CONF-9006234
Proceedings of the Symposium on the
Access and Use of
Information Resources in
Assessing Health Risks from
Chemical Exposure
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Access and Use of Information Resources in Assessing
Health Risks From Chemical Exposure
June 27-29,1990
Cosponsored
by
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
and
Biomedical and Environmental Information Analysis Section (BEIA)
Health and Safety Research Division
Environmental, Life, and Social Sciences
Oak Ridge National Laboratory
Prepared by the
Oak Ridge National Laboratory
Oak Ridge, Tennessee 37831-6050
managed by
Martin Marietta Energy Systems, Inc.
for the
U.S. Department of Energy
under contract DE-AC05-84OR21400
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Preface
Health risk assessment is based on access to comprehensive information about potentially hazardous agents in question. Relevant information
is scattered throughout the literature, and often is not readily accessible. To be useful in assessment efforts, emerging scientific findings, risk
assessment parameters, and associated data must be compiled and evaluated systematically. The U.S. Environmental Protection Agency
(EPA) and Oak Ridge National Laboratory (ORNL) are among the federal agencies heavify involved in this effort.
The ORNL involvement in this effort is effected primarily through its Biomedical and Environmental Information Analysis Section (BEIA).
This group has evolved in response to the 1961 recommendation of the President's Science Advisory Committee that information resources
should be developed that would focus on the data and information being generated from research on the interactions of potentially hazardous
agents within biological and environmental systems. BEIA fulfills this mission through the collection of experimental information from many
sources and the development of value-added information products and systems such as documents, databases, expert systems, and literature
collections.
One of EPA's primary responsibilities is to control and regulate chemical release to the environment. Because information is the foundation of
meaningful risk assessments on which to base environmental decisions, ready access to health, environmental, and regulatory information is
central to EPA's mission. State and heal agencies are becoming increasingly involved in risk assessment, particularly site-specific
assessments, making ER^'s information transfer and risk communication burden even heavier. Clearly, in today's environment, accurate,
consistent, and concise information is essential to ensure that all parties involved in risk assessment are appropriately informed
This symposium was a direct response by EPA and ORNL to the expressed needs of individuals involved in assessing risks from chemical
exposure. In an effort to examine the state of the risk assessment process, the availability of toxicological information, and the future
development and transfer of this information, the symposium provided an excellent cadre of speakers and participants from state and federal
agencies, academia, and research laboratories to address these topics. This stimulating and productive gathering discussed concerns
associated with (1) environmental contamination by chemicals; (2) laws regulating chemicals; (3) information needs and resources;
(4) applications; (5) challenges and priorities; and (6) future issues. Displays and hands-on demonstrations of EPA and ORNL information
resources were highlights of the symposium..
These proceedings consist of 38 papers contributed mostly by platform speakers and panel discussants. The papers are arranged to emulate
the symposium program, with a few editorial insertions, and organized into 9 sections as presented in the Table of Contents. In addition to the
complete text of papers presented during platform sessions, abstracts for the poster and demonstration presentations are included in the
Appendix.
A symposium of this magnitude requires the efforts and talents of many people, and we want to thank all of those who helped. We are
especially grateful to Wilma Barnard and Ida Miller for the many hours they devoted to making the symposium successful and to
Marilyn Langston and Dorla A mwinefor their work preparing this volume for publication. We would also like to thank David Reismanfor
his contribution in the planning of this symposium, as well as Norma Cardwell of the ORNL Conference Office for her help with arrangements.
Finally, the organizing committee would like to thank the more than 230 participants, speakers, and poster and demonstration presenters for
their contributions, which helped make the symposium a worthwhile effort for all.
Po-Ywg Lu and John S. Wassom, Oak Ridge National Laboratory
William H. Farland and Christopher DeRosa*, U.S. Environmental Protection Agency
*Now affiliated with Division of Toxicology, Agency for Toxic Substances and Disease Registry.
