Inc.).

Epstein, S. 1979. The politics of cancer (New York

Anchor Books).

Gori, B.G. 1992. Wither risk assessment?: an overall

perspective. Presented at the annual meeting of the

American Industrial Health Council (Washington,

DC), Dec. 1.

Graham, J., Green, L., and Roberts, M. 1988. In search

of safety: chemicals and cancer risk (Cambridge:

Harvard University Press).

Griesemer, R. 1992. U.S. National Institute of Environmental Health Sciences. Personal communication.

Hanson, D.J., bpkowski, W., Imng, J.R., and Zurer,

P.S. 1993. Reinventing government. ChemicaZ and

Engineering News. October 11, pp. 21-24.

Healy, B. 1992. Is this your father’s NIH? and other

strategic questions. Science 257:312.

Hudson, V. 1993. Hazards substance database, National Library of Medicine, Food and Drug Administration. Personal communication.

Jasanoff, S. 1989. Norms for evaluating regulatory

science. Risk Analysis 9:271-273.

Jasanoff, S. 1990. The fifth branch: science advisers as

policyrnakers (Cambridge, MA: Harvard University

Press).

Joseph, S. 1992. Dragon within the gates: the once and

future AIDS epidemic (New York: Carroll and Graf

Publishers, Inc.).

Kuhn, T 1962. The structure of scientific revolutions

(Chicago: University of Chicago Press).

Lakatos, I. 1978. The methodology of scientific

research programs (Cambridge, UK: Cambridge University Press).

Lao, H. 1993. ~lce of Pesticide Programs. Personal

communication.

Lee, P. 1993. Assistant Director for Safety and Health,

U.S. Department of Health and Human Semices.

Personal communication.

Lilienfeld, D. 1993. Senior Epidemiologist. EMMES

Corp. Personal communication.
116 I Researching Health Risks

Lindblom, C., and Cohen, D. 1979. Usable Knowledge: Social Science and Social Problem Solving

(New Haven, ~: Yale University Press).

Long, J.R. 1993. House budgets for modest growth in

1994 Federal R&D programs. CE News, Aug. 2.

Macys, D.A. 1993. Naval Medical Research Institute.

U.S. Department of Defense. Personal communication.

Marshall E. 1993. Toxicology goes molecular. Science

vol. 259, Mar. 5.

h-farton~ J. 1992. Deputy Director of the Health

Standards Program, Occupational Safety and Health

Administration, Department of Labor. Personal communication.

Merton, R. 1973. The Sociology of Science: Theoretical and Empirical Investigations (Chicago: University

of Chicago Press).

Mintz, B. 1984. OSHA: History, Law, and Policy

(Washington, DC: Bureau of National Affairs).

Moolenaar, R.J. 1992. Overhauling carcinogen classification. Issues in Science and Technology 8(4):70-75.

National Research Council, Commission of Life

Sciences, Committee on the Institutional Means for

Assessment of Risks to Public Health. 1983. Risk

assessment in the Federal Government: managing the

process (Washington, DC: National Academy Press).

Norns, F. 1993. Acting Director of NCTR. Department

of Health and Human Services. Personal communication.

Olden, K. 1992. U.S. National Institute of Environmental Health Sciences. Personal communication.

Olden, K. 1993. Environmental health science research

and human risk. Regulatory Toxicology and PharrnaCO/0~ 17(2):230-233.

Olson, E.D. 1984. The quiet shift of power: Office of

Management and Budget supervision of Environmental Protection Agency rulemaking under executive

order 12,291. Virginia Journal of Natural Resources

&ZW 4:1, pp. 3-80.

Paustenbach, D.J. 1989. Important recent advances in

the practice of health risk assessment: implications for

the 1990s. Regulatory Toxicology and Pharmacology

10:204-243.

Ringen, K. 1992. Comments on the National Toxicology program: final report of the advisory board.

Presented to the Board of Scientiilc Counselors,

National Toxicology Program, Washington, DC, Sept.

11.

Rodricks, J.V., Brett, S.M., and Wrenn, G,C. 1987.

Signi.llcant risk decisions in Fedeml regulatory agencies. Regulatory Toxicology and Pharmacology 307:310.

Rosenthal, A., Gray, G., and Graham, J. 1992.

Legislating acceptable cancer risk from exposure to

toxic chemicals. Ecology Law QuarterZy 19:269-362.

Rushefs&, M.E. 1986. Making Cancer Policy (Albany, NY: State University of New York Press).

Salter, L. 1987. Mandated Science: Science and

Scientists in the Making of Standards (Boston: Kluwer

Academic Publishers).

Schaefer, M. 1991. The Federal research puzzle:

making the pieces fit. Environment 33(9):16-20, 38-

42.

Schwetz, B.A. 1993. Chief, Systems Toxicity Branch,

National Institute of Environmental Health Sciences.

Personal communication.

Smith, B.L.R. 1990. American Science Policy Since

World War II (Washington, DC: The Brookings

Institution).

Smith, B.L.R. 1992. The Advisers: Scientists in the

Policy Process (Washington, DC: The Brookings

Institution).

Stone, R. 1993. Ken Olden heals NTEHS’S “split

brain”. Science vol. 259, Mar. 5.

Tennant, R. 1992. National Institute of Environmental

Health Sciences. Personal communication.

U.S. Congress, Congressional Research Service (CRS).

1993. Summary of environmental laws administered

by the Environmental Protection Agency. 93-53ENR.

U.S. Congress, General Accounting Office. 1992.

Superfund Program Management. GAO/HR-93-10.

U.S. Congress, House Committee on Science, Space,

and Technology, U.S. House of Representatives. 1992.

Report of the Task Force on the Health of Research,

July.

U.S. Congress, OTA (Oflice of Technology Assessment). 1990. How Has Federal Research on AIDS/HIV

Disease Contributed to Other Fields? Staff paper.

U.S. Congress, OTA. 1991. Federally Funded Research: Decisions for a Decade. OTA-SET490 (Washington, DC: U.S. Government Printing Office).
Chapter 4: Setting Priorities for Risk Assessment Research I 117

U.S. DOE (Department of Energy). 1990. Report to the

Secretary. The secretarial panel for the evaluation of

epidemiologic research.

U.S. DOE (Department of Energy)/DHHS (Department of Health and Human Sewices). 1991. The U.S.

Human genome project: The first five years. Fiscal year

1991-1995.

U.S. DHHS (Department of Health and Human

Services) .NTP(NationalToxicology Program). 1991a.

Review of current DHHS, DOE, and EPA research

related to toxicology.

U.S. DHHS. 1991b. Final report of the advisory

committee on the Food and Drug Administration.

U.S. DHHS. 1991c. Human health and the envimnment—

some research needs. National Institutes of Health,

National Institute of Environmental Health Sciences.

Draft report of Task Force IV, National Advisory

Environmental Health Sciences Council.

U.S. DHHS. NTP. 1992. Drafi Respmse of the

Program Recommendations in the Final Report of the

Advisory Review by the NIT Board of Scientific

Counselors; Request for Comments. Federal Register

57:61439-61444.

U.S. DHHS. NTP. In press. Review of current DHHS,

DOE, and EPA research related to toxicology.

U.S. EPA (Environmental Protection Agency). SAB

(Science Advisory Board). 1988. Future risk: research

strategies for the 1990s.

U.S. EPA. SAB 1990. Reducing risk: setting priorities

and strategies for environmental protection. Science

Advisory Board (SAB-EC-90-021).

U.S. EPA. 1991. Setting environmental priorities: the

debate about risk. EPA JournaZ 17(2):1-47.

U.S. EPA. 1992. Safeguarding the future: credible

science, credible decisions. EPA-600-9-91-050.

Vandenberg, J. 1992. U.S. Environmental Protection

Agency. Personal communication.

Wilson, J,Q. 1989. Bureaucracy: What government

agencies do and why they do it (U. S.: Basic Books,

Inc.).

Yosie, TF, 1987. ERA’s risk assessment culture.

Environmental Science and Technology 21:526-531.

Yosie, TF. 1991. The EPA science advisory board. In:

Harnessing Science for Environmental Regulation, pp.

11-25,

Young, F. 1993. U.S. Department of Health and

Human Services. Personal communication.

Zimmerman, R. 1990. Governmental management of

chemical risk: regulatory processes for environmental

health @wis Publishers).
Research

and

Decisionmaking 5

s

cience and policymaking are uneasy partners. In an

address at the press conference to release the 1983

National Research Council report on risk assessment in

the Federal Government, the former administrator of the

U.S. Environmental Protection Agency (EPA), William D.

Ruckelshaus, said: “The main reason for the uneasiness lies, I

think, in the conflict between the way science really works and

the public’s thirst for certitude that is written into EPA’s laws.

Science, as you all know, thrives on uncertainty” (Ruckelshaus,

1983).

Yet despite that uneasy relationship, the primary criterion for

health risk assessment research is that it be useful for decisionmaking. With that observation in mind, the Office of Technology

Assessment (OTA) examines three interrelated questions in this

chapter:

1.

2.

3.

How has research influenced Federal risk assessment

guidelines and risk assessment practices? r

What impact has research had on decisionmaking?

How can research be designed to make risk assessment

more useful in decisionmaking?

To answer those questions, we review the evolution of Federal

risk assessment guidelines and risk assessment practices and the

comments and criticisms made regarding them. The analysis

focuses on Federal activities in this area in part because the

record of Federal regulatory decisionmaking is more accessible

than the record of decisionmaking in the private sector.

Research findings from epidemiology and toxicology provide

the primary database for health risk assessment. But those data

119
120 ! Researching Health Risks

are seldom extensive enough for answering many

of the questions that arise in regulatory decisionmaking. Weinberg (1972) characterized such

issues as “transience questions"--questions

that “can be asked of science and yet . . . cannot

be answered by science. ” Agencies frequently

confront them, and because science cannot answer them, agencies adopt so-called science

policy assumptions in order to make decisions.

The assumptions can be divided into two general

types: those that are used to bridge gaps in

scientific knowledge and those that compensate

for a lack of agent-specific data (NRC, 1983).

IMPACT OF RESEARCH ON RISK

ASSESSMENT GUIDELINES AND

DECISIONMAKING

EPA is the main player in developing and

revising risk assessment guidelines. Although the

Consumer Product Safety Commission (CPSC),

the Food and Drug Administration (FDA), and the

Occupational Safety and Health Administration

have also published health risk assessment guidelines in the Federal Register, only EPA has

completed scientific reviews of some of its

guidelines and formally modified them in response to new scientific information. This chapter

considers three of EPA’s guidelines. The agency

first adopted guidelines for assessing the risks

of carcinogens in 1976; it formally modified

those guidelines in 1986 and is now revising

them further. It adopted its first guidelines for

developmental toxicants and for estimating

exposures in 1986, modifying the developmental toxicants guidelines in 1991 and the

exposure guidelines a year later. Also discussed

in this chapter is the International Agency for

Research on Cancer’s most recent revisions of its

procedures for evaluating the risks to humans

posed by carcinogens.

Reviewing the EPA risk assessment guidelines

and their revisions makes it clear that the agency

has changed relatively few of its science policy

assumptions in response to new scientific information. The impact of research on the guidelines

is more evident in EPA’s increased attention to

identifying all of the relevant scientific questions

that the guidelines should address. Often, new

questions reveal new uncertainties that have to be

bridged with assumptions.

 Guidelines for Risk Assessments

of Carcinogens

Reflecting society’s concern about cancers and

the Federal Government’s regulatory focus on

them, extensive scientific research has been and

is being conducted to identify the causes of

cancers and the mechanisms of carcinogenesis.

To date, that research has had only a modest effect

on efforts to revise the EPA’s carcinogen risk

assessment guidelines. It has, however, had a

substantial impact on chemical-specific risk assessments and consequently on regulatory actions. In addition, it is currently generating

considerable debate as EPA considers new revisions to its 1986 cancer policy (U.S. EPA, 1988b,

1992a). In general, research has had greater

impact in displacing assumptions that EPA adopted

to bridge inadequacies in the data than in changing assumptions to compensate for theoretical

uncertainties.

EPA’s 1976 interim guidelines for carcinogen

risk assessment (U.S. EPA, 1976) discussed the

assumptions underlying the agency’s regulatory

approach, but they provided no explicit list of

agency science policy positions. In contrast,

EPA’s 1986 guidelines on carcinogen assessment

(U.S. EPA, 1986a) detailed several major science

policy positions that guide the agency’s interpretation of incomplete or uncertain data (see box

5-A).

Among the most controversial agency policy

positions is the use of the results of animal tests

to predict human effects. The 1981 OTA report

Assessment of Technologies for Determining

Cancer Risks from the Environment (pp. 124-
Chapter 5: Research and Decisionmaking 1121

127) discussed a number of objections to the use

of animal bioassay data:i

1.

2.

3.

4.

5.

The doses given to test animals are too high,

and the results do not predict carcinogenic

effects in humans.

Routes of exposure in test animals are not

the same as routes of exposure in humans.

Some life processes of test animals (e.g.,

physiology and metabolism) are so different

from those of humans that the test results

may not be relevant for predicting human

cancer risks.

Some test animals and animal organs are so

sensitive to certain chemicals which induce

tumors that the test results do not predict

cancer risk in humans.

Benign tumors in test animals do not predict

human cancer risk.

Twelve years later, such objections are still

being raised—most often, of course, when tests

indicate that a commercially important chemical

causes cancer in animals and the chemical’s

manufacturer, distributors, and users face regulation. As long as the bioassay remains the basic

source of information for evaluating carcinogenic

risks to humans, those objections will be raised.

The sensitivity of test animals and test organs

is an issue because certain chemicals cause

tumors only in the liver of male B6C3F1 mice

(and not in other mouse organs), female mice, or

in rats. EPA’s 1986 guidelines describe the

problems posed by agents that cause cancer only

in certain organs in a single species. In discussing

the evaluation of animal test results for assessing

human risk, EPA has stated that it accords more

weight to conclusions based on results showing

that a chemical causes cancer in more than one

species. The agency classifies the evidence for

carcinogenicity in a descending scale that runs

from “sufficient,” through “limited,” “inadequate, ” and ‘‘no data, ’ to ‘‘no evidence. ’ EPA

defines “sufficient” as follows:

Sufficient evidence of carcinogenicity, which

indicates that there is an increased incidence of

malignant tumors or combined malignant and

benign tumors [footnote]: (a) in multiple species

or strains. . . (U.S. EPA, 1987b, pp. 1-11).

But EPA’s statement does not mean that it

always accords less weight to results that are

obtained in only one species. In fact, the two

footnotes in the definition of sufficient’ dismiss

two arguments that scientists have not been able

to resolve. The first footnote states:

An increased incidence of neoplasms that

occur with high spontaneous background incidence (e.g., mouse liver tumors and rat pituitary

tumors in certain strains) generally constitutes

‘‘sufficient’ evidence of carcinogenicity, but

may be changed to “limited” when warranted by

the specific information available on the agent

(U.S. EPA, 1987b, pp. 1-11).

The footnote not only gives the agency the

flexibility to judge sufficiency of evidence in the

absence of positive results from two species, but

it also allows agency staff to ignore the great

uncertainty that many scientists attach to any

conclusion based on a chemical’s causing only

mouse liver tumors. As EPA’s guidelines note:

For a number of reasons, there are widely

diverging scientific views about the validity of

mouse liver tumors as an indication of potential

carcinogenicity in humans when such tumors

occur in strains with high spontaneous background incidence and when they constitute the

only tumor response to that agent. These Guidelines take the position that when the other

conditions for a classification of “sufficient’

evidence in animal studies are met . . . the data

should be considered as ‘sufficient’ evidence of

1 Bioassay is a term used for long-term (e.g., 2 years for rodents) experimental studies for cancer induction. Rodent bioassays generally

employ both sexes of rats (Fischer 344/N) and mice (B6C3F1 hybrid), using two or three exposure levels plus untreated controls in groups of

50 animals for 2 years.
122 I Researching Health Risks

Box 5-A–Major Science Policy Positions for EPA Cancer Guidelines

● Benign tumors should generally be combined vvith malignant tumorsfor risk estimates unless the benign tumors

are not considered to have the potential to progress to the associated malignancies of the same histogenic

origin.

. Agents that are positive in long-term animal experiments and also show evidence of promoting cocarcinogenic

activity in specialized tests should be considered as complete carcinogens unless there is evidence to the

contrary because it is, at present, difficult to determine whether an agent is only a promoting or cocarcinogenic

agent.

. These guidelines take the position that when the only tumor response is in the mouse liver and when other

conditions for a classification of “sufficient” evidence in animal studies are met (e.g., replicate studies,

malignancy; see section IV), the data should be considered as “sufficient” evidence of carcinogenicity.

* Because it is possible that human sensitivity is as high as the most sensitive responding animal species, in the

absence of evidence to the contrary, the biologically acceptable data set from long-term animal studies showing

the greatest sensitivity should generally be given the greatest emphasis in estimating human carcinogenic risk

● Where two or more significantly elevated tumor sites or types are observed in the same study, extrapolation

may be conducted on selected sites or types. To obtain a total estimate of carcinogenic risk animals with one

or more tumor sites or types showing significantly elevated tumor incidence should be pooled and used for

extrapolation. The pooled estimates will generally be used in preference to risk estimates based on single sites

or types.

● In the absence of adequate information to the contrary, the linearized multistage procedure will be employed

for estimating human carcinogenic risks.

. In the absence of comparative toxicological, physiological, metabolic, and pharmacokinetic data for a given

suspect carcinogen, the Agency takes the position that the extrapolation on the basis of surface area is

considered to be appropriate because certain pharmacological effects commonly scale according to surface

area.

. Unless there is evidence to the contrary in a particular case, the cumulative dose received over a lifetime,

expressed as average daily exposure prorated over a lifetime, is commended as an appropriate measure of

exposure to a carcinogen. That is, the assumption is made that a high dose of a carcinogen received over a

short period of time is equivalent to a corresponding low dose spread over a lifetime.

. In characterizing the risk due to concurrent exposure to several carcinogens, the risks are combined on the basis

of additivity unless there is specific information to the contrary.

The basic source of information for most risk assessments is the carcinogenesis bioassay, which is a test

of the suspect carcinogen’s capacity to cause tumors in laboratory animals, generally rats and mice. Because of

reliance on the bioassay, much of the cancer risk assessment guidelines are devoted to the execution and

interpretation of the bioassay.

SOURCE: US. Environmental Protection Agency, “Guidelines for Carcinogen Risk Assessment,” Federal Re@ter 51(19SS)2X3992-

340Q3.

carcinogenicity. It is understood that this classifi- EPA’s science policy thus considers results

cation could be changed on a case-by-case basis that show that a chemical causes tumors only in

to ‘‘limited,” if warranted, when factors such as mouse livers as sufficient evidence of carcinogenthe following are observed: an increased inci- icity. The agency’s discussion of this policy

dence of tumors only in the highest dose group admits that not all scientists agree with that

and/or only at the end of the study (U.S. EPA, decision, but it does not address the arguments of

1987b, pp. 1-5). those who disagree. Instead, the guidelines discuss the replication of test results and consistent
Chapter 5: Research and Decisionmaking I 123

test design. But no matter how many times tests

are replicated or how well they are done, those

that generate false signals can do no more than

that.

Many observers believe that EPA persists in

treating mouse liver tumors as sufficient evidence

because the agency has regulated several chemicals on the basis of such findings. For example,

the agency banned the organochlorine pesticide

DDT ostensibly on the basis of potential liver

carcinogenicity (Dunlap, 1988). To back away

from the sufficient classification might open up

some of EPA’s past actions to renewed scrutiny

and criticism.

The second footnote in the paragraph about

sufficient evidence deals with benign tumors:

Benign and malignant tumors will be combined (to arrive at a count of total turners) unless

the benign tumors are not considered to have the

potential to progress to the associated malignancies of the same histogenic origin (U.S. EPA,

1987b, pp. 1-11).

The language of the footnote indicates that

EPA will consider other evidence in deciding how

to count benign tumors. But it stops short of

saying what kind of evidence would be considered, much less what kind would be considered

convincing. As a practical matter, it is probably

impossible to demonstrate that a “potential to

progress to the associated malignancies” does not

exist.

The guidelines about sensitive organs and

sensitive test animals retain the features that

caused objections more than a decade ago. Those

features, like most parts of the guidelines, are

designed to protect health, especially in circumstances of few or no data. That position is not

likely to change. Nevertheless, EPA has altered

some of its science policy assumptions to accommodate new information.

Extrapolating from the results of tests in

animals to predictions of risk to humans is at the

heart of most risk assessments, and recent years

have seen three examples of altered approaches to

it. The first is a change from a general ‘‘default’

extrapolation method to a particular ‘‘default’

factor derived from specific data and applicable to

all chemicals. The second example describes the

process used to develop specific data for a

chemical to replace a default approach. The last

example notes a few incidence in which specific

information about a chemical altered risk assessment decisions,

SCALING FACTOR FOR CROSS-SPECIES

EXTRAPOLATIONS

In extrapolating test results, allowances

must be made for the differences in size, shape,

life-span, physiology, and biochemistry between test animals and humans. When toxicologists and risk assessors lack specific information for making those adjustments, they have

traditionally used one or the other of two

standardized ‘‘scaling factors. ’ One scaling

factor is body weight; thus, a dose of 1 milligram

per kilogram body weight in a rat is treated as

equivalent to 1 milligram per kilogram body

weight in a human, The other factor is body

surface area. Surface area is difficult to measure,

but it can be approximated by raising body weight

to the 2/3 power. Although that approximation is

used, it has been challenged as likely to be in error

(Slone, 1993).

Regardless of the certainty of either factor

being appropriate, FDA uses the body weight

scale, and EPA uses the surface area scale, with

the result that EPA predicts higher risks than

FDA. Given the same data about toxicity, EPA

would predict a risk 14 times higher than the risk

FDA would predict when the tests are done in

mice and a risk 6 times higher when the tests are

done in rats (U.S. Congress, OTA, 1981).

Recently, EPA proposed, for itself and on

behalf of FDA and CPSC, changing its choice

of scaling factor. The proposal was made in

response to three events: an analysis of all

available interspecies scaling data (Travis and

White 1988), a reassessment of the rationale
124 I Researching Health Risks

underlying the use of the surface area factor

(Travis et al., 1990), and a political effort to

harmonize the approaches of different Federal

regulatory agencies. The new scaling factor that

EPA has proposed lies between the body weight

and surface area scaling factors. It will result in

risk estimates about midway between the estimates that would be produced by the two older

methods.

USING METABOLIC AND PHARMACOKINETIC DATA

FOR CROSS-SPECIES EXTRAPOLATION

Researchers have long believed that studies in

pharmacokinetics and metabolism provide important information for understanding the mechanisms by which agents evoke toxicity (see Slone,

1993). Pharmacokinetic studies examine the rates

of absorption, distribution, metabolism, and excretion of a compound. They also examine the

time-dependent features of those processes, as

they link to the compound’s toxicological effects.

Metabolic studies examine the coordinated reactions and pathways that transform the compound

into reactive or inactive intermediates that can be

toxic entities. Information from pharmacokinetic and metabolic studies provides a basis for

determining the internal dose and the validity

of various extrapolations from the level of

exposure to the expected response.

The case of methylene chloride is an example

of the use of pharmacokinetic and metabolic data,

by government and industry scientists to improve

animal-to-human extrapolation. Three factors seem

to have influenced the collaboration. First, influential members of the scientific community were

interested in using pharmacokinetic information

to obtain better estimates of the doses of methylene chloride necessary to produce turners in test

animals and doses that may affect humans.

Second, staff from various agencies wanted to

work with industry and each other to evaluate

metabolic data and determine how such information could be used in risk assessment. Third, the

EPA Science Advisory Board encouraged a

thorough review of the data obtained using

pharmacokinetic methods (Preuss, 1992).

The story begins in the early 1980s, when the

U.S. Air Force supported a research project at the

Wright-Patterson Air Force Base Inhalation Toxicology Laboratory to develop methods to better

assess the risks associated with human exposure

to organic solvents. The Air Force-supported

scientists first developed a generic, physiologically based pharmacokinetic (PBPK) model to

assess exposure of humans to organic solvents

through inhalation. Following a 1986 review of

EPA’s risk assessment of methylene chloride,

members of the advisory board concluded that the

PBPK model was a valid alternative to other

approaches for estimating the dose of methylene

chloride that can cause human toxicity based on

animal study results. As a result of that encouragement, scientists from EPA, CPSC, FDA, Dow

chemicals, ICI (a U.K. fro), and the European

Council of chemical Manufacturers Federation

began to hold periodic meetings to discuss their

research needs and share information. The meetings identified gaps in the database for methylene

chloride, produced a commitment to initiate

further studies, and provided a forum to share and

discuss protocols and experimental results.

The effort to understand the mechanisms by

which methylene chloride induces cancer stimulated research in PBPK modeling and enthusiasm

for improved interspecies extrapolations. For

methylene chloride specifically, both EPA (1987c)

and the California Department of Health and

Human Services (1988) have concluded that

additional data are necessary to clarify metabolic

differences between rodents and humans. The

agencies expect some of these data to come from

ongoing Navy-supported research at WrightPatterson (Gearhart, 1992). Additional information will be generated by a research program at the

National Institute of Environmental Health Sciences to better characterize the tumorigenic

response in mice exposed to methylene chloride.

The ongoing research on methylene chloride is

an example of collaborative research that has led
Chapter 5: Research and Decisionmaking I 125

to additional studies. To date, these investigations

have not resolved to EPA’s satisfaction the

question of how potent a carcinogen methylene

chloride is in humans. They have, however,

pointed to additional projects that may clarify

questions of human risk. More generally, the

methylene chloride experience underlines the

difficulties of animal-to-human extrapolation and

should caution risk assessors against too-ready an

acceptance of generalized approaches (e.g., scaling factors) in those extrapolations.

RESEARCH AND CHANGES OF PRESUMPTIONS

The fundamental premise of toxicology is

that animals and humans respond similarly to

chemicals. Some see accruing evidence for that

premise (Huff, 1993), For others, substantial

problems are surfacing in extrapolating results from animal models to human populations (Ames and Gold, 1990a,b; Cohen and

Ellwein, 1991, 1992). In carcinogenic risk assessments, regulators and scientists have established

criteria for evaluating the effects of chemicals in

animals to help in deciding whether the chemicals

present carcinogenic hazards to humans (IARC,

1992a; U.S. OSTP, 1985). Once a substance has

been classified as a potential human carcinogen,

U.S. regulatory agencies consider it appropriate

to use linear, no-threshold extrapolation models

to estimate the magnitude of human risk (see ch.

2). Arguing against these general procedures is

the increasing recognition that biological mechanisms, physiology, and biochemistry or differences in routes of exposure may affect the agent’s

interactions with the target tissue. Those effects

could alter the toxicological consequences in

humans compared with those observed in animals.

Demonstrating the validity of generalized extrapolation procedures requires information about

mechanisms of toxicity in sufficient detail such

that no important gaps remain. That’s seldom the

case. Instead, limited mechanistic data become

the focus of controversies about interpretation.

One such debate arises in assessing the risk of

cancer in humans from exposure to agents that are

not DNA-reactive but that test positive for

carcinogenicity in animals. The mechanisms by

which the diverse array of nonmutagenic, carcinogenic chemicals induce cancer are little understood. As a result, new generic approaches to

interpret those tests and project their results to

human risk estimates are not likely to be available

soon .

2 Nevertheless, specific studies of some

chemicals have led to deviations from the general

presumption of risks to humans and the application of the linear, no-threshold model.

Some substances induce cancer through indirect mechanisms that operate at high doses in test

animals but are unlikely to operate at lower doses.

Or they may operate through mechanisms that do

not exist in humans. An example of the former

mechanism, which renders linear, no-threshold

extrapolation inappropriate, is ethylene thiourea.

That chemical disrupts hormone levels in the

rodent thyroid gland only at high doses (U.S.

EPA, 1988c). An example of a situation in which

positive findings in animals are not applicable to

humans is the induction of kidney tumors in male

rats through the interaction of d-limonene and a

protein present in male rats but not in humans

(U.S. EPA, 1991a). Some chemicals that cause

bladder cancers in test animals (e.g., melamine,

aliette, and saccharin) are considered unlikely or

impossible human carcinogens because exposures in humans are unlikely to reach the extremely high levels required to cause urinary

calculi, which are the proximal cause of those

cancers induced at very high doses (see Huff,

1992, for a review). These examples demonstrate

the importance of chemical-specific mechanistic

data and the growing importance of understanding mechanisms of toxicity for more realistic

extrapolations from animals to humans.

j In contra~( t. I_I.S. ~WlatoW agencies, which use no-threshold models for all carcinogens, r@Xory agencies ~ some o~er com~es

assume a safe level of exposure exists in estimating risks from nongenotoxic carcinogens (see appendix A).
126 I Researching Health Risks

 Guidelines for Developmental Toxicity

EPA first formulated science policy assumptions for developmental toxicity in 1986 (U.S.

EPA, 1986c) and made few changes when the

guidelines were revised in 1991. Yet in response

to criticism from its Science Advisory Board,

EPA did modify one assumption. The agency

agreed to use results from a species most

relevant to humans for estimating potentially

toxic effects on human development whenever

data were available, rather than automatically

selecting results from the most sensitive responding species.

The most significant change, however, was the

agency’s decision to merge the hazard identification and dose-response phases of the risk assessment process to “reflect hazard within the context

of dose, route, duration and timing of exposure’

(U.S. EPA, 1991 b). The 1991 guidelines also

abandoned a proposed weight-of-the-evidence

scheme that would have classified substances as

having “definitive,” “adequate,” or “inadequate’ evidence of toxicity during human development (U.S. EPA, 1989b). The approach that

EPA adopted takes into account extensive scientific research that suggests that manifestations of

developmental toxicity depend strongly on species and exposure. EPA’s new approach thus

addresses scientific concerns about dependence

of developmental toxicity on the contexts of test

animal and duration and timing of exposures. But

it also clearly expands the extent of scientific

analysis required by the agency even to identify

a substance as a potential developmental toxicant.

There are both scientific and policy arguments

for replacing EPA’s current approach to noncancer risk assessment (the no-observed-adverseeffects level divided by uncertainty factors; see

ch. 2) (Pease et al., 1991). Most of the alternatives, however, demand significantly more data

and analysis. Looking beyond the relatively

simple modeling of the benchmark-dose approach, EPA is supporting research to develop

provide more accurate estimates of low-dose risk

to humans” (U.S. EPA, 1991 b).

 Guidelines for Exposure Assessment

The changes in EPA’s guidelines for assessing

exposures to toxic chemicals exemplify expanding scientific examination in the risk assessment

process. EPA’s initial 1986 guidelines (U.S. EPA,

1986b) were relatively brief (8 pages), “laying

out a set of questions to be considered in carrying

out an exposure assessment in order to help avoid

inadvertent mistakes of omission. ’ In contrast,

the 1992 revisions present a detailed discussion

(45 pages) of the scientific foundation of exposure assessment and state that extensive data

acquisition and analysis are necessary to produce

good assessments (U.S. EPA, 1992b).

Probably the most important change in agency

guidelines has been the development of methods

for displacing ‘‘worst-case’ assumptions about

exposure with more reasonable estimates of

“high-end” exposures. “The concept of highend exposure is fundamentally different from

terms such as worst case, in that the estimate is by

definition intended to fall on the actual exposure

distribution” (U.S. EPA 1992b). This change has

the advantage of basing risk estimates and potential regulation not on the maximum possible

exposure but on the exposures that are likely to be

occurring to some members of the actual population. However, this approach requires considerably more data and analysis to characterize those

exposures.

In contrast to other guidelines, the exposure

assessment guidelines require relatively few assumptions. Both EPA’s 1986 and 1992 exposure

assessment guidelines contain the same fundamental science policy assumption: in the absence

of measurement data, exposure assessment may

be based on mathematical models.

 The Limited Impact of Research

Given the length and breadth of EPA’s guide-

‘‘models that are more biologically based to lines, the agency has made few changes in the
assumptions and procedures included in those

directives. Three interacting factors account

for the limited impact of new scientific research on EPA’s science policy assumptions.

First, the nature of the assumption is a factor.

An assumption that bridges a specific, welldefined information gap that can be resolved

experimentally is more likely to be displaced

when the needed information is generated. In

contrast, an assumption bridging broad areas of

scientific uncertainty, especially gaps in scientific

knowledge, and understanding is less likely to be

replaced.

Second, the relative importance of the assumption to the paradigm underlying the

predominant regulatory approach is a major

factor in whether new research changes science policy. The no-threshold assumption for

carcinogens (no amount of exposure, however

small, is not without an effect) is central to EPA’s

cancer risk assessment guidelines (U.S. EPA,

1986a). In comparison, the assumption of surface

area as the appropriate default scaling factor

among species is more peripheral. Displacing the

no-threshold assumption for carcinogens has

proved difficult, not only because important

aspects of the question cannot be resolved experimentally but also because displacement requires

developing an alternative model of carcinogenesis that can command a scientific consensus.

Because it lacked such a consensus, EPA failed in

the early 1980s to modify the agency’s cancer

policy by separating carcinogens into two classes

based on their mechanism of action, which would

have allowed threshold-based risk assessment for

nonmutagenic carcinogens (Rushefsky, 1986).

The third and final factor influencing the

agency’s response to new scientific research

involves the policy reverberations associated

with changing specific default assumptions.

The policy consequences of changing some

agency default positions are slight: shifting interspecies scaling factors reduces EPA’s risk estimates slightly and raises FDA’s slightly, but it

also encourages interagency consistency and does

Chapter 5: Research and Decisionmaking I 127

not conflict with public expectations. In the area

of extrapolating from high to low doses, however,

existing agency guidelines have been significantly influenced by a policy commitment to err

on the side of public safety in order to fulfill

statutory mandates. Changing the default assumption of low-dose linearity can dramatically

reduce estimates of risk, as well as conflict with

public beliefs that no carcinogenic exposure is

safe. To a large extent, the predominant role

policy considerations played in their adoption

explains the resistance to changing EPA’s default

assumptions for establishing the relevance of

animal cancer to humans and estimating low-dose

risks.

New scientific findings that are promoted

because they result in less “conservative” estimates of risk are likely to be strongly contested

because they may be perceived as undermining

the government’s or a particular agency’s commitment to protect public health in the face of

uncertainty. Rushefsky (1986) referred to these

inferential choices as being either ‘‘risk averse’

or “risk tolerant, ’ depending on the choice of

assumption made (see table 5-l). In general,

public health agencies are risk averse and more

protective of public health to compensate for the

inherent uncertainties in the process. Whenever

changing a traditional assumption causes substantial policy reverberations, the change confronts very high hurdles indeed.

Which interest group introduces new scientific

information into the regulatory arena and how

that information is used in the political process

may affect the fate of those findings in the risk

assessment process. Often, research sponsored by

industry is perceived as less-than-objective science and as a self-interested effort to undercut

regulation. Federal agencies are not immune to

such suspicions. When the Office of Management

and Budget selectively used scientific information to attack regulatory risk assessment during

the Reagan and Bush Administrations, it may

have stigmatized pharmacokinetic and mechanismbased modeling as procedures that weaken regu-
128 I Researching Health Risks

Table 5-l—Patterns of Inferential Choices in Developing Cancer Policy

Position

Controversy Risk-averse Risk-tolerant

Evidence

Bioassays

Positive/negative

Conflicting studies

Benign/malignant

Dose Ievels

Mathematical models

Thresholds

initiators/promoters

Genotoxic/epigenetic

Bioassays sufficient

Indicate human carcinogenicity

Positive more important

Positive more important

Benign sufficient

High dose provides qualitative

evidence

Linear

Insuffident evidence

Cannot demonstrate distinction

Cannot demonstrate distinction

Epidemiology only

May not be accurate

Negative may indicate species

sensitivity y

All evidence should be weighed

Only malignant significant

At least three levels should

be used; iow doses show

reversibility; high doses may

overwhelm defense mechanisms

No-observed-effects level for

epigenetic carcinogens

May exist for promoters and

epigenetic carcinogens

Distinction important

Distinction important

SOURCE: M.E. Rushefsky, Ma/ung Carwer Poh’cy (Albany, NY: State University of New York Press 1986), p. 41.

lation rather than improve risk assessment (Pease,

1992).

 IARC Procedures for

Classifying Carcinogens

The International Agency for Research on

Cancer (IARC), a World Health Organization,

publishes monographs on the evaluation of carcinogenic risks to humans. The monographs are

used widely as source material for assessing risks

from exposure to carcinogens. Currently, IARC

classifies chemical agents into one of four groups

(see box 5-B).

IARC convenes working groups from time to

time to evaluate the need for procedural changes

in its methods for evaluating carcinogenic risks.

(See appendix A for a description of IARC and its

policies.) In 1983, a working group concluded

that classifying carcinogens according to their

mechanism of action could be neither exhaustive

nor definitive. Nine years later, in 1991, another

working group noted that mechanistic data have

always been used in determiningg human carcinogenic risks. It then considered whether the procedures that were currently in use might be revised

(IARC, 1992b).

The group concluded that it was impossible to

formulate definitive guidelines for all of the

possible situations in which mechanistic data may

influence the evaluation of carcinogens. Nevertheless, it identified two circumstances in which

alternative criteria could be considered for deciding to which category a chemical belongs.

Mechanistic data, according to the working

group, can be considered in deciding whether an

agent belongs in group 1 or group 3. For group 1,

the category ‘‘may be extended to include agents,

mixtures, or exposure circumstances for which

evidence of carcinogenicity in humans is less than

sufficient but there is sufficient evidence of

carcinogenicity in experimental animals and

strong evidence in exposed humans that the agent

acts on a relevant mechanism of carcinogenesis."

The working group agreed that group 3 “maybe

extended to include agents for which there is

sufficient evidence of carcinogenicity in animals

and strong evidence that the mechanism of

carcinogenicity in animals does not operate in

humans.
Chapter 5: Research and Decisionmaking I 129

Box 5-B—IARC’s System of Classifying Carcinogenic Risks to Humans

The International Agency for Research on Cancer (IARC) classifies carcinogenic risks into four groups:

Group l—The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that

are carcinogenic to humans.

This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent

(mixture) may be placed in this category when evidence in humans is less than sufficient but there is sufficient

evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent

(mixture) acts through a relevant mechanism of carcinogenicity.

Group 2—This category includes agents, mixtures, and exposure circumstances for which, at one extreme,

the degree of evidence of carcinogenicity in humans is almost sufficient, as wel as those for which, at the other

extreme, there are no human data but there is evidence of carcinogenicity in experimental animals. Agents,

mixtures, and exposure circumstances are assigned to either group 2A (probably caranogenic to humans) or

group 2B (possibly carcinogenic to humans) on the basis of epidemiologic and experimental evidence of

carcinogenicity and other relevant data.

Group 2A-The agent (mixture) is probably carcinogenic to humans. The exposure circumstance entails

exposures that are probably carcinogenic to humans.

This category is used when there is limited evidence of carcinogenicity in humans and sufficient evidence

of carcinogenicity in experimental animals. in some cases, an agent (mixture) may be classified in this category

when there is inadequate evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in

experimental animals and strong evidence that the carcinogenesis is mediated by a mechanism that also operates

in humans. Exceptionally, an agent, mixture, or exposure circumstance maybe classified in this category solely

on the basis of limited evidence of carcinogenicity in humans.

Group 2B-The agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails

exposures that are possibly carcinogenic to humans.

This category is used for agents, mixtures, and exposure circumstances for which there is limited evidence

of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. it may

also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of

carcinogeniaty in experimental animals. in some instances, an agent, mixture, or exposure circumstance for which

there is inadequate evidence of carcinogenicity in humans but limited evidence in experimental animals together

with supporting evidence from other relevant data may be placed in this group.

Group 3--The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to

humans.

This category is used most commonly for agents, mixtures, and exposure circumstances for which the

evidence for carcinogenicity is inadequate in humans and inadequate or limited in experimental animals.

Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but

sufficient in experimental animals may be placed in this category when there is strong evidence that the

mechanism of carcinogenicity in experimental animals does not operate in humans.

Agents, mixtures, and exposure circumstances that do not fall into any other group are also placed in this

category.

Group 4-The agent (mixture) is probably not carcinogenic to humans.

This category is used for agents or mixtures for which there is evidence suggesting lack of carcinogenicity

in humans and in experimental animals. in some instances, agents or mixtures for which there is inadequate

evidence of carcinogenicity in humans but evidence suggesting lack of carcinogenicity in experimental animals,

consistently and strongly supported by a broad range of other relevant data may be classified in this group.

SOURCE: International Agency for Resaarch on Gamer, Mmogr@, vol. 55 (Lyon, Frwwe, 1992), pp. S4-35.
130 I Researching Health Risks

THE INTERDEPENDENCY OF RESEARCH

AND DECISIONMAKING

As is evident from the above discussion of the

effects of research on EPA’s guidelines for risk

assessments and assessment practices and the

procedures used by IARC, the speed with which

science influences assessment procedures and

science policy assumptions is very slow indeed.