Ill
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Symposium Introduction
Seme time ago, Dr. Bill Farland, Dr. Chris DeRosa, Dave Reisman, John Wassom, and I discussed putting forth the effort to organize this
symposium. We decided to focus on information resources because people evaluating risk from environmental contaminants
must have access to the best information resources available to carry out their regulatory or research missions. To accomplish our purpose,
we provided a list of important topics to be addressed by subject experts during the symposium. We have brought together over 230 registered
participants from 30 states: representatives from federal agencies, academia, industry, and research laboratories throughout the continental
United States. We also have with us a special group of attendees, teachers from several local school systems and some consultants from the
Tennessee Department of Education.
We are indeed very excited about the program we have planned for the symposium. All of us are aware of the crucial need for reliable and
comprehensive information for use in assessing health risks from chemical exposure. Those who are specifically charged with the task of
making such assessments know that much pertinent information is scattered throughout the literature and is difficult to locate and obtain. New
scientific findings of interest to the risk assessment process must be systematically compiled, evaluated, and made available to those who need
it. This symposium will address this need.
During this 3-day symposium, through hands-on demonstrations, discussions, poster sessions, and formal platform presentations, many
speakers will address the symposium's basic theme— information resources for health risk assessment. We have developed sessions on
chemical health effects and information needs; toxicology information resources; and application of toxicology information for establishing
priorities for chemical testing, hazard ranking, and assessment. Guidelines used by the U.S. Environmental Protection Agency (EFft.) to assess
toxicological hazards will also be discussed. A poster and demonstration session will acquaint participants with some of the information
resources pertinent to health risk assessment that are available from EFA and ORNL. In addition, three different panel sessions will address
ways that federal and state agencies use information resources in health risk assessment applications. Presentation topics include information
files and data resources development, communication, and technology transfer. On the last day, a panel will review the issues, challenges, and
concepts discussed during the first two days. Finally, our concluding speaker will address the question, ' "Where do we go from here ? ' '
We appreciate the support of our symposium cohosts at the EFA Office of Health and Environmental Assessment in Washington, D. C. ;
Environmental Criteria and Assessment Office in Cincinnati, Ohio; and the Biomedical and Environmental Information Analysis Section of
Oak Ridge National Laboratory.
Po-Yung Lu, Oak Ridge National Laboratory
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CONTENTS
Chemicals, Health Effects, and Information Needs
The Problem of Living in a World Contaminated with Chemicals
Robert L Metcalf 1
Environmental Laws Regulating Chemicals: Uses of Information in Decision Making Under
Environmental Statutes
Jeffrey M. Gaba 13
Information Needs for Risk Assessment
Christopher T. DeRosa, H. Choudhury, and R. S. Schoeny 21
Information Needs for Risk Management/Communication
David A. Bennet 31
Toxicology Information Resources, Challenges, and Needs
Evolution of Toxicology Information Systems
John S. Wassom and Po-Yung Lit 35
Information and Technology: A Coexistence Without Limits, A Beginning With No Apparent Ending
David J. Reisman 43
The Challenge of Information Access
Linda A. Trovers 49
Application of Toxicology Information for Establishing Priorities for Chemical
Testing, Hazard Ranking, and Assessment
Structure Activity Relationships To Assess New Chemicals Under TSCA
Angela E. Auletta ....'. 53
Quantitative Genetic Activity Graphical Profiles for Use in Chemical Evaluation
Michael D. Waters, H. Frank Stack, Neil E. Garrett, and Marcus A. Jackson 61
The TSCA Interagency Testing Committee's Approaches to Screening and Scoring Chemicals and
Chemical Groups: 1977-1983
John D. Walker 71
Guidelines Used To Assess Toxicological Hazards
EPA's Program for Risk Assessment Guidelines: Overview
Dorothy E. Patton 95
EPA's Program for Risk Assessment Guidelines: Cancer Classification Issues
Jeanette Wiltse 97
VII
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EPA's Program for Risk Assessment Guidelines: Quantification Issues
Michael L Dourson 103
EPA's Program for Risk Assessment Guidelines: Exposure Issues
Michael A. Callahan *07
Information Applications: Rapporteur Summary
Sidney Siegel 109
How Information Resources are Used by Federal and State Agencies in Risk
Assessment Applications
How Information Resources Are Used by Federal Agencies in Risk Assessment Applications
William E. Legg H3
Tactical Approach to Maneuvering within the Chemical Contamination Labyrinth
Timothy W. Joseph 115
Information Resource Use and Need In Risk Assessment
Angela Turturro 119
Risk Assessment Activities at NIOSH: Information Resources and Needs
Leslie T. Stayner, Theodore Meinhardt, and Bryan Hardin 123
National Toxicology Program Chemical Nomination and Selection Process
James K. Selkirk 729
Assessing Human Health Risk in the USDA Forest Service
Dennis R. Hamel 133
Access and Use of Information Resources in Assessing Health Risks From Chemicals in Food
Wesley A. Jolmson 755
How Information Resources are Used by Federal Agencies in Risk Assessment Application:
Rapporteur Summary
Penelope Fenner-Crisp 747
Information Resources in State Regulatory Agencies—A California Perspective
Stephen M. DiZio 145
How Information Resources Are Used by State Agencies in Risk Assessment Applications—Illinois
Clark S. Olson 757
Information Resources: How They Are Utilized by Louisiana
Suzanne Gardner 755
Access and Use of Information Resources by Massachusetts
Carol Rowan West 759
VIII
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Information Resources Used in Health Risk Assessment by the New Jersey Department of
Environmental Protection
Gloria B. Post, Maria Baratta, Sharon Wolfson, and Leslie McGeorge 163
Use of Information Resources by the State of Tennessee in Risk Assessment Applications
Bonnie S. Bashor 169
Information Files and Data Base for Evaluating Health Hazards From
Chemical Agents
Integrated Risk Information System (IRIS)
LindaTuxen 173
Risk Assessment and Toxicology Databases for Health Effects Assessment
Po-Yung Lu and John S. Wassom 179
EPA and the Federal Technology Transfer Act: Opportunity Knocks
Annette M. Gatchett, Larry Fradkin, Michael Moore, Thomas Gorman, and Alan Ehrlich 195
Information Resources for Assessing Health Effects From Chemical Exposure:
Challenges, Priorities, and Future Issues
Information Resources for Assessing Health Effects from Chemical Exposure: Office of Pesticide Programs
Penelope Fenner-Crisp 203
Air Risk Information Support Center
ChonR. Shoaf and Daniel J. Guth 205
Chemical Substructure Analysis in Toxicology
Robert O. Beauchamp, Jr. 211
Information Resources and the Correlation of Response Patterns Between Biological End Points
Heinrich V Mailing and John S. Wassom 279
Information Resources for Assessing Health Effects From Chemical Exposure: Challenges, Priorities,
and Future Issues
Sidney Siegel 227
Concluding Remarks: Where Do We Go From Here?