Besides the factors noted above, other barriers

exist to incorporating the results of research into

agency actions.

In its 1989 report on improving risk communication, the National Research Council included a

guidance paper by B. Fischoff in which he

described the interrelationship of science and

policy:

Science is a product of society; as such, it

reflects the values of its creators. Conversely,

society is partly a product of science. And

understanding these inter-dependencies is essential to, on the one hand, discerning the objective

content versus inherently subjective science and,

on the other hand, directing science to serve

socially desired ends. An understanding of these

relationships is also necessary to appropriately

interpret the conflicts between lay and expert

opinions that constitute the visible core of many

risk controversies (NRC, 1989),

OTA has chosen two examples of environmental decisionmaking that illumin ate this interdependency. Each shows that research is driven

by public concern about risk and incomplete risk

data for decisionmaking. The dioxin case also

demonstrates that researchers and analysts can

produce decisionmaking tools in the absence of

desired information.

 Power-line Electromagnetic Fields

and Cancer

Recent public apprehension about the health

risks of exposure to power-line electromagnetic

fields (EMFs) has been driven by widespread

dissemination of the outcomes of epidemiologic

studies, even though the evidence was, and still is,

considered inconclusive by many scientists. In

response to the situation, EPA prepared a draft

report in 1990 evaluating the potential carcinogenicity of EMF exposures. But EPA’s Science

Advisory Board and the White House Committee

on Interagency Radiation Research and Policy

Coordination were critical of parts of the report

(an outcome that may have resulted in part from

inadequate analysis and imprecision in the writing of that report). The White House Committee

requested a review of the literature on EMF and

cancer by the Oak Ridge Associated Universities,

which assembled an expert panel.

The panel reported that the epidemiologic

findings about EMF and cancer were inconclusive, inconsistent, and without a plausible mechanism (ORAU, 1992; Young, 1993). It also concluded that, given the ever-decreasing resources

for basic health and science research, further

research investigation of this topic should not

receive high priority. Subsequent to the Oak

Ridge report, new epidemiologic data appeared

(Feychting and Ahlbom, 1992; Floderus et al.,

1992), which the interested parties interpreted to

support their original positions. The net effects

were polarization of the affected groups and

heightened public concern.
Chapter 5: Research and Decisionmaking I 131

Earlier, public concern about EMFs had

spurred political, legal, and market reactions. In

1989, a background paper prepared for an OTA

study proposed prudent avoidance as a policy

option if it could be achieved without significant

cost or inconvenience (U.S. Congress, OTA,

1989). But such a scenario was and still is

unlikely, given that prudent avoidance often

involves reconfiguring, rerouting, or burying

transmission lines.

The conflict between the public’s apprehension

about the potential risk posed by EMFs and

society’s need for reliable, inexpensive electricity

elicited political action. After a number of congressional hearings and legislative deliberations,

the 102d Congress passed legislation that provided funds for research and dissemination of

information to the public (P.L. 102-486, H.R.

776, Oct. 24, 1992). The Department of Energy

(DOE) was designated as the lead agency to

coordinate the Federal research effort. About $60

million was authorized over 5 years, including $5

million for information dissemination (CRS,

1993).

Interestingly, in the 1960s and 1970s, the U.S.

Navy was a major source of finding for studies of

the biological effects of extra-low-frequency (76

Hz) because of EMFs associated with submarine

communication systems. The research found no

significant biological impacts, and the available

data were judged inconclusive and controversial

(NRC, 1977). Since the 1970s, DOE has been the

primary source of support for research on the

health effects of exposure to power-line EMFs.

The Electric Power Research Institute, an industrysupported, private nonprofit organization, has

also been active in the field since the mid- 1970s.

Studies of the health effects of EMFs are continuing, but many observers expect that legislative

initiatives will be considered in the near future to

regulate or otherwise limit exposures. Court cases

in which nearby residents are claiming damages

to their health and losses in property values are

another force driving decisions about power lines,

 Dioxins

The polychlorinated dibenzo-p-dioxins (“diOxins," or PCDDs) and polychlorinated dibenzofurans ("furans," or PCDFs) make up a family

of 210 structurally related chemical compounds.

Many researchers believe that these substances

that often coexist as contaminants in various

materials produce similar effects on health. The

chemical most often called dioxin, 2,3,7,8-

tetrachlorodibenzo-p-dioxin (TCDD), is the most

thoroughly studied and most toxic of this group of

chemicals. Formerly, it was inadvertently produced during the manufacture of 2,4,5-

trichlorophenol, which was a precursor in the

production of some important disinfectants and

herbicides, including one of the herbicides in

Agent Orange, It is also formed as a byproduct of

combustion and chlorine bleaching of paper and

pulp.

Concerns about dioxins and furans are rooted

in toxicity studies that found TCDD the most

potent rodent carcinogen ever studied. Nevertheless, despite more than a decade of epidemiologic

studies, there is still no convincing proof that

dioxin causes cancer in humans (Bailar, 1991;

Gough, 1992/1993). Yet carcinogenicity is not

the only concern: TCDD causes adverse effects to

every organ system in at least one test animal

species (Gough, 1986). Is humankind more like

the most sensitive or the least sensitive species

tested-or is it somewhere in between? The

dioxin problem has prompted intense research to

support decisionmaking about TCDD as well as

about dioxins and furans in general. That research

has enhanced scientists’ ability to detect and

measure dioxins and furans in environmental and

biological materials and has expanded the body of

knowledge about dioxin’s effects and its mechanism of action. Nevertheless, an understanding of

the sensitivity of humans to dioxin remains

elusive.

The size of the dioxin research effort can be

measured by the number of research papers it has

produced. The frost dioxin symposium, held in
132 I Researching Health Risks

Rome in 1980, saw 50 papers presented. The 12th

symposium, held in Research Triangle Park in

1992, included 10 times that number. Both

government and industry have contributed to the

more than 20,000 dioxin-related papers and

presentations in circulation, and that number

continues to increase linearly (Gallo, 1993).

The expansion of dioxin research is due in part

to a belief by both scientists and decisionmakers

that intense research efforts could resolve the

problems that dioxin raises. Because dioxin is a

contaminant and has no commercial value, no one

has a vested interest in keeping it in the market,

and much attention is being given to ways to

control its release and to mitigate TCDD already

in the environment. But arguments continue to

arise about how much such mitigation is worth

and who should pay for it.

In 1985, EPA prepared a health assessment

document on PCDDs (U.S. EPA, 1985). Because

IARC (1987) and EPA (1985) considered the

evidence for carcinogenicity in humans inadequate, EPA based its risk estimate on the Dow

Chemical Company’s study of dioxin and cancer

in rats (Kociba et al., 1978). In 1988, pathologists

reevaluated the Dow pathology data using revised

criteria from the National Toxicology Program

for classifying liver tumors. In response to the

reevaluation, EPA prepared a draft report that

proposed revising the “potency” estimate for

TCDD (U.S. EPA, 1988a). The report also

proposed methods to derive average risk estimates with models using different mechanistic

underpinnings. EPA’s Science Advisory Board

rejected the methodology, however, and the

document remains in draft form while research

continues.

Prompted by publication of a new epidemiologic study of cancer mortality in workers exposed

to TCDD (Fingerhut et al., 1991) and the conclusions about dioxin toxicity mechanisms from the

1990 Banbury Conference (Banbury, 1991), EPA

announced that in 1991 it was reassessing dioxins. The agency held workshops in September of

1992 to review its draft reports and continues to

work on the report, with release expected soon.

To involve the public and invite its participation,

EPA has held public meetings as part of its

assessment process.

Studies of TCDD have produced almost all of

the current knowledge of dioxins and furans, but

most human exposures are to mixtures of dioxins

and furans, about which very little is known. The

need to address the risks posed by other dioxins

and furans has stimulated development of an

interim procedure, the toxicity equivalency factor

(TEF) procedure. This interim method is being

used to estimate risks from exposure to mixtures

of PCDDs and PCDFs in the absence of specific

information about their specific toxicities. The

TEF method is a science-based response to a

regulatory need—to estimate the toxicity of

dozens of chemicals that have not been tested. In

many respects, it represents the response of

scientists to the demands of regulators.

The TEF approach is a numerical procedure

based on scientific data and scientific judgment.

It was first considered for use in the late 1970s and

early 1980s when data began to reveal the relative

toxicity of some of the different dioxins and

furans. In 1986, EPA’s Risk Assessment Forum

requested that the Science Advisory Board convene a panel of experts to review the TEF

methodology and its scientific support. The

board’s panel of scientists accepted the procedure

with some reservations. First, the panel emphasized that the procedure should be considered an

interim method. Second, it noted that the procedure lacked scientific validity and therefore

needed validation. Third, it accepted the report

with the understanding that EPA would fulfill its

commitment to periodically review and update

the procedure. The frost report on dioxin and furan

toxicity equivalency factors was published by the

Risk Assessment Forum in 1987 (U.S. EPA,

1987a); it was updated by the forum and republished in 1989 (U.S. EPA, 1989a).

Because of the universality of the dioxin

problem, the North Atlantic Treaty Organization

(NATO) adopted a TEF procedure for use in
Chapter 5: Research and Decisionmaking I 133

Europe. The NATO committee that adopted a

TEF scheme expressed some of the same reservations that the EPA Science Advisory Board noted.

It said that the procedure should be considered an

interim one and recommended that a ‘‘vigorous

program of research be conducted to address areas

of uncertainty, to test, refine, or replace the

TEFs” (U.S. EPA, 1989a).

 Research Into Feedback From

Decisionmakers to Researchers

At its most basic level, the relationship between research and decisionmaking can be seen

as a feedback loop: one-half of the loop is the

impact of research on decisionmaking, and the

other half is the impact of decisionmaking on the

research that needs to be done. Taken together,

the relationship provides a panoply of options, not

only for possible decisions but for research

priorities as well.

The first half of the loop, which has already

been discussed, allows the results of risk assessment (and by extension, risk assessment research)

to provide the range of options to be considered

in decisions about how to manage particular risks.

The past decade witnessed the increasing use of

risk assessment in decisionmaking, whether for

standard-setting or as a tool for screening and

priority-setting (Rosenthal et al., 1992). As described earlier in this chapter, the impact of

research on risk assessment may be felt slowly

and can be difficult to measure. Nevertheless,

changes in agency guidelines for risk assessment

and in case-specific regulatory decisions have

been observed.

Few inquiries have been made about the other

half of the feedback loop, in which policy

decisions influence priorities for research. Based

on meager evidence, some analysts argue that the

poor record of applying analytical thinking to

developing research priorities will change as

research resources dwindle. In that case, studies

will be planned, ranked, and ultimately funded in

the light of the decisions on which they will have

an impact (Finkel, 1993). Agencies, in turn, will

give high priority to the research that is most

likely to reduce compliance costs, minimize

controversies, and reduce the health toll that

hazardous agents may pose. In such circumstances, the value of information to the decisionmaker, not just the increase of knowledge, should

influence what research will be given high

priority.

The few researchers who are examining feedback from decisionmakers to researchers expect

to obtain some insight into this portion of the

feedback loop. The notion that information has a

measurable value allows decisionmakers to use a

quantitative process to evaluate both the need for

additional information and the nature of that

information.

An additional line of research is the exploration

of the relative value and costs of various types of

studies for decisionmaking. Lave and Omenn

(1986), for example, developed a framework for

decision analysis that examines the costeffectiveness of short-term tests as predictors of

carcinogenicity. Their framework estimates both

the direct cost of testing and the total social costs

of correctly classifying true-positive and truenegative carcinogenic chemicals; it also calculates the costs of misclassifying chemicals. Similar work has been done on the value of animal

bioassays and the information they provide (Lave

et al., 1988; Taylor et al., 1993). Based on this

modeling, decisionmakers can decide on the

relative worth of different testing schemes.

THE LIMITS OF SCIENCE IN

SOCIAL DECISIONS

Whatever is expected of risk assessment in any

given set of circumstances, it is only one of the

elements in the formulating regulatory actions.

Legislative mandates, social values, technical

feasibility, economic factors, and the achievements or shortcomings of the research that feeds

into risk assessment may assume a more prominent role than expert projections of risk (figure
134 I Researching Health Risks

5-1). The case study about regulating radon in

. . drinking water in the next chapter illustrates some

of the interplay between science and decisionmaking.

Scientific research can provide a more solid

foundation for the decisionmaker in choosing

among alternatives to manage risk, but by itself it

will not necessarily influence decisions so as to

control the most significant risks. Moreover, the

capacity of science to inform decisions even on

many technical risk-related issues is limited.

The limits of science manifest themselves at

a variety of levels. Uncertainty in measurements and observations constrains science at

the most fundamental level, and the scientific

underpinnings of risk assessment are more

subject to that limitation than are experimental sciences. At a higher level of complexity, the

interpretation of data and observations to

predict outcomes introduces additional uncertainties. And risk management actions can

themselves produce uncertainty.

 Measurements and Observations

Information for assessing risks to human health

comes from epidemiologic observations, animal

toxicity testing, various laboratory studies, and

measures and estimates of human exposures. As

detailed in this report, guidelines are available for

the use of this information, but all measurements

and estimates are subject to the limits of the

methods used and uncertainties. There are technical bounds to the experimental methodologies

and equipment as well as limitations that prevail

in interpreting and analyzing data.

 Epidemiologic Data for Assessing Risks

The availability of epidemiologic data eliminates the problem of extrapolating from animal

data to humans, but epidemiologic data can suffer

from a number of substantial limitations. Some

are methodological in nature and may be overcome with new techniques. For instance, many

investigators attempt to couple epidemiologic

studies with cellular-molecular techniques so that

Figure 5-l-Research as an Element

in Regulatory Decisionmaking

((Risk)

Economic

assessment factors

Technical

feasibility

SOURCE: U.S. Congress, Office of Technology Assessment, 1993.

the results will provide information about the

mechanism of carcinogenesis.

The lack of exposure measurements can limit

the usefulness of results from epidemiologic

investigations because it forces researchers to rely

on estimates and can lead to errors. For example,

scientists who are studying health effects in the

“Ranch Hands,” the men who sprayed dioxincontaminated Agent Orange in Vietnam, used

records of job assignments and recall by the men

to estimate exposure to the chemical. When

techniques became available for measuring exposure directly, researchers found flaws in the

classification of exposures on the basis of job

category, a standard practice in many epidemiologic studies (Air Force Health Study, 1991a). In

a related study, Needham (1991) reported few, if

any, correlations between activities around dioxincontaminated soils and measured exposure levels.

More generally, “confounders” complicate

the design and interpretation of epidemiologic

studies. As an example, Air Force scientists

reported that diabetes is more common in Ranch

Hand veterans with higher dioxin levels (Air

Force Health Study, 1991 b). But a connection

between that disease and dioxin exposures was
Chapter 5: Research and Decisionmaking 135

confounded by the finding that more obese

veterans, who are more likely to have diabetes,

also tend to have higher dioxin levels. The

connection between obesity and dioxin levels is

largely explained by differing rates of dioxin

elimination from Ranch Hand veterans: dioxin

persists longer in more obese men (Wolfe et al.,

1993). Therefore, although the details remain to

be sorted out, the connection between obesity and

dioxin metabolism confounds the interpretation

that can be put on the observation that diabetes is

more common in men with higher levels of

dioxin.

More common confounders are exposure to

multiple agents in the environment, the effects of

different lifestyles-including eating, drinking,

and smoking habits—and genetic differences. All

of these factors complicate extrapolating from

study data to estimations of risk to the general

population.

 Results From Animal Toxicity Testing

Most often, information about the toxicity of

substances comes from tests in animals, and all

tests are compromises. To compensate for the

small number of animals (usually rodents) that

can be tested, rodents are exposed to higher

concentrations of the agent than the levels that

humans are expected to experience. There maybe

differences in response to high and low doses or

to particular routes and patterns of exposure, and

between species.

Some of these limitations can be overcome by

appropriate pharmacokinetic studies and analysis, which relates exposure to time-dependent

distribution of the chemical in the body, and by

pharmacodynamic analysis, which examines internal doses and effects at the organ, tissue,

cellular, and molecular levels and relates them to

the development of toxic effects. Almost always,

however, comparative metabolic and pharmacokinetic data are incomplete; frequently, they are

simply unavailable. Even when data are available,

sites of toxic action can vary among species,

further complicating interpretation and prediction. Unless the target organ is known, physiologically based pharmacokinetic modeling is of

limited value.

A further complication is that a chemical

frequently causes several effects in test animals.

In evaluating animal studies, toxicologists must

decide whether the response caused by the agent

is well within the range of normal physiological

adjustments (homeostatic response) or an abnormality that constitutes a toxic response. In many

instances, homeostatic and toxic responses represent different parts of the same continuum. Put

more simply, the question is, when does a

response represent an adverse effect on health?

In carcinogenesis, a process that involves many

etiologic factors, more than one mechanism may

be operative in each of the steps or stages, which

are often called initiation, promotion, and progression. Sometimes, information on the mechanism of carcinogenic action of a chemical or

product are developed years after it is found to be

carcinogenic in rodent studies. Sorting through

the possible mechanisms can involve a broad

range of issues and fields-for example, direct

interactions with DNA, disturbance of hormonal

balances, changes in cell organelles, organspecific cytotoxicity, immunomodulation, perturbation of DNA methylation, peroxisome proliferation, and inhibition of intercellular communication. In some (perhaps many or most) cases, the

explanation may be found in combinations of

those mechanisms. When the information about a

substance is incomplete, interpretations that draw

connections between animal data and estimates of

human cancer can produce great disagreement

among scientists. As far as scientific understanding of the mechanisms of carcinogenicity has

come, it remains far short of certainty.

 Information on Exposure

After a chemical is released into the environment, it maybe transported or transformed, it may

persist, enter, and be concentrated in the food
136 I Researching Health Risks

chain, or it may be degraded or deposited where

humans cannot come in contact with it. It can

reach humans through the air they breathe, the

food they eat, or the water they drink, or by

contact with their skin. There are many ways to

predict, estimate, and measure the exposures of

humans to environmental agents, but it is a

complex, uncertain undertaking.

Typically, researchers measure levels of pollutants at the sources of their discharge into the

environment and then use models to predict the

concentrations reaching humans. Personal monitoring devices produce more realistic measurements of human exposure. Even so, age, physical

activity, nutritional conditions, and other factors

related to lifestyle can affect the body’s uptake of

the pollutant, leading to uncertainty about the

dose that any one individual receives.

The most direct measure of human exposure is

through biological monitoring of body fluids or

tissues. But these techniques are expensive and

not without risk if they require biological samples. Generally, estimates of exposure are generated by reconstruction of behavior and surveys of

recall as in early parts of the Ranch Hand study

mentioned above.

 Social and Political Factors

in Decisionmaking

As research identifies the potential adverse

health effects of toxicants to which humans may

be exposed, the public conveys its concerns to

Congress, and Congress considers and often

passes laws to address those concerns. This

reactive mode may limit the capacity of agencies,

such as EPA, to structure long-term solutions that

are both efficient and effective. In 1991, then EPA

Administrator William K. Reilly stated:

For 20 years we have established goals on a

pollutant-by-pollutant and medium-by-medium

basis without adequately considering broader

environmental quality objectives. We have seldom if ever been directed by law to seek out the

best opportunities to reduce environmental risks,

in toto, or to employ the most efficient, costeffective procedures.

Regulatory decisions are often made with

inadequate data and in response to statutory

mandates. This limits the capacity of science to

support regulatory decisions. Furthermore, scientific input is but one element in the formulation of

regulatory decisions. As in all kinds of human

activity, change is difficult, and various factors—

risk perception, economic impact, social values,

lack of trust between the public and industry, and

less than complete confidence in government—

play a role in decisionmaking. In such a context,

new facts from science may have little impact.

Some analysts and scientists (e.g., Abelson,

1993; Gori, 1992; Moolenaar, 1992) maintain that

more scientific information is needed to support

environmental rulemaking by the agencies. Openly

critical, they contend that advances in the biological and biomedical sciences make their way too

slowly into regulatory decisionmaking and that

those decisions remain mired in the science of the

past two decades. Jasanoff (1990) characterizes

the contention that better decisionmaking will

result from more and better scientific information

as the ‘‘technocratic viewpoint. ’

Not everyone shares that view. First, it is

difficult to prove that better (or “more,” as some

detractors say) science has improved decisionmaking. Since the risks that most regulations

address are below the limits of detection by

epidemiology, it is impossible to know if one

approach or the other produced better results in

protecting health. Understandably, few examples

of improved decisionmaking exist, and the social

and political implications of decisionmaking may

mask any effect science has on the process

(Jasanoff, 1990).

A more basic point is that risk assessment is

contentious because scientific data are seldom

definitive and consensus on some issues appears

unlikely. A recent National Research Council

report on risk assessment included rare majority

and minority recommendations; the issue with no
Chapter 5: Research and Decisionmaking I 137

agreement was whether toxic effects observed at

the maximum tolerated dose are predictive of

human risk. This topic has been debated for

decades (NRC, 1993).

Moreover, research findings can complicate

risk assessment (Huff, 1993). Research takes

time, and more research can be used to serve the

political objective of delaying regulatory action

(O’Brien, 1993; Olson, 1984; Silbergeld, 1993).

Finally, risk assessment may be the last point at

which science is considered because of the power

of policy mandates that place more weight on the

side of safety (Graham, 1991).

 Tradeoffs, Teamwork, Trust,

and Leadership

An optimistic view is that the field of health

risk assessment is still young. With the advances

being made in the biological and biomedical

sciences, the field of toxicology will evolve to

provide better data; combinations of epidemiologic and laboratory-based investigations will

produce more revealing information; and measurements of exposure to environmental chemicals

will sharpen risk assessments.

Nevertheless, it is unrealistic to expect research to resolve all uncertainty and eliminate

all differences in interpreting data. Solving the

problems in environmental risk assessment

goes beyond more and better science: it requires building trust among government, industry, and citizens. It also requires leadership

in setting realistic goals and arranging collaborations of researchers from various disciplines

and sectors of society.

In 1983, the National Research Council Committee on the Institutional Means for Assessment

of Risks to Public Health called for separating risk

assessment and risk management (NRC, 1983).

This recommendation was taken up by the

agencies, which separated the functions of scientists and decisionmakers to prevent ‘subtle value

judgments” from influencing empirical analyses

before they reached the regulators. Now, a decade

later, some scientists argue that opportunities are

being lost in an inefficient system whereby those

making decisions are unaware of the process

generating the information on which their decisions are based. One of the principal deficiencies

of that system, according to Finkel (1990), is that

decisionmakers remain insulated from the inherent uncertainty in the process.

Still, the division between risk management

and risk assessment has never been complete.

All kinds of policy judgments reach back into the

risk assessment process. For example, the decision to accord greater weight to public health than

to industrial output greatly influences the default

position that estimates cancer risk using a nothreshold model. However rigid or flexible the

boundary between risk assessment and management, it is clear that the relationships between the

two are under discussion and perhaps in flux.

Moreover, as Congress expresses interest in risk

assessment, its discussions and mandates will

influence both the process itself and risk assessment research.

LINKING HEALTH RISK RESEARCH

TO DECISIONMAKING

The relationship between research and decisionmaking is complex. OTA developed figure

5-2 to describe the relationships among the

various research activities in health risk assessment and decisionmaking. Previously, the National Research Council (NRC, 1983) depicted a

unidirectional flow of information from research

to decisionmaking, which emphasized the compartmentalization of the process for providing

public transparency (see figure 2-1). Yet information sharing throughout the process is important

to increase the efficiency of research for decisionmaking. Thus, figure 5-2 highlights the bidirectional flow of information as well as the integration and synthesis of information from the various

disciplines and types of research. The evaluation

and validation of methods can serve as the focal

point for integrating all the areas of health risk
138 I Researching Health Risks

x

.

in

=

c

=

(u

$’

.-v

(/I

$

A

t --- ---- ----

+

1 ----

“h

‘“-1 ‘ --
Chapter 5: Research and Decisionmaking 1139

research, given that a new model or method must

be examined and compared with methods of

known and established veracity. Figure 5-2 also

indicates OTA’s stress on the interdependency of

research activities, the risk assessment process,

and policymaking.

The link between health effects research and

the basic biological, chemical, and physical

sciences has often been neglected in discussions

about health risk assessment research. Now,

however, bridges are being constructed between

basic and health risk research in response to calls

from Congress (Brown, 1993; U.S. Congress,

House Committee, 1992) and the private sector

(Carnegie Commission, 1992) for linking science

to social needs. Although some basic scientists

may respond grudgingly at first, later they may

actually find it rewarding to modify and redirect

their research to serve health risk assessment.

Much as research on AIDS or cancer links social

needs and unexplored avenues of research, improving risk assessment can similarly endow

toxicological research with an objective that

transcends the purely scientific.

Health risk assessments, to be valid, require the

participation of scientists from many disciplines.

Those from the toxicological and biomedical

sciences are best qualified to critique the validity

of the scientific underpinnings of assessments.

But when data are lacking, assumptions and

policy positions with embedded value judgments

are used, arguably, as tools to complete the

assessment, their selection may benefit from

involving practitioners of disciplines other than

the biological, chemical, or physical sciences.

Jasanoff (1993) argues for “bridging the two

cultures of risk analysis’ ‘—the ‘‘hard, ’ or quantitative, sciences and the ‘‘soft, ’ or nonquantitative, disciplines, such as the behavioral and

political sciences.

Although OTA did not address whether risk

assessment itself should be formally considered a

scientific endeavor, making risk assessment an

active field of research may well be what is

needed to facilitate the application to health risk

assessments of the new biological understanding

of diseases and toxicological mechanisms. From

that perspective, OTA sees risk assessment as

involving the analysis and synthesis of all that is

known about the risk at hand, such as a specific

chemical or class of chemicals. For example, risk

assessments use findings from epidemiologic

studies or results from animal toxicity tests to

generate hypotheses about risks to human health.

A substantial amount of reasoning and judgment

is required in determining whether the composite

data on toxic effects, exposure, and dose-response

characteristics as a whole make the risk hypothesis tenable.

In contrast to the approach described here, risk

assessments are all too frequently performed by

merely stacking up the positive findings that

imply that risk exists, without careful attention to

conflicting results and alternative interpretations.

A more iterative process of questioning can reveal

the strengths and weaknesses of the case for the

existence of risk and identify the need for further

research at each step. In that way, gaps in the data

can be recognized and research conducted in

response. Not every alternative interpretation

need be considered or presented every time. Risk

characterization and communication can serve as

a focus for the iterative process of risk assessment

and abridge between risk assessors and decisionmakers.

Risk characterization summarizes and interprets the information available about a given risk

for risk managers and the public. There is general

agreement that methods of risk characterization

are poorly developed and that efforts to improve

them have been neglected (Gray, 1993). Research

to improve risk characterization is directed toward developing methods to describe more completely the uncertainties and assumptions and to

express the full range to plausible estimates of

risk.

For example, one of the methods frequently

proposed for distinguishing among alternative

estimates of risk is the distributional approach,

which is an outgrowth of uncertainty analysis in
140 I Researching Health Risks

the decision sciences (Morgan and Henrion,

1990). It uses explicit expert judgment to analyze

and quantify the plausibility of alternative interpretations of available data (Otway and von

Winterfeldt, 1992). This method can capture the

range of scientific evidence and opinion on key

biological uncertainties. Proponents of describing

ranges of risk believe that it avoids the focus on

a single numerical estimate of risk and requires

risk managers to confront qualitative uncertainties, such as the likelihood that a compound is or

is not a carcinogenic hazard to humans (Gray,

1993).

The purpose of risk characterization is to help

risk managers and others understand the results of

complex risk assessments. For a risk manager,

good risk characterization will aid decisionmaking. But for that to occur, a risk manager must

understand the basis for risk estimates including

the scientific, analytical, and policy choices that

underlie the assessment. Improving risk characterization will also help legislators, journalists,

and the public understand the nature and magnitude of the day-to-day risks citizens in this

country face.

Two Federal programs support research on risk

communication and decisionmaking. EPA’s Office of Policy, Planning, and Evaluation conducts

and supports research in risk communication. In

addition, the agency holds workshops and offers

training in risk communication and decisionmaking. The National Science Foundation funds

research on decisionmaking through the Decision, Risk, and Management Science (DRMS)

program in the Division of Social and Economic

Sciences. For the past decade, DRMS has operated a competitive grants program that supports

research to develop new methods in the field of

decision theory and methods to optimize the

technical handling of risk probability. The program funds research on social factors that influences risk assessment, and it seeks to distinguish

between technical and social definitions of risk

(Cantor, 1993).

SUMMARY

Research has had only a modest effect on

efforts to revise the science policy assumptions

adopted in EPA’s risk assessment guidelines. It

has, however, had a substantial impact on chemicalspecific risk assessment and consequently on

regulatory actions, and it is currently generating

considerable debate as EPA considers revisions to

its 1986 cancer risk assessment guidelines.

Three interacting factors account for the limited impact of new scientific research on the

science policy assumption adopted in EPA’s risk

assessment guidelines. The nature of the assumptions, the importance of the assumption to the

paradigm underlying the regulatory approach,

and the policy reverberations associated with

changing specific default positions all jointly

limit any expedient change of the agency’s

science policy assumptions based on new knowledge.

Health risk research and decisionrnaking are

interdependent. As research identifies potential

adverse effects on health, the public conveys its

concern to Congress, and Congress considers and

passes laws to address those concerns. This

reactive mode limits the capacity of agencies to

structure long-term solutions including appropriate research.

Although the sciences can provide solid foundations for choices about reducing health risks,

their contribution is limited because measurements and interpretations of data are inherently

uncertain. In addition, science is only one of the

elements in regulatory decisions. Legislative

mandates, social values, technical feasibility, and

economic factors may assume more prominent

roles, depending on the specific issue. Solving the

problems in health risk assessment goes beyond

more and better science, it requires building trust

among government, industry, and citizens. It also

requires leadership in setting realistic goals and

encouraging collaboration in research.
Chapter 5: Research and Decisionmaking I 141

CHAPTER 5 REFERENCES

Abelson, P.H. 1993. Editorial: regulatory costs. Science 259:159.

Airl?orce Health Study. 1991a. Serum dioxin: analysis

of 1987 examination results, vol. 1. Epidemiology

research division, Brooks Air Force Base.

Air Force Health Study. 1991b. Serum dioxin analysis

of 1987 examination results, vol. 4. Epidemiology

research division, Brooks Air Force Base.

Ames, B. N., and Gold, L.S. 1990a. Chemical carcinogenesis: too many rodent carcinogens. Proceedings of

the National Academy of Sciences USA 87:7772-7776.

Ames, B. N., and Gold, L.S. 1990b. Too many rodent

carcinogens: mitogenesis increases mutagenesis. Science 248:970-971.

Bailer, J. 1991. How dangerous is dioxin? New

England Journal of Medicine 324:260-262.

Banbury. 1991. Biological basis for risk assessment of

dioxins and related compounds, M.A. Gallo, R.J.

Scheuplein, and K.A. Van DerHeijden (eds.). Banbwy

Report 35 (Cold Spring Harbor, NY: Cold Spring

Harbor Laboratory Press).

Brown, G.E. 1993. Science’s real role in policymaking. Chemical and Engineering News, May31, pp.

9-110

California Department of Health and Human Services.

1988. Health effects of methylene chloride, N. Gavitz

(cd.) Sacramento, December.

Cantor, R. 1993. Director, Decision, Risk, and Management Science Program, National Science Foundation. Personal communication.

Carnegie Commission. 1992. Environmental Research

and Development: Strengthening the Federal Infrastructure. A report of the Carnegie Commission on

Science, Technology, and Government.

Cohen, S. M., and Ellwein, L. 1991. htters: carcinogenesis mechanisms+e debate continues. Science

252:902-903, May 17.

Cohen, S. M., and Ellwein, L.B. 1992, Risk assessment

based on high-dose animal exposure experiments,

Chemical Research in Toxicology 5(6):742-748.

CRS (Congressional Research Service). 1993. Health

Efiects of Power-Line Electromagnetic Fields

(EMFs), C.S. Redhead and C.H. Dodge. CRS Issue

Brief IB921 18. Science Policy and Research Division.

Feb. 8.

Dunlap, T. 1988. DDT: Scientists, Citizens, and Public

Policy (Princeton, NJ: Princeton University Press).

Feychting, M., and Ahlbom, A. 1992. Magnetic FieZa3

and Cancer in People Residing Near Swedish High

Voltage Power Lines (IMM-rapport, June 1992, Stockholm: Karolinska Institute).

Fingerhut, M. A., Halperin, W, E., Marlow, D. A., et al.

1991. Cancer mortality in workers exposed to 2,3,7,8-

tetrachorodibenzo-p-dioxin. New England Journal of

Medicine 324:212-218.

Finkel, A.M. 1990, Confronting Uncertainty in Risk

Management: A Guide for Decisionrnakers (lVashington, DC: Resources for the Future),

Finkel, A. 1993. Fellow, Resources for the Future.

Personal communication,

Floderus, B. et al. 1992. Occupational Exposure to

Electromagnetic Fielak in Relation to Leukemia and

Brain Tumors: A Case-Control Study (Solna, Swaien:

National Institute of Occupational Health) (P. M.: MI.).

Gallo, M. 1993. Professor. Department of Environmental and Community Medicine, Robert Wood

Johnson Medical School. Personal communication.

Gearhart, R. 1992. California Department of Health

and Human Services. Personal communication.

Gori, B.G. 1992. Whither risk assessment? An overall

perspective. Presented at the annual meeting of the

American Industrial Health Council, Washington, DC,

Dec. 1.

Gough, M. 1986. Dioxin, Agen! Orange (New York

and hndon: Plenum Press).

Gough, M. 1992/1993. chemical risk assessment is

not science. Chemistry, December/January :23-26.

Graham, J.D. 1991. The failure of agency-forcing: the

regulation of airborne carcinogens under Section 112

of the Clean Air Act. Dub Luw Journal 1985:100-

150.

Gray, G. 1993. The challenge of risk characterization.

National Technical Information Service. PB93-

218857.

Huff, J,E. 1992. Chemical toxicity and chemical

carcinogenesis: is there causal connection? A comparative morphological evaluation of 1,500 experiments.

In: Mechanisms of Carcirwgenesis in Risk Ident@$ca-
142 I Researching Health Risks

tion, H. Va.inio (cd.), IARC Scientific Publications 116

(Lyon, France: International Agency for Research on

Cancer), pp. 437-475.

Huff, J. 1993. Issues and controversies surrounding

qualitative strategies for identifying and forecasting

cancer-causing agents in ‘the human environment.

Pharmacology and Toxicology 72(Suppl. 1):12-27.

IARC (International Agency for Research on Cancer).

1987. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Overall Evaluations of

Carcinogenicity. An updating of IARC monographs,

vol. 1 to 42, supplement 7, pp. 350-354.

IARC. 1992a. IARC Monographs on the Evaluation of

Carcinogenic Risks to Humans: Solar and Ultraviolet

Radiation. IARC Working Group on the Evaluation of

Carcinogenic Risks to Humans. (Lyon, France), Feb.

11-18.

LARC. 1992b. Mechanisms of C’arcinogenesis in Risk

Identification, H. Vaino, P.N. Magee, D.B. McGregor

et al. (eds.). Scientific Publication 116 (Lyon, France).

Jasanoff, S. 1990. The Fljlh Branch: Science Advisors

as PoZicyrnakers (Cambridge, MA: Harvard University

Press).

Jasanoff, S. 1993. Bridging the Two Cultures of Risk

Analysis. Risk Analysis 13:123-129.

Kociba, R., Keyes, D., Beyer, J. et al. 1978. Results of

a twoyear chronic toxicity and oncogenicity study of

2,3,7,8 -tetrachlorodibenzo-p-dioxin (TCDD) in rats.

Toxicology and Applied Pharmacology 46;279.

Lave, L. B,, and Omem, G.S. 1986. Cost-effectiveness

of shcxt-termtests forcaminogenicity, Nature 324(6092):29-

34, NOV. 6.

Lave, L. B., Ennever, F. K., Rosenkranz, H.S. et al.

1988. Information value of the rodent bioassay, Nature

336:631-633.

Moolenaar, R.J. 1992. Overhauling carcinogen classification. Issues in Science and Technology 8(4):70-75.

Morgan, M. G,, and Henrion, M. 1990. Uncertainty:A

Gui& to Dealing with uncertainty in Quantitative Risk

and Policy AnaZysis (Cambridge: Cambridge University Press).

Needham, L.L. 1991. Remarks reported in: Human

exposures from dioxin in soil, M. Gough. Journal of

Tom”cology and Environmental Health 32:205-245.

NRC (National Research Council). 1977. Biologic

Effects of Electric and Magnetic Fieldi Associated

with Proposed Project Seafarer. Committee on biosphere effects of extremely-low-frequency radiation

(Washington, DC: National Academy Press).

NRC. 1983. Risk Assessment in the Federal Government: Managing the Process (Washington, DC: National Academy Press).

NRC. 1989. Improving Risk Communication (Washington, DC: National Academy Press).

NRC. 1993, Scientific debate continues over cancer

risk assessment methods. Press release, Jan. 28.

O’Brien, M.H. 1993. Alternatives to risk assessment.

New Solutions Winter:39-42.

Olson, E.D. 1984. The quiet shift of power: Office of

Management and Budget supervision of Environmental Protection Agency rulemaking under Executive Order 12,291. Virginia Journal of Natural Resources Luw 4(1):3-80.

ORAU (Oak Ridge Associated Universities). 1992.

Health Effects of Low-Frequency Electric and Magnetic FieZds, ORAU 92/F8 (Oak Ridge, TN), June.

Otway, H., and von Winterfeldt, D. 1992. Expert

judgment in risk analysis and management: process,

context, and pitfalls. Risk AnaZysis 12:83-93.

Pease, W. 1992. Environmental Health Policy Program, School of Public Health, University of California at Berkeley. Personal communication.

Pease, W., Vandenberg, J., and Hooper, K. 1991.

Comparing alternative approaches to establishing

regulatory levels for reproductive toxicants: DBCP as

a case study. Environmental Health Perspectives

91:141-155.

Preuss, P. 1992. Office of Science, Plaming, and

Regulatory Support, U.S. Environmental Protection

Agency. Personal communication.

Reilly, W.K. 1991. Why I propose a national debate on

risk. EPA Journal March/April:2-5.

Rosenthal, A., Gray, G. M., and Graham, J.D. 1992.

Legislating acceptable cancer risk horn exposure to

toxic chemicals. Ecology L.uw Quarterly 19(2):269-

362,

Ruckelshaus, W,D. 1983. Science, risk and public

policy. Presentation to the National Academy of

Sciences, Washington, DC, June 22.
Chapter 5: Research and Decisionmaking I 143

Rushefsky, M.E. 1986. Making Cancer Policy (Albany: State Universities of New York Press), pp.

107-150.

Silbergeld, E. 1993, Guest editorial: the risks of risk

assessment. New Solutions, winter:43-44,

Slone, T.H. 1993. Body Surface Area Misconceptions.

Risk Analysis Vol. 13, No. 4.

Taylor, A., Evans, J., and McKone, T. 1993. The value

of animal testing information in environmental control

dwisions. Risk Analysis 13:403-412.

Travis, C. C., and White, R. 1988. Interspecies scaling

of toxicity data. Risk Analysis 8:119-125.

Travis, C.C. et al. 1990. Interspecies extrapolation of

pharmacokinetics, Journal of Theoretical Biology

142:285-304.

U.S. Congress, House Committee on Science, Space,

and Technology. 1992. Report of the Task Force on the

Heahh of Research (Washington, DC: Government

Printing Office).

U.S. Congress, OTA (Oftlce of Technology Assessment). 1981. Assessment of Techrwlogies for Determining Cancer Risks From the Environment, OTA-H138.

U.S. Congress, OTA. 1989. Biological effects of

power frequency electric and magnetic fields. BP-E53.

U.S. EPA (Envi.ronmentd Protection Agency), 1976.

Interim procedures and guidelines for health risk and

economic impact assessment of suspected carcinogens. Fe&ral Register 41:21402-21407.

U.S. EPA. 1985. Health Assessment Document for

PolychlorinatedDiberuo-p-d”oxins. Final Report. 01-IQ

EPA/600/8 -84/014F. September.

U.S. EPA. 1986a. Guidelines for carcinogen risk

assessment. Fea%v-al Register 51:33992-34003.

U.S. EPA, 1986b. Guidelines for exposure assessment.

Fe&ral Register 51 :34042-34154.

U.S. EPA. 1986c. Guidelines for the health assessment

of suspect developmental toxicants. FederaZ Regis~er

51(185):34028-34040.

U.S. EPA. 1987a. Interim Procedures for Estimating

Risks Associated with Exposures to Mixtures of

Chlorinated Dibenzo-p-dioxins and -Dibenzofirans

(CDDsandCDFs). Risk Assessment Forum, EPN625/

3-87/012.