WlliamH.Farland 237
Appendix
1 Biomedical and Environmental Information Analysis Section: Computing Resources
Sherry J. Campbell, Roswitha T.Haas, Donald G. Kilgore,and Kathy C. Miller 239
2 Application of Expert System Shells to the Areas of Health, Safety, and Environmental Accountability
Kathy C. Miller, Roswitha T.Haas, Donald G.Kilgore, and Helen A. Pfuderer 239
IX
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3 ROADMAPS to Information Sources on EPCRA Section 313 (TRI) Chemicals
John S. Leitzke and James F. Dorr
4 EPA/OTS Information Resources
LindaA Trovers 24°
5 Dose-Duration Plot
Christopher H. Cubbison 241
6 Toxicology Information Response Center: Customized Information Acquisition
Kimberly G. Slusher, Mary W. Francis, and Ida C. Miller 241
7 The U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS)
Linda Tuxen and Jacqueline Patterson 242
8 Graphical Activity Profiles in Genetic Toxicology and Developmental Teratology
Elizabeth T. Owens, T. Owens Vaughan, H. Frank Stack, Marcus A. Jackson, Robert J. Kavlock,
and Michael D. Waters 242
9 Human Genome Management Information System
Betty K. Mansfield, Anne E. Adamson, Roswitha T. Haas, Donald G. Kilgore, Michael D. Mayes,
Elizabeth T. Owens, Judy M. Wyrick, and Laura N. Yust 243
10 Chemical Unit Record Estimates Database
David J. Reisman, Christopher T. DeRosa, Mary W. Francis, Ida C. Miller, Robert S. Stafford,
Andrew A. Francis, Cheryl B. Bast, andPo-YungLu 244
11 Environmental Mutagen Information Center File
Elizabeth S. Von Halle, Kathleen H. Mavoumin, Bradford L Whitfteld, Mary Ann C. Davidson,
Karen A. Weaver, and John S. Wassom 244
12 Environmental Teratology Information Center File
Geraldine S. Danford, Shigeko Y. Uppuluri, and Florence M. Holland 245
13 Gene-Tox Agent Registry File
Roswitha T. Haas and Angela E. Auletta 245
14 Genetic Toxicology Chemical Structure File
Roswitha T. Haas, Mary Ann C. Davidson, and K. S. Rao 246
15 Environmental Restoration and Waste Management Data Bases
Park T. Owen, Linda F. Coins, and Nancy P. Knox 246
16 Development of Applicable or Relevant and Appropriate Requirements (ARARs) for
Remediation of Hazardous Waste Sites Under Superfund
Elizabeth L Etnier, Patricia S. Hovatter, Sylvia S. Talmage, Rose S. Weaver, Linda M. Houlberg,
Robert H. Ross, and Robert Muhly 247
17 Selection of Indicator Chemicals at Hazardous Waste Sites
Patricia S. Hovatter, Robert E. Gibson, and Robert Muhly . 245
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18 Less-Than-Lifetime Risk Assessment: Estimation of No-Effect Levels for Nonlethal Toxic End
Points By Analogy to Acute Toxicity
Cheryl B. Bast, Robert E. Gibson, Christopher H. Cubbison, and Christopher T. DeRosa 248
19 PATS: Packaging and Transportation Safety Program Data Base
Ruth M. Gave, Andrea A Richmond, Miriam J. Welch, and Richard R. Rawl 249
20 Toxicology Guide for Installation Restoration Program Application
Robert A. Young, Po-Yung Lu, Mary W. Francis, Robert H. Ross, G. W. Jepson, andJ. W. Fisher .... 249
21 Hypertext System Demonstration: Information on the Symposium and BEIA
Gloria M. Colon and Suzanne E Joy 250
22 Activities of the Federal-State Toxicology and Regulatory Alliance Committee
Robert Cantilli 250
23 The Rodent Dominant Lethal Assay
4
BradfordL Whitfteld 257
24 In Vivo Micronucleus Assay in Mammalian Bone Marrow and Peripheral Blood
Kathleen H. Mavournin, David H. Blakely, Michael C. Cimino, Michael F. Salamone,
andJohnAHeddle 252
25 Inhalation Reference Dose Methodology: Development, Dosimetric Adjustments,
and Human Equivalent Concentrations
ChonR. Shoaf and Annie M. Jarabek 252
26 Animal Testing Alternatives: A Selected Annotated Bibliography
Robert S. Stafford, Po-Yung Lu, and George J. Cosmides 255
27 Superfund Technology Support Center for Health Risk Assessment
Pei-Fung Hurst, W. Bruce Peirano, and Christopher T. DeRosa 255
28 Chemical Hazard Assessment
Robert H. Ross, Cheryl B. Bast, MaryL Dougherty, KowethaA Davidson, Rosemarie Faust,
Andrew A. Francis, Patricia S. Hovatter, Dennis M. Opresko, Sylvia S. Talmage, Robert A. Young,