U.S. EPA. 1987b. The Risk Assessment Guidelines of

1986, EP’600/8-87/045.

U.S. EPA, 1987c. Technical analysis of new methodologies and data regarding dichloromethane hazard

assessment. External review draft.

U.S. EPA. 1988a. Cancer risk: specific dose estimate

for 2,3,7,8-TCDD. External review draft (EPA 600/6/

88/007 Aa).

U.S. EPA. 1988b, Intent to review guidelines for

carcinogenic risk assessment. FederaZRegister 53:32656-

32658.

U.S. EPA. 1988c. Thyroid follicular cell carcinogene -

sis: mechanistic and science policy considerations.

EPA 625/3-88/014A. Risk Assessment Forum.

U.S. EPA. 1989a. Interim Procedures for Estimating

Risks Associated with Exposures to Mixtures of

Chlorinated Dibenzo-p-Dioxins and -Dibenzofirans

(CDDS and CDFS) and the 1989 Updute. Risk

Assessment Forum. EPA 625/3-89/016.

U.S. EPA. 1989b. Proposed amendments to the

guidelines for the health assessment of suspect developmental toxicants. Federal Register 54:9399.

U.S. EPA. 1991a. Alpha -2u-globulin: association with

chemically induced rend toxicity and neoplaria in the

nude rat. Risk Assessment Forum. EPA 625/3-91/

019F.

U.S. EPA. 1991b. Guidelines for developmental toxicity risk assessment. Federal Register 56:63798-63826.

U.S. EPA. 1992a. Working paper for considering draft

revisions to the U.S. EPA guidelines for cancer risk

assessment (Washington, DC: EPA 600/AP-92-O03).

U.S. ERA. 1992b. Guidelines for exposure assessment.

Federal Register 57;22888-22932.

U.S. OSTP (Office of Science and Technology Policy).

1985. Chemical carcinogenesis: a review of the science

and its associated principles. FederaZRegister50: 10372-

104OO.

Weinberg, A. 1972. Science and trans-science. Minerva 10:209-222.

Wolfe, W.H., Michalek, J.E., Miner, J,C. et al. 1993.

Determinants of TCDD half-life in veterans of operation ranch hand. Submitted for publication.

Young, F, 1993. Deputy Assistant Secretary for

Health/Science and Environment, U.S. Department of

Health and Human Services. Personal communication.
—.. —

Indoor

Radon:

A Case

Study in

Decisionmaking 6

w

hen radon gas, which originates in the Earth’s crust,

is emitted into the open air, it is rapidly diluted to the

low ‘background’ or ‘outside’ levels that are found

everywhere and are inevitable. When it is emitted into

a home, school, or other building, dilution is slower, and the

concentrations of radon inside structures are usually higher than

the concentrations outside. These higher levels raise health

concerns because studies have shown higher levels of radon are

associated with higher rates of lung cancer in uranium miners and

other workers exposed.

Responding to those concerns, Congress and the Environmental Protection Agency (EPA) have considered methods to

reduce the risks posed by indoor radon. Most indoor radon enters

buildings directly from the soil, and efforts to reduce those

exposures include EPA programs to inform homeowners about

the radon risks and how to reduce radon inflow into buildings.

The private sector has also acted to reduce radon in homes by

imposing requirements for measuring and, if deemed necessary,

reducing indoor radon as a condition in real estate contracts.

EPA cannot, of course, regulate radon from soil because radon

from that source enters homes directly without passage through

any entity that can be regulated. Some radon, however, enters

buildings through the water supply, and the agency can regulate

radon in water just as it regulates other contaminants under the

Safe Drinking Water Act (SDWA) (P.L. 93-523 and 99-339).

Some Members of Congress, including the Chairman of the

House Committee on Science, Space, and Technology, asked the

0ffice of Technology Assessment (OTA) to examine an ‘ ‘inconsistency’ in EPA’s approach to radon. The request, which

145
146 ! Researching Health Risks

arrived after this study of health risk assessment

research had begun, resulted in an analysis of

issues related to radon, which is included in this

report.

This chapter reviews and comments on the

bases for assessing the risks posed by indoor

radon and radon in water and discusses ongoing

and possible future research projects. It also

discusses the policy issues surrounding the congressionally identified “inconsistency’ that arises

because of differences between the goal of the

Indoor Radon Abatement Act (IRAA) (P.L. 100-

551), EPA’s proposed level for the regulation

of radon in drinking water under the SDWA,

and the level of indoor radon at which EPA

urges homeowners to take voluntary action to

reduce radon infiltration (box 6-A). The inconsistency is quantitative: The IRAA sets the target for

indoor air concentrations of radon as equal to

concentrations in outdoor air. The proposed

regulation under the SDWA sets a stricter level,

imposing regulations on water suppliers so that

emissions of radon from water to air would be

reduced to about one-tenth of the level of radon in

outdoor air. The voluntary action level EPA urges

for homeowners-about eight-times higher than

the level of radon in out-door air-is higher than

either the IRAA goal or the SDWA regulatory

limit. In response to the congressional request,

this chapter also includes a rationale for “policy

options for developing a consistent approach to

reducing the risk from radon. ’

HOW LARGE IS THE WATERBORNE

RADON PROBLEM?

EPA (U.S. EPA, 1993b) estimates that about

19 million people are served by water systems

that exceed its proposed regulatory limit for radon

in water of 300 picoCuries per liter (pCi/L).l To

reduce current concentrations that exceed that

hit, the agency has selected aeration as the Best

Available Technology (BAT). A number of

aeration methods are available, which, according

to EPA, will eliminate up to 99.9 percent of the

radon as well as some fraction of other volatile,

toxic contaminants from water (U.S. EPA, 1991).

The volatility of radon, which makes aeration

EPA’s treatment of choice, results in waterborne

radon being a problem primarily in water supplies

that depend on groundwater because radon in

surface water volatilizes into the outdoor air

before it enters buildings.

Some background information is necessary to

put the proposed regulation of radon in water into

perspective. The proposed regulation depends

upon the interpretation of epidemiologic studies,

congressional actions in response to the projected

regulation, some risk assessment models developed by EPA, and a series of reviews by EPA’s

Science Advisory Board (SAB).

RADON, MINING, AND INDOOR

EXPOSURES

Radon is a decay product of radium, which

itself is a decay product of the uranium found

ubiquitously in the Earth’s crust. Radon also

undergoes radioactive decay, and it is the products of radon decay (called radioactive “progeny’ or “daughters”) that are associated with

lung cancer. Radium and radon, of course, are

especially abundant in radioactive deposits, and

the Federal Government’s demand for uranium to

make atomic bombs during and after World War

II resulted in a rush to mine such deposits. As a

consequence, miners were exposed to high levels

of radon. Beginning in the 1950s, results from

1 A pico (p) Curie (Ci) is a measure of radioactivity. “Pico” means one-trilliont@ so a pico Curie (p@ is one-trillionth of a curie. One

Curie is equal to 3.7 X 1010 radioactive disintegrations per second and a pCi is then 3.7 X 10_2 per second or 2.2 disintegrations per minute.

The measure 4 pCi/L means that the radioactivity in one liter (L) of air (or water) produces 4 X 2.2 disintegrations per minute = 8.8

disintegrations per minute. Although pc,m is the unit of measure most often used in the United States to express concentrations of radioactivity,

in other countries, “Bq/rn3’ is more commonly used. A becquerel (B@ is equal to 37 pCi, and one cubic meter (m3) is equal to one L. ‘1’kmforc,

1 pCi/L is @ to 37 Bq/LU3. (Usually, when conversions between the two units of measure are made and no calculator is available, the

conversion factor is @, that is, 1 pCi/L is about equal to 40 Bq/rn3.) Various detectors are available to measure radioactive disintegrations.
——

Chapter 6: Indoor Radon: A Case Study in Decisionmaking I 147

Box 6-A--Reducing Exposures to Radon: A Goal, an Action Level,

and a Regulatory Standard

Nazaroff and Teichman (1990)1 calculate that current exposures to radon are associated with about 15,700

lung cancer deaths annually. They estimate that 97 percent of those deaths will occur in smokers, and 3 percent

will occur in nonsmokers. Indoor concentrations of radon are higher than those outdoors, and the Federal

Government is directing several efforts at reducing indoor exposures. At present, there is a goal for reducing indoor

radon concentrations, an action level to guide voluntary reductions, and a proposed regulation to reduce

concentrations of radon in water.

A Goal: The Indoor Radon Abatement Act sets the goal of reducing indoor radon concentrations to the

concentrations found outdoors-0.4 pCi/L. Currently, the average indoor concentration is about 1.5 pCi/L, with

about 6 percent of all houses having concentrations greater than 4 pCi/L. The Environmental Protection Agency

states that it is difficult to reduce indoor levels below 2 pCi/L (apparently for houses that have levels greater than

4 pCi/L).

An Action Level: EPA recommends that indoor radon concentrations be reduced to 4 pCi/L or below, a level

considered technologically feasible for all houses. Reducing all indoor radon concentrations that are now greater

than 4 to 2.7 pCi/L is expected to eliminate about 3,500 deaths (a reduction of about 17 percent). (The level of

2.7 pCi/L is the mean between the national average of about 1.5 pCi/L and the action level of 4 pCi/L.)

A Regulatory Standard: Under provisions of the Safe Drinking Water Act, EPA proposes regulating radon

in drinking water so t hat t he concentration of radon in air that results from the volatilization of radon from drinking

water is no more than 0.03 pCi/L. According to EPA, reducing all higher concentrations of radon in water to this

level would eliminate 80 radon-associated lung cancer deaths annually (a reduction of about one-hatf of 1 percent).

1 W,W, Nazaroff and K. Teichman, “Indoor Radon,” IEnvlrorvnenta/ S&nC61 and 7bchno@Y24(1990):774-782.

SOURCE: Office of Technology Assessment, 1993.

studies by the Atomic Energy Commission a result of studying human populations. Usually,

showed that lung cancer was more common in

U.S. uranium miners than in other men, and

studies of miners elsewhere—in Czechoslovakia,

Sweden, and Canada—reported similar results

(Brill, 1990).

Results from studies of miners identify radon

as a hazard to human health, and assessing the risk

that radon poses to human health is free from the

problem of animal-to-human extrapolation that

besets most health risk assessments. Those results

identify radon as a hazard, but they leave risk

assessors and decisionmakers with the problem of

extrapolating from the effects seen at ‘‘high

exposure levels’ in the miners to estimates of

expected effects at the, generally, ‘‘low exposure

levels” found in houses, Such high-to-low extrapolations are a common issue with substances

that are identified as a hazard to human health as

researchers accumulate the human data from

studies of people exposed to high concentrations

of chemicals or radiation in the workplace or in

medical practice. Then those data must be used to

extrapolate to the risks at lower ‘‘environmental’

exposures (U.S. Congress, OTA, 198 1; U.S.

DHHS, National Toxicology Program, 1991).

In the late 1970s, Congress recognized some

risks posed by nonoccupational exposures to

radon and passed the Uranium Mill Tailings

Radiation Control Act of 1978 (P.L. 95-604).

That act directed EPA to set limits on radon

emissions from inactive uranium processing sites

and to establish acceptable levels for indoor radon

in buildings associated with those sites.

That narrow focus on occupational or residual

exposures that remained from closed-down mining and refining operations disappeared in 1984.
148 I Researching Health Risks

As the story is commonly told, it ended when

Stanley Watras, an engineer at the Limerick

Nuclear Power Plant in eastern Pennsylvania,

passed through a radiation detector at the plant.

He triggered the detector’s alarm every day for

almost 2 weeks in a row, which was surprising

given that his co-workers seldom triggered the

alarm. Mr. Watras guessed that his radioactive

contamination might be coming from a source

other than his work, and as an experiment one

morning, he went directly to the detector before

he went to his job. The alarm sounded. A

subsequent inspection showed that Mr. Watras

was bringing in radon from his house on his

clothing and his person. Measurements in his

house showed radon levels that resulted in a

radiation dose well above those permitted in

industrial settings (Taylor, 1990). What is less

commonly reported is that Mr. Watras’ house was

directly over the tunnel of a uranium mine and

that the house next door had only background

levels of radon, about one-thousandth of those

detected in his house (Moeller, 1989).

Although some scientists had identified indoor

radon as a hazard by the late 1970s (Nero, 1990),

Mr. Watras’s saga began the process that widely

publicized radon in homes as a health risk. Within

2 years, EPA (1986) published A Citizen’s Guide

to Radon, which” attributed between 5,000 and

20,000 lung cancer deaths annually to exposure to

radon. A year later, when the agency (U.S. EPA,

1987) cataloged sources of environmental cancer

risks, the numerical estimate for cancer mortality

from indoor radon (between 5,000 and 20,000

annual deaths) was about the same as the estimate

for mortality from skin cancer (10,000) caused by

exposure to sunlight. Both of those estimates

were much higher than risks of cancer associated

with other sources (table 6-l). In the 1992

revision of A Citizen’s Guide to Radon, EPA and

the Department of Health and Human Services

(DHHS) estimated that radon causes about 14,000

cancer deaths annually (U.S. EPA and DHHS,

1992). Although EPA’s estimates have varied

across the years, they have consistently associTable 6-1—Major Environmental Cancer Risks

and Cancer Risks From Water

Estimated annual

Source of risk cancer mortality

Indoor radon . . . . . . . . . . . . . . . . . . . . . 5,000-20,000’

Sunlight . . . . . . . . . . . . . . . . . . . . . . . . 10,000

All airborne cancer risks (excluding radon 2,267-3,294

and environmental

tobacco smoke) . . . . . . . . . . . . . . .

Pesticides . . . . . . . . . . . . . . . . . . . . . . . 3,075-6,150

Radiation in drinking water. . . . . . . . . 37-730 b

All chemicals in drinking water . . . . . . 215-430

a ~her EPA estimates vary upwards from this range.

b ~her EPA estimates vary within this range.

SOURCE: M. Gough. 1989. “Estimating Cancer Mortality.” l%timm

rner?td Sdeme and T@no/ogy 23:925-930, based on U.S. Environmental Protection Agency. 1987. Unfkdshed Business.

ated several thousand cancer deaths with exposures to radon.

Smokers are much more likely than nonsmokers to develop lung cancer as a result of radon

exposure. Nazaroff and Teichman (1990) estimate that only 3 percent of the projected mortality

from radon-associated lung cancer will occur in

nonsmokers; EPA (1992a) estimates that 70

percent of deaths from radon-related lung cancer

will occur in smokers, 24 percent in former

smokers, and 6 percent in nonsmokers. In the

1992 Citizen’s Guide (U.S. EPA and DHHS,

1992), EPA and DHHS point out that, for

smokers, the most important step to reduce risks

from radon is to quit smoking.

Currently, EPA recommends that homeowners

take action to reduce indoor radon concentrations

to 4 pCi/L, a level that can be reached in almost

every home. The agency also states that levels in

many homes can be reduced even more, to about

2 pCi/L (U.S. EPA and DHHS, 1992). This goal

of 2 pCi/L is a little higher than the average indoor

concentration in the United States (1.25 pCi/L),

and it is from about 3 to 6 times higher than the

outdoor average concentration of 0.3 to 0.5 pCi/L.

Remediation methods recommended by EPA

include increasing ventilation below slabs and

sealing basements and foundations to reduce

entry of radon.
Chapter 6: Indoor Radon: A Case Study in Decisionmaking 1149

Interest in the health effects of indoor radon has

prompted more than a dozen epidemiologic

studies comparing the rates of lung cancer in

people who live in homes with higher levels of

radon with those of people who live in homes with

lower levels. Interpreting results from the various

studies and attempting to reconcile conflicting

results require that some attention be given to

how the studies were designed and executed.

EPIDEMIOLOGIC STUDIES OF

RADON-RELATED LUNG CANCER

Epidemiology is the study of the distributions

of diseases in populations and the conditions that

contribute to the appearance or progression of

diseases. The most basic epidemiologic information is provided in a case report, which

describes the occurrence of a disease (usually rare

and therefore attracting attention) or a cluster of

cases of a disease. Such reports identify populations for further investigation or study, but they

provide no analysis of the putative links between

exposure and disease, For example, a report of a

rare form of muscle disease in a worker in a

chemical plant would alert health professionals to

a possible link between that disease and exposures to some toxic agent in the plant. But the

disease could have occurred completely by

chance, and further investigation would be necessary to examine the worker’s exposures to specific chemicals and other studies would be needed

to see whether other exposed workers suffered

from the same disease or some precursor to it.

Beyond case reports, most epidemiologic research can be classified as one of three kinds:

ecological studies, case-control studies, and

cohort studies. Researchers have used all three

types to investigate relationships between radon

exposure and lung cancer. In general, ecological

and case-control studies have been used to

examine questions about indoor radon and casecontrol, and cohort studies have been employed

for investigations in occupational populations.

In ecological studies, scientists compare rates

of lung cancer in populations in geographical

areas that have different average levels of exposure to radon. Case-control studies involve locating cases (persons who have lung cancer or the

records of people who have died from lung

cancer) and comparing the exposures of the cases

to the exposures of controls (people who do not

have lung cancer). In a cohort2 study, scientists

compare the rates of lung cancer in a group of

people, such as miners, who share types, times,

and intensities of radon exposure that differ from

those of other groups. In ecologic and cohort

studies of a disease as common as lung cancer,

many cases of the disease will be expected in all

the studied populations. Finding that the rate of

the disease is higher in a population exposed to

higher levels of radon is taken as evidence of a

connection between exposure and disease after

ruling out other factors that might account for the

difference. For instance, if smoking was more

common in the group with higher rates of lung

cancer, a careful analysis would be necessary to

ascertain the separate and combined effects of

smoking and radon.

Ecological studies provide no direct comparisons between the exposures of individuals and

their diseases. Such studies are relatively easy to

do in areas in which records of disease incidence

or deaths are available and in which there have

been enough measurements of indoor radon that

scientists can estimate average levels of exposure

for the area. When completed, however, ecological studies provide no information about whether

the persons who developed the disease had

exposures near the average level or well above or

below it.

Case-control studies are useful for studies of

both indoor radon and exposures in the

workplace, and they can provide information

z As an epidemiologic teq a‘ ‘cohort’ is a group of people who share certain cha.racteristics (the word cohort originally identified on-tenth

of a Roman legion).
150 I Researching Health Risks

about individual exposures and frequency of

disease. One stumbling block for such studies is

the difficulty of determining all past exposures to

radon. For instance, many people move several

times during their lifetimes, and a complete

inventory of their exposures to indoor radon

would require measurements in each of their

homes. A further complication in interpreting

such studies is how to make allowances for

‘‘competing risks’ that contribute to the risks of

developing lung cancer. The most important is

smoking; the second most important is probably

environmental tobacco smoke (Brownson et al.,

1992).

Most of the available quantitative information

about the risks posed by radon comes from cohort

studies of uranium miners that compare the rates

of lung cancer among the miners with rates

among other workers. Because of the latent period

of 20 or more years between exposure to radon

and the appearance of lung cancer, scientists who

study rates of lung cancer among miners are most

interested in their levels of exposure over two

decades ago and more. That need for a long-term

view complicates interpretation of the studies

because accurate measurements are seldom available for past exposures.

 Ecological Studies

The absence of direct ties between the exposure

of an individual and his or her health status

complicates interpreting the results of ecological

studies. Using average (or group) information to

estimate exposures results in the “ecological

fallacy,’ which links together specific health

consequences among individuals and estimates or

measures of average exposures. Only careful (and

perhaps impossible) analysis would clarify whether

the group measure was appropriate to describe the

exposure of a person with a disease.

Although it may seem reasonable to conclude

that people with an illness in a group exposed to

a higher average level of radon were exposed to

more radon than people exposed (on average) to

lower levels of radon, there is no way to be certain

of that. No single ecological study nor the

complete set of such studies taken together will

resolve the question of whether nonoccupational

exposure to radon increases the rate of lung

cancer.

Samet (1989) reviewed 11 ecological studies:

In spite of crude exposure measures, most of

these studies showed associations between exposure to radon decay products and the incidence of

or mortality from lung cancer. Two studies of

counties in the Reading Prong [the area of

Pennsylvania in which Mr. Watras lived] are of

particular interest because of the high number of

homes in this region with high radon concentrations.

Of particular interest in discussions of radon in

water and health risks are two studies reviewed by

Samet (1989) that analyzed rates of lung cancer in

relation to levels of radioactivity in water supplies. One of the two studies found an increase in

rates of lung cancer in both men and women as a

function of estimated greater exposures to radon;

the other found an increase in men but not in

women. The latter result would be an unexpected

one if radon in household water made a significant contribution to the risk of lung cancer.

Overall, Samet (1989) concluded that 5 of the

11 studies were consistent with a correlation

between exposure of higher levels of radon

exposure and lung cancer, and one (one of the

“water’ studies) found an increase in men but

not in women. Four of the 11 found no statistically significant increase in rates of lung cancer;

one study reported an inverse correlation between

exposures to radon and rates of lung cancer. That

‘‘negative study and others done by the same

scientist and his colleagues have received a great

deal of attention, perhaps because the associations run counter to conventional ideas about

radon and risk (Hanson, 1989).

Cohen (Cohen, 1990, 1992) investigated associations between rates of lung cancer and levels of

radon using tens of thousands of measurements in
Chapter 6: Indoor Radon: A Case Study in Decisionmaking I 151

living areas and basements in houses in the 48

contiguous States of the United States. On the one

hand, Cohen accepts that the ecological fallacy

means that such studies cannot shed light on the

question whether radon causes lung cancer because there is no way of knowing the levels of

exposure of the people who develop lung cancer.

On the other hand, he argues that the ecological

fallacy does not prevent such studies from answering the question of whether a linear, nothreshold relationship exists between exposure to

radon and lung cancer (see the discussion in ch.

2). According to Cohen, if that relationship is

correct, cancer rates should vary directly with

average countywide exposures. Cohen found that

rates went down as exposures increased.

Immediately, objections were raised to Cohen’s

finding. For instance, how does smoking vary

from county to county? Cohen’s response was to

compare cigarette sales in different States, factor

that information into his analysis, and demonstrate that the negative correlation between levels

of radon and lung cancer persists. What kind of

correlation would be expected between current

rates of lung cancer and current household

exposures? Given the latent period between

exposure and manifestation of disease, the exposures of interest occurred many years ago. Cohen

has adjusted his analysis to consider that fact and

has accumulated measurements of radon levels in

far more houses than any other investigator.

Nevertheless, other investigators have reported

no replications of Cohen’s results.

Taken together, the ecological studies present

a confusing picture. Each additional study, whether

it shows a positive association, no association, or

a negative association, can be added to the tally,

but no one study by itself nor all the ecological

studies taken altogether will convince everyone

about whether low-level radon is associated with

lung cancer. Moreover, calculating reliable, quantitative estimates of risk from such studies is

impossible.

 Case-Control Studies

Case-control studies provide more definitive

information about exposure than do ecological

studies. In case-control studies of indoor radon,

scientists (Blot et al., 1990; Schoenberg et al.,

1990; Svensson, Pershagen and Klominek, 1989)

often focus on women because fewer women

smoke compared with men, and women typically

spend more time at home.

Like the ecological studies, the case-control

studies have yielded contradictory results. For

instance, both Schoenberg et al. (1990) and

Svensson et al. (1989) reported elevated levels of

lung cancer among women who lived in houses

with higher levels of radon. As the authors of

those papers pointed out, the numbers of women

included in the studies, especially the numbers of

women exposed to higher levels of radon, were

quite small. Only 24 of 433 women with lung

cancer in the Schoenberg et al. (1990) study had

lived in homes with concentrations of radon

greater than 2 pCi/L. The small number of cases

makes it difficult to interpret those studies, and

many results showing excesses of cancer in the

more highly exposed women were not statistically significant; that is, the excesses that were

detected might have arisen by chance. Furthermore, no consistent relationship was found between smoking habits and lung cancer in the

Schoenberg et al. (1990) and Svensson et al.

(1989) studies, which introduces some uncertainty in interpretation because smoking and rates

of lung cancer rates usually vary directly with

each other.

Blot et al. (1990) studied women in a province

of China and found that ‘No association between

radon and lung cancer was observed regardless of

cigarette-smoking status, except for a nonsignificant trend among heavy smokers. ’ Those authors

go on to interpret their results as indicating that

“projections (of cancer risk) from surveys of

miners exposed to high radon levels may have

overestimated the overall risks of lung cancer

associated with levels typically seen in this
152 I Researching Health Risks

Chinese City. ” Letourneau et al. (1993) reported

comparable results from a case-control study of

750 people with lung cancer in Winnipeg, Canada. They found that ‘‘no increase in the relative

risk of any of the histologic types of lung cancer

observed among cases was detected in relation to

cumulative exposure to radon. ’

Lubin et al. (1993) prepared an analysis and

comparison of the Blot, Schoenberg, and Svensson studies and concluded that any link between

exposure to radon and risk of lung cancer is only

weakly demonstrated in the studies, if it is present

at all. Nevertheless, the fact that no increase was

detected does not necessarily mean that none was

there. It might have been present but undetectable

because of the (small) size of the study.

Similarly, Ruosteenoja (1991) found “no significant correlation between the average radon

exposure and incidence of male lung cancer.

Yet, as the author pointed out, her study had little

chance to detect the level of risk predicted from

the miner studies. As in other studies, the small

number of cases made it possible that any effect

of radon that was present went undetected against

the number of lung cancer cases expected regardless of the presence or absence of radon.

So far, case-control studies leave open the two

possibilities that either the risk of developing lung

cancer from exposures to indoor radon are zero

(or at least below the limit of detection) or that it

is compatible with the level of risk estimated from

the miner studies. Additional case-control studies

of sufficient size and ‘‘power’ might provide the

information needed to determine whether risks

projected from the miner studies are realized in

people exposed to lower levels.

One alternative to a single large study is to

carry out a meta-analysis of the already completed and soon to be completed studies and to

combine those results to produce a more definitive answer. Meta-analysis is not a panacea, but it

is a developing subdiscipline with applications to

epidemiology (Dickersin and Berlin, 1992) and

risk analysis (Society for Risk Analysis, 1993) as

well as in health and behavioral sciences in

general (Olkin, 1992). The Department of Energy

has begun preparations for conducting a metaanalysis of case-control studies to begin in about

2 years when some ongoing studies will have

been completed.

Researchers expect important findings from

two ongoing studies in the United States that

involve Midwesterners who tend to live in one

house for long periods and who live in either

Missouri or Iowa, States with relatively high

radon concentrations. Of 524 homes examined in

Missouri, 33(8 percent) had radon concentrations

of 4 pCi/L or greater, and 8 (2 percent) had

concentrations more than 8 pCi/L. Results already reported from that study verified predictions by Lubin et al. (1990) that people who move

frequently have lower exposures than people who

remain in a single home. Given the relative rarity

of ‘hot homes, ’ a person who moves from such

a home is more likely than not to move to a house

with lower levels. Alavanja et al. (1992) report

that 11 percent of Missouri women who lived in

a single house for 30 years had been exposed to

concentrations greater than 4 pCi/L for that time;

6 percent of women who lived in two houses had

exposures that high; and none of the women who

lived in three or more houses had such exposures.

Investigators expect to complete their analysis of

the relationships between levels of radon and

cancer incidence in the 600 nonsmoking women

with lung cancer in the study by mid-1993 and to

publish them by the end of the year.

A research team at the University of Iowa is

conducting the second Midwestern study. The

investigators are studying women who smoke, to

shed light on interactions between smoking and

radon in cancer causation; studies of women who

do not smoke are expected to identify any direct

relationships between radon and lung cancer

(Lynch, 1993). Equal in size to the Missouri

study, the Iowa study includes a total of 600 cases

of lung cancer and 1,400 controls. From the

results of the EPA survey of radon in homes, it

appears that about 70 percent of Iowa homes have

radon concentrations greater than 4 pCi/L, and
Chapter 6: Indoor Radon: A Case Study in Decisionmaking I 153

those higher radon 1evels favor detecting associations between exposures and lung cancer-if they

exist. The principal investigator of the study

expects results to be published in late 1997.

 Cohort Studies

Since the 1950s, scientists have studied the

health of miners (in particular, uranium miners,

who were frost seen to be at risk) and determined

that exposure to radon increases the incidence of

lung cancers. Samet (Samet, 1989) reviewed 20

studies of underground uranium miners and

concluded that the data show consistent relationships between exposure to radon and elevated

rates of lung cancer.

Exposure levels of the miners are expressed in

working-level months (WLM), which are an

approximation of the radiation exposure experienced by a uranium miner in 1 month’s work.

Miners in the various epidemiologic studies of

radon had histories consistent with cumulative

occupational exposures that ranged from 1 to

10,000 WLM. The current occupational limit for

exposure to radon is 4 WLM annually (NRC,

1988), and a miner exposed at the current limit for

40 years would accumulate 160 WLM from his

workplace. In comparison, the 70 years lifetime

cumulative exposure of residents of homes with

average concentrations of indoor radon is about

20 WLM (Samet, 1989).

As might be expected, cancer is far more

frequent in the miners exposed to hundreds or

thousands of WLM than in those exposed to lower

levels. However, Bodansky (1990), in a review of

those data, stated “ . . . miner studies do seem to

suggest a statistically significant positive effect,

for cumulative exposures as low as 20 to 50

WLM. When the cumulative exposure is low,

however, either due to low radon levels or short

duration of employment, the data is vulnerable to

confounding factors. ’ Despite the suggested

effect at exposures below 100 WLM, correlations

between rates of lung cancer and higher levels of

exposure dominate the risk assessment.

A question is raised whether the relationships

seen between cancer and radon at hundreds of

WLM, which are experienced in a few years,

accurately predict cancer risks at levels of 10 or

20 WLM accumulated over a lifetime. Some

scientists in EPA’s Office of Science, Planning

and Regulatory Support (Ulsamer, 1993) describe

the problem this way: “The potential effects of

differences in dose rates between miners (who

are exposed for an average of 7 years to

20+ WLM/yr) and home residents (who are

exposed for an average of 72 years to 0.22

WLM/yr from soil radon and 0.01 WLM/yr

from water radon) . . . needs to be discussed.”

In this respect, indoor radon is a prime example of

a problem in high-to-low-dose extrapolation.

 Other Cancers

Henshaw and his colleagues (Henshaw et al.,

1990; 1992) reported associations between levels

of radon and the incidence of some cancers other

than lung cancer in several countries. Those

investigators relied upon ecological studies, making their results subject to the ecological fallacy,

which reduces their value for decisionmaking.

Although some scientists have treated the associations as possibly indicating a role for radon in

other cancers (Pete, 1990), Doll (1992) points out

that rates for none of the cancers that Henshaw et

al. (1990) associate with radon exposure were

elevated among miners, and a recently published

study of 4,000 Czech miners found no association

between radon exposure and leukemia (Anon,

1993a). Moreover, Miller et al. (1993) directly

examined the possibility of an association between residential exposure to radon and the

occurrence of a form of leukemia that had been

suggested by Henshaw et al. (1990). They found

no evidence for the association. Currently, there

is little support for an association between

exposures to radon and other cancers.
154 I Researching Health Risks

POLICY

EPA divides its regulatory programs along

media lines-air, water, industrial wastes, and so

forth. It has approached the issue of indoor radon

as a media problem; thus, it has different policies

toward radon entering buildings in air and water.

The agency has not proposed regulating radon

that is emitted directly from the soil, but it has

proposed regulation of water suppliers as a

method to reduce exposures to radon. Some

scientists, Members of Congress, and other policymakers have recognized that indoor radon is

only a single part of the larger issue of indoor air

pollution, which presents assessment, remediation, and regulatory difficulties different from

those associated with pollutants in outside air.

Table 6-2-Comparison of Short-Term In-Basement

Measurements of Radon in Air and Estimated

Annual Exposures in Living Areas

If short-term Then estimated annual

result is: radon level is:

1 pCi/L 0.3 pCi/L

2 0.7

3 1.0

4 1.3

5 1.7

6 2.0

7 2.3

8 2.7

9 3.0

10 3.3

11 3.7

12 4.0

 Air

In 1986, EPA estimated that 7 million U.S.

homes had concentrations of radon above 4

pCi/L, the level at which the agency would

recommend remedial action. Subsequently, as a

result of its National Residential Radon Survey

(EPA, 1992b) which involved measurements of

radon in houses around the country, the agency

reduced that estimate. Based on that survey, EPA

now estimates that between 60,000 and 100,000

homes have concentrations of radon of 4 pCi/L or

more and that the average home has a concentration of around 1.25 pCi/L.

The fact that EPA does not regulate airborne

radon does not mean that those exposures have

gone unaddressed. EPA distributed A Citizen’s

Guide to Radon in 1988 and a revised document

in 1992 as part of an information program to alert

citizens about the risks from indoor radon. Some

experts have questioned whether the guides

provide the appropriate information. In particular,

Nero (1992) and others have criticized EPA for

urging that all houses be tested because they see

that policy as distracting attention from homes in

the areas with the highest concentrations of radon.

The critics have also faulted EPA for not focusing

on persuading residents to mitigate concentraNOTE: pCi/L = pico Curies per liter.

SOURCE: Office of Technology Assessment, baeed on U.S. Environmental Protection Agency, F?eporthg on Radon (1989), pereonal

communication from M. Reimer, U.S. Geological Survey.

tions of radon in houses with levels of 20 pCi/L

or higher. Those levels are higher than the

exposures currently allowed for miners and other

workers exposed to radon. According to those

critics, EPA has dissipated the force of its

message by calling for remediation in any house

with levels greater than 4 pCi/L. Some experts

have also objected to EPA’s telling citizens to act

on the basis of short tests of 2 to 7 days rather than

testing for a year to obtain more accurate results.

The data in table 6-2 demonstrate the importance of appropriate testing techniques. Several

years ago, EPA recommended that testing for

radon be done with radiation detectors placed in

the basements of homes and that the homes be

kept closed up during the measurement period. As

a result, the measurements were taken in the area

of the house with the highest level of radon,

regardless of whether anyone spent any time in

that area, and under conditions that reduced

dilution of indoor radon by outside air entering

through open doors and windows. As shown in

the table, measurements under those conditions

were three times higher than the year-round
Chapter 6: Indoor Radon: A Case Study in Decisionmaking I 155

Table 6-3-Current Estimates of Radon-Associated Lung Cancer Deaths and

Reductions Expected From Reducing Indoor Exposures

Former NonSource Smokers smokers smokers Total

Estimated number of annual radon-associated cancer deaths

Nazaroff and Teichman . . . . . . . . . . . . . . . . . . . . . 15,200’ 500 15,700

Environmental Protection Agency . . . . . . . . . . . . 9,600 3,200 800 13,700

Estimated number of annual averted deaths at reduced exposures

Exposures Former Nonreduced to Smokers smokers smokers Total

Nazaroff and Teichman . . . . . . . . . . . . . . . . . . . . . 2.7 pCi/L 2,300 200 2,500

Environmental Protection Agency . . . . . . . . . . . . 4.0 1,500 500 100 2,200

Environmental Protection Agency ., . . . . . . . . . . 3.0 1,800 600 200 2,600

Environmental Protection Agency ... , . . . . . . . . 2.0 2,300 700 200 3,100

Office of Technology Assessment . . . . . . . . . . . . 1.3b

5,000’

NOTE: pCi/L - pico Curies per liter.

a Nazaroff and Tekhman combine current and former smokers in their CalCUktiOnS.

b Average indoor mmetltratlon of radon in the Unitf3d states.

c lnteTolat~ from figure 6-1.

SOURCES: W.W, Nazaroff and K. Teichman, “indoor Radon,” Erwionmentd Sckwwe and TAno/ogy 24(1990):774-782; U.S. Environmental

Protection Agency, Technical Support Dowment for the 1992 Citizen’s Guide to Radon, EPA 400-R-92-011 (Office of Technology Assessment,

1993).

average measurement of radiation in the living

quarters of the house with ordinary ventilation

and household traffic. EPA now recommends that

measurements be made in the lowest living

quarters of the house rather than in the basement.

Despite disagreements about the content of

EPA’s information materials, some people have

clearly heard the message that indoor radon is a

risk that can be addressed. Indeed, in some States

and counties, radon inspections, like inspections

for termites, are now part of real estate transactions. As a rule, inspecting for radon is not

required by law or regulation but is part of the

agreement between buyer and seller. For example, in Montgomery County, Maryland, most

sales contracts require a 2-day sampling for

radon. If the concentration is 4 pCi/L or higher,

the buyer may require the seller to take remedial

action to reduce the level.

Both Nazaroff and Teichman (1990) and EPA

(1992a) have calculated the number of deaths

from lung cancer that might be avoided by

reducing exposures to indoor radon. Nazaroff and

Teichman (table 6-3) estimate that reducing

concentrations of radon to 2.7 pCi/L in all homes

that currently have concentrations above 4 pCi/L

would prevent 200 deaths per year from lung

cancer among nonsmokers and 2,300 deaths per

year among smokers (leaving about 12,000 radonassociated lung cancer deaths).

EPA’s (1992a) estimates are quite similar. EPA

currently recommends that all homeowners take

action to reduce any exposure in excess of

4 pCi/L, and that level is often called the ‘‘action

level.’ Reductions of all current exposures above

the action level to 4 pCi/L are calculated to reduce

the lung cancer death rate by 2,200, with 100

deaths being prevented in nonsmokers (table 6-3).

The expected reductions in death rates increase

with further reductions in exposures to radon:

reducing all indoor exposures now above 3 pCi/L

to 3 pCi/L would prevent about 2,400 deaths

annually in smokers and former smokers and 200

deaths among nonsmokers; reducing exposures to

2 pCi/L, which EPA (1992a) considers near the

practical limit for mitigation efforts, is calculated
156 I Researching Health Risks

to lower the annual death rate from lung cancer by

about 3,100, leaving about 10,500 such deaths

associated with radon (figure 6-l).

As is apparent from figure 6-1, the bulk of

cancers associated with radon exposure occurs in

the population exposed to low levels, below 2

pCi/L. The primary reason for that is that many

more people are exposed to those levels than to

higher levels. Given EPA’s conclusion that it is

impossible to reduce levels below 2 pCi/L in

some houses, the practical lower limit on the

number of deaths associated with radon maybe as

high as 10,500. This estimate is based, of course,

on extrapolations from the miners studies, and

refinement of those extrapolations might reduce

or increase the estimate of the number of cancers

associated with radon.

Interpolating from the data on figure 6-1, OTA

estimates that reducing all indoor exposures now

above 1.25 pCi/L to that level, which is the U.S.

average, would avert about 5,800 radonassociated lung cancer deaths annually (table

6-3). That would leave 7,900, a little over half, of

radon-associated lung cancer deaths unabated.

Because radon is present in all air, both inside

and outside, it is impossible to have zero radon

exposures. Thus, some risk of death from radonassociated lung cancer is always present if it is

assumed that there is no threshold for radonassociated lung cancer deaths, and as is shown on

figure 6-1, exposures to radon in outside air are

associated with about 500 lung cancer deaths

annually.

The National Research Council’s (NRC, 1983)

distinction between risk assessment and risk

management calls for deliberations at two levels:

1. Is there a risk?

2. If there is one, what methods are most suited

for its control?

For radon in homes, EPA’s Technical Support

Document for the 1992 Citizen’s Guide to Radon

(EPA, 1992a) provides the agency’s reasoning

behind choosing 4 pCi/L as the level at which

Figure 6-1—Estimates of Deaths From Lung Cancer

at Different Levels of Radon Exposure

14,000

●

g 12,000-

s

6 10,000-

k

n

~ 8,000-

c

a

2 6,000-

:

2

4,000-

.-

fi 2,000 -

●

01 r 1 I [ I

o 4 8 12 16 20 24

Maximum exposure level (pCi/L)

SOURCE: Office of Thnology Assessment, 1993.

homeowners should obtain more information

about exposure and remediate to bring levels

below that concentration. But, because EPA does

not regulate radon in air, the Federal Government

did not have to provide an administrative forum

to debate whether the projected benefits of

reaching 4 pCi/L of radon justified the associated

costs. Figure 6-2 summarizes EPA’s costeffectiveness analysis for reducing concentrations of indoor radon to various levels. Reducing

exposures to 8 pCi/L is expected to save lives at

a cost of less than $0.5 million per life; the cost

per life saved just about doubles (to a little less

than $1.0 million) at 4 pCi/L and increases further

at lower action levels.

 Water

The Safe Drinkin- g Water Act Amendments of

1986 require EPA to develop regulations for toxic

chemicals in water. The agency has decided to

regulate radon like any other waterborne carcinogen; it also considers radon to pose, quantitatively, the greatest risk of cancer from water (table

6-l). That regulatory process can be considered in

two time periods. Before the summer of 1992,

EPA was developing the regulation under its
Chapter 6: Indoor Radon: A Case Study in Decisionmaking I 157

usual procedures, but at that time Congress

intervened in the process. Congress mandated

EPA to make a reassessment of its estimates of

risks and costs in relation to radon in water. In its

action, Congress reflected some opinions expressed by EPA’s Science Advisory Board.

THE SCIENCE ADVISORY BOARD’S COMMENTS

EPA’s Science Advisory Board weighed into

the radon in water issue in 1992. It w-rote a letter

to the EPA Administrator:

. . . to convey its concern about the inconsistent

approach within the Agency regarding reducing

risks from radon exposures in homes. . . .

The purpose of this letter is two-fold: (a) to

address the fragmented and inconsistent approach

regarding reduction of radon risk, and (b) to

provide our closing comments on the revised

. . drinking water criteria documents that support the

proposed regulations (Loehr et al., 1992).

The letter points out the proposed regulation

would reduce the concentration of radon in water

so that the amount that volatilizes from water to

air would be more than 100 times smaller than

EPA’s action level (a voluntary guideline) of

4 pCi/L for indoor air. It also notes that that

concentration is well within normal variations in

levels of radon in homes, and about 10 times

smaller than the average concentration of radon in

outdoor air.

The SAB concluded that “Frankly, radon in

. . drinking water is a very small contributor to radon

risk except in rare cases and the Committee

suggests that the Agency focus its efforts on

primary rather than secondary sources of risk”

(Loehr et al., 1992). The board also acknowledged that it understood that the SDWA required

the regulation of radon in water. But it returned to

a theme developed in its 1990 report Reducing

Risk (U.S. EPA, SAB, 1990) and urged EPA to

base its plans on “ongoing assessments of

remaining environmental risks, the explicit comparison of those risks, and the analysis of

opportunities available for reducing risks, rather

Figure 6-2—Cost-Effectiveness of Different

Action Levels for Reducing Indoor

Radon Exposures

v—c

0 —-—- —r-——.. ~. ,.

0 4 8 12 16 20

Maximum exposure level (pCi/L)

I

24

SOURCE: Office of Technology Assessment, 1993.

than on past efforts at risk reduction or existing

programmatic considerations. It went on to urge

EPA to conduct a multimedia risk assessment of

the options for regulating radon in drinking water

and to include risks engendered by the treatment

process and the disposal of any wastes produced

from it. The board recommended that EPA

develop and present better treatments of uncertainty in the water criteria documents.

Several of the SAB’s recommendations, including the multimedia risk assessment, became

part of the 1992 congressional mandate.

PUBLIC LAW 102-389 AND THE MULTIMEDIA

RADON RISK ASSESSMENT

Section 591 of the Housing and Urban Development, Veterans Administration, and Independent Agencies Appropriations Bill of 1992 put a

hold on EPA’s proposed regulation of radon in

water. That section, commonly called the ChaffeeLautenberg Amendment after its senatorial sponsors, directed EPA to complete a study July 6,

1993, that considers “the risks from various

pathways of radon exposure-air and water,

inhalation and ingestion. ” The study was also to

examine the costs of controlling various pathways, detailing the costs to households and

communities (including small communities), and

any risks posed by disposing of materials used to
158 I Researching Health Risks

remove radon from water. The study was to be

reviewed by EPA’s Science Advisory Board, and

the board was to submit its recommendations to

the EPA Administrator, who would then report to

Congress. After completing the analyses and

reviews, EPA was to issue regulations for radon

in water by October 1, 1993.

Congress adopted the Chaffee-Lautenberg Amendment after the Senate narrowly defeated the

broader Domenici Amendment that would have

placed an outright moratorium on EPA’s capacity

to promulgate drinking water standards. According to Senator Chaffee's discussion of the amendment:

The dispute here is about the relative risk of

radon in drinking water. And since the Federal

Government does not require that any steps be

taken to correct the principal source of the risk,

namely the gas that comes from the soil, the

. . drinking water suppliers, quite rightfully, wonder

why they should be required to clean up drinking

water at a great expense. In other words, yes,

some radon comes up with the drinking water, but

more of it comes from infiltration through basement walls, et cetera.

So there is much to be said for the line of

reasoning for those who object to the testing of it

in water. Thus our amendment delays promulgation of the radon standard until the end of 1993.

During the interim, the EPA is asked to provide

better data on the relative risk of radon from

various sources, from water, from cellars, and so

forth. So we can revisit that next year in 1993,

because this postponement goes to the end of

1993 (Chaffee, 1992).

Given the time the amendment allotted for the

risk assessment, EPA could do Little more than

review the existing literature about radon risks

and address specifically some uncertainties in its

risk assessment. Although the conclusions from

the reassessment were very close to those in

EPA’s (1991) water criteria document for radon

in water, the multimedia risk assessment (or

reassessment) did not answer all the questions

raised by the SAB and by the amendment.

PROPOSED REGULATION

The SDWA imposes a goal of zero for concentrations of carcinogens in water. That goal is

unattainable for radon (extensive aeration of

radon-bearing water would discharge the radon

into the air but there would always be radon at

least at the concentration found in outside air).

EPA bases its proposed regulation on its determination that the lowest ‘‘practical quantification

level” for radon in water is 150 pCi/L, and it set

the regulatory maximum-contaminant level at

that value in its proposed rule in 1991 (U.S. EPA,

1991). The half-life of radon is 4 days; that is, half

of the radon decays in 4 days. Because EPA

allows up to 4 days for transporting the water to

the testing lab, the agency decided that a measurement of 300 pCi/L was the lowest feasible level

for its regulation. Differences in procedures for

measuring radon in air and water account for the

fact that airborne measurements of 2 pCi/L of air

are routinely obtained while EPA contends that

measurements below 150 pCi/L in water are not

practical.

There is general agreement that 10,000 pCi/L

of radon in groundwater results in 1 pCi/L of

radon in air from volatilization (U.S. EPA, 1991).

Therefore, the 300-pCi/L limit on radon in water,

if imposed, would mean that no more than

0.03 pCi/L of radon in indoor air would result

from the waterborne radon. That concentration is

10 percent or less of the radon in outdoor air, and

it would contribute about 5 percent to total indoor

exposures. Supplying a house with water that

contains 1,000 pCi/L of radon does not increase

the airborne radon content by 1 pCi/L because

when no water is running, there is little transfer of

radon from water to air. EPA has carefully

examined such things as how much radon is

released into the air from water during showering,

laundering, and flushing the toilet in order to

estimate the contribution of radon from water to

indoor air.

The Natural Resources Defense Council (NRDC)

and the Friends of the Earth (FOE) dispute EPA’s

claim that 150 pCi/L in water is the lowest
Chapter 6: Indoor Radon: A Case Study in Decisionmaking I 159

practical quantification level (Olson et al., 1991)0

They point to published studies that show that

changes in sampling and methods of analysis for

radioactivity can lower the detection level to

25 pCi/L, which makes it possible to set a

standard 12 times more stringent than the one

EPA proposed. EPA’s own analysis of amounts of

radon in water casts doubt on 150 pCi/L being the

minimal detection level because it reports on the

number of water systems that exceed 100 pCi/L

and presents some information about those between 50 and 100 pCi/L (U.S. EPA, 1991).

NRDC and FOE also point out that EPA

calculates that the cancer risk at the proposed

regulatory limit of 300 pCi/L is 2 X 10-4. Not only

is that risk level twice as high as the 10-4 level that

is EPA’s usual upper limit on acceptable risk; it

is also much higher than the risks from other

waterborne carcinogens, which are often in the

range of 10-6

.

Arguing from the viewpoint that concentrations of radon in water below 300 pCi/L can be

measured, NRDC and FOE also claim that

imposing regulations on water supplies with

concentrations below 300 pCi/L would greatly

reduce exposures and risks at little additional

cost. In particular, they calculate that such a

regulation could avert twice as many cancers for

an increase in cost of between 28 and 40 percent.

Water suppliers also disagree with EPA’s

proposed standard. They question whether the

risk assessment is accurate and whether the

proposed standard will save 80 deaths annually as

EPA calculates; they also draw attention to the

estimate that about 90 percent of the risk of lung

cancer risk is confined to smokers. Like NRDC

and FOE, but for very different reasons and by

reaching very different conclusions, water suppliers draw attention to the fact that the proposed

standard is based on a measurement level. Improvements in the capacity to measure radon in

water (which NRDC and FOE contend are already

here) could be translated into a constantly shifting, and constantly decreasing, standard. That

kind of situation would leave the water suppliers

facing an uncertain future of tighter standards and

higher costs.

RISK

In 1991, EPA (1991) estimated that current

concentrations of radon in water were associated

with about 200 deaths annually from cancer, and

the agency estimated that lowering all water

supplies that were then higher than 300 pCi/L to

300 pCi/L would avert about 80 cancer deaths. At

that time, EPA associated 80 percent of the risk

from waterborne radon with radon that volatilized

from water and was inhaled. Because of a

National Research Council (1991) study that said

certain adjustments were necessary to allow for

differences between radon exposures in mines

and in homes, EPA, in its reassessment, reduced

its estimate of the number of cancer deaths

associated with volatilized radon. At the same

time, it increased its estimate of the number of

deaths from cancer expected to result from

ingested radon. When EPA (1993) added together the number of deaths from cancer that

it associates with inhalation and ingestion of

radon from water, the total came to about 160

annually, a number not different from the

approximately 200 deaths from cancer that it

previously associated with inhaled radon from

water. 3

EPA predicts ingested radon will cause cancer

of the stomach and other digestive system organs.

However, unlike other estimates of radon risk, the

risk from ingested radon is not based on direct

evidence of adverse effects in miners or other

s EPA calculates precise point estimates for risks along with a range of possible risks, For example, its estimate for annual deaths from

ingested radon is 46, with a range of 11 to 212. Such precision is unwarranted because of uncertainties in measurement and models, and OTA

prefers to present EPA results in less precise terms, such as ‘about 50.’ More importantly, the calculated range is not the same as the uncertainty

that surrounds the estimate. As the Science Advisory Board noted (behr and McClellan, 1993), the uncertainty of the risk from ingested radon

is so great that them may be zero risk.
160 I Researching Health Risks

populations. Indeed, there is no evidence for

increases of those cancers in miners. Moreover,

according to the Agency for Toxic Substances

and Disease Registry (1992), there is no evidence

for an association between groundwater radon

and gastrointestinal cancers or leukemias. EPA

bases its estimates of risk for ingested radon on

modeling of the distribution of xenon gas in the

human body and on the observed increase of

stomach and other digestive system cancers in

survivors of atomic bomb blasts. The modeling,

which is the basis for estimating doses of internal

radiation from ingested radon, is taken from a

paper that has not been peer-reviewed. And,

although both radon and atomic bombs release

radiation, they release different kinds of radiation—

alpha particles are released from radon, and

gamma rays and neutrons from atomic bombs.

Moreover, the two sources deliver radiation quite

differently: ingested radon is a long-term internal

exposure, and atomic bombs produced an external, one-time exposure. Those differences point

to the problems involved in estimating the risk

from ingested radon.

The upward revision of the number of

deaths expected from ingested radon elicited

several negative comments. In particular, Harley

and Robbins (1993) estimated that the exposure

of the stomach to radiation from ingested radon is

about 100 times less than did EPA. EPA scientists defended their process (Chiu, Puskin, and

Barry, 1993), but Crawford-Brown (1993), the

author of the paper on which EPA depends for its

estimate of radiation exposure to the stomach,

agrees with Harley and Robbins that the estimate

of exposure may be too high.

More fundamentally, Crawford-Brown (1993)

objects to EPA’s assuming that the mathematical

equation it used to extrapolate risk is correct: "I

believe the USEPA is both philosophically and

scientifically far from the mark in suggesting

that uncertainties in extrapolation equations

are to be characterized . . . (as if) . . . there is no

uncertainty in these equations . . . ." This

comment questions the risk assessment based on

miner data that EPA has used to estimate the

cancer risks from radon in water. Some scientists

within EPA have made parallel comments about

the uncertainties in the dose-response equation

that is used in EPA’s risk assessment (Ulsamer,

1993).

Scientists at Brookhaven National Laboratory

(BNL) responded to a request from EPA’s Office

of Research and Development that the Department of Energy (DOE) review EPA’s risk assessment of radon in water. The resulting review was

sent from DOE to EPA accompanied by a letter

(Pelletier, 1993) that summarized the DOE position: “BNL concludes that the draft report

contains significant flaws which seriously detract

from its usefulness. ” The review itself is quite

critical of EPA’s risk analysis (Morris, Rowe, and

Baxter, 1993). The BNL scientists agree with

Crawford-Brown (1993) that EPA may have

overestimated exposures from ingested radon by

a factor of 100, and they point to a number of

computational errors that they found in the EPA

report. The EPA scientists who developed the risk

assessment profoundly disagreed with the DOE

review (Chiu, Puskin, and Barry, 1993) and

responded to its summary comments.

In its review of the reassessment, EPA’s

Science Advisory Board was quite critical of the

methods used to estimate cancer rates from

ingested radon. It characterized the methods as

more indirect than those used to estimate risks

from airborne radon and concluded: “In the

absence of direct evidence, it is not possible to

exclude the possibility of zero risk from ingested

radon” (Loehr and McClellan, 1993). As it did in

1992, the SAB drew attention to the small risk

associated with radon in water as compared to the

overall risks from radon. The SAB also, as in

1992, made comparisons between the number of

deaths that might be associated with waterborne

radon (about 160) and the 2,500 deaths that are

expected to occur annually from radioactive

potassium that occurs in the human body and the

500 or so expected from outdoor radon.
Chapter 6: Indoor Radon: A Case Study in Decisionmaking I 161

COSTS

The three parties-EPA, NRDC, and FOE, and

the water suppliers-also disagree about expected costs. In 1991, EPA estimated that the

costs to reduce radon to 300 pCi/L in all 25,907

water supplies that exceeded that level would be

$1.6 billion in capital costs and $0.18 billion in

annualized costs (U.S. EPA, 1991). The cost of

averting a case of radon-associated cancer was

estimated at $2.3 million. In February 1993, EPA

increased those estimates. Currently, its best

estimate is that 41,000 water supplies exceed

300 pCi/L and that the best estimates for capital

and annualized costs are $1.8 billion and

$0.26 billion, respectively (U.S. EPA, 1993a).

NRDC and FOE accept EPA’s cost estimates

for reducing concentrations to 300 pCi/L and use

the agency’s estimates to project the additional

cost of reducing radon in water to lower levels

(Olson et al., 1991). EPA’s proposed regulation

would reduce current levels by 80 percent.

NRDC and FOE contend that reducing levels

to 1 percent of current levels, which might

double the expected health benefits, would cost

only an additional 28 to 40 percent, and in fact,

the greater reductions might be achieved at

even smaller cost increments. (Experts who

work for water suppliers have said that they

would expect costs to fall as more efficient

aeration systems are developed to remove radon

from water.)

The SAB (U.S. EPA, SAB 1993) did not

endorse EPA’s proposal for wholesale adoption

of aeration to reduce radon concentrations in

water. EPA had considered and rejected granulated activated charcoal (GAC) as a control

measure, in part because of the problems raised by

disposing of the radioactive charcoal after its use.

The SAB urged the agency to look again at GAC

because of its potential to hold down costs as

compared to the costs of aeration in some

applications. The Board made no projections of

the costs. The board also urged EPA to revisit its

estimates of costs for water supplies of different

sizes and to consult with the water suppliers to

obtain more information. Whether aeration or

GAC is used to remove radon, either technique

allows the introduction of microbes into water

supplies, and SAB (U.S. EPA, SAB 1993) cautions that “costs of disinfection, especially in

small systems, needs to be reviewed thoroughly.

The Association of California Water Agencies

commissioned an engineering study of the costs

of bringing public water suppliers in California

into compliance with the 300-pCi/L standard

(Fensterheim, 1992). According to the association, the capital costs to bring 9,420 California

wells into compliance would be $3.73 billion; the

annualized costs would be $0.7 billion. According to one projection from the associations

results, total national capital costs are expected of

between $12 and $20 billion; those expenditures

are expected to reduce total radon exposures by

about 1 percent (Abelson, 1993).

The SAB (U.S. EPA, SAB 1993) compares

EPA’s estimate of $3.2 million to avert a death

from lung cancer from waterborne radon to the

EPA estimate that remediation to reduce airborne

radon to 4 pCi/L will avert a death for about

$700,000. The Association of California Water

Agencies calculates much higher costs; it estimates that the cost to avert a death from radonassociated lung cancer would range between $65

and $87 million in California. The cost to avert a

death from lung cancer in a nonsmoker in that

State would be between $433 and $592 million.

(The much higher cost for averting the deaths of

nonsmokers results from the fact that lung cancer

is so much rarer among them.)

Part of the reason for the California Association’s much higher cost estimate is its survey that

shows many more water supplies exceed the

proposed 300-pCi/L regulatory limit than is

estimated by EPA. The SAB (Loehr and McClellan, 1993) also points to uncertainty in the

estimates of how many water supplies would be

subject to regulation (’‘may seriously underestimate the number of community water systems

impacted . . . “) and states that “this uncertainty
162 I Researching Health Risks

in exposure estimates ultimately impacts the costs

of mitigation.

EPA has estimated that the average annual cost

for radon reduction for houses served by the

smallest water utilities would be $120; most

houses are served by larger systems and would

pay about $50 per year (Wilcher, 1991). Based on

Association of California Water Agencies estimates, former Senator William E. Dannemeyer

wrote to EPA that every household that has to pay

for radon reduction would pay an extra $340 per

year (Dannemeyer, 1991). The town of Hastings,

Nebraska, has a population of 23,000 and water

that exceeds EPA’s proposed limit for radon in

water. According to an analysis that the town conducted, a water treatment plant to remove the

radon would cost $65 million and be the single

largest drain on the town’s treasury (Schneider,

1993).

NRDC and FOE do not accept that small water

suppliers will bear sizable new costs as a result of

setting a standard of 300 pCi/L or lower for radon

in water (Olson et al., 1991). They argue that

smaller suppliers could tie into larger suppliers to

gain economies of scale or look for water that

contains less radioactivity. Moreover, Olson et al.

(1991) cite experts who state that technologies are

available that are much less costly than those EPA

considered in its 1991 cost estimates. In EPA’s

1993 recalculation of estimated costs, total capital

costs increased by 20 percent and annual costs

increased by 44 percent, whereas the number of

water suppliers increased by 60 percent, indicating that EPA had found some savings in costs per

supplier.

The costs of the proposed regulation on radon

in water regulation can also be compared with the

costs of a public health measure that has become

more expensive in recent years and that has

produced public outcries for reducing the profits

of pharmaceutical companies. The cost of childhood immunizations has increased from between

$7 and $23 in 1982 to between $129 and $244 in

1992 (Orenstein, 1993). Even so, the annual cost

of the radon-in-water regulation-estimated by

EPA to be about $50 per family served by

averaged-sized systems and $120 per family

served by small systems-ranges from between a

fifth to a little less than half the one-time cost of

immunization. The estimate of the Association of

California’s Water Agencies of $340 per family

per year for the radon-in-water regulation exceeds

the one-time cost of immunization.

The continuing, annual estimated family cost

of the regulation, which will affect about 1

percent of all exposures to radon, of between $50

and $340 can also be compared with EPA’s

estimate of the one-time cost of bringing indoor

radon concentrations down to 4 pCi/L or lower.

EPA (1992a) estimates for the one-time cost for

remediation of a house ranges from $500 to

$2,500 with an average of $1,200 and average

operating expenses of $68.

SCIENCE ADVISORY BOARD COMMENTS,

JULY 1993

The Science Advisory Board review gave EPA

high marks for its general approach to the

multimedia risk assessment, but it focused on

areas such as estimates of the population exposed

to concentrations of radon greater than 300 pCi/L

in water, calculated risks from ingested radon,

and capital cost estimates in which it thought the

agency could make efforts to refine its approaches

and calculations. A letter from the chair of the

SAB Executive Committee and the chair of the

SAB Chafee-Lautenberg Study Review Committee (Loehr and McClellan, 1993) returned to the

Board’s 1992 position that EPA should apply

relative risk approaches in its consideration of

risks from radon. The relative risk approach

‘‘caLls for giving the highest priority to mitigating

the largest sources of risks first, especially when

the cost-effectiveness of risk reduction of such

sources is high. ’

As part of that approach, Loehr and McClellan

(1993) encourage EPA to continue its efforts “to

encourage voluntary actions to reduce indoor air

radon in view of the cost effectiveness of this

approach for reducing risks. ” About radon in
Chapter 6: Indoor Radon: A Case Study in Decisionmaking I 163

water, they conclude that the proposed regulatory

limit of 300 pCi/L is “the most costly in terms of

costs per cancer death avoided. ” They suggest

that EPA also consider setting limits for radon in

water at either 1,000 or 3,000 pCi/L. Even the

higher numbers would result in water contributing no more radon to indoor air than is present in

outdoor air.

Nero (1993) has also suggested alternatives to

the 300-pCi/L limit on radon in water. Like the

SAB, he suggests setting the water limit so that

radon from water would make no more of a

contribution to indoor air than does the radon in

outside air, which would be in the range of 1,000

to 3,000 pCi/L in water. An EPA official also

reported to a newspaper that agency staff were

forwarding at least three options for a radon-inwater rule to the EPA Administrator: 300, 1,000,

and 2,000 pCi/L (Anon, 1993 b).

Should a limit of 1,000 to 3,000 pCi/L in water

be set, EPA could continue to accumulate information about the levels of radon in water, the

number of water supplies with various concentrations, and the risks from ingestion of radon. The

additional information would reduce the uncertainties in the estimates of risks, costs, and cost

per life saved, and pave the way for alterations in

the regulation if needed.

 “Inconsistency” in EPA’s

Approach to Radon

The letter that requested this OTA examination

of indoor radon cited the SAB 1992 concerns

about inconsistencies in EPA’s approach to reducing risks from radon. It contrasted the goals of

the IRAA both with EPA’s action level for indoor

radon and with its proposed level for regulating

radon in water under the SDWA: The IRAA goal

is to bring indoor radon level down to those

commonly found outdoors (0.1 to 0.5 pCi/L),

whereas EPA urges that remediation be undertaken to reduce concentrations of radon in homes

to 4 pCi/L or lower. In contrast, EPA’s proposed

regulation would set 300 pCi/L of radon in

. . drinking water as the highest permitted level,

limiting radon in indoor air to 0.03 pCi/L from

this source (given the assumption that 10,000

pCi/L of radon in water produces 1 pCi/L of radon

in air because of volitalization). Clearly, the goal,

the action level, and the proposed regulation set

different exposures as acceptable (box 6-A).

These inconsistencies are no surprise given the

way that the goal, the action level, and the

regulation were derived. Congress, in the IRAA,

acknowledged that the outdoor level of radon in

air is unavoidable and that concentrations cannot

be reduced below that level. At the same time,

reducing concentrations to that level would be as

health protective as possible.

EPA, in setting the 4-pCi/L action level,

accepts a risk of cancer from radon that is far

higher than the 1 X 10_6 (one excess cancer per

million people) exposed for a lifetime that the

agency routinely uses as a goal in regulating

exposures to toxic chemicals. The Citizen’s Guide

to Radon (U.S. EPA and U.S. DHHS, 1992)

provides some examples of comparative risk; for

instance, the risk that a nonsmoker bears from

constant exposure to radon at 4 pCi/L is roughly

the same as that person’s risk of drowning.

The proposed radon-in-water standard under

the SDWA is risk- and measurement-based. The

level of 300 pCi/L of radon in water, set at what

EPA had determined is the practical limit on

quantification, was projected to reduce risks to

about 2 X IN. In its preamble to the proposed

rule, EPA raised the question of the significance

of waterborne radon to the total radon issue: ‘‘In

evaluating the various alternatives for proposing

a radon MCL [maximum contaminant level; the

regulatory standard], EPA considered the critical

policy questions of whether radon in water should

be regulated like other drinking water contaminants, or whether it should be regulated more in

accord with its importance compared to overall

radon exposure. EPA decided to regulate radon

as other waterborne contaminants, and the SAB

(Loehr et al., 1992) criticized that action because
164 I Researching Health Risks

of the small contribution that waterborne radon

makes to overall exposure to radon.

Congress’s mandating of the multimedia risk

assessment produced some refinements in EPA’s

risk and cost assessment, but whether it will make

a difference in regulation remains to be seen. The

risk estimate hardly changed at all, and, according to EPA% assessment, radon in water

remains associated with a risk greater than

10-4, which is the usual upper limit on the risk

that EPA finds tolerable.

 Indoor Air

Risks to health from contaminants in indoor

air-lead paint, asbestos in buildings, environmental tobacco smoke (ETS), and other substances—have spotlighted the indoor environment as a source of hazards. In the 102d Congress,

Representative Joseph Kennedy and Senator

George Mitchell introduced the Indoor Air Quality Act of 1991 in the House and Senate,

respectively (H.R. 1066 and S. 455). Had either

bill passed, it would have authorized research,

development, and demonstration projects concerned with improving air quality; the House bill

would have imposed some regulations. Both

Kennedy and Mitchell have introduced bills in the

103d Congress that focus on research and development.

The contents of the bills demonstrate the

complexity of the issues arising in legislation

regarding the quality of indoor air. In addition to

the agents mentioned above, indoor air can

contain hazardous chemicals that are carried

home in clothes and on the skin from the

workplace; any number of volatile organic compounds from common household chemicals such

as paints and soaps; and allergens that arise from

pets, insects, molds, and mildews. The bills

addressed indoor air quality in homes, which are

probably the setting that is most often considered

when thinking about indoor air, but they also

treated air in educational facilities and commercial and Federal buildings. Clearly, legislation

dealing with indoor air would apply to many

substances and various kinds of buildings.

A decade ago, Spengler and Sexton (1983)

discussed the special problems of indoor air

pollution; more recently, Nero (1992) has argued

that indoor air problems merit approaches different from other environmental issues. As shown on

figure 6-3, risks from substances in indoor air fall

over a wide range, with the radon-related risk of

death for smokers as high as 8 percent and the risk

from waterborne radon about 0.006 percent (more

than 1,000 times lower). [Because of computational differences, figure 6-3 shows that the risk

of death from waterborne radon is less that 0.01

percent, which is less than the approximately 0.02

percent (2 X l@) risk that EPA associates with

waterborne radon.] The highest risk shown on the

figure is for smoking, which increases the risk of

premature death by about 25 percent. Accidents

and certain occupations are associated with levels

of risk around the level associated with radon.

EPA has concluded that the risks associated

with indoor radon are greater than any other that

it contends with (with the exception of risks of

cancer posed by sunlight). The agency thus argues

that indoor radon and waterborne radon require

immediate attention. Nero (1993) counters that

the risks from indoor radon are not put in the

proper context when compared with outdoor

risks. Instead, he maintains that indoor radon

should be considered in the context of indoor risks

that are typically higher than outdoor risks.

Considering the risks posed by indoor radon in

the context of indoor risks would create monumental obstacles to setting the SDWA’s limit of

10-4 (0.01 percent) on cancer risks as a consistent

goal for risk reduction. As shown in figure 6-3,

many indoor risks are far above the proposed

regulatory limit for radon in water. It is very

unlikely that the risks from radon in indoor air can

be lowered from the nearly 1 percent associated

with the average concentration in U.S. homes of

1.3 pCi/L or that the risk of fatal home accidents

can be lowered from about 0.8 to 0.01 percent.
Chapter 6: Indoor Radon: A Case Study in Decisionmaking I 165

Figure 6-3-Estimated

Radon

(smokers)

20 y at 20 pCi/L

20 y at 4 pCi/L

Lifetime at 1.3 pCi/L

Radon

(nonsmokers)

20 y at 4 pCi/L

20 y at 20 pCi/L

Lifetime at 1.3 pCi/L

Passive smoking

Volatile organic compounds

Asbestosa

Radon from domestic watera

Lifetime Risk of Premature Death From Various Sources

\

\

\

/

/

/

f

/

/

PERCENTAGE

100

10

1

0.1

— 0.0 1

— 0.001

— 0.0001 J

Cigarette smoking

Automobile accidents

Uranium mining

Home accidents

Jobs at chemical

Outdoor radona

plants

Benzene in outdoor air

Chloroform in domestic water

Ethylene dibromide in

grains (banned)

SOURCE: Offics of Technology Assessment, 1993.

Treating the risks presented by indoor air in a

concerted fashion, which might result from legislation on indoor air quality, would probably lead

to greater reductions in overall exposures than

would be achieved under current laws. For

instance, improved ventilation could be designed

to reduce the concentrations of environmental

tobacco smoke, volatile organic compounds,

radon and other substances in the air, with an

expected decrease in risks. In general, the solutions to indoor air problems are likely to follow

similar paths-that is improving ventilation and

filtration, considering the volatility of substances

introduced into the indoor environment, and so

forth. A single piece of legislation might facilitate

considering the risks together rather than piecemeal.

The SAB (Loehr and McClellan, 1993) recognized ‘that the large number of laws under which

EPA operates makes it difficult to implement

a relative risk reduction strategy across the

Agency. . . . The SAB strongly encourages the

Agency and the Congress to work together to

consider changes in existing statues that would

permit implementation of relative risk reduction

strategies in a more efficient and effective manner .

THE FUTURE

‘‘Enforcement’ of the 4 pCi/L level for radon

in indoor air is being accomplished through

nonregulatory means, and given the possible

liability concerns that might result if a house were

sold with a higher level, realtors, attorneys,
166 I Researching Health Risks

buyers, and sellers probably will not alter their

practices even if research findings show that risks

at that level are smaller than is now believed. On

the other hand, an increase in the estimate of risk

would probably be quickly reflected in real estate

transactions because of reasons of liability.

EPA’s proposed regulation of radon has been

delayed beyond October 1, 1993. The Agency is,

reportedly, still deciding on its response to the

Science Advisory Board’s comments on its multimedia risk assessment. It is expected that work on

the proposed regulation will follow that response.

The regulation may be delayed for 1 year by

Congress, if an amendment passed by the Senate

is also approved by the House. Whenever EPA

writes the regulation, the Science Advisory Board

has offered alternatives to its proposed limit of

300 pCi/L radon in water. It is possible that the

agency could set a higher limit that would, in

effect, apply only to water systems that contribute

a significant fraction of overall radon exposures.

Setting a limit higher than 300 pCi/L would be

expected to engender lawsuits from citizens and

organizations concerned about risks from waterborne radon.

In contrast, if NRDC’s and FOE’s petition to

set a stricter standard were successful, it would

require that EPA reduce concentrations of waterborne radon, tightening the standard. Alternatively, Congress could relieve EPA of the responsibility for regulating radon in water, or shift it

from the SDWA to the IRAA, or enact a new law

on indoor air. Any shift might result in a standard

different from 300 pCi/L.

No regulatory agenda requires a new study

about the level of risk presented by indoor radon.

The current risk assessment, based on the

miner studies, is sufficient for regulatory action and indeed, being based on studies of

humans, is more certain than animal-based

risk assessments that form the basis for many

regulations. Nevertheless, a convincing study

of the risks associated with indoor radon

would provide a great deal of information as

well as a technical foundation for future policy

decisions. A study that answered the question of

whether the risks predicted from the miners

studies were accurate would do more than inform

the radon debate. It would also provide the first

test of the accuracy of any extrapolated estimate

of an environmental risk. Moreover, because it

would provide more certain information about

risks from radon in air at low levels, it would

reduce the uncertainty of the risk assessment for

radon in water because the major part of that risk

is associated with inhalation.

Such a study would make a real contribution to

scientific understanding and, depending on what

it reveals, could have different effects on debates

about regulatory levels. If the study revealed that

the current levels were about right, it would

confirm the appropriateness of the methods used

to generate current risk estimates. If the study

showed that current risk estimates were too low,

EPA could tighten up the regulations. If, however,

the results of the study indicated that the risks

were lower than are now estimated, EPA might be

confronted with the problem of backing off on

some of its regulations and guidelines.

Doll (1992) is confident that studies now being

performed will produce valid data about relationships between indoor radon and cancer within the

next few years. In anticipation of the completion

of those studies, both EPA and DOE are planning

to carry out meta-analyses of the findings from

those studies. Yet, despite Doll’s optimism, there

is no guarantee that the ongoing studies will

produce a clear-cut answer about cancer risks

from indoor radon. In that case, the government

could assemble a group of experts to decide

whether it is possible to design such a study, and

design it, if it is feasible. A study of that kind

would probably have to be larger than any done

to date, and it would have to be carried out in areas

(such as Missouri and Iowa) in which radon

exposures are higher than average. To have

scientific and political credibility, the study

would have to be planned in an open process with

explicit discussions of what results would be

expected under different planning assumptions.
Chapter 6: Indoor Radon: A Case Study in Decisionmaking I 167

Furthermore, the planning would have to determine the study’s chances of resolving the issue. If

the chances were low, policymakers could decide

not to go ahead with the study. Still another

nonconvincing, nonconclusive study would not

justify the expenditure of resources necessary for

its completion.

At quite a different level of research, studies of

molecular mechanisms of radon-caused carcinogenesis and of movements of radon in buildings

(for examples, see DOE, 1993) and of carcinogenesis in general (see chs. 3 and 4) may provide

more information about risks from radon. Scientists can design epidemiologic studies and decide,

in advance of doing them, whether the studies

have sufficient power to answer questions important for policymaking and how long the studies

will take---certainly they will take years. But,

advances in molecular studies, which may provide better estimates of exposure, pre-disease

conditions, or mechanisms of action, cannot be

put on a timetable. They may come in months, or

they may take years.

The specific questions raised by radon maybe

answered by congressional or EPA decisions that

impose new regulations or that leave the current

approaches intact. New epidemiologic results

may inform those decisions by revealing more

certain evidence of the level of risk posed by

radon at environmental levels. And it is possible

that research into mechanisms of carcinogenesis

may shed some light on such risks. More generally, radon is a case that illustrates the difficulties

posed by an environmental risk of uncertain size

that reaches human beings through different

media.

As of mid-October 1993, Senator Baucus had

introduced a bill that would direct EPA to

regulate radon in water by a method different

from that now being considered. In addition,

Senator Chaffee was considering introduction of

legislation as was Representative Slattery. This

legislative action indicates that policy on radon in

water may well be set by legislative modifications

to the SDWA.

CHAPTER 6 REFERENCES

Abelson, P.H. 1993, Regulatory costs (editorial).

Science 259:159.

Agency for Toxic Substances and Disease Registry.

1992. ATSDR Case Studies in Environmental Medicine; 14, Radon Toxicity. Atlanta, GA: U.S. Department of Health and Human Services, p. 9.

Alavanja, M. C. R., Brownson, R., Wood, M. et al.

1992. Radon dosimetry for a lung cancer study in

Missouri. In: F.T Cross (cd.) Indoor Radon and Lung

Cancer: Reality or Myth. Columbus, OH; Richland,

WA: Battelle Press, pp. 871-887.

Anon. 1993a. No radon-leukemia link [a description of

a study published in Lancet], Environmental HeaZth

&tter. Apr. 16, p. 72.

Anon. 1993b. Final rule to control radionuclides will

be issued by October, Environrnenta.l protection Agency

says, Daily Report for Executives (Washington, DC:

Bureau of National Affairs), June 3, p. A-6.

Blot, W.J,, Xu, Z-Y., Boice, J, D., Jr. et al. 1990. Indoor

radon and lung cancer in China. Journal of the

National Cancer Institute 82: 1025-1030.

Bodans@, D. 1990. Radon induced lung cancer and

mortality. In: S.K. Majumdar, R.F. Schrnalz, and E.W.

Miller (eds.) Environmental Radon: Occurrence, ControZ and Health Hazards (Phillipsburg, NJ: Typehouse

of Easton).

Brill, D.R. 1990. Radon and health. In: S.K. Majumdar, R.F. Schmalz, and E.W. Miller (eds.) Environmental Radon: Occurrence, Control, and Health

Hazards (Phillipsburg, NJ: Typehouse of Easton,

1990).

Brownson, R. C., Alavanja, M. C. R., Hock. T.T. et al.

1992. Passive smoking and lung cancer in nonsmoking

women. American Journal of Public Health 82:1525-

1530.

Chaffee, J. 1992. Remarks. Congressional Record

138:13033, Sept. 9.

Chiu, N., Puskin, J., and Barry, T. 1993. Response to

S.C. Morris, M.D. Rowe, S.J. Baxter on their comments on EPA draft Jan. 29, ‘‘Uncertainty Analysis of

Risks Associated with Exposure to Radon in Drinking

Water. ” Photocopied memo. May 3.
168 I Researching Health Risks

Cohen, B.L. 1990. Experimental tests of the linear-no

threshold thmry of radiation carcinogenesis. In: C.R.

Cothern and P.A. Rebers (eds.) 1990. Racibn, Radium

and Uranium in Drinking Water. Cheka, Ml Lewis

Publishers, pp. 69-82.

Cohen, B.L. 1992. Multi-stratified multiple regression

tests of the linear/ncxthreshold theory of radoninduced lung cancer. In: F.T. Cross (cd.) ]nakxw Radbn

and Lung Cancer: Reali~ or Myth? Columbus, OH;

Richland, WA: Battelle Press, pp. 959-975.

Crawford-Brown, D.J. 1993. Utter to Genevieve

Matanoski, chairman of the EPA Science Advisory

Board Committee on Radon. Mar. 27.

Damemeyer, W.E. 1991. U.S. Senator. Letter to the

Honorable William E. Reilly, Administrator, U.S.

Environmental Protection Agency. November 14.

Dickersin, K., and Berlin, J.A. 1992. Meta-analysis:

State-of-the-science. Epi&miologic Reviews 14:154-

176.

Doll, R. 1992. Risks from radon. Radiation Protection

Dosimetry 42:149-153.

Fensterheim, R.J. 1992. Demands to regulate radon in

drinking water in an environment of evolving risk

estimates. Paper presented at Annual Meeting of the

American Association for the Advancement of Science, Chicago, Feb. 11.

Hanson, D.J. 1989. Radon tagged as cancer hazard by

most studies. Chemical Engineering News 67:7-13.

Harley, N. H., and Robbins, E.S. 1993. A biogenetic

model for the distribution of ‘% gas in the body

following ingestion. Submitted to the Science Advisory Board, Environmental Protection Agency, Mar.

17.

Henshaw, D. L., Eatough, J.P., and Richardson, R.B.

1990. Radon as a causative factor in induction of

myeloid leukemia and other cancers. The Lancet

335:1008-1012.

Henshaw, D.L., Eatough, J.P., and Richardson, R.B.

1992. Is radon a causative factor in inducing myeloid

leukemia and other cancers in adults and children? In:

F.T. Cross (cd.) Indoor Radon and Lung Cancer:

Reality or Myth? Columbus, OH; Richland, WA:

Battelle Press, pp. 935-958.

htoumeau, E. G., Krewski, D., and Choi, J. 1993. A

case-control study of residential radon and lung cancer

in Winnipeg, Manitoba. In press, American JournaZ of

Epidemiology.

Lo&r, R.C., Nygaard, O.F., and Voilleque, P.G. 1992.

Letter to W.M. Reilly, Administrator. U.S. Emironmental Protection Agency. Subject: Reducing Risks

from Radon: Drinkm“ g Water Criteria Documents. Jan.

29.

Loehr, R. C., and McClellan, R.O. 1993. Letter to

Honorable Carol M. Browner, Administrator, U.S.

Environmental Protection Agency. Re: SAB Review

of Multimedia Risk and Cost Assessment of Radon in

. . Drmkmg Water. July 30.

Lubin, J.H., Sarnet, J. M., and Weinberg, C. 1990.

Design issues in epidemiologic studies of indoor

exposure to radon and lung cancer. Health Physics

59:8070817.

Lubin, J.H., Lang, Z., Hrubec, Z. et al. 1993. Radon

exposure in residences and lung cancer among women:

Combined analysis of three studies. Cancer Cause and

ControZ (in press).

Lynch, C. 1993. University of Iowa, Iowa City. 1993.

Personal communication.

Miller, D., Morrison, H., Semenciw, R. et al. 1993.

Leukemia and residential exposure to radon. Canadian

Journal of Public Health (in press).

Moeller, D.W. 1989. Controlling levels of airborne

radon. Forum for Applied Research Public Policy

4:5-11.

Morris, S. C., Rowe, M.D., and Baxter, S.L. 1993.

Comments on EPA draft Jan. 29, 1993, “Uncertainty

Analysis of Risks Associated with Exposure to Radon

in Drinkul “ g Water. ” Photocopied typescript.

Nazaroff, W. W., and Teichman, K. 1990. Indoor

Radon. Environmental Science and Technology 34:774-

782.

Nero, A.V., Jr. Lawrence Berkeley Laboratory. 1990.

Letter to M.L. Oge, U.S. Environmental Protection

Agency, Sept. 20.

Nero, A.V., Jr. 1992. A national strategy for indoor

radon. Issues in Science and Technology IX:334.

Nero, A. V., Jr. 1993. Developing a conceptual fiarnework for evaluating environmental risks and control

strategies: The case of indoor air. Paper presented at

the meeting Indoor Air 1993. Helsinki, FinlanL July

4-8.
Chapter 6: Indoor Radon: A Case Study in Decisionmaking I 169

NRC (National Research Council). 1983. Risk Assessment in the Federal Government: Managing the

Process. Washington, DC: National Academy Press.

NRC. 1988. Health Risks of Radon and other Internally Deposited Alpha-Emitters. BEIR IV (Washington, DC: National Academy Press),

NRC. 1991. Comparative Dosimetry in Mines and

Homes. Washington, DC: National Academy Press.

Olkin, I. 1992. Reconcilable differences. The Sciences,

July/August, pp. 30-36.

Olson, E.E., Guth, J., and Hu, D. 1991. Comments of

the Natural Resources Defense Council and the

Friends of the Earth on EPA’s Proposed National

*D*g Water Regulations for Radionuelides. photocopied typescript. Nov. 15 (corrected

NOV. 25, 1991).

Orenstein, W.A. 1993. Director of Immunization.

Centers for Disease Control and Prevention. Quoted in

R. Pear, 1993. Clinton considers plan to vaccinate all

U.S. children. New York Times, Feb. 1, pp. Al and

A16.

Pelletier, R,F. 1993. Mter to Peter W. Preuss, Of13ce

of Science, Plaming and Regulatory Evaluation, U.S.

Environmental Protection Agency. Apr. 22.

Pete, J, 1990. Radon and the risk of cancer. Nature

345:389-390.

Ruosteenoja, E. 1991. Indoor radon and risk of lung

cancer: An epidemiological study in Finland. Finnish

Centre for Radiation and Nuclear Safety: Helsinki.

Samet, J.M. 1989. Review: Radon and Lung Cancer.

Journal of the National Cancer Institute 81 ;745-757.

Schneider, K. 1993. How a rebellion over environmental rules grew from a patch of weeds. New York

Times, Mar. 24, p. A16.

Schoenberg, J. B., Klotz, J. B., Wilcox, H.B. et al. 1990.

Case-control study of residential radon and lung cancer

among New Jersey women. Cancer Research 50:6520-

6524.

Society for Risk Analysis. 1993. Panel Report on the

Use of Meta-Analysis in the Assessment of Human

Data for Cancer Risk Assessment. Photocopied typescript.

Spengler, J. D., and Sexton, K. 1983. Indoor air

pollution: A pubhc health perspective. Science 221:9-

17.

Svensson, C., Pershagen, G., and Klorninek, J. 1989.

Lung cancer in women and type of dwelling in relation

to radon exposure. Cancer Research 49:1861-1865.

Taylor, R. 1990. Facts on Radon and Asbestos. New

York: Franklin Watts,

U.S. Congress, OTA (Office of Technology Assessment). 1981. Assessment of Technologies for Determining Cancer Risks From the Environment. OTA-H138. Washington, DC: U.S. Government Printing

Office, June 1981.

U.S. DOE (Department of Energy). 1993. Radon

Research Program, Fiscal Year 1992. DOE/ER-0588.

Washington, DC: U.S. Department of Energy.

U.S. DHHS (Department of Health and Human

Semices). 1991. National Toxicology Program. Sixth

Annual Report on Carcinogens. Summary. Rockville,

MD: Technical Resources, Inc., 1991.

U.S. EPA (Environmental Protection Agency) and

U.S. DHHS (Department of Health and Human

Semices). 1992. A Citizen’s Guide to Radon (2d cd.).

EPA/ANR44. Washington, DC: Environmental Protection Agency.

U.S. EPA (Environmental Protection Agency). 1986.

A Citizen’s Guide to Radon: What Is It and What Does

It Do? Washington, DC: Environmental Protection

Agency.

U.S. EPA. 1987. Unfinished Business: A Comparative

Assessment of Environmental Problems: Appendix I.

Cancer Risk Work Group. Washington, DC: Erwironmental Protection Agency.

U.S. EPA. 1991. National primary drinking water

regulations; radionuclides. Fed2ra/ Register 56:33050-

33127.

U.S. EPA. 1992b. Technical Support Document for

the 1992 Citizen’s Guide to Radon. EPA 400-R-92-

011.

US. EPA. 1992a. National Residential Radon Survey:

Summary Report. EPA 402-R-92-01 1.

U.S. EPA. 1993a. Draft national cost estimates for

radon table. Feb. 7,

U.S. EPA. 1993b. Report to the United States Congress on Radionuclides in Drinkz”ng Water. Multimedia and Cost Assessment of Raabn in Drinking Water.

Prepared for P.L. 102-389. EPA-SAB-RAC-93-014.
170 I Researching Health Risks

U.S. EPA, SAB (Science Advisory Board). 1990.

Reducing Risk: Setting Priorities and Strategies for

Environmental Protection. SAB-EC-90-021. Washington, DC: U.S. Environmental Protection Agency.

U.S. ERA, SAB. 1993. An SAB Report: Review of

Issues Related to the Cost of Mitigating Indoor Radon

Resulting from Drinkm“ g Water. EI?A-SAB-DWC-93-

015. Washington, DC: lhinmrnentalPmtectionAgency.

Ulsamer, A.G. 1993, Memorandum to P.W. Preuss.

Director. OffIce of Science, Plaming, and Regulatory

Support, Environmental Protection Agency. Review

of the draft uncertainty analysis of risks associated

with exposure to mdon in -

drinking water. Office of

Science, Planning and Regulatory Support. Environmental Protection Agency. May 11.

Wilcher, L.S. 1991. Assistant Administrator. U.S.

Environmental Protection Agency. Letter to the Honorable William E. Damemeyer. Dec. 11.
Structuring

the Future of

Health Risk

Assessment

Research 7

Rnew avenues for preventing, treating, or remediating

esearch provides the foundation for risk assessment and

risk management. It can lead to new ways of performing

risk assessment, new approaches to regulating risks, and

risks that have already been identified. Simply put, research

offers innovation in approaches and decisions about whether and

how to control exposures to hazards.

Research in health risk assessment plays such a diverse and

important role that its vitality should concern policy-makers. Yet

this Office of Technology Assessment (OTA) study finds that

health risk assessment research is itself “at risk” because

Federal agencies have not demonstrated the

high quality research:

characteristics of

●

●

●

●

Given what is at stake--both in health and dollars-for

decisions based on health risk assessment, health risk

assessment research is not at an appropriate level of priority.

Approximately $600 million is available for health risk

assessment research in 1993.

Too little research is targeted toward areas expected to have

the greatest impact on policy decisions and regulatory

actions. For example, only an estimated $65 million in 1993

is devoted to research on risk assessment methodology.

Health risk assessment research is fragmented within and

across Federal agencies, resulting in inefficient and ineffective use of resources.

Opportunities to link government, university, and industry

are being lost.

171
172 I Researching Health Risks

If policymakers want to create a better climate

to advance health risk assessment research, how

would they structure the research environment,

what scientific areas would they nurture, and what

types of research linkages would they pursue to

achieve their goals?

This chapter describes the characteristics of

high-quality research programs and discusses the

benefits of fostering appropriate research linkages among the Federal Government, universities, and industry. This chapter ends by illuminating promising scientific areas to advance health

risk assessment, with a special emphasis on

research in risk assessment methodology.

STRUCTURING A HIGH-QUALITY

RESEARCH PROGRAM

OTA, along with many in the scientific community, associates scientific excellence with highquality research programs that share certain

characteristics: leadership, defined objectives,

investigator initiation of research, competitive

awards and peer review, criteria for evaluating

success, collaboration and coordination, training

opportunities, and advisory input. Each of the

characteristics is described below in the context

of health risk assessment research, regardless of

whether the Federal Government supports or

conducts the research.

 Leadership

Leaders-at all levels of management—guide

a research program by instilling a sense of

collective purpose, ensuring the coherence of the

program, linking it to policy, encouraging collaboration and cooperation, conferring stature, ensuring communication of research findings, and

attracting resources. Whether a research program

is carried out within an agency or outside it, the

leader of the program must be given the responsibility and authority to make decisions and set

priorities. He or she must also be held accountable

when a program is evaluated. One attribute of

leadership in research is recognizing that innovation is most likely to occur when investigators are

free to explore.

 Defined Objectives

Clear, well-defined goals are critical to all

research endeavors. The goals of basic research

are guided by the pursuit of fundamental knowledge, whereas applied research is linked to

problem solving-in support of agency objectives or societal goals. Yet despite the difference

in orientation, clarity of purpose should underlie

both.

Health risk assessment by its very nature

requires input from abroad portfolio of basic and

applied research-although in practice the distinction between the two is usually ambiguous

(U.S. Congress, OTA, 1991). Whatever the balance, it is generally agreed that research goals

should also incorporate flexibility in order to take

advantage of the unexpected-the hallmark of

scientific research.

 Investigator Initiation

Investigator-initiated research comes from the

ideas of scientists who then seek funding and

institutional support for carrying out their work.

It is often contrasted with research in which the

objective and the methods are dictated in advance

by managers, often at agencies with mandated

social missions.

Investigator-initiated research need not be

limited to basic research. In practice, another

type, “targeted research,” either basic or applied,

is designed to solve a specific problem or meet an

objective set in advance by an agency. Such

programs can capitalize on investigator-initiation

of research to solve the problems that are targeted.

That situation often occurs when an agency sets

research objectives, solicits proposals to meet

those objectives, and competitively awards funds

through a grant or contract to the most creative

approach. An objection can and is raised, however, when targeted research is seen as constrain-
Chapter 7: Structuring the Future of Health Risk Assessment Research 173

ing the investigator and taking resources away

from basic research.

 Competitive Awards and Peer Review

Allocating funds to projects of scientific excellence is best accomplished through competition

and peer review—the ranking of prospective

projects by scientific experts external to the

funding agency. Peer reviewers are asked to

evaluate the technical merit of a proposal, the

competence of the investigator, and the proposal’s potential scientific impact. Competition

and peer review have gained general support as

principles for funding research.

 Criteria and Plans for Evaluating Success

How do we know whether a research program

has successfully met its objectives? There is no

uniform or perfect way to judge the effectiveness

and excellence of a program, but there are

common indicators. For example, were important

discoveries made? Were the scientific publications that resulted cited by scientists in subsequent publications (IOM, 1988)? In the case of

health risk assessment research, were the results

useful for risk assessment and decisionmaking?

Ideally, researchers and program administrators would agree in advance on the criteria for

evaluating a program’s success, and those criteria

would be tailored to the nature of research

inquiries. Once the criteria for success are decided

upon, a plan can be devised to determine how

effectively the criteria were met. The National

Institutes of Health, for example, has a formal

means of retrospective review for each of its

intramural laboratories that employs outside periodic evaluations by panels of experts called

boards of scientific counselors,

 Coordination and Collaboration Within

and Across Disciplines and Organizations

Health risk assessment research encompasses a

broad spectrum of scientific disciplines, Coordination within and across those disciplines is so

critical that without it, communication may be

impaired, important gaps in the research may

remain, unnecessary duplication may occur, and

research progress may be stymied. Linkage to

regulatory decisions is also a distinctive feature of

health risk assessment research and a compelling

reason for coordination among researchers and

policymakers. A high-quality research program

can be structured to encourage coordination

within and across agencies formally through

leadership, and the creation of committees, and

through a variety of informal methods.

Coordination can be achieved through formalized research collaborations. Given the need for

multidisciplinary research, collaborations have

the advantages of sharing resources and bringing

together individuals with appropriate expertise.

Some factors are considered essential to a successful collaborative effort: the goals must be

clear and understood by all participants; each

participating unit must see the potential gains of

the effort as greater than its costs; the leaders of

the collaborative effort must act as honest brokers; and ongoing relationships between individuals must be supported (Needleman et al., 1984).

Collaborations between the public and private

sectors are discussed later in this chapter.

 Training Opportunities

Training opportunities must be available to

educate researchers. They are also critical for

overcoming a national shortage of professional

environmental health scientists and engineers

with advanced, yet practical, knowledge of how

to develop scientific data for improved health risk

assessments and to solve environmental problems

(U.S. DHHS, 1991a; U.S. EPA, 1990). Those

fields of environmental health science considered

to have the most pressing needs for researchers

include environmental epidemiology, the study of

human exposures to toxicants, and clinical environmental medicine (U.S. DHHS, 1991 b).
174 I Researching Health Risks

Biomedical

sciences

m ! I

 Advisory Input

Advisory input, either through chartered, independent committees or informal means, provides

guidance to an agency in establishing a research

program, setting its priorities, and ensuring that

the program remains scientifically productive,

credible, and responsive to societal goals. Advice

can be sought from the public and from outside

experts on scientific topics, management, or

policy.

PROSPECTS FOR RESEARCH

Breakthroughs and rapid developments in the

biological sciences-especially in molecular biology and genetics-coupled with improved microelectronics and high-speed computers provide

scientists with new research opportunities in

environmental health and toxicology that were

previously unavailable and virtually unimaginable.

The knowledge developed using new techniques has already had a significant impact in

stimulating new “thinking about the role of toxic

substances in the development of diseases. A

more in-depth mechanistic understanding of toxicity can replace some traditional assumptions

used in inferring and estimating risk. In addition,

this new mechanistic understanding now calls

into question certain accepted practices in health

risk assessments that can now be examined for

their validity using new techniques.
Chapter 7: Structuring the Future of Health Risk Assessment Research I 175

 Methodological Research

Toxicological and biomedical research in the

past decade has produced a large volume of

information. But areas still in need of improvement or development are methods for identifying

toxicants, exposed individuals, and populations;

models for inferring the effects and estimating the

magnitude of risk of toxic substances on human

health from the results of animal studies; and

techniques for estimating risks and predicting

health effects with few data. Some observers

expect the most immediate impact to come from

evaluations of existing data to determin e the

credibility of current methods and to guide the

development of alternative approaches. This evaluation can also identify specific short-term and

long-term research to improve health risk assessment.

NEW METHODS FOR TOXICITY STUDIES

With nearly 1,500 new chemicals introduced

worldwide into commerce each year (Environmental Health Letter, 1993), improved methods

to determine which chemicals pose hazards to

human health will remain an important and

integral component of health risk assessment

research. Improvements are expected in new

cost-effective tests for identifying toxic agents

and in methods to evaluate relationships between

the structure of a chemical and its biological

activity.

Model toxicity systems were developed in the

past decade using transgenic animals, cells and

tissues (both animal and human), and biomolecules. Such systems need to be integrated,

evaluated, and validated as new testing methods.

These new methods can then be used for acquiring toxicity information based on mechanisms of

action.

Using research tools and methods borrowed

from molecular biology, animals can be genetically constructed to study the role of toxicants in

the development of specific diseases. For example, by inserting genes that predispose the animal

to certain types of cancers, such transgenic

animals can be developed to study the actions of

specific carcinogens.

These improvements will not be restricted to

studies of the carcinogenicity of chemicals. Currently, new testing methods are being developed

for identifyinagents with toxic effects on human

development and on the human immune, respiratory, reproductive, and neural systems.

Improving structure-activity relationship methods enhances scientists abilities to predict toxicological activities of untested chemicals. This

effort requires the collaboration between chemists, biologists, and, increasingly, computer scientists. With new computational techniques such

as artificial intelligence systems, virtual reality,

and improved mechanistic understanding of toxicity, this area of research promises to deliver

more than it has in the past.

BIOCHEMICAL AND MOLECULAR EPIDEMIOLOGY

The greatest obstacle to designing efficient,

sensitive epidemiologic studies is the limited

ability of epidemiologists to characterize individual exposures to toxicants or environmental

hazards of concern (Shore et al., 1992). Using

biochemical and molecular techniques in epidemiological studies can overcome this difficulty

(box 7-A). Biomarkers (e.g., DNA adducts, which

are complexes of environmental chemicals and

DNA) can provide direct evidence and quantitative measures of exposure to environmental

agents. However, they require researchers to

obtain biological samples from study subjects.

A variety of factors, including genetics, diet,

age, and lifestyle, makes some individuals more

susceptible to the effects of toxic agents. Such

factors may be shared by members of groups and

place the group at increased risk. Biomarkers can

be developed for some of those characteristics to

identify individuals or subpopulations at higher

risk. Such biomarkers of susceptibility can be

used in preventing exposures to the most sensitive

populations.
176 Researching Health Risks

Box 7-A–A New Branch of Health Risk Research:

Molecular Epidemiology and Biomarkers

In the past decade, research in molecular biology has advanced our understanding of the genetic and

environmental factors in disease processes. These advances provide a common ground for the molecular

biologist, toxicologist, and epidemiologist to join forces in studying environmentally induced diseases. Molecular

epidemiology-the exploitation of molecular laboratory techniques in analytical epidemiologic studies-has the

promise of overcoming a number of methodological difficulties confronting epidemiology.

This field of research can be described as the multidisciplinary efforts integrating molecular biology,

laboratory models, biochemistry, and epidemiology in the study of diseases. Molecular epidemiology holds

potential benefits for the design and conduct of epidemiologic research by identifying etiologic factors for disease,

determining the internal dose of those factors and the relationship between the dose and the response, and

understanding the mechanism of disease processes.

In addition to understanding disease etiology, molecular epidemiology promises to develop new tools and

open up new strategies for preventing disease. The results of this research can provide early markers of disease

and identify susceptible high-risk groups for intervention through treatment Furthermore, it can be used to validate

new animal and laboratory studies for testing toxicants.

An important component of molecular epidemiology is the biological marker, or biomarker. Biomarkers are

measurable indicators of events or changes in cellular, molecular, or biochemical systems, such as human tissues,

cells, fluids, or organs.

Biological markers can be divided into three general types: markers of exposure or dose, markers of health

effects or response, and markers of susceptibility. The first type, biomarkers of exposure or dose, can be measures

of original contaminants in the body and thus provide clear-cut evidence of a specific environmental exposure; an

example is lead in the bloodstream. Markers of exposure can be a transformed original contaminant; an example

is cotinine, a metabolite of nicotine, in a person’s blood as a marker of exposure to tobacco. The next type,

biomarkers of effect or response, are those indicators that represent changes between exposure and the clinical

manifestation of disease. One example is reduced plasma acetytcholinesterase levels fallowing exposure to

organophosphate insecticides. Finally, biomarkers of susceptibility are indicators of inherited or acquired factors

that affect an individual’s response to exposure to an etiologic factor. An example is a mutant adenomatous

polyosis coli gene in people with familial adenomatous polyosis as a predisposing factor for colon cancer.

Biomarkers can be used to improve epidemiologic studies in Providing quantitative dose and response data

for risk assessments. Typically estimates of exposure are the weakest aspect of epidemiologic studies, which

makes many epidemiologic associations of exposure and disease uncertain. Biomarkers of exposure or dose can

be used to replace job history or recall of activities as ways to estimate exposures. Some markers can be used

for exposure and response, and provide data for dose-effect analysis. Biomarkers of effect can be used to quantify

the response to a toxic agent. These applications of biomarkers can increase the accuracy of exposure

assessment, which enhances the power of an epidemiologic study by providing firmer evidence linking exposure

with disease.

At present, the use of biomarkers remains limited. Most of them are still being developed and need testing

or validating, pointing to important areas of future research.

SOURCES: B. Hulka, T Wiicmky, and J. Griffith. 1090. Wo@ca/Markere in @kkunlo@y, Oxford University press, New Yodq National

Research Councii. 1991. Human Ekposure Aeeeaamat lbrAkbome Po#utanis:Adwmoes and O-/fhq National Aoademy Press,

Washington DC; P. Schuite and F. Perera. 199S. k4#ecuiar fpldami+fi Princ@ee andl?actkxw, Aoademic Press, San Diego.
Chapter 7: Structuring the Future of Health Risk Assessment Research 177

HUMAN EXPOSURE METHODS

Many people in the risk assessment community

whom OTA interviewed contend that research on

human exposure is currently underdeveloped and

inadequately supported, despite its significant

short- and long-term implications for both policy

and public health. A report by the National

Research Council (NRC, 1991) recommended

measuring contamin ant concentrations in air,

water, and soil, to characterize the exposures of

individuals and populations. The council sees the

measuring of human exposures as advancing

prevention efforts and thereby mitigating the

health effects of exposure to hazardous substances. Carrying out the council’s recommendation will require scientists to improve personal

monitoring, identify and measure biological markers of exposures, and develop and validate

mathematical models for estimating exposures

among individuals and populations.

Currently, most exposure estimates depend on

models that have not been validated. To understand the relationship between the emission of

pollutants from a source and human exposures,

researchers are developing models of the transport and transformation of chemicals released

into the environment and on human exposure

pathways. Data are critically needed to test and

eventually validate these exposure models.

MECHANISTICALLY BASED EFFECTS AND

DOSE-RESPONSE EXTRAPOLATIONS

The advances in understanding the biology of,

for example, cancer will influence testing and

data collection, as well as the methods used for

constructing dose-response models for estimating

risks from exposure to carcinogens. The roles of

oncogenes and tumor suppressor genes (box 7-B)

that have been uncovered during the past decade

have changed the way environmental health

scientists approach their studies of environmental

carcinogens. Research results affirm that cancer

develops through a multistep process that can involve the accretion of multiple genetic alterations

(Aaronson, 1992; Barrett, 1993; Weinberg, 1992).

Understanding how carcinogens affect the critical

steps of cancer development will improve knowledge of environmentally mediated carcinogenesis

and methods for assessing carcinogenic risks.

Many scientists argue that advancing the field

of mechanistically based dose-response modeling

will substantially reduce uncertainty in risk assessments of potential carcinogens. The objectives of these models are to base risk estimates on

understanding how the agent produces its carcinogenic effects. To promote such modeling, researchers are integrating knowledge from testing,

epidemiologic, exposure, mechanistic, and pharmacokinetic studies in an iterative fashion for

some compounds, including tetrachlorodibenzodioxin (TCDD) (Vanden Heuvel and Lucier,

1993).

Physiologically based pharmacokinetic (PBPK)

models estimate both the concentration of a

toxicant, or an active metabolize of it, at the target

site and the time it spends there. As the next step

in the process, biologically based dose-response

(BBDR) models use pharmacodynamic information to examine the relationship between the

concentration and persistence of a toxicant at the

target site and the observed adverse effects on

health. Computer models can incorporate both

PBPK and BBDR data, to offer a closer representation of the human body. Such improved models

should reduce the reliance of risk assessors on the

assumptions that have been used in risk assessments. Furthermore, computer simulations can

describe not only the action of chemicals throughout the body but also identify gaps in the

information base, suggesting areas of additional

research.

Biological and biomedical research is building

our knowledge of the normal life processes. This

understanding is demonstrating the complexities

of the various levels of control at the cellular,

tissue, and organismal functions. Yet, little is

known about the effects of exposures to toxic

agents at different stages of the life cycle.

Research suggests that exposures at different

times can cause different effects on health. The
178 I Researching Health Risks

Box 7-B-The Biology of Oncogenes and Tumor Suppressor Genes

During the normal development of an organism, a chemical “conversation” occurs among the developing

cells that directs their specialization and maturation into tissues. This chemical “conversation” is mediated by a

variety of biological molecules, some of which are the products of genes.

Genes and gene products are potential targets for radiation and chemical damage. Damaged genes or gene

products can disrupt the ability of cells to carry out their business or change the information being communicated

to other cells. Altered information sent to cells can cause some of them to become “confused” and proliferate

uncontrollably, which can result in cancer. Before cancerous growth begins, however, several specific genetic

changes may have to accumulate within a cell and cause normal cell functioning to break down.

At present, scientists have identified at least two families of interacting genes--proto-oncogenes and tumor

suppressor genes-that are linked to cancer in humans and other animals. Under normal circumstances, both of

these kinds of genes are necessary for the proper growth and development of an organism. Working in balance

to maintain cell growth and differentiation, the two families of genes have been termed the “yin and yang of cancer

biology.”

Proto-Oncogenes and Oncogenes

Proto-oncogenes, as their name implies, are genetic precursors of oncogenes, or cancer-causing genes.

Found in all healthy cells, proto-oncogenes are involved in regulating ceil growth, or cell division and differentiation.

Proto-oncogenes produce growth factors that play a role in normal cellular growth.

Oncogenes arise when critical parts of proto-oncogenes undergo structural changes brought about by,

among other things, exposure of cells to radiation or chemicals. These altered genes may maintain the role of the

original proto-oncogenes in directing ceil proliferation but ignore the influence of information coming from outside

the cell. Consequently, cells divide regardless of the content of the chemical conversation.

Tumor-Suppressor Genes

Recent findings suggest however, that creating oncogenes alone is insufficient to induce malignancy in most

cells. Tumor suppressor genes must also be dissuaded from functioning normally.

Tumor suppressor genes, also known as anti-oncogenes, act to restrain cell division, providing a balancing

force against the growth-promoting proto-oncogenes in normal cells. They also seem to be successful in overriding

the uncontrolled-growth instructions that oncogenes put out. For a cell to become malignant, therefore, one or

more proto-oncogenes are converted to an oncogene, and one or more tumor suppressor genes are removed or

becomes inactivated. The same types of exposures that create oncogenes can remove or inactivate tumor

suppressor genes—namely, exposure to DNA-damaging chemicals or radiation.

A useful analogy of the relationship of proto-oncogenes, oncogenes, and tumor suppressor genes is to

imagine the cell as a car. The normal proto-oncogene is like a car’s accelerator pedal. Once changed into an

oncogene, one could imagine the car’s accelerator welded to the floor. Tumor suppressor genes might be viewed

as the car’s brakes, holding back the effects of the oncogenes. When agents damage the tumor suppressor genes,

it is similar to the car's brakes being removed, sending the cell careening down the path toward cancer.

SOURCES: S. Aaronson. 19S1. Grouth factors and cancer. Scknoe 2S4:1 14S; J. Barrett. 199S. Medlanlama of multietep Oardnogenoab

and cardnogen risk aeseeement. Erwhunmmhd IkMh Perspecthws 100S-20; E. Solomon, J. Borrow, and A Gxfdard. 1991.

Chromosome aberratkns and carxar. Sc+ence 254:1 153; N. Toudrette, 1S92. Dying c-elk reveal new role forcamxrgenee. Jowna/ufMf

Reseamh4:4S; H. Varmus. 19S7. Oncogenes and transcriptional oontrol. Sc&ncs 2S8:1SS7-1SS9; R. VWnbarg. 1991. Tumor supprewor

genes. Sdenco 254:1141; S. Young. 1992, Dangerous danoe of the dividing cell. Msw SdeWst 92S.

endocrine system, for example, is integrally may lead to different adverse effects (e.g., reprorelated to the growth and functioning of nearly all ductive effects or cancer). As with many new

cells. Depending on its stage of development, discoveries in risk-related research, opportunities

chemical perturbation of the endocrine system exist for multidisciplinary collaboration— linking
Chapter 7: Structuring the Future of Health Risk Assessment Research 179

biomathematicians, molecular biologists, toxicologists, and epidemiologists-to develop new

models of biological processes and to understand

how chemicals disturb those systems.

 Basic Biomedical Research

The results of ongoing basic biological research have long-term implications for future

health risk assessment research. Applying the

knowledge gained from studies in basic biology

to basic toxicological research may happen quickly,

but usually it requires a considerable amount of

time and resources. Scientists and decisionmakers interviewed by OTA stressed the importance of the relationship between conducting

basic research and improving risk assessment

methodology. Of arguably the greatest long-term

signtificance for the environmental health sciences is the study of the interaction between

genetic susceptibility and environmental factors.

Molecular techniques give scientists the capacity

to tease out specific genetic damage associated

with environmentally related diseases and to

monitor damage to DNA following exposure to

environmental toxic agents. Such studies can

identify those genes that are susceptible to

damage by toxicants, as well as groups of people

who are particularly sensitive to the adverse

health effects of environmental exposures (box

7-c).

Basic biomedical research is likely to influence

the direction of health risk research in unanticipated ways. For example, if successful, the

Human Genome Project now underway will

eventually provide information on the entire

nucleotide sequence of the human genome, which

will in turn contribute to risk assessment by

providing information about the molecular basis

of disease. Biomedical researchers are expanding

our knowledge about the normal relationships of

specific human genes, their gene products, and

biological functions. That information greatly

facilitates the studies of how toxic agents can

affect biological processes.

An exciting recent discovery for understanding

developmental toxicology has been an understanding of homeobox genes. Studies in mice

show that these genes encode proteins that specify

the development of, say, the head and neck.

Damage to the homeobox genes by environmental agents could lead to abnormal development. Knowledge of the location and function of

these genes can focus toxicologists in their

research on understanding how chemicals might

alter development.

Studies of the biology of diseases in general

provide an understanding of the functioning of

various organ systems. For example, research

related to the acquired immunodeficiency syndrome (AIDS) has revealed much about the

immune system; similarly, studies of the lung

diseases cystic fibrosis and emphysema have

contributed to basic knowledge of pulmonary

biology. Studying the behavioral disorders arising from Alzheimers and Parkinson’s disease has

helped researchers to discern the connection

between the functioning of the nervous system

and behavior. Such disease-specific research may

provide clues for studying how toxicants interact

with biological systems and understanding the

types and nature of adverse effects that may result

from exposure to them.

 Data Development and Management

Keeping abreast of the need for toxicity information of new chemicals will require new technologies to generate the data and to manage the

burgeoning database. While data development

and management are important for advancing

health risk assessment, some scientists may not

consider it research. Whether or not this activity

is considered research, data on the toxic properties of specific compounds and of human exposure is the basis for health risk assessment. With

new tools for the study of toxicology and exposure, traditional approaches are constantly being

challenged for their information value. Moreover,

estimates are that only about 10 percent of the
180 Researching Health Risks

Box 7-C-Genetic Predisposition to Cancer:

The Role of Oncogenes and Tumor Suppressor Genes

Cancer is a multitude of diseases. The nature and the number of genetic and nongenetic changes associated

with each type of cancer differ. However, both Iaboratory and human studies confirm that the pathogenesis occurs

in stages and multiple genetic and environmental factors can affect its development.

Most genes in humans come in pairs. Usually both copies of the gene carry out an identical job. The large

number of genes in the human genome makes it relatively rare that a damaging alteration will take place in both

copies of a gene when the cell is subjected to damaging radiation or chemicals.

Conversion of one of a pair of suppressor genes to an inactive form is not sufficient to cause cancer; the

remaining active gene is sufficient to maintain normal growth. When both members of the pair of suppressor genes

are made inactive, cancer can result. Such a case occurs with retinoblastoma, a cancer of the retina in children.

Carriers of the defective gene are born with one of a pair of the suppressor gene, the rb gene, defective. Such

carriers have a much higher risk of retinoblastoma: inactivation of the remaining rb gene in a retina cell results in

this cancer. Noncarriers require two such changes to develop retinobtastoma Thus carriers of the defective rb

gene, compared with someone who has two working copies of the rb gene, are predisposed or have a greater

“susceptibility” for developing retinoblastoma.

Susceptibility can be identified among families. Such at-risk families are susceptible to a specific type of

cancer, corresponding to the specific damaged gene that is inherited. Familial polyposis coli is a common

hereditary predisposition to colon cancer and has an incidence of about one in every 10,000 individuals.

Oncogenes have not yet become useful tools for identifying an individual’s predisposition to cancer. Most

identified oncogenes are “dominant;" only one member of the gene pair has to be converted to an oncogene to

cause unregulated growth of the cell. These oncogenes are seldom passed from parents to child; even one

oncogene of the pair would wreak havoc with the growing embryo long before it could mature to birth.

What is imaginable, however, is that less “dominant” oncogenes might exist and could be inherited in

humans. These would probably not be strong initiators of cancer but would act in tandem with other “weak”

oncogenes to predispose individuals to a variety of tumors. Such “weak” oncogenes have not yet been tied to any

particular location in the human genome.

In contrast to oncogenes, several tumor suppressor genes have become quite valuable in identifying genetic

predispositions to specific cancers. Notable among them are the Rb gene discussed earlier and the p53 gene in

Li-Fraumeni syndrome. The Li-Fraumeni syndrome predisposes carriers to a wide variety of cancers. The study

of a family predisposition for retinoblastoma identified Rb as the first known tumor suppressor gene.

SOURCES:J. Barrett. 1SS3. M*an&m&multktep =dnqewsb andcardnogen riskassessrnent. &tiwwta/*thPerspecf/v@

1003-20; H. Evans, J. Rosser and J. Presser. 1SS2. Tumor-suppressor genes: oardinal factors in Inherited predisposition to human

oancers. &w&unrrMr?ta/ ~a/t/r Perspecthmr SS25; A. Knudson. 1999. The @meUc pfBd@OdfkVl to arww. GtMet/c Shme@Mty to

Erwkwrnentd kfutagms and Cauhogens. March of Dimsa. White Plains, NY; J. Marx. 1991. Possible new don cancer gene found.

$dswca 91:1317; E. Solomon, BJ. Borrow, and A.D. Goddard. 1SS1. Chmmoaome aberrations and cancer. Sdence 254:1153; H.

Yarnaeald, LAlexandre, and L. Tomatis. 1992. Perinatalandmuitigenerational effect ofcardnogens: posslblecontribution to determination

of oanoer susceptibility. Erwirwmmtd Health Perspectkes 9S:39,

chemicals in commerce have data available for a chemical agent present in air, food, water, soil, or

risk assessment (Environmental Health titter, consumer products. As discussed in other chap1993). Baseline data on human exposure are also ters of this report, uncertainty about such data

lacking because of the limitations of current affects the confidence that can be placed in the

methods and resources. Toxicity data have been results of risk assessments. The validity of new

developed through epidemiologic studies or tests methods for toxicity testing and human exposure

using animals or microorganisms. Information on monitoring must be demonstrated before the

exposure comes from measuring the levels of a methods are adopted. This should be an iterative
Chapter 7: Structuring the Future of Health Risk Assessment Research 1181

process whereby the generation of data is linked

to validation.

The explosion of research data applicable to

risk assessments combined with a greater need for

data to support regulatory action necessitates

improving the access to this information. Storing

and analyzing that information will require more

advanced computational tools. In time, the broad

task of data synthesis will play an increasingly

important role in characterizing and comparing

risks posed by different environmental problems.

Scientists are seeking ways to improve the size

and reliability of the toxicological database on

environmental agents.

With improved techniques for analyzing and

managing information, researchers may be able to

connect disparate pieces of data, which could lead

to conceptual breakthroughs. They could assemble information about metabolic transformations,

for example, into a database on metabolism that

could anticipate metabolic products of other

environmental agents. In addition, ways could be

devised to examine and analyze old databases, as

well as new data, for useful information that may

not be detectable with existing methods.

One example of a new method for analyzing

data is meta-analysis. Meta-analysis is a broad

label for a variety of statistical and mathematical

methods for assessing and summarizing a body of

data. In the most restrictive sense, scientists use

formal meta-analytic techniques to summarize

the information in several studies of very similar

design. But methods are also needed to synthesize

complex databases to include the results of more

methodologically distinct studies involving, for

example, data on exposure and health effects in

animal and human systems. The science of

meta-analysis is still in its infancy. Nevertheless,

it offers the potential to help researchers assess

data on the health effects of environmental

pollutants in new and more meaningful ways. It

may also provide opportunities to predict toxicity

for a chemical or class of chemicals for which few

data exist.

FOSTERING RESEARCH LiNKAGES

Research linkages and collaborations offer

enduring benefits to all participants. They bring

together researchers with different strengths and

expertise, foster the dissemination of knowledge,

and permit the sharing of resources. Research

linkages also allow researchers to undertake

projects that otherwise might not be possible.

Linkages can occur within and between Federal agencies as well as between Federal and

nonfederal institutions. Traditionally, linkages in

health risk assessment research were forged

between government and university researchers;

fewer such linkages exist between government

and industry. Although not all areas of health risk

assessment research lend themselves to industry

linkages, some topics have commercial potential

and would benefit from public-private partnerships. The paucity of those linkages also stems, in

part, from the primary focus of publicly funded

health risk research, which is to identify toxicants

and determine risks to public health. Because

some of these risks come from industrial activities, those linkages could create conflicts of

interest between public and industry concerns.

 Building Disciplinary Bridges

Multidisciplinary interactions in most scientific endeavors require various resources—

intellectual, personal, and financial. Because the

requirements are great and the barriers are high,

many collaborations across disciplines do not

succeed (Chubin et al., 1986; Klein, 1990). Yet

for those that do, the benefits often include

establishing new, even revolutionary, frontiers of

science, arising from the exchange of information

across disciplines (Kuhn, 1962).

Health risk assessment can be viewed as the

overlap between chemical- physical sciences,

biological-biomedical sciences, and environmental

health sciences (figure 7-l). To develop as a field,

health risk assessment research must be linked

with broader areas of research. From bridges built

between different research disciplines, new per-
182 I Researching Health Risks

Figure 7-l—Linking Scientific Disciplines in

Health Risk Research

approaches may differ, but the results can be

complementary; and, information sharing by the

fl~ researchers can enhance the value of the results of

everyone’s efforts for the advancement of knowl-

/

Chemical // Biological

I and Physical 1 \ and Biomedical

Sciences

SOURCE: Office of Technology Assessment, 1993.

spectives and insights can emerge. In addition to

the invaluable expansion of scientific knowledge,

basic science is the basis for developing the ‘risk

sciences. ” Risk science, under appropriate leadership, could be a magnet for collaborative

research. It could become analogous to the

Human Genome Project, in which collaborations

have been formed among scientists working to

sequence the human genome. Its goal is different,

of course; yet, a similar process could occur.

Researchers from many disciplines could work

together to improve health risk assessments as a

desirable social and scientific goal.

Research is traditionally structured along disciplinary lines and separated conceptually, if not

actually, into basic and applied research as away

to highlight the goal of the activities. Because

research in support of risk assessment is generally

multidisciplinary, the differences between basic

and applied research are often subtle and difficult

to discern. For example, researchers using chemicals as investigative tools for probing fundamental biological systems (basic biological research)

are nearly indistinguishable from those investigating the basic underlying mechanisms of the

adverse health effects of specific chemicals (applied toxicological research). The objectives and

edge and improving risk assessment. Similarly,

because health risk is essentially a composite of

toxicity and exposure, health effects and exposure

research should be linked and integrated as well,

especially when planning research programs and

./ activities.

 Partnership With the Private Sector

In addition to scientists’ collaborating to improve risk assessments, federally supported researchers can transfer knowledge to the private

sector to foster economic growth and competitiveness, now a vital part of the mission of many

research agencies. Revenue raised through technology transfers could be used to bolster research

in health risk research. Such additional funding

could be important because, as this report describes, resources are currently inadequate to

provide stable, long-term support for research in

this area.

Increasingly, mechanisms are being developed

to facilitate the transfer of research results developed with public funds to the private sector. In

particular, legislation enacted during the 1980s—

the Bayh-Dole Act of 1980 (P.L. 96-517) and the

Federal Technology Transfer Act of 1986 (P.L.

99-502)-provides Federal agencies with incentives to promote technology transfer. That legislation encourages the commercialization of research by permitting Federal grantee institutions,

contractors, and laboratories to retain the rights to

inventions that they develop with Federal funding. In addition, scientists at those institutions can

collect a portion of the royalties. The legislation

also authorizes Federal agencies to enter into

research with the private sector through cooperative research and development agreements

(CRADAs). Those agreements can be put into

place very early in the development process—

well before the invention stage. Although conflict
Chapter 7: Structuring the Future of Health Risk Assessment Research 183

of interest is still of concern in some circumstances, public and commercial interests converge in selected areas of health risk assessment

research. Examples include toxicological tests

and exposure monitoring technologies that will

be quicker, more accurate, and less expensive. To

date, only a few such cooperative ventures have

been established.

 Ties to Universities

Many areas of health risk assessment research

do not lend themselves to product development.

Basic research is an example, but basic research

is ripe for collaborative efforts between and

within agencies of the Federal Government and

between Federal agencies and universities (box

7-D). Many of the specific research opportunities

in health risk assessment research described in the

previous section would benefit from linkages and

collaborations between Federal and university

researchers.

This need to exchange views, results, developments, and insights led to calls for a forurn of

coalescing research interests. One result was the

Society for Risk Analysis, which was founded in

1982 to focus on the risk analysis debate and

publish relevant work on the topic. Interest in the

society has grown over time, as has the number of

papers submitted to its publication, Risk Analysis;

An International Journal (Travis, 1993), and

health risk research articles are frequently published in the journal. Other avenues of expression

are opening up as well. Of note is a recent

conversion by Environmental Health Perspectives, a journal published by the National Institute

of Environmental Health Sciences. That journal

traditionally published scientific articles on environmental health and toxicology. In April 1993,

the journal began incorporating news features,

editorials, commentaries, and perspectives relevant to health risk, including policy. The editors

say they want the journal to be a printed nexus of

the various perspectives in the environmental

health sciences (Lucier, 1993). In the final analysis, perhaps an integrated risk assessment culture

may be emerging from the disparate strands of its

disciplinary origins.

SUMMARY AND CONCLUSIONS

Recognizing the potential of research to narrow

the uncertainty of risk assessment, OTA noted

several characteristics common to high-quality

research programs that should be considered in

structuring future research efforts. These include

leadership, well-defined objectives, investigator

initiation of research, competitive awards and

peer review, planning and criteria for evaluating

success, collaboration and coordination, training,

and advisory input.

OTA identified several areas that promise to

improve risk assessment. They include research

into new methods for toxicity studies; biomedical

and molecular epidemiology; mechanistically

based effects and dose-response extrapolation

methods; improved methods for measuring or

estimating human exposures; mechanistic studies

of the actions of toxic substances; attention to

methods evaluation and validation; techniques

for characterizing and communicating risks; and

information management.

Exploitation of the many promising research

avenues for improving health risk assessment

requires establishing linkages not only within and

among various scientific disciplines but also with

various organizations. Furthermore, as discussed

in chapter 5, an important criteria to judge success

for health risk research is that it be useful for

decisionmaking . Linkages with risk assessments

and decisionmaking too should be fostered. No

one category of research can be classified as most

useful for decisionmaking. Instead, risk assessments will increasingly require multidisciplinary

approaches and analyses of all available information. Moreover, the nature of the health risk being

addressed, the nature of the information already at

hand, and other factors that affect decisionmaking

should be considered when structuring a research

program for solving health risk problems.
184 Researching Health Risks

Box 7-D–The Environmental Health Sciences Center at the Johns Hopkins University

The Environmental Health Sciences Center at the Johns Hopkins School of Hygiene and Public Health is

supported by the National Institute of Environmental Health Sciences (NIEHS), through an NIEHS Centers Grant.

The goals of the center focus on understanding the impact of potentially toxic environmental agents on health by

investigating mechanisms of action at the molecular, whale animal, and human levels of interaction. In addition,

the center attempts to stimulate research interactions between individual faculty and faculty of other existing

environmental and occupational health-oriented centers throughout the university, such as the Educational

Resource Center, supported by the National Institute for Occupational Safety and Health, and the Injury Prevention

Center, supported by the Centers for Disease Control and Prevention.

An underlying theme of the center is “molecules to man.” This theme is in accord with the concept that it is

critical to understand the basic biological and molecular mechanisms by which environmental agents cause

disease in man so that they can be prevented. Currently, the center draws upon the Departments of Biochemistry,

Biostatistics, Environmental Health Sciences, Epidemiology and immunology and Infectious Diseases for its

members. The rationale for the Johns Hopkins NIEHS Center is that the many scientific disciplinary investigatory

talents at the university benefit from an environment which promotes collaborative, interdisciplinary research.

The center also provides a suitable environment for the education and training of future Environmental Health

Research Scientists by incorporating pm-and post-doctoral students and fellows, respectively, into the research

activities of the center. The center also conducts outreach programs for the continuing education and training of

environmental health professionals.

The center is organized into six research core units each having its own area of emphasis and specific aims:

Epidemiology and Exposure Assessment; Molecular Dosimetry and Biological Monitoring; Environmental

Carcinogenesis; Physiologic Responses to Inhaled Pollutants; Cellular and Immune Defense Mechanisms; and

Neurotoxicology. These programs conduct studies on a spectrum of environmental agents as well as a number

of human diseases.

Some highlights of the scientific accomplishments include the research findings made by the Environmental

Carcinogenesis program in the area of chemoprevention. Aflatoxin, a widespread contaminant in the environment,

particularly in Africa and Asia has been associated with increased incidence of hepatocellular carcinoma Center

researchers found that an antioxidant known as oltipraz can prevent hepatotoxicity and the ultimate appearance

of liver tumors when given at the same time as aflatoxin. This research provides new insights into the mechanism

of the protective action of oltipraz, which may represent a compound that could be given to individuals at high risk

of aflatoxin exposure.

Another center project collected data about exposure to electromagnetic fieids (EMF), as part of a national

case-control study of telephone linemen. The study identified individuals working in telephone switching offices

who had electric and magnetic field exposures that were different from those produced by 60-HZ alternating

current. Some studies suggest that complex electromagnetic field exposure environments may impact biological

activity differenty than fields produced by 60-Hz alternating currents. The center investigation found that telephone

linemen working in switching offices had an increased risk to male breast cancer.

SOURCE: The Johns Hopkins UnivwWySchool of Hygiene and Publk Health, 1993.

CHAPTER 7 REFERENCES of an Ad Hoc study group on Risk Assessment

Aaronson, S.A. 1992. Growth factors and cancer. Presentation. Washington, DC.

Science 254:1 146-1153. Barrett, J.C. 1993. Mechanisms of multistep ca.minoAIHC (American Industrial Health Council). 1989. genesis and carcinogen risk assessment. EnvironPresentation of risk assessment of carcinogens. Report mental Health Perspectives 100:9-20.
Chapter 7: Structuring the Future of Health Risk Assessment Research I 185

Chubin, D., Porter, A., Rossini, F., Connolly, T. 1986.

Interdisciplinary Analysis and Research (Lomond,

MD).

Environmental Health Letter. 1993. Vol. 32, No. 10.

Finkel, A., and Evans, J. 1987. Evaluating the benefits

of uncertainty reduction in environmental health risk

management. Journal of the Air Pollution Control

Association 37:1 164-1171.

IOM (Institute of Medicine). 1988. A HeaZthy NIH

Intramural Program: Structural Change or Administrative Remedies. Report of a study by a Committee of

the Institute of Medicine (Washington, DC: National

Academy Press).

Klein, J.T. 1990. Interdisciplinarity: Histo~, Theory

and Practice (Detroit, MI: Wayne State University

Press).

Kuhn, T 1962. The Structure of Scient@c Revolutions

(Chicago: University of Chicago Press).

Moynihan, D.P. 1993. Acid precipitation and scientific

fallout. Forum forAppliedandPublic Policy. Summe~61-

65.

Needleman, J. et al,, 1984. Managerial approaches to

improving collaboration and coordination in the Public

Health Semice. Contract No. 282-83-0072. Office of

Health Plaming and Evaluation, Office of the Assistant Secretary for Health, U.S. Public Health Service,

Department of Health and Human Semices.

NIEHS (National Institute of Environmental Health

Sciences). 1992. J. Huff (cd.) Absence of morphologic

correlation between chemical toxicity and chemical

carcinogenesis. July 13.

NRC (National Research Council). 1991. Human

Exposure Assessment for Airborne Pollutants: Advances and Opportunities (Washington, DC: National

Academy of Sciences).

Olden, K. 1993. Testimony before the Subcommittee

on Labor, Health and Human Services, Education, and

Related Agencies, Committee on Appropriations, U.S.

House, Mar. 22.

Shore, R., Iyer, V., Altschuler, B, et al., 1992. Use of

human data in quantitative risk assessment of carcinogens: impact on epidemiologic practice and the

regulatory process. Regulatory Toxicology and PharnulcoIO~ 15:180-221.

U.S. Congress, OTA (Office of Technology Assessment). 1991. Fe&rally Fun&d Research: Decisions

for a Decade. OTA-SET-490.

U.S. DHHS (Department of Health and Human

Services). 1991a. Educating Environmental Health

Science andProtection Professionals : Problems, Challenges, and Recommendations.

U.S. DHHS. 1991b. Human health and the environment—

some research needs. Draft report of Task Force IV,

National Advisory Environmental Health Series Council. National Institute of Environmental Health Sciences,

U.S. DHHS, CDC (Centers for Disease Control and

Prevention), 1992. Fiscal year 1992-1993 Program

Briefing. Delivering on the nation’s promise: safety

and health at work for all people through prevention.

National Institute of Occupational Safety and Health.

U.S. EPA (Environmental Protection Agency). 1990.

Reducing Risk: Setting Priorities and Strategies for

Environmental Protection. SAB-EC-90-021.

Vanden Heuvel, J.P., and Lucier, G. 1993. Environmental toxicology of pcdychlorinated dibenzo-pdioxins and polychlorinated dibenzofurans. Environmental Health Perspectives 100:189-200.

Weinberg, R. 1992. llunor suppressor genes. Science

254:1138-1 146.

Young, F. 1993. Deputy Assistant Secretary for

Health, Science and Environment. Department of

Health and Human Services. Personal communication.
T

his appendix provides a snapshot of how

other countries and international agencies

practice health risk assessments. It highlights the risk assessment of chemical carcinogens because the methodologies for that type of

assessment are better developed than those for other

health endpoints. It also focuses on the various types

of health risk assessment used by different countries

and international bodies, specifically noting those

cases in which quantitative risk assessments (QRAs)

are employed. The definition of a QRA is subject to

controversy and differs from country to country. For

the purposes of this discussion, a risk assessment is

characterized as quantitative when it generates numerical estimates relating the risk of developing cancer to

particular levels of exposure to a chemical. Adding to

the lack of uniformity internationally is the fact that

countries and international bodies involved in monitoring human exposure to chemical carcinogens and

other toxic substances have adopted their own processes of health risk assessment. The differences in their

methods and definitions are due to a number of

variables, including legislative and regulatory histories, government structure, public involvement, research and development, and cultural characteristics.

The information used to generate this appendix was

obtained through written and oral correspondence with

the relevant officials in each of the countries and

international bodies that the Office of Technology

Appendix A:

International

Risk

Assessment

Assessment (OTA) surveyed. OTA chose the countries

and organizations that participated based on their

activity in the field of risk assessment and availability

of resources. A minimum of three sources for each

country or body was examined; the same sources also

had an opportunity to review and comment on a draft

of this text.

How do these countries approach risk assessment?

An important prerequisite for many of them in

conducting QRAs is knowledge about the mechanism

of carcinogenic action of a substance. Usually, only

QRAs are performed for genotoxic carcinogens.1 In

addition, many industrialized nations that regulate

chemical carcinogens tend to use a case-by-case

approach: each chemical is subjected to an individual

review that considers cancer mechanisms. Such countries as the United Kingdom and Germany rely

primarily on expert judgment in risk assessments and

regulatory decisionmaking, The risk assessment process in those nations involves the formation of expert

advisory committees that make the actual decisions

regarding exposure standards or regulations instead of

the agencies. Those advisory bodies commonly use a

‘‘ weight-of-the-evidence’ approach, in which all of

the available information and test data are evaluated in

formulating a decision concerning a carcinogen.

Finally, the countries OTA surveyed support a

variety of regulatory agencies, a characteristic common to the United States as well. As a result, just as the

1 When a carcinogen acts by a genotoxic mechanism, it damages DNA and causes genetic changes (e.g., mutation of a gene), which may

in turn lead to the abnormal development of human cells that may sexve as a precursor for cancer (see ch. 2).

187
188 I Researching Health Risks

use (or nonuse) of QRA may differ among countries,

QRA policies among a country’s regulatory organizations may also vary. Because one agency uses QRA

does not mean that other regulatory bodies in the same

country also practice it. Moreover, regulatory organizations may use QRA for different purposes to develop

standards of exposure or to establish regulatory or

research priorities.

INTERNATIONAL BODIES AND

RISK ASSESSMENT

Their increasing awareness of the risk of exposure

to toxic chemicals has led several international bodies

to develop programs addressing the need to identify,

monitor, and assess toxic agents. The focus of each

program differs, based on its structure and clientele.

Nevertheless, these international bodies, along with

regulatory agencies in the United States and other

countries, have developed significant collaborations in

fulfilling their overall missions to protect humans from

exposure to hazardous substances.

The activities of these organizations encompass

collecting data on hazardous chemicals, evaluating

additives and pesticide residues in food, labeling and

classifying both new and old chemicals, reviewing

occupational exposure to hazardous chemicals, and

promulgating guidelines for assessing chemicals. Much

of the work of these international organizations is

targeted at improving trade between countries by

promoting the use of standardized testing, classification, and labeling procedures. OTA, in the following

discussion, focuses on the more prominent chemical

risk reduction programs and highlights any use of

human health risk assessment, either qualitative or

quantitative. The United States makes a substantial

contribution to many of these organziations (table

A-l). We emphasize the regulation of exposures to

carcinogens, but not to the exclusion of noncarcinogenic chemicals.

 International Agency for

Research on Cancer

As part of the World Health Organization (WHO),

the International Agency for Research on Cancer

(IARC) was established in 1965 to promote international collaboration in cancer research. The main

activities of IARC currently encompass collecting and

disseminating data on cancer occurrence, searching for

the causes of cancer, and conducting research aimed at

preventing cancer. IARC is also exploring other

aspects of cancer, including mechanistic aspects of

carcinogenesis, genetic disposition toward cancer, and

quantitative estimation and prediction (QEP) of cancer

risks. QEP is IARC’s approach to quantitative risk

assessment.

Currently, 16 participating nations contribute resources for research and provide expert advice to

IARC (IARC, 1991). Participating states also make

financial contributions. Yet, despite that assistance, the

agency reports that it is experiencing financial difficulties, which makes it difficult to recruit additional

personnel to pursue all of its objectives. Notwithstanding these problems, the agency has initiated some new

projects and is continuing those already under way

(IARC, 1992b).

In addition to its affiliation with participating

countries, IARC is also involved in numerous collaborations with other international agencies and national

institutes. Numerous countries, especially those lacking resources, use publications containing the agency’s

evaluations and classifications of chemical carcinogens in formulating their policies on carcinogens.

Although IARC does not perform risk assessments

in their entirety, it serves an important role in the initial

stage of risk assessment—that is, in hazard identification of carcinogens using rodent bioassays. Participating countries, including the United States, conduct

them and submit the results to IARC for review,

evaluation, and publication in its series Monographs

on the Evaluation of Carcinogenic Risks to Humans.

During its review and evaluation process, IARC

subjects chemicals to a classification scheme it developed to characterize their degree of carcinogenicity.

One of the agency’s major accomplishments has been

establishing a process for evaluating and analyzing

data based on the consensus of multidisciplinary

experts and not on the basis of administrative or

political concerns (Richter and Goldsmith, 1991).

IARC’s Monographs series is one of its most

important contributions to cancer research, To date,

IARC has published 57 volumes of the series, which

qualitatively evaluates and classifies more than 750

agents and complex exposures for carcinogenicity

(IARC, 1993). The process begins by choosing candidates for hazard identification and classification from
Appendix A: International Risk Assessment I 189

Table A-l—Assessed and Voluntary Contributions by the United States to International Organizations

1991 1992

assessed Percentage assessed Percentage

(millions of of total (millions of of total

U.S. dollars) budget Voluntaryb U.S. dollars) budget Voluntary

World Health Organization . . . . . . . . . $78.3 25% N/A $94.2 2 5 % N/A

Organisation for Economic

Cooperation and Development. . . . 45.6 25 $0.015 44.6 25 $0.005

International Labor Organisation . . . . 61.8 25 N/A N/A N/A N/A

Food and Agriculture Organization . . . 70.0 25 N/A N/A N/A N/A

Pan American Health Organization . . 42.0 61 N/A 45.4 61 N/A

International Agency for Research

on Cancer . . . . . . . . . . . . . . . . . . . . . 1.4 10 N/A 1.5 11 N/A

NOTE: N/A- not available.

a In many ~.e~, there is a ~p of 25 per~nt on the total bu@et per~ntage that the unit~ states may contribute tO an organization.

b Totals are inmmplete. Voluntaw ~ntdbutions originate from a variety of sources, not necessadly the F~eral Government.

SOURCE: U.S. State Department, World Health Organization/International Prograrnme on Chemical Safety, 1993.

the results of surveys sent to governments of participating countries and to cancer experts (Richter and

Goldsmith, 1991). IARC then uses international working groups of experts to evaluate a selected number of

agents or exposures. The categorization of an agent or

exposure is a matter of scientific judgment, reflecting

the strength of the evidence derived from studies in

humans, studies in experimental animals, and other

relevant data. In cases in which there is sufficient

evidence of human carcinogenicity, an agent or

exposure is classified as carcinogenic to humans.

Subsequent categories characterize agents as probably

or possibly carcinogenic to humans, impossible to

classify, and probably noncarcinogenic to humans

(IARC, 1992a).

In the area of quantitative risk assessment, IARC is

planning a workshop entitled ‘Scientific Principles of

Quantitative Risk Estimation and Prediction of Carcinogenic Risk’ in October 1993. The workshop’s main

product will be a comprehensive publication on the

scientific bases and state-of-the-art of QEP. Its main

focus will be to review existing methods, but it will

also describe the relevance of QEP for policy setting

and attempt to provide some scientifically based

guidelines for the use of QEP. The publication will be

designed for a wide audience, including the scientific

community, regulators, and national governments

(IARC, 1992c). In addition, the workshop will serve as

a forum to discuss and recommend the extent to which

IARC should be involved in developing and conducting QEP (specifically, whether the state-of-the-art

allows the definition of a scientific procedure) (IARC,

1992c).

 The European Community

The European Community’s (EC) pursuit of a

unified internal market has forced it to address

environmental issues directly. As a consequence, the

EC has been working toward the “harmonization’ of

health, safety, and environmental regulations, to reduce competitive imbalances among EC countries and

keep regulations from acting as trade barriers (U.S.

Congress, OTA, 1992) (box A-l). The EC has also

sought to protect the public and the working population from exposure to hazardous chemicals. With all of

this in mind, the EC has turned to risk assessment for

determining g standards of exposure and levels of risk

and for harmonizing testing standards for chemicals.

EC legislation pertaining to human health risk

assessments has been mainly directed at: chemical

safety, pesticide residues, food additives, and occupational exposure to chemicals. A common characteristic

of most of the directives passed or proposed in those

fields is that the member states or individual employers

are responsible for performing any risk assessments,

not the EC, Bodies of experts are used throughout this

process, both by those performing the risk assessments

and by the EC to design its directives and evaluate the

end results.

EC directives mandate both qualitative and quantitative risk assessments, depending on the type of

chemical and its usage. In the area of chemical control
190 I Researching Health Risks

Box A-l-Organization of the European Community

The European Community, which was established by a series of treaties in the 1950s, currently has 12

members, all Western European countries. Representatives of these member states serve on the various

committees and institutions that comprise the EC. In addition to its select membership, the EC is unique among

international bodies in that it has the power to mandate the adoption of its legislation by member states.

The EC legislates through regulations, directives, decisions, and recommendations. Regulations, the most

stringent of the EC’s legislation, mandate compliance by EC member states in direct accordance with the language

of the regulation. Directives, which are the most common form of environmental legislation, are also binding on

member states. However, member states have varying degrees of technological capability for complying with EC

directives and in addition are free to choose a method of national implementation. Those factors and the EC’s

limited enforcement mechanisms can lead to significant time delays in a member state’s compliance with a

directive, despite assistance provided through temporary exceptions or financial support.

The original Treaty of Rome, which created the EC, did not include an explicit legal basis for addressing

environmental issues. That deficit was remedied by the adoption of the 1987 Single European Act (SEA). The SEA,

which amended the Treaty of Rome, addressed further areas of fragmentation and noncooperation within the EC

and included an environmental amendment to the original treaty. The act codified a basis for the EC to require

that members harmonize their national environmental regulations. It also allowed the EC to create environmental

laws when the preservation of the environment was better ensured by its actions than by those of individual

countries.

Before and after the existence of the SEA, the EC has approached the growing need for environmental

legislation by developing environmental action programs. The first program was ratified in 1973, and the fifth was

adopted in 1992. These programs have addressed a wide range of environmental regulation, including air, water,

chemicals, waste, wildlife, environmental assessments, and site safety. To date, nearly 300 environment-related

directives have been passed, but fewer have actually been implemented by the member states.

EC policy is executed by the European Commission, which has about 20 divisions or directorates-generals.

The Environment Directorate-General is knownasDG-XI(11) and is somewhat similar to the U.S. Environmental

Protection Agency. But, in response to a growing need for a centralized body to deal with environmental matters,

an European Environment Agency (EEA) has been planned since 1990, with the role of collecting information and

providing objective and comparative data on the state of the environment in member states. Unlike the U.S. EPA

EEA is not designed to have enforcement power and will operate on a first-year budget of only $1.4 million,

compared with to the U.S. EPA’s current $6.5 billion. The EEA also lacks the authority to fund research, but

supporters hope that it will eventuality be able to direct projects aimed at filling gaps in its database. lronically, EEA

has yet to begin collecting and disseminating data because of an ongoing debate about its geographic location.

SOURCES: Commission of the European Communities, 1990. Completing the single market The removal of technical barriers to trade

within the European Ecxmornk Community (Srussels); Hurwitz, L. 1992. The European Community and the Single European Act of 19S7:

What Does It Mean? Ph/KiIppa Ph/Jouma/, spring; KeyeL$, C. 1991. The European Community and Environmental Poi@ An Introduction

for Arntsrfcans (Saltimore, MD: Worfd Wlldfife Publication, 1991).

and safety, very basic qualitative risk assessments are established a harmonized testing and notification

used in evaluating “new’ chemicals. The EC’s initial

effort at environmental policy came in this area with

the 1967 directive on classification, packaging, and

labeling of dangerous substances. After the passage of

this directive, chemical control and safety became a

prominent issue in EC environmental policy. An

important addition to the 1967 directive came in 1979:

known as the “sixth amendment, ” this document

scheme for new chemicals. A seventh amendment,

which further updates EC guidelines for chemical

testing and assessment, was approved in April 1992

(Official Journal of the EC, 1992).

The EC’s procedure for chemical testing was an

important advance in harmonizing the chemical assessment guidelines of the various member nations,

and, subsequently, the 1967 directive and its compo-
— .

nents have served as a model for environmental

regulation in other countries and through international

organizations (e.g., the Organisation for Economic

Co-operation and Development (OECD)) (CEC, 1987).

The EC’s tests mainly identify hazardous chemicals

(box A-2). Qualitative risk assessments can be performed if more data are available, but risk assessments

evaluating new chemicals are usually quite minimal.

The results of these assessments, along with additional

data on the chemical, are circulated among the EC

member states to allow them to challenge the chemical’s approval if they find fault with the information.

These data may also be used to set priorities for testing.

In regulating workplace exposure to hazardous

chemicals, EC directives mandate that employers

perform risk assessments to determine occupational

exposure limits (OELs) for toxic substances.2 At this

point, QRA has been performed by industry for

genotoxic carcinogens for which there are sufficient

data. In these cases, ad hoc expert advisory bodies are

used on a case-by-case basis. Experts also determine

no-observed-adverse-effect levels (NOAELS)

3 for nongenotoxic carcinogens and other toxic noncarcinogenic chemicals on a case-by-case basis. These figures

are subsequently translated into OEL using the appropriate variables (Haigh, 1992).

One EC Council directive governs food additives.

This framework directive requires that the EC consult

a scientific expert body, the Scientific Committee on

Food, on any matter that might affect public health. In

practice, this legislation means that no food additive

can be approved for use in the EC without a positive

evaluation of its safety.

Risk assessments for food additives are generally

qualitative and follow the determination of a NOAEL

on the basis of extensive toxicity data. Industry (as a

supplier or user) must provide the data, and the EC

expert body evaluates them. The scope of the data

required is similar to that required by WHO and other

international groups that evaluate food additives (Official Journal of the EC, 1980). EC guidelines toward

pesticide residues are based on WHO principles. The

EC addresses the approach used in the case of the

majority of pesticides in which the acceptable daily

.

Appendix A: International Risk Assessment I 191

intake (ADI) is based on a chronic effect and this value

is combined with other data to develop a maximum

residue limit (MRL) for a pesticide.

The major thrusts of EC environmental policy are to

ease trade barriers, protect public health, and prevent

chemical accidents. As part of this agenda, the EC has

played a direct role in the international harmonization

of chemical testing and standardization. In addition to

updating and developing new directives, there are

plans under way to develop a set of harmonized

procedures for member states to perform risk assessments (Murphy, 1992). Simultaneously, the EC is also

involved in collaborations with other international

bodies to establish harmonized risk assessment guidelines.

1 International Programme on

Chemical Safety

The International Programme on Chemical Safety

(IPCS) was officially organized in 1980 as a cooperative effort of WHO, the International Labor Organisation (ILO), and the United Nations Environment

Program (UNEP) (box A-3). The program has two

specific roles: to provide an international scientific

consensus for assessments of chemical risks to human

health and the environment and to promote the

development of chemical safety measures by member

states (IPCS, 1992a; Becking, 1992). In addition to

coordinating IPCS’s activities, the program’s small

staff also organizes the meetings of expert committees.

Through these consensus committees, IPCS evaluates

data for its publications. The resources for these

activities come mostly from contributions by individual countries but also horn contributions by WHO and

UNEP (figure A-l).

IPCS develops environmental health criteria (EHC)

that define, whenever possible, guidance values that

member states may use to establish their own exposure

limits for chemicals (Mercier, 1992). An EHC document primarily provides evaluated scientific information on a particular chemical that a member state may

use to implement its own chemical safety program and

determine national exposure standards or regulations.

2 o~~ ~~ ~tS Set ~ ~Ov~m~nt agacie5 t. protect workers from ~~patio~ expo~c to tido~ substances fo~d in the

workplace.

3 The NOAEL for a chemical is the highest dose tested in which no adverse effect is obsenwd. The no-observed-effect level (NOEL) is the

highest dose tested in which no health effect is observed.
192 Researching Health Risks

Box A-2–Research in the European Community

The organizational structure of the European Community for research and technological development covers

many disciplines and promotes joint research between research teams across member states. Since 1984, the

EC has organized those activities through muitiyear framework programs that comprise multipl;e areas of research.

Currently, the EC is in its Third Framework Program (1990-94) and is involved in research in 15 major areas.

The EC’s first framework program was initiated in 1984, but it was the 1987 Single European Act that

amended the founding EC treaty to include specific mention of an EC research and technological development

strategy. With the development of this policy came some important trademarks of EC research. First, the

development of the EC’s framework programs is based on the expert advice of industry, the scientific community,

and public authorities. The EC encourages research participants from these three groups; in addition,

EC-sponsored research requires the collaboration of scientists from at least two different member states.

EC research funding comes in three forms: shared-cost projects in which the EC pays up to 50 20 percent

of the total costs, concerted research actions in which the EC only covers meeting or travel expenses, and in-house

research atone of the four establishments of the EC’s Joint Research Center (JRC). At this point, approximately

80 20 percent of the EC’s research is extramural, and 20 20 percent is intramural. The total amount that the EC

spends on research is less than 5 percent of the total financial resources allocated to research and development

by the EC member states.

Most of the intramural environmental research takes place at the newly organized Environment institute within

JRC. To date, the risk assessment-related research 20 that has taken place has been primarily in the field of

nuclear safety and waste. But, the emphasis on nuclear research has since decreased, thus allowing more

research in other areas reated to the environment and human health.

Much of the research done at JRC is in support of corresponding EC legislation, with the collaboration of the

relevant directorates. The Environment Institute has worked with DG Xl, the Environment Directorate-General, in

classifying various carcinogens, and there is ongoing collaboration to establish harmonized guidelines for chemical

risk assessments. The Environment institute has aso extended its resources to DG V, the Health and Safety

Directorate-General, to generate monographs on chemical carcinogens.

Since 1989, the Environment institute has helped collect data for determining the carcinogenicity of chemical

agents. in conjunction with this work, the institute also maintains a chemical databank the Environmental

Chemicals Data and information Network (ECDIN). This database contains exposure information and data on the

effects of chemicas that are harmful or suspected to be hazardous to the environment or humans, or both. The

database also has a specific data file on carcinogenicity.

The Maastricht Treaty, designed to enhance cooperation among member states, confirms the objective of

EC research and development policy: to strengthen the scientific and technological bases of EC industry and

encourage it to become more competitive internationally. Regarding issues related to the environment and health

in the Fourth Framework Program (1994-98), the EC intends to improve the scientific basis of its environmental

health policies and regulations, in addition to performing quantitative risk assessments for major pollutants.

SOURCES: Commission of the European Communitbs. 1990. completing the single market The removal oftechnkal barriers totrada

within the European Eoonomk Community (Brussels); Commission of the European Communities. 1991. Directorate general X11 for

science, research, and development. Environment 1991-1994, informatbn pachga (Brussels); Commission of the European

Communities. 1992. Research after Maastricht An assassmant, a strategy (Luxembourg, Brusseb; CEC); Commission of the European

Communities. 1992. Treaty on European Union; Commission of the European Communities. 1992. EC researoh funding: A guide for

applicants (Bon, Germany: Economka Verfag); Commission of the European Communities. 1992. Workkrg documents of the commission

concerning the fourth framework program of community activities in the fiald of research and technological development, 1994-199S

(Srws&).
Appendix A: International Risk Assessment I 193

Figure A-l--Contributions to the International

Programme on Chemical Safety, 1980-91

~ Voluntary contributions

_ UNEP

~ WHO

1

1980-81 1982-83 1984-85 1986-87 1988-89 1990-91

SOURCE: World Health Organization, /nternationa/ Prograrmne cm

ChernkdSafety: Progress Report (April 10, 1992), p.5.

Chemical information provided by IPCS is also

available to other specialized organizations and the

United Nations (Stober, 1992).

Through international consultation, IPCS sets priorities for chemicals to be assessed, based on criteria that

include the threat of adverse health and environmental

effects, levels of exposure, and national and international concerns. The evaluation process involves

several steps, including a draft document based on

available scientific literature and a consensus meeting

of independent experts. The groups of experts develop

consensus evaluations that are incorporated into various published documents (the more substantive being

EHCs), more than 140 of which have been produced to

date (IPCS, 1992b). In their deliberations, the groups

consider only the scientific questions. Socioeconomic

and political factors do not have a part in this process

because those risk management decisions are the

responsibility of member states (Becking, 1992).

The final product of this evaluation process (generally an EHC document) can be used as a reference for

making regulatory health policies, especially by those

countries that lack the resources to perform their own

assessments. EHC documents may also be monographs addressing methodological issues. The monographs critically analyze current methods of testing

and approaches to predicting health and environmental

risks and discuss improved testing strategies for

producing reliable and comparable results (IPCS,

1992b).

When IPCS addresses carcinogenicity, it treats both

the issue of mechanism and the need to evaluate

carcinogens on a case-by-case basis. In the WHO

. .

Drinking-water Quality Guidelines and the WHO Air

Quality Guidelines for Europe, QRA methodology is

used for estimating human exposure risks for genotoxic carcinogens (WHO, 1984; 1987a; 1989). In

making those recommendations, WHO adopted some

aspects of the U.S. Environmental Protection Agency

(EPA) quantitative risk assessment methodology. Member states and other regulatory bodies have the

prerogative to perform their own QRA.

IPCS is also responsible for the toxicological

assessments of food additives and contaminants, and

pesticide and veterinary drug residues that are carried

out jointly by WHO (through IPCS) and the Food and

Agriculture Organization (FAO). The results of these

collaborations are recommendations on the levels of

ingestion that are considered to be safe. They are used

for setting standards, primarily through the Codex

Alimentarius Commission (box A-4). Member States

may also use these recommendations in setting their

standards of exposure.

IPCS has a growing interest in exploring QRA

methodology and in using this process to enhance its

work in promoting chemical safety. A comprehensive

EHC document, Principles for the Assessment of

Health Risks from Exposure to Chemicals, is planned

for publication in late 1993; the document examines

QRA and the estimation of risks from epidemiology

and animal data (Secretariat of IPCS, 1992; Becking,

1992). In addition, IPCS is conducting an extensive

survey of human health risk assessment approaches

and procedures in various countries, the results of

which should be available in late 1993. The primary

goal of this project is to harmonize risk assessment

guidelines among different countries. That goal also

applies to several of IPCS’s ongoing and upcoming

collaborations.

The future holds an expanded role for IPCS as a

result of the Agenda 21 document adopted at the

United Nations Conference on Environment and

Development (UNCED) held in June 1992. Planning

and discussions were held prior to the conference,

specifically at a December 1991 meeting of government-
194 I Researching Health Risks

Box A-3--Organization of the International Programme on Chemical Safety

Out of the three cooperating agencies of the International Programme on Chemical Safety, the World Health

Organization serves as the executing body for the program and has an important role in human health risk

assessments. The International Labor Organisation coordinates with the IPCS by providing scientific support and

using IPCS data in an effort to harmonize their methodology for classifying, labeling, and identifying hazardous

chemicals found in the workplace. The United Nations Environment Program participates in IPCS mainly through

its International Register for Potentially Toxic Chemicals, a program that prepares chemical data profiles for risk

evaluation candidates and maintains a list of chemicals undergoing toxicity testing and review. The International

Agency for Research on Cancer also participates in evacuating information on chemicals, but with a focus on

carcinogens.

In addition to its cooperating agencies, IPCS also works closely with other international governmental and

nongovernmental organizations, associations, and professional bodies that are active in the field of chemical

safety. One of the more significant collaborations is with the Food and Agriculture Organization to jointly evaluate

chemicals found in food. The IPCS also works closely with the Organisation for Economic Co-operation and

Development, the European Community, and numerous other bodies involved in chemical risk assessment and

management

IPCS’s central organizing body is located within the WHO headquarters in Geneva, Switzerland, except for

one section located at the National Institute of Environmental Health Sciences, Research Triangle Park, North

Carolina. One of the roles of the central unit is to plan and coordinate work being done by the member states, often

through participating institutions, or individual scientists working with IPCS. Although all member states benefit

from the work of IPCS, only a small number of countries (currently 30) have actually formally agreed to support

the program; fewer still provide financial aid or intellectual resources, or establish participating institutions to work

with the program. Regulatory and research agencies in the United States-namely, the U.S. Environmental

Protection Agency (EPA), the Food and Drug Administration, the National Institute for occupational Safety and

Health, the Agency for Toxic Substances and Disease Registry, and the National Institute for Envvironmental Health

Sciences--make a significant contribution to the work of IPCS, with EPA being prominent in the area of risk

assessment methodology.

SOURCES: International Propmon Chemical Safety (l PCS). 1992a. Information brochure; International Programmeon Chemfcal Safety.

1992b. Progreea report by the Director-General, 45th Wrid Health Amembfy. Geneva: WHO; Becldng, G. 1992. International Programme

on Chemical Safety Dew40pment of Environmental Health Criteria for kd. Research Triangle Pam NC.

designated experts, convened at the request” of the Organisation for Economic Co-operation

Preparatory Committee for UNCED. As a result,

Chapter 19 of Agenda 21 calls for developing an

intergovernmental mechanism for promoting risk assessment and management of chemicals internationally (UNEP, 1991).

In its new capacity under the Agenda 21 mandate,

IPCS will coordinate an intergovernmental forum,

sometime in late 1993, on the environmentally sound

management of chemicals. IPCS’s enhanced role will

also entail undertaking technical work in this area,

providing mechanisms for ensuring coordination of

relevant international activities, as defined by UNCED

(IPCS, 1992b). IPCS will use a series of advisory

conferences to further define its new role.

.

and Development

The Organisation for Economic Co-operation and

Development (OECD) is an intergovernmental organization of 23 industrialized countries and the EC (box

A-5). Several Central and Eastern European countries

participate in the activities on an observer basis. OECD

was established in 1%1 to provide a forum for member

counties to discuss issues of common interest and

coordinate and harmonize their national policies. In

1970, this forum was officially expanded to include

environmental issues with the establishment of the

Environment Committee (OECD, 1989). To address

the control of chemical risks to health, the OECD

Environment Committee established the Chemicals
Appendix A: International Risk Assessment I 195

Box A--Codex Alimentarius Commission

The Codex Alimentarius Commission (CAC) is an expert body jointly supported by the Food and Agriculture

Organization (FAO) and the World Health Organization (WHO), both of which are specialized agencies of the

United Nations. The codex was established in 1962 to protect consumer health and ensure fair practices in the

food trade. Standards promulgated by CAC most often serve as references and recommendations for less

developed countries that lack resources to determine their own food standards.

CAC is an intergovernmental body composed of 137 countries. It carries out its duties related to food

standards through a variety of committees. Three committees are involved in qualitative risk assessments: the

Codex Committee on Pesticide Residues (CCPR), the Codex Committee on Food Additives and Contaminants

(CCFAC), and the Codex Committee on Residues of Veterinary Drugs in Foods (CCRVDF).

The bodies that complete scientific evaluations of chemicals (but are not a part of CAC) are the Joint

FAO/WHO Meeting on Pesticide Residues (JMPR) and the Joint FAO/WHO Expert Committee on Food Additives

(JECFA). JMPR, which is composed of scientists invited by both WHO and FAO, determines acceptable daily

intake (ADIs) for additives and contaminants in food and maximum residue limits (MRLs) for pesticides in food.

The scientists invited by WHO use toxicological information to develop ADIs for pesticide residues whereas FAO

committee members use Good Agricultural Practices data to develop MRLs for pesticide residues in food

commodities. The information developed by JMPR, which is purely scientific, is passed on to CCPR for

consideration in establishing standards.

Participants in sessions of CCPR are delegates from member States. CCPR considers the recommendations

of JMPR and generally adopts MRLs that JMPR has developed. These recommendations go through a long

stepwise procedure that, in most cases, ultimately results in the adoption of MRLs by CAC. CAC and its committees

are much more politically oriented and make recommendations about exposure after considering nonscientific

variables (Kaferstein, personal communication). The entire procedure surrounding the development and adoption

of MRLs takes several years to complete.

JECFA operates in much the same way as JMPR, except that FAO representatives develop specifications

for the identity and purity of food additives. The JECFA’s Scientific evaluations are passed along to CCFAC, which

operates in a manner similar to that of CCPR. Principles for assessing food additives and contaminants and for

pesticide residues have been prepared by the International Programme on Chemical Safety and published by

WHO.

SOURCES: World Health Organization. Description of the Joint FAOANHO Expert Committee on Food Additives and the Codex

Afimentarius Commission, 1992; World Health Organization. Guidelines for Drinking Water Quality, Vol. 1 (Geneva: WHO, 1984); World

Health Organization. Prinaples for the Safety Assessment of Food Additives and Contaminants in Food. IPCS Environmental Health

Crfteria No. 70; Genev% V/odd Health Organization, 1987; World Health Organization. Description of the Joint FAO/WHO Meeting on

Pesticide Residues (JMPR) and the Codex Alimentarius Commission, 1992b.

Programme in 1971. In its evaluations, the Chemicals technologies come into practice (OECD, 1989; Visser,

Programm e does not perform risk assessments; rather,

it focuses more on identifying chemicals that pose

hazards to both man and the environment and the needs

of management. One of the Chemical Programme’s

early accomplishments was the creation of the Chemicals Testing Program in 1978 to prepare “state-of-theart” reports on the best testing methods for generating

data useful for the hazard assessment of a chemical.

The program test developed guidelines and these are

being continuously updated as new methods and

1992).

In addition to guidelines for assessing new chemicals, the Chemicals Programme has also promulgated

principles for good laboratory practice (GLP) (Visser,

1992). The testing guidelines, in combination with

GLP, provided support for the decision by the OECD

council on mutual acceptance of data among member

countries. That decision states that data generated

during the testing of chemicals in an OECD member

country in accordance with OECD test guidelines and
196 I Researching Health Risks

Box A-5--Organization of the OECD

The central authority of the Organisation for Economic Co-operation (OECD) and Development is the Council,

a body composed of representatives of each of the member countries and the CEC. The Council and OECD itself

operate by consensus in part because OECD is not a supranational organization but a center for discussion in

which governments express their views, share information, and seek to harmonize policies. in some instances,

the Council may wish to formally state its consensus, and in those eases, it publishes a decision or a

recommendation. Because the Council works by consensus, its actions often take a long time to prepare. As a

basis for its decisions, the Council adopts the standards employed by its most advanced members. consequently,

decisions are more substantive for countries with less developed environmental legislation and regulations. in

contrast to decisions, recommendations are not legally binding, but countries must consider them very seriously.

Environmental issues are addressed through both mechanisms.

Much of the Council’s supporting work is done by working parties, expert advisory groups, and committees.

Committees that cover expansive topics are further divided into specific groups, such as the Chemicals Group.

The main focus of the Chemicals Programme is generating information about specific chemicals, preventing and

reducing the risk of exposure to chemicals, and harmonizing chemical testing procedures to reduce trade barriers

and minimize duplicative testing among member countries.

SOURCES: Organisation for Economic Co-operatbn and Devebpment, Environment Directorate, OECD Co-operatlva Risk Reduction

Activities. Paris, 1992; Organisation for Economic b-operation and Development. OECD Environment Directorate. Chembais Divisbn,

The OECD Chemicaia Programme. Paris: OECD, 19S9.

GLP shall be accepted in other member countries for basis, using gross national products as a guide for

purposes of assessment and other uses relating to the

protection of man and the environment (OECD, 1989).

OECD member countries that comply with the

council’s decision and the recommendations for testing guidelines and GLP apply these approaches to

several types of chemicals, including pesticides, drugs,

and food additives. The OECD recommendations

present guidelines for testing chemicals, but not

candidates for testing. The latter are determined by

member countries, each of which uses the data and

performs a risk assessment on that chemical to

determine a level of risk.

Another important OECD endeavor relating to

chemical management is collecting and disseminating

information about existing chemicals. Through the

1987 Screening Information Data Set (SIDS) project,

the OECD Chemicals Programme is coordinating a

multicountry effort to develop data on a number of

high production volume (HIV) chemicals, generally

chemicals that existed before recently introduced

regulations required large amounts of data prior to

production and marketing. Basic information is unavailable on many of these chemicals, and to promote

cooperation and reduce costs, the burden of testing is

divided among member countries on a voluntary

dividing the tasks. The United States plays a prominent

role in this international joint effort, assuming responsibility for testing 25 percent of the SIDS chemicals

(Van boy, 1992).

Once SIDS data have been collected and evaluated,

they are placed in the United Nations International

Register for Potentially Toxic Chemicals, which is

available worldwide. OECD will collaborate with

IPCS for a more comprehensive review when enough

data are collected or generated, and OECD member

countries will jointly assess the data gathered for the

HPV chemicals. The data are also evaluated to

determine if risk reduction measures should be taken

(Visser, 1992).

Developing risk reduction strategies for existing

chemicals is fast becoming an important part of the

Chemicals Pro-e’s function. In this effort, OECD

uses risk assessments performed by member countries;

in addition, IPCS publications review the life cycle of

specific chemicals and examine current national risk

reduction and chemical control measures. Subsequently, OECD prepares a strategy for regulating and

reducing exposure to toxic chemicals. This risk

reduction activity was initiated in May 1990 with a

five-chemical pilot project. A meeting in November
Appendix A: International Risk Assessment I 197

1992 determined that the OECD approach to risk

reduction would rely on sharing and exchanging

information on the management of specific chemicals.

Information concerning national risk reduction strategies will make comparative analyses possible and may

assist member countries in developing their national

strategies (OECD, 1992).

Currently, OCED is collaborating with IPCS to

develop harmonized risk assessment guidelines and

explore quantitative risk assessment methodologies.

This collaboration is significant in promoting the use

of risk assessment, but to date OECD’s more important

role has been in harmonizing chemical assessment

guidelines. These efforts will facilitate trade among

member countries and, by cooperating with other

countries and international organizations, will increase

the body of knowledge on hazardous chemicals.

 International Labor Organisation

The International Labor Organisation has been a

specialized agency of the United Nations since 1946,

but it has been in existence since 1919 (box A-6). ILO

is a tripartite body that serves as an international

meeting ground for delegates from governments,

workers, and employers, and as a central source of

information on labor and social policy (ILO, 1991).

ILO has examined many issues in the workplace,

including occupational safety and health. In addressing

occupational exposure to hazardous chemicals, ILO

does not perform risk assessments or set occupational

exposure limits (OELs). Rather, it promulgates statements based on information that has already been

compiled by such bodies as PCS, which it helps to

support (Clevenstine, 1992). ILO’s work is primarily

targeted toward disseminating information to developing countries that lack the necessary resources and

expertise to monitor occupational exposure to hazardous chemicals (Obadia, 1992).

 Pan American Health Organization

The Pan American Health Organization (PAHO) is

a regional office of the World Health Organization and

thus part of the United Nations. Incorporated into

WHO in 1949, PAHO acts as a public health agency

serving Latin American and Caribbean countries.

Together with WHO, PAHO and other regional offices

including implementing and establishing programs,

strengthening health services, and training health

workers (PAHO, 1992).

PAHO’s policies are determined by its governing

bodies: the Pan American Sanitary Conference, the

Directing Council, and the Executive Committee. Each

authority includes representatives from member states

and is responsible for approving recommendations to

the members of PAHO for improving the standards of

health for their particular countries and for the region

as a whole (PAHO, 1992).

PAHO is involved in a number of activities in the

area of environmental health, including the preparation

of technical and training materials on toxicology,

environmental epidemiology, and risk assessment.

The organization gives special emphasis to reducing

environmental and occupational exposures to pesticides and heavy metals (PAHO, 1992). With regard to

standards generated from risk assessments of exposure

to various chemicals, PAHO generally refers to values

developed by WHO/IPCS and the Codex Alimentarius

Commission.

PAHO not only relies on risk assessments conducted by WHO and its supporting agencies, but it also

participates in the process itself through its Pan

American Center of Human Ecology and Health in

Mexico. One aspect of the center’s role is to provide

relevant authorities with training in different aspects of

risk assessment. For example, the center offers courses

on using risk assessment for regulatory purposes and

to identify a population at risk of exposure to toxic

chemicals. Quantitative risk assessment is approached,

but other options are usually pursued because there is

not enough information available to conduct QRA.

Much of the training done at the Pan American Center

is supported by financial and expert assistance from

EPA (Finkelman, 1993).

Another facet of PAHO’s activities is coordinating

research on various aspects of environmental health,

including quantitative risk assessment for carcinogens.

Under PAHO oversight, QRA has been conducted for

some heavy metals (e.g., lead and arsenic) and a few

pesticides. At this point, no QRA has been completed

for food additives. Funding for this research generally

comes from sources outside PAHO, but PAHO and the

Pan American Center act as facilitators.

plan and coordinate health activities on a global basis,
198 I Researching Health Risks

Box A-6-Organization of the International Labor Organisation

The International Labor Organisation (ILO) has a number of operating mechanisms, including a yearly

general assembly (International Labor Conference), an executive council (Governing Body), and permanent staff

(International Labor Office). ILO also employs subsidiary bodies such as regional conferences, industrial

committees, and meetings of experts. These subsidiary bodies, coupled with formal contacts between ILO and

its constituents, provide the impetus for drafting international standards, Suoh standards are prepared by ILO and

adopted by the International Labor Conference after open discussion. ILO reports on compliance among

members, which is monitored by panels of experts.

At the yearly assembly, members pass the standards in the form of conventions or recommendations.

Conventions require ratification by member states; the ratification serves as a pledge by a state that it will adapt

its national legislation accordingly. Recommendations do not require ratification; they serve mainly as guidelines

for members in developing their policies for the workplace. In both instances, ILO does not have the power to

enforce its labor standards, but it does monitor compliance.

In addition to its conventions and recommendations, ILO produces numerous publications, including the

Encyclopedia of Occupational Health and Safety, which contains information about many aspects of workers’

health, accident prevention, and improvement of occupational health. ILO also supports the International

Occupational Safety and Health information Center. The center evaluates relevant data on occupational safety

and health, making its databases, bibliographies, and analyses available worldwide through on-line computer

access, CD-ROM, and printed publications.

SOURCE: The International Labor Organization. F-for Amedoans. 1SS1.

QUANTITATIVE RISK ASSESSMENT The Dutch advocate a conservative approach in their

IN OTHER COUNTRIES

 The Netherlands

In the Netherlands, regulators use quantitative risk

assessments to determine the probability of risks to

human health from carcinogens that have been definitively categorized as genotoxic. Figure A-2 outlines

the Dutch process for risk assessment. The method is

currently used by all Dutch agencies involved in health

risk assessments and is based on knowledge about the

mechanism of action of a chemical carcinogen.

In the Dutch QRA process, researchers initially

evaluated a chemical to determine its genotoxicity in

animals they use. They use subsequent information

about functional effects and chemical structure, the

results of bioassays, and other relevant data to lessen

uncertainties relating to the carcinogen’s genotoxicity

in humans. When it is impossible to eliminate completely the risk of exposure to a genotoxic carcinogen,

the Dutch opt to use a very simple linear extrapolation

model to determine a dose-response value for human

exposure (Kroes, 1979, 1987; Health Council of the

Netherlands, 1980, 1988).

regulatory actions. In performing QRA, they generally

prefer a basic, conservative linear extrapolation model,

based on the lowest dose that produces an effect, unless

experimental data suggest otherwise (Kroes, 1987). If

there are sufficient data, they may use more appropriate extrapolation models, which the Dutch feel creates

more flexibility in their risk assessment process. At

this time, the Dutch have considered highly sophisticated extrapolation models. But, because the data that

are available are often insufficient and variable, Dutch

regulators believe that such highly developed models

would create a false sense of certainty (Swaen, 1992,

1993). The Dutch defend their use of a simple linear

extrapolation of animal data to humans with several

arguments: linear extrapolation is a very conservative

approach; the metabolic rate of humans is lower than

that of animals and is also inversely proportional to age

and weight; DNA repair processes appear proportional

to body weight; and the sensitivity of man to known

human carcinogens is about equal to that of experimental animals (Kroes, 1987).

In comparison to genotoxic chemicals, carcinogens

that act by a nongenotoxic mechanism are evaluated by

the same process but using a different pathway (figure
Appendix A: International Risk Assessment 199

Figure A-2—Risk Assessment Procedure for Carcinogens in the Netherlands

Genotoxicity

in systems

— +~

—? —+

Additional

information

+ Chemical structure

+ Biotransformation

+ Toxicokinetics

+ Functional effects

+ Morphological effects

+ Results of bioassay

+ Results of limited

in vivo tests

+ Results of in vitro

(promotion) test

-1

Genotoxicity

to man

‘~

# E

Human

studies

? ~ warrant

other

decision

Human risk

assessment

Linear extrapolation

“Appropriate” extrapolation

\. 3. Conventional food

toxicology approach

SOURCE: R. Kroes, Contributions to toxicology towards risk assessment of carcinogens. Mives of Toxic010gy80:224-228, 1987.

A-2). The final risk estimate for a nongenotoxic

chemical carcinogen constitutes a NOAEL divided by

an appropriate safety factor of 10 to 1,000, depending

on the amount of uncertainty in the data. The final

value represents an acceptable daily intake4 for the

substance.

Several agencies in the Netherlands employ QRA as

a means of regulating human exposure to carcinogens,

but those health risk assessments are not performed by

the agencies themselves. Instead, expert advisory

committees recommend limits on exposure using a

‘‘ weight-of-the-evidence’ approach on a case-by-case

basis. In the Netherlands, Advisory Committee 246 of

the Dutch Health Council, assisted by ad hoc experts

in the field, addresses questions about the risk of

carcinogenic compounds to the general population. In

its deliberations, the committee usually considers the

National Institute of Public Health and Environmental

Hygiene’s review of the literature on suspected carcinogens and the institute’s proposals for classifying and

assessing the risk of these agents. The Ministry of

Welfare, Health, and Cultural Affairs and the Ministry

of Housing, Physical Planning, are the regulatory

bodies that most often request advice from Committee

246 concerning human health risks from exposure to

carcinogen’s (Swaen, 1992, 1993).

The responsibility for establishing occupational

health standards lies with the Ministry of Social Affairs

and Employment and another expert advisory panel,

the Dutch Expert Committee on Occupational Standards (DECOS). Together, these bodies formulate

priorities regarding chemical evaluation. DECOS fulfills its role by determiningg a health-based occupational exposure limit (OEL); in turn, a separate

tripartite committee evaluates the economic and social

impact of the OEL (Swaen, 1993). After considering

recommendations from DECOS and the tripartite

committee, the ministry then establishes a maximum

accepted concentration (MAC), the greatest exposure

level permitted for a chemical carcinogen in the

workplace. The MAC is similar to the ADI, but it

applies to the workplace rather than to exposures from

food or the environment.

Most risk assessment-related research is conducted

through government institutes, universities, or private

org anizations. The Dutch Government supports no

internal research facilities; instead, it provides extramural grants. At this point, a wide range of topics is

being explored (van der Heijden, 1992).

 Canada

In 1988, the enactment of the Canada Environmental Protection Act (CEPA) created a mandate for

carrying out risk assessments. (Up to that point, QRA

had been conducted only for a few select chemicals.)

As a result of CEPA, Canada has developed an agenda

4 This value rcflecta a threshold or level at which there is no longer evidence of harmful effects caused by expoaure to a carcinogen or othcm

toxic substance.
200 I Researching Health Risks

to assess 44 potentially toxic chemicals by March 1994

and to perform QRA if they are found to be toxic

(Granville, 1992, 1993).

CEPA and other recent developments in risk assessment have led to numbers of increasing examples of

nationally or provincially developed exposure standards in Canada Historically, Canadian regulatory

bodies have relied on exposure standards and occupational exposure limits generated by other countries

(e.g., Sweden, Denmark, and the United States) and

organizations (e.g., WHO and the American Conference of Governmental and Industrial Hygienists). In

some instances, the Canadian Government has not

considered using risk estimates developed by the U.S.

EPA because Canadian authorities see these figures as

overly conservative. They also contend that the

adversarial nature of the political system in the United

States can distort the evaluation of scientific data

(Granville, 1992 and 1993).

In regulating chemical substances, the responsible

Canadian authorities do consider carcinogenic mechanisms. For nongenotoxic chemicals, researchers determine a NOAEL and tolerable daily intake (similar to

an acceptable daily intake). Conversely, for genotoxic

carcinogens, authorities previously used unspecified

methods under a policy that aimed to reduce health

risks as much as possible. The mandate to perform

assessments of toxicity for chemicals under CEPA has

since given rise to a need for an established QRA

process in Canada. In response, Canadian Federal

regulatory agencies have adopted QR.A methodologies, although their QRA process is constantly evolving as new information is incorporated.

At this time, the QRA approach being taken under

CEPA for genotoxic carcinogens involves estimating

an ‘‘exposure/potency index’ (EPI). This index compares the expected exposure of a population with an

estimate of the potency of the carcinogenicity of a

chemical. The potency estimate is derived from

experimental epidemiologic or animal data by determining the dose that would cause a carcinogenic

response in 5 percent of the test subjects in the study.

The resulting EPI provides the agencies with a tool to

prioritize possible future control options (Granville,

1992, 1993; Health and Welfare Canada, 1992). In

general, QRA in Canada is performed on a case-bycase basis, and the most appropriate model is chosen

in each instance. The Canadians believe that allowing

for flexibility in the use of models will lead to a more

accurate assessment.

Within Canada, the separate provinces have jurisdiction over occupational health matters (including the

setting of OELS), and most public health and environmental issues within a province’s borders are subject

to various Federal/Provincial agreements and legislative mandates. The Canadian Government regulates

issues of national relevance, under such legislation as

the Food and Drugs Act and CEPA.

Canada has two primary national regulatory agencies involved in environmental protection. The Department of the Environment (called Environment Canada)

regulates the quality of the environment (e.g., ambient

air and water), and Health and Welfare Canada (HWC)

oversees the human health component with activities

such as generating air and drinking water quality

guidelines. HWC is also responsible for regulating

hazardous substances in food and drugs, as well as

providing advice to other agencies about human

exposure to pesticides and hazardous consumer products. Risk assessment, both qualitative and quantitative, is widely conducted within HWC (Granville,

1992, 1993; St-Aubin, 1992, 1993).

As noted above, regulating hazardous substance in

the workplace falls predominantly under the direction

of the individual provinces. The Canadian Government, however, is responsible for Federal workplaces

and federally regulated industries (e.g., interprovincial

transportation and communications) (St-Aubin, 1992,

1993). It uses primarily expert judgment and, in the

case of Ontario, advisory committees such as the

Ontario Joint Steering Committee on Hazardous Substances in the workplace. That committee, which

makes recommendations to the Ontario Minister of

Labor, also comprises a task force that evaluates the

process and criteria for establishing exposure values

and limits for hazardous substances in the workplace

(St-Aubin, 1992, 1993). Because each province adopts

its own OELs, they vary across Canada. The ministers

responsible for such regulation in the provinces meet

regularly, but they do not always coordinate their

choices of OELs.

Risk assessment research in Canada is evolving, and

a wide range of sponsors and topics, such as modeling

and mutagenicity, are being actively explored within

the research agenda. Health and Welfare Canada

performs the majority of health assessment research
Appendix A: International Risk Assessment 201

and provides several extramural grants to universities

and private organizations. Overall, in comparison to

the amount of risk assessment-related research conducted in the United States, the level of such research

in Canada is significantly less and on a much smaller

scale (Granville, 1992, 1993).

 United Kingdom

In the United Kingdom, the government does not

use QRA to generate a probability for the risk of cancer

from exposure to certain chemicals. British regulators

place little reliance on the quantitative assessment of

carcinogens because they believe that the statistical

models used to extrapolate dose-response effects from

animals to humans are not valid and are fraught with

uncertainty (Department of Health, 1991).

Regulatory approaches to controlling exposure to

chemical carcinogens in the United Kingdom are based

on mechanistic considerations. If a chemical acts by a

genotoxic mechanism, the British Government assumes, as a matter of prudence, that the compound

does not have a threshold; that is, any exposure will be

associated with an increase in the risk of cancer in the

exposed population. If a nongenotoxic mechanism is

involved, regulators consider it possible to identify a

safe level of exposure, provided that they can understand the mechanism involved (Department of Health,

1991).

Chemicals displaying genotoxicity are evaluated

using expert judgment and a weight-of-the-evidence

approach. In evaluating such compounds, expert

advisory committees consider all of the available

evidence (including human data, animal data, mutagenicity data, and structure/activity relationships).5 If

they conclude that the compound should be considered

a potential human carcinogen that acts by a genotoxic

mechanism, they then recommend action to reduce

levels of exposure to as low as is reasonably practical

or to eliminate exposure entirely (Fielder, 1992, 1993).

As noted earlier, the United Kingdom does not

endorse the use of mathematical models to generate

risk estimates for genotoxic carcinogens. Such models

have been developed to relate responses from exposures in high doses in animal tests to low-dose human

exposure. Although U.K. researchers say they are

interested in mathematical models, U.K. regulatory

authorities and their expert advisers remain unconvinced about their utility. They note several reservations: no model has been validated; the data used with

the models are incomplete or inappropriate; the models

are based more on mathematical assumptions than on

established biochemical mechanisms; risk estimates

vary widely depending on the model us@ and the

models give the impression of precision, which cannot

be justified from the approximations and assumptions

on which they are based (Department of Health, 1991).

For suspected carcinogenic compounds operating

through well-understood nongenotoxic mechanisms,

researchers evaluate animal studies to determine the

NOEL, which is then divided by a safety factor to

derive an ADI. The safety factor reflects the uncertainties of extrapolating findings in animals to humans and

of interindividual variation (Department of Health,

1991). ADIs are also used to calculate maximum

residue levels for pesticides on food (Fisher, 1992).

In the United Kingdom, the Health and Safety

Executive is responsible for all aspects of occupational

safety. The work of the Executive is overseen by the

Health and Safety Commission. The expert Working

Group for the Assessment of Toxic Chemicals (WATCH),

which reports to the Commission’s Advisory Committee of Toxic Chemicals (ACTS), reviews the scientific

evidence required to establish occupational exposure

limits. In its evaluations, WATCH considers only

scientific information, but ACTS may also assess the

socioeconomic aspects or technical feasibility of

controlling exposure. As a consequence, two types of

occupational exposure limits are established in legislation: occupational exposure standards and maximum

exposure limits. Occupational exposure standards are

set at a level at which there is no indication of risk to

the health of employees; a maximum exposure limit is

set when such a level cannot be identified and any

exposure may involve some residual risk, or when

such a level cannot be achieved in practice and

socioeconomic factors need to be taken into account

(Health and Safety Executive, 1992).

The Ministry of Agriculture, Fisheries, and Food

specializes in setting tolerances for chemicals in food.

For pesticides and nongenotoxic carcinogens, the

s Structure-activity relationships compare the chemical structures of substances to make inferences about toxicity and identify candidates

for further testing (see ch. 3).
202 I Researching Health Risks

ministry formulates maximum residue levels using

ADIs. Instead of performing a QRA for genotoxic

carcinogens, exposure to those pesticides is either

eliminated or reduced to the lowest practicable levels

(Fisher, 1992).

Finally, the Environment Food (Medical) Division

of the Department of Health advises the British

Government on the health aspects of chemical toxicity

in food, consumer products, and the environment in

general. In this regard, the division provides the

Secretariat with a number of independent expert

advisory committees, such as the Committee on

Carcinogenicity of chemicals in Food, Consumer

Products, and the Environment, which advises the

British Government on all aspects of chemical carcinogenicity. In 1991, this committee revised its guidelines

for evaluating chemicals for carcinogenicity (Department of Health, 1991).

 Germany

In Germany, QRA is relatively new to the regulatory

field (Turck, 1992, 1993). Previously, German regulatory authorities did not quantify the risk from exposure

to carcinogens or other toxic substances because the

inherent acceptance of a qualitative risk estimate does

not comply with principles established by German

environmental laws (Turck 1992, 1993). But, as the

need for a quantitative form of risk assessment became

increasingly necessary, the Germans surveyed QRA

methodologies used by other countries.

The QRA methodology of the U.S. EPA has had a

strong impact on the German regulatory committees

exploring the process, but the committees have not

mandated use of the U.S. methodology. Believing that

a case-by-case determination of candidates for QRA

leads toward more accurate estimations of risk the

committees have advocated greater flexibility in the

choice of modeling. Despite these precautions, however, there are still many critics of QRA in Germany.

The notion of allowing any degree of risk to humans

diverges from the German emphasis on eliminating

dangers to the public’s health, a basic objective of

German environmental laws. To date, little QRA has

been completed, and intense debate and discussion

regarding the ideas and methodology surrounding

QRA are currently under way (Turck 1992, 1993;

Pott, 1992).

Although German authorities do not widely practice

QRA, strict regulation of known human carcinogens

does occur. To date, all proven human carcinogens

have been subjected to stringent regulations focusing

partially on the best available technology (BAT) or, in

the case of drinking water regulations, on international

EC directives. It is also commonplace for decisions

concerning the regulation of chemical carcinogens and

other hazardous chemicals in Germany to be made by

multipartite expert committees on a case-by-case

basis. Those committees use a NOAEL/ADI approach

to QRA for other hazardous noncarcinogenic chemical (Turck, 1992, 1993).

In Germany, expert advisory committees and other

Federal agencies provide regulatory agencies with

information and recommendations on exposure levels

for hazardous chemicals and carcinogens. The recommendations of the advisory committees are not binding; as regulatory bodies, only the ministries are

capable of requiring compliance with exposure standards through ordinances or by law (Turck, 1992, 1993).

One of the better known advisory bodies is the

Deutsche Forschungsgemeinschaft (DFG), or German

Research Agency. This body receives financing from

the German Government to engage groups of experts

to study issues pertaining to occupational exposure to

toxic substances. Within DFG is a commission that

uses qualitative risk assessments of carcinogens and

makes recommendations to the Ministry of Labor on

maximum allowable concentrations (MACs) of noncarcinogenic hazardous chemicals in the workplace.

Those MAC values are similar to ADIs for pesticides

or food additives, except that no safety factors are

applied. The list of values in Germany is similar to

(though not necessarily in number) the OELs set by the

U.S. Occupational Safety and Health Organization

(OSHA) in the United States (Brickman et al., 1985;

Greim, 1992; Turck, 1992 and 1993).

In addition to the Ministry of Labor, other German

regulatory agencies include the Ministries of the

Environment and of Health. The Ministry of the

Environment legislates emissions, air pollutants, food

contaminants, and the overall state of the environment;

the Ministry of Health determines standards for

exposure to hazardous chemicals in drinking water,

food, and drugs and establishes pesticide residue levels

in food. As is the case in many countries, Germany

often considers other exposure levels that have been
Appendix A: International Risk Assessment 1203

established by other bodies or nations for the purpose

of setting standards for hazardous chemicals. Although

German authorities give primary attention to values

generated by WHO, they also consider, although to a

lesser extent, values generated in the United States.

When determining ADIs for food contaminants or

MRLs for pesticides found in food, the expert committees that advise the Ministry of Health often consider

values promulgated by the Codex Alimentarius Commission (box A-2).

 Denmark

Regulatory agencies in Denmark employ QRA to a

limited extent when determining exposure standards

for carcinogens (Dragsted, 1992). In cases in which a

toxic substance is a potential candidate for QRA,

substitutes for that chemical are first examined in an

effort to eliminate exposure to the original carcinogen,

Subsequently, QRA is used when a nonthreshold,

genotoxic carcinogen cannot be replaced by another

chemical, if the necessary data exists (Larsen, 1993),

In the control of toxic substances, Danish regulatory

authorities recognize carcinogenic mechanisms (and

thus apply QRA methods to genotoxic carcinogens),

and determine ADIs for nongenotoxic carcinogens and

other noncarcinogens. The basic toxicological data

used to generate exposure standards are generally the

same across the various regulatory agencies in

Denmark, but the reamer in which the data are used

differs according to the problem being addressed. The

Danes also use a case-by-case approach when evaluating data for a toxic substance, although reliance on

expert advisory committees is not as extensive in

Denmark as in other countries, such as the United

Kingdom (Carlsen, 1992).

The central authorities or, to a much lesser extent,

regional authorities are the most likely source of risk

assessment of toxic substances (Carlsen, 1992). One of

the central regulatory bodies in Denmark is the Danish

Environmental Protection Agency, which has jurisdiction over the monitoring of human exposure to

pollutants in air and drinking water. Like other

regulatory agencies in Denmark, the Danish EPA

attempts to harmonize and modify its exposure standards according to guidelines and data published by

WHO, OECD, and the EC (ATV, 1992a). QRA is used

specifically in establishing values for exposure limits

(tolerable daily intakes) for genotoxic carcinogens that

cannot readily be eliminated from drinking water

(Carlsen, 1992).

Currently, Denmark’s National Food Agency of the

Ministry of Health administers regulations for food

additives. ADIs are determined by using principles

outlined by the Joint FAO/WHO Committee on Food

Additives to form the basis of permitted use levels

(Larsen, 1992a). Denmark bans all food additives that

are characterized as genotoxic carcinogens; it sets

ADI’s for nongenotoxic carcinogens and other noncarcinogenic agents.

Food contaminants and pesticide residues are also

regulated by the National Food Agency. The agency

uses guidelines promulgated by the Joint WHO/FAO

Committee on Pesticide Residues and risk assessment

to determine such exposure limits as tolerable daily

and weekly intakes for various contaminants and ADIs

and minimum residue levels for pesticides (Larsen,

1992). QRA has been used for proven genotoxic

carcinogens but only to a very limited extent. One

major reason for its constrained use is the lack of

proper toxicological data, especially from wellconducted studies. Such data are deemed unnecessary

for performing a scientifically sound QRA. In 1993,

assessment and regulation of pesticide residues will

gradually be transferred to the EC (Larsen, 1993).

Occupational exposure standards (e.g., threshold

limited values) are published by the Directorate of

National Labour Inspection after discussions and

agreements with the authorities and representatives of

labor and employer organizations (ATV, 1992b). As

part of those negotiations, the parties consider threshold limit values proposed in the United States and

similar MAK (Maximale Arbeitsplatz Koncentrationen) values established by the German Research

Council (Poulsen, 1992).

 Sweden

Sweden uses QRA to determine exposure risks, but

Primarily it employs quantitative approaches for assessing the impact of industrial “point-source’ emissions, QRA is almost nonexistent in the methods used

to determine the carcinogenic risk of pesticides and

occupational chemicals. Yet, despite this limited use of

QRA, some parts of the Swedish regulatory community have expressed the desire to “modernize [Sweden’s] treatment of chemical carcinogens and have risk
204 Researching Health Risks

assessment become common practice (Nilsson, 1992

and 1993).

In the general process Sweden uses to evaluate

chemicals, the initial step is identifying a carcinogen or

toxic substance, which is termed “hazard identification” in the United States. At this point, Swedish

authorities pursue a weight-of-the-evidence approach

as they consider published data and publications by the

International Agency for Research on Cancer in

deciding whether to classify a chemical as a carcinogen. After this initial determination, a carcinogen may

be handled in different ways, depending on its path of

exposure to humans and the agency that regulates it.

The Swedish Government generally regulates genotoxic carcinogens to ensure the lowest possible levels

of exposure. They evaluate compounds with a nongenotoxic profile through a QRA. Regulators calculate

either NOAEL or a lowest-observed-adverse-effect

level (LOAEL) using available data. ADIs in turn are

used to calculate maximum residue levels of pesticides

in food and OELs for occupational carcinogens.

One of the more prominent regulatory organizations

is the Swedish Environmental Protection Agency. It is

comparable to the U.S. Environmental Protection

Agency, except that chemicals entering into commerce

for national and international trade is handled by

another body, the National Swedish Chemicals Inspectorate. The Swedish EPA sets exposure standards for

a variety of carcinogenic and noncarcinogenic chemicals and uses QRA to assess the risks from human

health for industrial emissions. Like other European

countries that practice QRAs, Sweden considers carcinogens with a pronounced genotoxic mechanism as

prime candidates for QRA (Ahlborg, 1992), As part of

that process, the Swedish EPA performs mathematical

modeling to extrapolate from the responses of animals

exposed to high doses of potential carcinogens to

humans exposed to lower doses. The agency also

evaluates these carcinogens using a case-by-case

approach in which each chemical is assessed individually, as opposed to the more generic approach common

in U.S. regulatory agencies, which use guidelines for

risk assessments (see ch. 5).

The National Swedish Chemicals Inspectorate (NSCI)

regulates human exposure to all chemicals used in

trade, including pesticides. In the case of new chemicals, NSCI places the burden of testing on industry. For

existing chemicals, once NSCI has identified a carcinogen, it looks for a possible replacement so that the

chemical carcinogen may be banned. In addition, it

permits low-potency carcinogens (often nongenotoxic) to be used only by professionals, in conjunction

with protective equipment. Use of these carcinogens in

nonprofessional settings is illegal, a policy similar to

the zero-tolerance approach promulgated by the Delaney clause in the United States. NSCI does not

perform quantitative risk assessments (Nilsson, 1992,

1993).

The Swedish Food Authorities monitor, the level of

pesticide residues and additives in food. In assessing

carcinogens, this body turns to the Codex Alimentarius

Commission, the Joint Meeting on Pesticide Residuies/

World Health Organization, and the Joint Expert

Committee on Food Addictives/World Health Organization for information on ADIs and maximum residue

levels. The Food Authorities evaluate carcinogens and

other hazardous chemicals case-by-case. The also

work to enforce good agricultural practices as dictated

by the EC.

The Swedish National Board of Occupational Safety

and Health regulates exposures in the workplace. It

also categorizes carcinogens and uses these classifications to create the Swedish list of occupational

exposure limits, which are similar to standards published by the U.S. Occupational Health and Safety

Administration.

 Italy

Compared with the United States, chemical regulation is less developed in Italy.6 To date, the Italians

have not attempted QRA for chemical carcinogens

(Forni, 1992), although they have explored the statistical modeling used in QRA (Galli, 1992). Instead of

QRA, they conduct qualitative risk assessments, with

international organizations serving as the primary

source of information on methodology.

In setting standards for exposure, it is common

practice in Italy to analyze all published and unpublished data and to consider risk assessment-related

information and exposure standards promulgated at

s AS ~nti~tive risk msmsment and risk assessment pm se is much less developed in Italy, a smaller numher Of Sources was used in

developing this discussion as compared to other countries.
Appendix A: International Risk Assessment 205

the international level by organizations such as WHO,

EC, IARC, the U.S. Food and Drug Administration,

and the U.S. EPA (Galli, 1992). Such a process is

especially common for nations that lack expertise and

resources in risk assessment.

Much of Italy’s exposure level-setting effort comes

from the National Advisory Committee on Toxicology, which serves as an advisory body to the Italian

Ministry of Health on several issues, including the

regulation of carcinogens in the workplace. This

committee has also established guidelines for identifying and classifying carcinogens and maintains a list of

chemical carcinogens based on data from IARC

publications, Yet despite its responsibilities, this

committee does not have the authority to propose

exposure limits. Legislation limiting exposure to

hazardous chemicals generally comes in the form of

decrees by the Italian Government or the ministries of

health or labor (Foa and D’Angelo, 1985).

The task of proposing exposure limits is also

addressed by ISPESL (Istituto Superiore per la Prevenzione e la Sicurezza del Lavoro), which relies on

recommendations by the ILO or EC directives that

address occupational exposure to carcinogens and

other hazardous chemicals in the workplace (Foa and

D’Angelo, 1985). As a member of the European

Community, Italian policy regarding occupational

exposure reflects relevant EC directives (Forni, 1992).

 Japan

Japan practices some risk reduction and regulation

of hazardous chemicals. However, very little information was available on this subject, and efforts to obtain

it from the appropriate Japanese authorities were

unsuccessful.

 Developing Countries

Risk assessments in developing countries are usually conducted with assistance from international

organizations, such as WHO, PAHO, Codex Alimentarius Commission, or the U.S. EPA. Most developing

countries do not have adequate mechanisms or resources for developing chemical safety regulations,

much less enforcing them.

 Summary

Internationally, risk assessment is undergoing evolution and expansion. The United States is at the

forefront of research and methodology in this field,

especially for QRA. But several other countries and a

number of international organizations have also adopted

or increased their utilization of risk assessment to

enhance the protection they offer against exposure to

hazardous chemicals. Most of the countries OTA

surveyed perform some form of qualitative risk

assessment; in contrast, evidence of QRA was rare.

OTA found however that QRA was an established part

of regulatory practice in the Netherlands and Canada

and is becoming more apparent in the regulatory

policies of Germany and Sweden.

International bodies, such as IARC, IPCS and

OECD, play an important role in controlling and

monitoring human exposure to hazardous chemicals.

They also have a strong influence on international

trade and are invaluable in disseminating information

about chemical safety to developing countries and

nations that lack the necessary resources to perform

their own assessments. Moreover, these organizations

serve as central coordinating bodies for both interagency collaborations and cooperation between different countries.

In examining how various countries used risk

assessment, OTA identified many characteristics of

their risk assessment processes. Those countries that

do perform QRA do so only for genotoxic carcinogens.

Many also preferred case-by-case and weight-of-theevidence approaches when considering data for use in

a risk assessment.

Finally, many foreign regulatory authorities have

indicated that they disagree with several aspects of the

QRA process used in the United States, including the

way U.S. regulators handle the uncertainty of extrapolation models and their overly conservative estimates

of risk. As a result, many countries that look to the

United States for guidance in QRA have at the same

time attempted to remedy the problems they perceive

in the process. They have also tried to make their

systems more flexible and to allow for improved

estimates in risk calculations.

The countries and international organizations discussed in this appendix use risk assessment to varying

degrees, depending on the function and clientele of

their programs. Qualitative risk assessment is much
206 I Researching Health Risks

more prevalent than

ments will probably

methodologies.

THE FUTURE OF

QRA, although recent developlead to increased use of QRA

RISK ASSESSMENTS:

COLLABORATION, HARMONIZATION,

AND TRADE

The issues of guideline harmonization, trade, and

interagency cooperation are inseparable when addressing risk assessment in a global context. For several

reasons-developments at the 1992 United Nations

Conference on Environment and Development in Rio

de Janeiro, the desire to reduce nontariff barriers to

trade, and ongoing efforts to promote chemical safety—

risk assessment has become an important component

of the agendas of environmental health bodies worldwide. These factors have motivated several international groups to pursue harmonization of risk assessment guidelines and form collaborative efforts to

explore and promote the utilization of risk assessment

methodologies.

The benefits of international collaboration on risk

assessment and chemical safety appear quite logical.

Cooperative efforts bring about a more efficient use of

expertise and financial resources. They also provide an

opportunity to share data and reduce the chance of

duplicate testing. As noted earlier, collaborations in the

areas of chemical testing and test guideline harmonization are influential in eliminating trade barriers as well

as advancing the state of the science. Finally, global

partnerships allow government and industry in the

industrialized nations to assist developing countries

with chemical safety and assessment (Mercier, 1992).

On the agency level, international organizations

have taken the initiative to develop harmonized

guidelines for risk assessment. PCS, through its

Environmental Health Criteria documents, has published common principles for risk assessments pertaining to “ drinking water, air quality, pesticide residues,

and food additives. IPCS is also coordinating a global

survey of risk assessment practices related to human

health, with the formal purpose of working toward

more harmonization in procedures for risk assessment.

Another international organization, OECD, has

taken important steps toward harmonizing guidelines

for hazard assessment and avoiding the creation of

nontariff barriers to trade. Through its Chemicals

Program, OECD updates its guidelines for testing in

accordance with advancements in technology and

methodology. The OECD chemicals Program also

provides its member states with standards for good

laboratory practice in an effort to promote the mutual

acceptance of data between member countries. Finally,

OECD is involved in an international effort to harmonize the classification of hazardous chemicals.

The EC has also taken measures to reduce barriers

to trade among its members and concentrate its efforts

in the area of chemical safety. Although the EC has

already implemented harmonized testing, classification, and labeling of toxic chemicals, a recent amendment (Directive 92/32/EEC) to the 1967 directive on

classification and labeling further updates the EC’s

guidelines for chemical testing and assessment (Official Journal of the EC, 1992).

In addition to the international bodies and organizations that are developing individualized policies concerning risk assessment guidelines and the enhancement of trade, they are also collaborating on some of

these same issues. One established example is IPCS, a

cooperative program of WHO, FAO, and ILO. Under

a formal agreement, OECD and IPCS have also been

sharing information and resources to harmonize risk

assessment methodologies, with IPCS focusing more

on the human health aspects and OECD on the

environment. That collaboration has been enhanced by

Agenda 21 at the 1992 UNCED in Rio de Janeiro (see

below) (Smith, 1992, 1993). Finally, several conferences have taken place--and several more are plannedthat examine national and international approaches to

QRA principles and methodologies.

Arguably, the most significant development in such

collaborations is a result of the 1992 United Nations

Conference on Environment and Development in Rio

de Janeiro. Chapter 19 of the Agenda 21 document

ratified at the conference deals with the environmentally sound management of toxic chemicals (UNCED,

1992). It proposes six areas of chemical safety and

management that should be addressed by international

collaborations (table A-2). As noted earlier, a UNCED

preparatory meeting in London in 1991 proposed an

intergovernmental mechanism (IGM) to address risk

assessment and chemical management internationally.

Chapter 19, which was recently approved by the

United Nations General Assembly (Mercier, 1992),

contains an invitation to the executive heads of WHO,

ILO, and UNEP to convene intergovernmental meet-
———. . .

Appendix A: International Risk Assessment 207

Table A-2-Six Proposed Program Areas

from Chapter 19, Agenda 21 of the June 1992

UNCED in Rio de Janeiro

● (a)

● (b)

● (c)

● (d)

. (e)

● (9

Expanding and accelerating international assessment of

Chemicl risks.

Harmonizing classification and labeling of chemicals.

Establishing an information exchange on toxic

chemicals and chemical risks.

Establishing risk reduction programs.

Strengthening national capabilities and capacities for

management of chemicals.

Preventing illegal international traffic in toxic and

dangerous products.

SOURCE: United Nations Conference on Environment and Develop

ment, Agenda 21, Chapter 19: Environmentally Sound Management of

Toxic Chemieals Including Prevention of Illegal International Traffic in

Toxic and Dangerous Products. Plenary session in Rio de Janeiro, June

14, 1992.

ing within a year. Through an expansion of its

activities, IPCS will become the central executer of

this IGM proposal and will recruit the assistance and

expertise of several other international organizations

(e.g., OECD, FAO, and CEC), national authorities

such as the U.S. EPA, and relevant nongovernmental

organizations (IPCS, 1992b).

International cooperation in dealing with chemical

safety and risk assessment is extensive and will be

enhanced even more through the proposals of Chapter

19. Negotiations on world trade, especially the General

Agreement on Tariffs and Trade (GAIT’) and the North

American Free Trade Agreement, will also benefit

from the ongoing collaborations. A common problem

that arises in those negotiations and in the world trade

arena is the difference in standards between two or

more countries and the unwillingness of the country

with more stringent regulations to compromise. This

complex situation may also arise in negotiating

harmonized risk assessments and chemical safety

guidelines. However, the potential benefits for human

health, world trade, and the environment of harmonizing chemical safety and assessment guidelines may

make such international collaborations worthwhile.

APPENDIX A REFERENCES

Ahlborg, U. 1992. Institute of Environmental Medicine

(Sweden). Personal communication.

Am (Danish Academy of Technical Sciences). Report on

discussion on “drinking water. Risk Management and Risk

Assessment in Different Sectors of Denmark (Danish Academy of Technical Sciences, ATV), pp. 18-20.

ATV, 1992b. Report on discussion of work environment.

Risk Management and Risk Assessment in Diflerent Sectors

of Denmark (Danish Academy of Technical Sciences, An),

pp. 32-36.

Becking, G. 1992, International Progr amme on Chemical

Safety. Personal communication.

Becking, G, 1992. International Programme on Chemical

Safety: Development of Environmental Health Criteria of

bad (Research Triangle Park, NC).

Becking, G. 1993. International Programme on Chemical

Safety. Personal communication.

Brickman, R,, Jasanoff, S., and Ilgen, T. 1985. Controlling

chemicals: The politics of regulation in Europe and the

United States (Ithaca, NY and Lnndon: Cornell University

Press).

Carlsen, A. 1992. Drinlcm“ g water. Risk Management and

Risk Assessment in Different Sectors of Denmark (Danish

Academy of Technical Sciences, AlY), pp. 155-162.

Carlsen, A. 1992. Ministxy of Environment. National Agency

for Environmental Protection, Denmark. Personal cornrnunication.

Carlsen, J.C, 1993. National Food Agency, Denmark.

Personal communication to Ginger Roehrig, Office of

Technology Assessment.

Clevenstine, E. 1992. International Labor Organization.

Personal communication.

CEC (Commis sion of the European Communities. 1987.

Chemical risk control in the European Community (Brussels:

CEC).

CEC. 1990. Completing the single market: The removal of

technical barriers to trade within the European Economic

Community (Brussels).

CEC. 1991a. Directorate general XLI for science, research,

and development. Environment 1991-1994, information

package (Brussels).

CEC. 1992. EC research funding: A guide for applicants

(Bonn, Germany: Economica Verlag).

CEC. 1992a. Working documents of the cornmis sion concerning the fourth hxnework program of community activities in the field of research and technological development

(1994-1998) (Brussels).

CEC. 1992b. Research after Maastricht: An assessment, a

stiategy (Luxembourg, Brussels: CEC).

CEC. 1992c. Treaty on European Union.

Department of Health. 1991. Committee on Carcinogenicity

of chemicals in Food. Consumer Products and the Environ-
208 Researching Health Risks

ment. Report on Health and Social Subjects No. 42: (lleNetherlands, Government Publishing Office, the Hague).

Guidelines for the Evaluation of Chemicals for Carcinogen- Health Council of the Netherlands. 1988. Committee on the

icity (Imndon). evaluation of the carcinogenicity of chemical substances.

Dragsted, L. 1992. Low dose extrapolation of data horn Risk assessment of carcinogenic chemicals in the Netheranimal bioassays. Risk Management and Risk Assessment in lands,

DiflerenrSectors ofDenrnark (Danish Academy of Technical

Sciences, Am), pp. 77-107. Hurwitz, L. 1992. The European Community and the Single

European Act of 1987: What Does it Mean? Phi Kappa Phi

Fielder, R.J. 1992. Health Environment Food (M) Division, Journal, Spring.

United Kingdom Department of Health. Personal communication. LARC (International Agency for Research on Cancer). 1991.

Fielder, R.J, 1993. Health Environment Food (’M) Division, Biennial Repofl 1990-91 (Lyon: International Agency for

United Kingdom Department of Health. Personal communi- Research on Cancer).

cation. IARC. 1992s. IARC monographs on the evaluation of

Finkelman, J. 1992. Pan American Center of Human Ecology

and Health. Personal communication.

Finkelman, J. 1993. Pan American Center of Human Ecology

and Health. Personal communication.

Fisher, C,E. 1992. Ministry of Agriculture, Fisheries, and

Food, United Kingdom. Personal communication.

Foa, V., and D’Angelo, V. 1985. Ugislation concerning

carcinogens at work, the Situation in Italy, La Medicina de

Lavoro 77:393-395.

Fomi, A. 1992. Associate Professor. Institute of Occupational Health, University of Milan, Italy. Personal communication.

GalIi, C.L. 1992. Head. Toxicology Laboratory, Institute of

Pharmacological Sciences, University of Milan, Italy. Personal communication.

carcinogenic risks to humans: Solar and ultraviolet radiation

(UNted Kingdom: International Agency for Research on

Cancer), Vol. 55.

IARC. 1992b. Interim Annual Report 1992 (Lyon: International Agency for Research on Cancer).

IARC. 1992c. Ad-Hoc Meeting of Experts on Quantitative

Estimation and Prediction of Canmr Risks to Humans,

Technical Proposal.

IARC. 1993. IARC monographs on the evaluation of

carcinogenic risks to Humans: lists of IARC evaluations

(Lyon, International Agency for Research on Cancer).

ILO (International Labor Organization). 1991. Facts for

Americans.

PCS (Mmnat.ional Prograrnme on Chemical Safety). 1992a..

Information brochwe (PCS).

Granville, G, 1992. Associate Director. Environmental IPCS. 1992b. Progress report by the Director-General, 45th

Health Directorate, Health Protection Branch, Health and

Welfare Canada. Personal communication.

World Health Assembly (Genevtx WHO).

Granvi.lle, G. 1993. Associate Director. Environmental

Health Directorate, Health Protection Branch, Health and

Welfare Canada. Personal communication.

Greim, H. 1992. German Institute for Toxicology. Personal

communication.

Haigh, R. 1992. Comrnission of the European Communities.

Industrial Medicine and Hygiene Unit. Personal communication.

Health and Safety Executive. 1992. Occupational Exposure

Limits (EH40/92) (Xmndon: HMSO).

Health and Welfare Canada. NOV. 20, 1992, Bureau of

Chemical Hazards. Environmental Health Directorate.

Health Protection Branch. Determination of “Toxic” under

Paragraph 1lc) of the Canadian Environmental Protection

Act, First Edition.

Health Council of the Netherlands. 1980. Report on the

Evaluation of the Carcinogenecity of Chemical Substances

Joint Research Center. 1991. Commission of the European

Communities. Directorate general for telecommunication.

Information industries, and innovation. Environment Institute (Luxembourg, Brussels: CEC).

Kaferstein, F. 1992. World Health Organization. Personal

communication.

Keyes, C. 1991. The European Community and environmental policy: an introduction for Americans (Baltimore,

MD: World Wildlife Publication).

Koppen, IJ. 1987. The European Community’s environment

policy: fiomthe sunum‘tin Paris, 1972 to the single European

act. EUI working paper No. 88/328 (Italy: European University Institute, 1988).

Kroes, R. 1979. Animal Data. Interpretation and Consequences, Environmental Carcinogenesis, P. Emmelot and E.

Kriek (eds.) (Amsterdam: Elsevier/North-Holland BiomediCd h5SS), pp. 287-302.
Appendix A: International Risk Assessment 209

Kroes, R. 1987, Contribution of toxicology towards risk

assessment of carcinogens, Archives of Toxicology 60:224-

228.

Larsen, J.C. 1992, Food contarninant.s. RiskiUanagement and

Risk Assessment in Di#erent Sectors of Denmark (Danish

Academy of Technical Sciences, Am, pp. 125-138.

Larsen, J.C. 1992a. Food additives, positive list. Risk

iUanagement and Risk Assessment in Diflerent Sectors of

Denmark (Danish Academy of Technical Sciences, ATV),

pp. 109-124,

Larsen, J.C. 1993. National Food Agency of Denmark,

Institute of Toxicology. Personal communication.

Markus, C.M. 1992. International harmonization of pesticide

tolerances-legal, procedural, and policy issues, Food,

Drug, and Law Journal 47:701-738.

Mercier, M. 1992. Speech re: international program for

chemical safety. American Industrial Health Council Conference, Washington, DC, Dec. 1.

Mundell, I. 1992, Maastrich drives R&D to the market.

Nature 356:650, 1992.

Murphy, P. 1992. Comrnission of the European Communities. Personal communication.

Nilsson, R. 1992. National Swedish Chemicals Inspectorate.

Personal communications.

Nilsson, R. 1993. National Swedish Chemicals Inspectorate,

Personal communications.

Obadia, I. 1992, International Labor Organization. Personal

communication.

Office for Oi%cial Publications of the European Communities. 1990. European documentation, Environmental policy

in the European Community (Luxembourg),

Ofllcial Journal of the EC (European Communities), Nov.

27, 1980.

Oficial Journal of the EC, Vol. 35, June 5, 1992.

OECD (Organisation for Economic Co-operation and Development). 1989. OECD Environment Directorate, Chemicals

Division, The OCED Chemicals Programme (Paris: OCED).

OECD. 1992. Environment Directorate, OECD Co-operative

Risk Reduction Activities (Paris).

Pan American Health Organization. 1991. Annual report of

the Director (Washington, DC: PAHO, 1992).

Pott, F. 1992. Medical Institute of Environmental Hygiene

(Dusseldorf, Germany). Personal communication.

Poulsen, E. 1992. Setting of limit values for chemicals and

chemical compounds. Risk Management and Risk Assessment in Diflerent Sectors of Denmark (Danish Academy of

Technical Sciences, ATV), pp. 3747.

Richter, E. D., and Goldsmith, J. 1991. The IARC classtilcation system: input, internal logic, output, and impact.

American Journal of Industrial Medicine 19:385-397.

Secretariat of the international programme on chemical

safety. 1992. Preliminary proposal: harmonization of approaches to the risk assessment of chemicals (lPCS).

Smith, T. 1992. International prograrnme on chemical safety.

Personal communication.

Smith, T. 1993. International programme on chemical safety.

Personal communication.

St. Aubin, J. 1992. Canadian centre for occupational health

and safety. Personal communication,

St. Aubin, J. 1993. Canadian centre for occupational health

and safety. Personal communication.

Stober, J. 1992. International programmeon chemical safety,

Personal communication,

Swaen, G. 1992. Department of Epidemiology/Health Care

Research (The Netherlands). Personal communication.

Swaen, G. 1993. Department of Epidemiology/Health Cm

Research (The Netherlands). Personal communication,

l%rck, R, 1992. Federal Mi.nhy of the Environment. Nature

conservation and nuclear safety (Germany). Personal communication.

‘Thrck, R. 1993. Federal Ministry of the Environment. Nature

conservation and nuclear safety (Germany). Personal communication.

U.S. Congress, OTA (Office of Technology Assessment).

1992. Trade and environment: conflicts and opportunities.

OTA-BP-ITE-94, Washington, DC: U.S Government Printing Office, May 1992.

UNCED (United Nations Conference on Environment and

Development). 1992. Agenda 21, chapter 19, Environmentally sound management of toxic chemicals including

prevention of illegal international tra.t%c in toxic and

dangerous products. Plenary in Rio de Janeiro, June 14.

UNEP (United Nations Environment Programmed). 1991.

Report of the meeting of experts to discuss draft proposals for

an intergovernmental mechanism for chemical risk assessment and management (Lxmdon), Dec. 16-19.

Van der Heijden, K. 1992. Assistant Director for the

European Center for Environment and Health (The Netherlands). Personal communication.

Van boy, H, 1992. Organisation for Economic Cooperation and Development (Paris). Personal communication.

Visser, R. 1992. The OECD existing chemicals programme:

sharing the burden, Risk Analysis 12: 169-172.
210 I Researching Health Risks

WHO (World Health Organization). 1984. Guidelines for

., drmkmg water quality (Geneviu WHO), Vol. 1.

WHO. 1987a. Air quality guidelines for Europe. WHO

Regional Publication,

European Series No. 23. Copenhagen, World Health Organization.

WHO. 1987b. Principles for the safety assessment of food

additives and contaminants in food. IPCS Environmental

Health Criteria No. 70 (Geneva: WHO).

WHO. 1989. Revisions of the World Health organization

guidelines for drinlun“ g water quality (Geneva: WHO).

WHO. 1990. Principles for the toxicological assessment of

pesticide residues in food. PCS Environmental Health

Criteria No. 104 (Genevz WHO).

WHO. 1992a. Description of the joint FAO/WHO expert

committee on food additives and the codex alimentarius

commission.

WHO. 1992b. Description of the joint FAO/WHO meeting

on pesticide residues (JMPR) and the codex alirnentarius

commission.
Appendix B:

Department of

Health and

Human Services

Organization Chart

.------I Department of Health and Human Services (HHS)

Off Ice of the Secretary

I

\ k

Public Health Service (PHS)

-------- E

Office of Desease

Office of the Prevention and

Assistant Secretary of Health Health Promotion

(OASH) (ODPHP)

.— ‘T I

E ‘E===1

The National

Institutes of

Health (NIH)

I-!?B&l

Centers for

Disease

Control and

Prevention (CDC)

El 1 Institute

5 Centers a

Agency for

Health Care Policy

and Research

(AHCPR)

m6 Centersa

a For more detail, see appendix D.

SOURCE: Congressional Research Service, 1993, LT93-2533.
Appendix C:

Federal Obligations

for Health R&D by

Source or Performer

212
Appendix C: Federal Obligations for Health R&D by Source or Performer 213

C-9

o

In

04

idm

1-

0)

ti

m

ii

TIq

a)

C9

o

0)

r+

w

. . . . . . .

. . . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . .

. . . .

,.. ,

::E : :

. . . . ‘i!! : : . .-

. . . . .- :6 : : : : : :
w
——

Appendix D: FY 1992 Estimates of Funding Support by DHHS Agencies 215

FY 1992 ESTIMATES OF FUNDING SUPPORT BY DHHS AGENCIES

FOR RESEARCH I RELATED TO CHEMICAL TOXICOLOGY IN BASIC

RESEARCH, TESTING AND METHODS DEVELOPMENT1

($ in Thousands)

Basi c Method s

Research Tes t i n g Develop men t Total

4,371

4,198

o

0

0

0

0

0

0

0

0

()

980

980

0

10,896

64,034
Appendix E:

List

of

Abbreviations

AAAS

ACTS

ACGIH

ADI

AIDS

AIHC

AMS

AREAL

ATSDR

BAT

BBDR

BMDs

CAC

CAG

CA-HHS

CCFAC

CCPR

CCRVFD

CCTN

American Association for the

Advancement of Science

Advisory Committee of Toxic

Chemicals (of Health and Safety

Commission, UK)

American Conference of

Governmental and Industrial

Hygienists

acceptable daily intake

acquired immunodeficiency syndrome

American Industrial Health Council

Agricultural Marketing Service (USDA)

Atmospheric Research and Exposure

Assessment Laboratory (EPA)

Agency for Toxic Substances and

Disease Registry (DHHS)

best available technology

biologically based dose response

benchmark doses

Codex Alimentarius Commission

Carcinogen Assessment Group (EPA)

California Department of Health and

Human Services

Codex Committee on Food Additives

and Contaminants

Codex Committee on Pesticide

Residues

Codex Committee on Residues of

Veterinary Drugs

Italian National Advisory Committee

on Toxicology

CDC

CDRH

CEC

CEFIC

CEHIC

CEMBL

CEPA

CFSAN

CIIT

CIRRPC

co

CPSC

CRADAS

DBBS

DBRA

DCE

DECOS

DES

Centers for Disease Control and

Prevention

Center for Devices and Radiological

Health

Commission for European

Communities

European Council of Chemical

Manufacturers

Center for Environmental Health and

Injury Control

Center for Environmental and

Molecular Biology of the Lung (UNC)

Canada Environmental Protection Act

Center for Food Safety and Applied

Nutrition

Chemical Industry Institute of

Technology

Committee on Interagency Radiation

Research and Policy Coordination

carbon monoxide

Consumer Product Safety Commission

cooperative research and development

agreements

Division of Biomedical and Behavioral

Science (NIOSH)

Division of Biometry and Risk

Assessment (NIEHS)

Division of Cancer Etiology (NCI)

Dutch Expert Committee on

occupational standards

diethylstilbestrol

216
Appendix E: List of Abbreviations 217

DFG

DHHS

DOD

DOE

DRDS

DRMS

DSDTT

DSHEFS

EC

ECAO

ECDIN

EEA

EH

ELF

EM

EMF

EPA

ER

ETD

E&M

FACA

FAO

FAP

FCCSET

FDA

FHSA

FOE

GAC

GAO

GATT

GLP

GTD

HEI

HERL

Deutsche Forshungsgemeinschaft

(German Research Agency)

U.S. Department of Health and Human

Services

U.S. Department of Defense

U.S. Department of Energy

Division of Respiratory Disease

Studies (NIOSH)

Decision, Risk, and Management

Science (NSF)

Division of Standards Development

and Technology Transfer (NIOSH)

Division of Surveillance, Hazard

Evaluations and Field Studies (NIOSH)

European Community

Environmental Criteria Assessment

Office (EPA)

Environmental Chemicals Data and

Information Network (EC)

European Environment Agency (EC)

Office of the Assistant Secretary for

Environment, Safety, and Health

extremely low frequency

Office of Environmental Restoration

and Waste Management (DOE)

electromagnetic forces

U.S. Environmental Protection Agency

Office of Energy Research (DOE)

Environmental Toxicology Division

(HERL)

Division of Energy and Material (NRC)

Federal Advisory Committee Act

United Nations Food and Agriculture

Organization

familial adenomatous polyposis

Federal Coordinating Council on

Science, Engineering and Technology

Food and Drug Administration

Federal Hazardous Substances Act

Friends of the Earth

granulated activated charcoal

General Accounting Office (U.S.

Congress)

General Agreement on Tariffs and Trade

good laboratory practice

Genetic Toxicology Division (HERL)

Health Effects Institute

Health Effects Research Laboratory

HPAB

HPV

HSC

HSD

HSE

HUD

HWC

IARC

ICO

IGM

ILO

IOM

IPCS

IRAA

IRLG

IRPCT

ITB

ITRI

JECFA

JMPR

JRC

LBL

LLNL

LMS

LOAEL

LOEL

LQCB

MAC

MAFF

MEL

MIACC

MLE

MRC

MRI

(ERA)

Hazard Pollutants Assessments Branch

(ECAO)

high production volume

Health and Safety Commission (U.K.)

Human Studies Division (HERL)

Health and Safety Executive (U.K.)

U.S. Department of Housing and Urban

Development

Health and Welfare Canada

International Agency for Research on

Cancer

International Coffee Organization

intergovernmental mechanism

International Labor Organization

Institute of Medicine

International Programme on Chemical

Safety

Indoor Radon Abatement Act

Interagency Regulatory Liaison Group

International Register for Potentially

Toxic Chemicals (UNEP)

Irnmunotoxicology Branch (HERL)

Inhalation Toxicology Research

Institute

Joint Expert Committee on Food

Additives

Joint Meeting on Pesticide Residues

Joint Research Centers (EC)

Lawrence Berkeley National

Laboratory

Lawrence Livermore National

Laboratory

linearized multistage

lowest-observed-adverse-effect level

lowest-observed-effect level

Laboratory of Quantitative and

Computational Biology (NIEHS)

maximum allowable concentration

Ministry of Agriculture, Fisheries, and

Food (U.K.)

maximum exposure standard (OEL)

Major Industrial Accidents Council of

Canada

maximum likelihood estimate

Multi-Media Research committee

(RIHRA)

magnetic resonance imaging
218 I Researching Health Risks

MRL

MSHA

MTD

NAFTA

NAS

NATO

NCA

NCAB

NCEH

NCI

NCTR

NIEHS

NIH

NIOSH

NOAEL

NOEL

NRC

NRDC

NSCI

NSF

NTD

NTP

OECD

OEL

OES

OHEA

OHR

OMB

OMMSQA

OPPTS

ORAU

ORD

OSHA

OSH Act

OST

maximum residue limit

Mining Safety and Health

Administration

maximum tolerated dose

North American Free Trade Agreement

National Academy of Sciences

North Atlantic Treaty Organization

National Coffee Association

National Cancer Advisory Board (NCI)

National Center for Environmental

Health

National Cancer Institute

National Center for Toxicology

Research

National Institute for the

Environmental Health Sciences

National Institutes of Health

National Institute for Occupational

Safety and Health

no-observed adverse-effect level

no observed effect level

National Research Council or Nuclear

Regulatory Commission

National Resources Defense Council

National Swedish Chemicals

Inspectorate

National Science Foundation

Neurotoxicology Division (HERL)

National Toxicology Program

Organisation for Economic Cooperation and Development

occupational exposure limit

occupational exposure standards (OEL)

Office of Health Effects Assessment

(EPA)

Office of Health Effects Research (HERL)

Office of Management and Budget

Office of Monitoring Research and

Quality Assurance (EPA)

Office of Prevention, Pesticides, and

Toxic Substances (EPA)

Oak Ridge Associated Universities

Office of Research and Development

(EPA)

Occupational Safety and Health

Administration

Occupational Safety and Health Act

Office of Science and Technology

OSTP

OTA

OTS

PAHO

PBPK

PCB

PCCDs

PCDF

pCi/L

PHS

PI

PIC

PMA

ppm

PTB

QEP

QRA

RAC

Rb

RCRA

RfC

RfD

RIHRA

RSAC

RTD&E

RTP

SAB

SAR

SCE

SDWA

SEA

SIDS

TCDD

TEFs

UNC

UNCED

UNEP

Office of Science and Technology

Policy

Office of Technology Assessment

(U.S. Congress)

Office of Toxicological Sciences (EEA)

Pan American Health Organization

physiologically based pharmacokinetic

polychlorinated biphenyl

polychlorinated dibenzo-p-dioxins

polychlorinated dibenzofurans

picocuries per liter

Public Health Service

participating institution

products of incomplete combustion

Pharmaceutical Manufacturer’s

Association

parts per million

Pulmonary Toxicology Branch (HERL)

quantitative estimation and prediction

quantitative risk assessment

Risk Assessment Council (ERA)

Risk Assessment Forum (EPA)

retinoblastoma

Resources Conservation and Recovery

Act

inhalation reference concentration

reference dose

Research to Improve Health Risk

Assessment program (EFA)

Research Strategies Advisory

committee (SAB)

Research Development Testing and

Evaluation (DOD)

Research Triangle Park

Science Advisory Board (EPA)

structure-activity relationships

sister chromatid exchange

Safe Drinking Water Act

Single European Act

Screening Information Data Set Project

(OECD)

tetrachlorodibenzodioxin

toxicity equivalency factors

University of North Carolina

United Nations Conference on

Environment and Development

United Nations Environment

Programme
USDA U.S. Department of Agriculture

VOCs volatile organic compounds

WATCH Workplace Assessment of Toxic

Chemicals (HSE)

Appendix E: List of Abbreviations 219

WHO World Health Organization

WLM working-level months

WPAFB Wright-Patterson Air Force Base
Appendix F:

Acknowledgments

OTA thanks the members of the advisory panel, conference and workshop participants, contractors, and

the many individuals and organizations that supplied information for this report. In addition, OTA acknowledges

the following individuals for their comments on drafts of this report:

Richard Adamson

National Cancer Institute

Bruce Ames

University of California, Berkeley

Jeanne Anson

National Center for Toxicological Research

Lynn Anspaugh

Lawrence Livermore Laboratory

Donald Barnes

U.S. Environmental Protection Agency

James Bean

U.S. Department of Energy

Thomas Borelli

Philip Morris

Daniel M. Byrd, III

Distilled Spirits Council of the United States, Inc.

Samuel M. Cohen

University of Nebraska Medical Center

Murray Cohn

Consumer Product Safety Commission

Paul Deisler

Houston, TX

Christopher DeRosa

Agency for Toxic Substances and Disease Registry

Helen Donoghue

Delegation of the European Communities

John Doull

University of Kansas

Leon Ellwein

National Institutes of Health

Spencer Farr

Xenometrix, Inc.

Bob Fensterheim

RegNet Environmental Services

Gary J. Foley

U.S. Environmental Protection Agency

David Gaylor

National Center for Toxicological Research

Lois Gold

Lawrence Berkeley Laboratory

Gio Gori

Health Policy Seminar

John D. Graham

Harvard University

Richard Griesemer

National Institute for Environmental Health Sciences

Fred Hoerger

American Industrial Health Council

Vernon Houk

Centers for Disease Control
Appendix F: Acknowledgments 221

Peter Infante

Occupational Safety and Health Administration

Barry Johnson

Agency for Toxic Substances and Disease Registry

Philip J. Landrigan

The Mount Sinai Medical Center

Joe LeBeau

Carnegie-Mellon University

Mayada A. Logue

Robert Wood Johnson Medical School

George Lucier

National Institute for Environmental Health Sciences

Thomas McKone

Lawrence Livermore Laboratories

Barry Milcarek

Mobil Oil

Franklin Mirer

United Auto Workers

A. Alan Moghissi

University of Maryland

Richard Niemeier

National Institute for Occupational Safety and Health

Anthony V. Nero

Lawrence Berkeley Laboratory

Arthur R. Norris

National Center for Toxicological Research

Carole O’Toole

American Industrial Health Council

Stephen Page

U.S. Environmental Protection Agency

D.J. Paustenbach

McLaren/Hart Environmental Engineering

Mary Paxton

American Petroleum Institute

William Pease

University of California, Berkeley

Richard Peto

Oxford

Henry C. Pitot

University of Wisconsin

Gerald V. Poje

National Institute for Environmental Health Sciences

James A. Popp

Chemical Industry Institute for Toxicology

Lawrence Rhomberg

U.S. Environmental Protection Agency

Kathryn Rosica

Chemical Manufacturers Association

Paul Roney

Public Citizen

Mark E. Rushefsky

Southwest Missouri State University

Marvin Schneiderman

National Research Council

Bern A. Schwetz

National Institute for Environmental Health Sciences

Robert Sielken

Sielken, Inc.

Ellen Silbergeld

University of Maryland

Hugh Spitzer

International Life Science Institute

Leslie T. Stayner

National Institute for Occupational Safety and Health

Gerhard Stohrer

Science and Environmental Policy Project

John Vandenberg

U.S. Environmental Protection Agency

Andrew Wallo

U.S. Department of Energy

John Whysner

American Health Foundation

I. Bernard Weinstein

Columbia University

Richard Wilson

Harvard University

Sidney Wolfe

Public Citizen

Harold Zenick

U.S. Environmental Protection Agency
222 I Researching Health Risks

OTA acknowledges the following individuals for their comments on drafts of the appendix on International

Risk Assessment:

Ulf G. Ahlborg

Karolinska Institute

Sweden

Ake E. Anderson

Institute for Future Studies

Sweden

Charlie Auer

U.S. Environmental Protection Agency

George Becking

World Health Organization-International Programme

on Chemical Safety

Edward Bennett

Directorate-General of Environment, Nuclear Safety,

and Civil Protection

European Economic Community

Jim Brydon

Organisation for Economic Co-operation and

Development

J. Takala

International Labor Organisation

Kees A. Vander Heijden

The Netherlands

Pierre Claret de Fleurieu

Chef du Division des Services du Senat

France

Helen Donoghue

Delegation of the Commission of European

Communities

Robin J. Fielder

Department of Health

England

Jacobo Finkelman

Pan American Health Organisation

Corrado Galli

University Degli Studi DiMilano

Italy

Herman Gibb

Office of International Activities

U.S. Environmental Protection Agency

Geoff Granville

Environmental Health Directorate

Canada

Terry Harvey

Office of International Activities

U.S. Environmental Protection Agency

Wilfred Kreisel

World Health Organization

Dan Krewski

Health & Welfare Canada

Canada

M. Maurice Laurent

Conseiller des Services de l’Assemb1ee Nationale

France

M. Jean-Yves Le Deaut

Assemb1ee Nationale

France

Victor Morgenroth

Organisation for Economic Co-operation and

Development

Patrick Murphy

Commission of the European Communities

Robert Nilsson

National Swedish Chemicals

Sweden

Michael Norton

Parliamentary Office of Science and Technology

England

David Ogden

Office of International Activities

U.S. Environmental Protection Agency

Herbert Paschen

Buro fur Technikfolgen-Abschatzung des Deutschen

Bundestages

Germany

Frederick Pott

Medical Institute of Environmental Hygeine

Germany

Jorn Ravn

Danish Board of Technology

Denmark

Edward Smith

World Health Organisation/International Programme

on Chemical Safety
Gerard M.H. Swaen

University of Limburg

The Netherlands

John Whysner

American Health Foundation

Kees A. Van der Heijden

Bilthoven, The Netherlands

Appendix F: Acknowledgments 223

Josee C.M. Van Eijnhoven

Nederlandse Organisatie voor Technologist

Aspectenonderzoak

The Netherlands

Hugo van Lioy

Organisation for Economic Co-operation

and Development
Index

Acceptable daily intake (ADI), 53

Acquired immunodeficiency syndrome (AIDS), 87, 100

Advisory Committees, 109-110

Agency for Toxic Substances and Disease Registry (ATSDR),

46,78,98

Agent Orange, 131, 134-135

Agricultural Health Study, 75

Ambient monitoring, 50

Animal bioassays, 55,68, 120-121, 135

Association of California Water Agencies, 161-162

Assumptions, conservative; see Science policy assumptions

Basic research, 4-5,92, 179

Benzene, 46, 102

Biological monitoring, 50, 136

Biologically based dose-response models, 177

Biomarkers, 175, 176

Bridging studies, 82

Bromley, D. Allan, 101

Brookhaven National Laboratory, 160

Cancer

genetic predisposition to, 180

and power-line electromagnetic fields, 130-131

risk from indoor radon, 159-161

role of oncogenes and tumor suppressor genes in, 178, 180

Carcinogens

animal bioassays in assessing, 55,58

guidelines for risk assessments of, 120-125

and International Agency for Research on Cancer

guidelines, 128, 129

linearized, multistage model for, 52,59

risk assessment of, 46

thresholds for, 46,52, 127

Center for Devices and Radiological Health, 77

Center for Environmental and Molecular Biology of the

Lung, 69

Center for Food Safety and Applied Nutrition, 8,74,109,

104, 105

Centers for Disease Control and Prevention (CDC), 46,77-78

Chaffee-Lautenberg Amendment, 157-158

Chemical mixtures, 59-60

chemical-specific data development, 5,92-93

Clean Air Act, 102, 106

Collaboration, 19, 173

disciplinary bridges, 181-182

government interagency, 75

need for, 82

with the private sector, 182-183

with universities, 183, 184

Compliance costs, see Costs

Comprehensive Environmental Response, Compensation,

and Liability Act (CERCLA), 102, 107

Consumer Product Safety Commission (CPSC)

health risk assessment at, 46

health risk assessment research at, 80

research priorities for, 102

and scaling factors, 123-124

costs

of compliance with regulations, 2, 61-62

of environmental cleanup, 61

of environmentally related illnesses, 2, 62-63

Crosscuts, 101

Cross-species extrapolation, 124-125

Cross-species extrapolation factors, see Scaling factors

Data development and management, 179-181

Decision, Risk, and Management Science (DRMS) program,

140

Decisionmaking, see Regulatory decisionmaking

Department of Agriculture, 80-81,98

Department of Defense

federal support for health risk assessment research, 98

health risk assessment research at, 79-80

priority-setting, 80, 103

influence of management style on priorities, 109

Department of Energy

federal support for health risk assessment research, 98

health effects research at, 78-79

health risk assessment research budget at, 78,79

priority-setting, 79, 103, 109

225
226 I Researching Health Risks

priority-setting, 79, 103, 109

role of national laboratories in health risk assessment

research, 79

and study of electromagnetic fields, 131

targeted vs. basic research, 112-113

Department of Health and Human Services, 70-78; see also

specific constituent agencies

Dioxin

and carcinogenicity, 131

effects in chemical mixtures, 59-60

National Institute of Environmental Health Sciences

research on, 73

and the “Ranch Hands,” 134-135

Dose-response assessment, 51-52, 177-179

Electric Power Research Institute, 131

Electromagnetic fields (EMFs), power-line, 130-131

Environmental Health Sciences Center, 184

Environmental Protection Agency (EPA)

and Agricultural Health Study, 75

as expert agency, 99

developmental toxicity guidelines, 126

and dioxin, 132-133

factors determining response to new research, 127-128

federal support for health risk assessment research at, 95,

98

exposure assessment guidelines, 126

guidelines for risk assessment of carcinogens, 120-123

health risk assessment at, 46

health risk assessment research at, 68-69

lack of data analysis at, 82

and no-threshold assumption for carcinogens, 127

priority-setting at, 6,70, 102, 109

and regulation of indoor radon, 145-167

resources for health risk assessment research, 9, 104, 105

risk communication research, 140

Science Advisory Board, 109-110, 157

and scaling factors, 123-124

science policy positions for carcinogen assessment

guidelines, 122

validation studies at, 82

Environmental Research and Development Demonstration

Act (ERDDA), 102, 109

Epidemiologic studies

on indoor radon, 149-153

limitations for assessing risk, 134-135

as primary data source for health risk assessment, 48-49

Exposure assessment 50,52-53,95,126,177

Extrapolations, 1,20,52,59

Federal agencies, see also specific agencies

collaborations with universities, 69

health risk assessment research at, 67-83

priorities for health risk assessment research, 102-108

resources for health risk assessment research, 103

Federal Coordinating Council on science, Engineering, and

Technology (FCCSET), 7,100-102

Federal Insecticide, Fungicide, and Rodenticide Act, 92, 102,

106

Food and Drug Administration

early use of extrapolation models, 46

federal support for health risk assessment research, 98

health risk asses-t research at, 74,776-77

lack of data analysis at, 82

priority setting at, 6

and scaling factors, 123-124

Friends of the Earth, 159, 161, 162

Funding mechanisms, 110-111

Guidelines

for developmental toxicity, 126

for exposure assessment, 126

for carcinogens, 120-123

Habicht, F. Henry, 54,60

Hazard identification, 50-51,60,71-72

Health Effects Research Laboratory (HERL), 68, 102

Health risk assessment

controversial issues in, 54-60

coordination of, 46

definition, 20,47

as formal scientific field, 139

as four-step process, 1, 50-54

growth m federal government, 46

numerical expression of, 1,47

relationship of research and management to, 51

and risk managers, 48

strengths of, 54

uses of, 47

uncertainty in, 60

Health risk assessment research

agency priorities for, 102-108

bridging studies in, 82

classification of, 3-4, 88-93; see also specific categories

and changes in presumptions for extrapolations, 125

characteristics of high-quality studies, 19, 172-174

definition of, 67

federal government activities in, 67-83; see also specific

agencies

federal resources for, 5-6,93-98

future prospects, 174-181

influence of legislative branch on priorities for, 101

issues and options, 20-44

limits of impact on guidelines, 126-128

multidisciplinary efforts in, 81-82

normal vs. mandated, 88-89

rationale for, 60-63

by regulatory agencies, 102-103
Index 227

and regulatory decisionmaking, 119-140

by research agencies, 103

resources for, 103, 104, 105

setting priorities for, 7-10, 87-1 15; see also specific

agencies

structuring future efforts, 171-184

trends and gaps in federal activities, 10-12, 81-82

Homeobox genes, 179

Human exposure testing methods, 177

Human Genome Project, 19, 78, 112, 179, 182

Immunotoxicity, 49

Indoor air pollution, 164

Indoor Radon Abatement Act (IRAA), 17, 146, 163

Interagency Regulatory Group, 46

International Agency for Research on Cancer (IARC), 128,

128

International risk assessment, 187-207

Lead poisoning, 62-63

Linearized, multistage model (LMS), 52,59

Lowest-observed-adverse-effect level (LOAEL), 53

Lowest-observed+ffect level (LOEL), 53

Management, program, 10, 108-109

Margin of safety, 53

Maximum tolerated dose (MTD), 55,58

Mechanisms of toxicity, 68

Mechanistically based dose-response modeling, 177

Meta-analysis, 181

Methodological research, 4,91-92

federal support for, 6,95,96

new methods for toxicity studies, 175

lack of incentives for, 103, 108

Methylene-chloride, 124-125

Mine Safety and Health Administration (MM-IA), 77

Mission-oriented research, 98

Molecular epidemiology, 175, 176

Multidisciplinary research, 81-82, 139; see also

Collaboration

National Cancer Institute

and Agricultural Health Study, 75

epidemiologic research at, 74

federal support for health risk assessment research, 93,95,

98

health risk assessment research at, 73-75

priority-setting, 6,74, 109

resources for health risk assessment research, 8, 104, 105

role of advisory committees, 110

National Center for Environmental Health (NCEH), 77

National Center for Toxicological Research (NCTR)

federal support for health risk assessment research, 95,98

health risk assessment research at, 74,76-77

resources for health risk assessment research, 9, 104, 105

role of advisory committees, 110

targeted research at, 112

National Institute of Environmental Health Sciences

(NIEHS)

and Agricultural Health Study, 75

carcinogenicity-related research at, 72, 82

federal support for health risk assessment research, 95,98

health risk assessment research at, 72-73

methodological research at, 73

priority-setting, 6,72-73, 109

quantitative health risk assessment research at, 73

resourses for health risk assessment research, 9, 104, 105

role of advisory committees, 110

National Institute for Occupational Safety and Health

(NIOSH)

collaborative evaluation studies at, 82

federal support for health risk assessment research, 8,98

health risk assessment at, 46,78

health risk assessment research at, 77-78

National Research Council, 2,54,56-58, 137

National Research Council Committee on the Institutional

Means for Assessment of Risks to Public Health, 137

National Science Foundation (NSF), 140

National Science and Technology Council, 10, 101

National Toxicology program (NIT)

as arbiter of toxicity testing priorities, 99

collaborative evaluation studies at, 82

controversy over testing priorities, 89

lack of data analysis at, 82

health risk assessment research at, 71-72

toxicity testing at, 71-73

National Resources Defense Council, 159, 161, 162

Neurotoxicity, 49

No-observed-adverse-effect level (NOAEL), 51-52,53

No-observed-effect level (NOEL), 46,51-53,53

North Atlantic Treaty Organization (NATO), 132-133

Nuclear Regulatory Commission, 46,81

Occupational Safety and Health Act, 102, 103, 107

Occupational Safety and Health Administration (OSHA)

and benzene regulation, 46, 102

health risk assessment at, 46

priorities for research, 102

as regulatory office, 77

Office of Management and Budget (OMB)

and conservative science policy assumptions, 55

as influence on national priorities for health risk

assessment research, 101

use of science to attack risk assessment, 127-128

Oncogenes, 178

One-hit model, 59

Office of Science and Technology Policy (OSTP), 46, 101

Peer review, 110-111
228 Researching Health Risks

Personal monitoring, 50, 136

Physiologically based pharmacokinetic (PBPK) model, 124-

125, 177

Priority-setting, 7-10,87-115

administrative tools for, 109-113

at the agency level, 10, 102-108; see also specific agencies

funding mechanisms to support, 110-111

influence of agency “culture” on, 108

influence of leadership on, 109

at the national level, 7-8,98-102

at the program level, 10, 108-109

Proto-oncogenes, 178

Radon, indoor, 14-19, 145-167

action levels for, 16, 17, 155-156

benefits of new studies of, 166-167

cancer risk estimates, 15, 17, 159-161

and Chaffee-Lautenberg Amendment, 157-158

cost-effectiveness analysis for reducing concentrations,

16, 156, 157

costs of regulation, 161-162

ecological fallacy, 150, 151

EPA Science Advisory Board comments on, 17, 18, 157,

161, 162-163

epidemiologic studies of, 149-153

exposure levels for airborne, 16, 155-156

exposures from uranium mines, 146-147

importance of appropriate testing techniques, 154-155

inconsistency in EPA’s approach to, 17-19, 163-164

and lung cancer, 16, 145, 148, 150-153, 155

magnitude of waterborne problem, 146

policy on airborne radon, 154-156

regulatory decisionmaking on waterborne radon, 156-163

role in other cancers, 153-154

and smoking, 148, 151-152

Reference dose (Rfd), 53

Regulatory decisionmaking

and benzene, 46

compliance costs of, 61-62

conservative science policy assumptions as basis for, 55

and costs of environmentally related illnesses, 62-63

and dioxin, 131-133

and indoor radon, 145-167

legislation regulating toxic substances, 106-107

limits of science in, 14, 133-137

links to research, 12-14, 137-140

social and political factors in, 136-137

studies on feedback to researchers from, 133

Reilly, William K.j 136

Reproductive and developmental toxicity, 49

Research to Improve Health Risk Assessment (RIHRA)

program

health risk assessment research at, 68-70

program emphases, 113

targeted research at, 112

Research linkages, see Collaboration

Resource Conservation and Recovery Act (RCRA), 102,107

Risk

definition, 1

from familiar hazards, 47

from indoor air pollution, 164-165

public perception of, 47-48

quantification of, 1,47

regulation of, 48

Risk assessment, see Health risk assessment

Risk-based planning, 70

Risk characterization

for carcinogens, 53-54

for noncarcinogens, 53

single numerical risk estimate in, 54

uncertainty factors in, 53

use of distributional approach in, 139-140

Risk communication, 140

Risk management, 51

Safe Drinking Water Act, 15, 16, 102, 107, 145, 156-157,

158, 163

Safety factors, see Uncertainty factors

Scaling factors, 52,54, 123-124

Science policy assumptions, 1, 12-14,20,54-55

Structure-activity relationships, 50,70, 175

Superfund Amendments and Reauthorization Act, 107

Targeted research, 112-113

2,3,7,8 -tetrachlorodibenzo-p-dioxin (TCDD), see Dioxin

Toxic Substances Control Act, 92, 102, 106

Toxicity equivalence factor (TEF) procedure, 132-133

Toxicological studies, 49-50

basic vs. applied, 88

chemical specific, 92-93

endpoints of, 49

as primary data source for health risk assessment, 49-50

and mechanistic research, 99-100

Tri-Services Center for Toxicology and R&k Assessment, 80

Tumor suppressor genes, 178

Uncertainty characterization, 60

Uncertainty factors, 46,52,53

Uranium Mill Tailings Radiation Control Act, 147-148

Validation studies, 68

Watras, Stanley, 148

d U.S. GOVERNMENT PRINTING OFFICE:l 994-301 -804/96974