Christopher T. DeRosa, Harlal Choudhury, V J, Cogliano, Christopher H. Cubbison,
andBennett G. Smith 254
29 Mutagenicity Testing Guidelines for the U.S. EPA Office of Toxic Substances (OTS)
Michael C. Cimino and Angela E. Auletta 255
30 Material Safety Data Sheets for Hazard Communication
Sibyll M. Hubner, Betty W Kline, Po-Yung Lu, Linda B. Pierce, and James R. Crawl 255
31 DART and Other Information Resources in Developmental and Reproductive Toxicology
Carole A Kimme,l, StaceyJ. Arnesen, Henry M, Kissman, and Bernard A. Schwetz 256
32 The Ames/Salmonella Microsome Assay for Genotoxicity
Mary M. Brown, Elizabeth S. Von Halle, and Angela E Auletta 257
XI
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33 Proposed Changes to the Toxic Substances Control Act (TSCA) Tier Testing Scheme for Mutagenicity
Angela E. Auletta and Michael C. Cimino 257
34 Radiological Site Characterization Surveys and Data Analyses
MaryS. Uziel, LoisM. Floyd, and Judy W. Cnttcher. . 258
35 Biomedical and Environmental Information Analysis Section Communication Resources:
Printed and Electronic
Gloria M. Colon, Linda M. Houlbefg, Marilyn E. Langston, and Judy M. Wyrick 259
36 Environmental Guidance Program: Reference Books and Regulatory Update Table
Cynthia G. Heckman, Linda M. Houlberg, Marilyn E. Langston, Patricia A. Nikbakht, Marti S. Salk, and Julia
M. Stockstill '. 259
37 Air Risk Information Support Center (Air RISC) — Technical Support to State and Local
Agencies for Risk Assessment
ChonR. Shoaf and Daniel J. Guth 260
38 Risk Assistant
John Schaum and John Young 257
39 Development and Application of Numeric Files Derived from Toxicologic Experimentation
Sidney Siegel 261
Agenda 263
Author Index 269
Addresses 271
xu
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The Problem of Living in a World Contaminated
With Chemicals
Robert L. Metcalf, University of Illinois
The proliferation of xenobiotic chemicals in the global environment poses living problems for each of us aboard "spaceship earth'
Seven case studies are presented that illustrate the magnitude of the problem that can result from waiting to identify toxic hazards
until there have been decades of "human guinea pig" exposure.
Introduction
The past century witnessed
an exponential growth in
the number of synthetic
chemicals considered essential to
science and technology. The
Merck Index, 1st edition (1889),
listed only 828 chemicals; the
llth edition (1990) lists more
than 10,000. More than 44,000
different chemicals are identified
in the U.S. Environmental Protec-
tion Agency (EPA) Toxic Sub-
stances Control Act Inventory
(1979). During the past 50 years,
the volume of synthetic organic
chemical production in the
United States has increased 20-
fold, from 10 billion pounds
annually in 1943 to about 200 bil-
lion pounds in 1989 (U.S. Tariff
Commission data).
The proliferation of these xenobi-
otic chemicals in the global envi-
ronment poses living problems
for each of us aboard "spaceship
earth," whether these chemicals
are micropollutants of air, water,
and food; are bioconcentrated
through food chains; permeate
the work place; or ate destructive
to the ozone layer. The problems
of living with these chemicals
will become more acute as the
world population increases from
5.3 billion in 1990 to an esti-
mated 17 billion by the year
2050. This huge population
increase will be accompanied by
a concomitant demand for even
greater chemical production for
use in the manufacture of fuels,
plastics, plasticizers, fibers, elas-
tomers, solvents, detergents,
paints, pesticides, food additives,
and Pharmaceuticals. It has been
estimated that every year more
than 500 new and potentially
toxic chemicals are produced on
a scale large enough that traces
of them enter the environment
through air, water, and directly
and indirectly into food. We are
well along into a period pic-
turesquely described by Time
Magazine as the "Age of Efflu-
ence" (May 10, 1968).
A World Health Organization
(WHO) report, "Microchemical
Pollution in the Environment"
(1963), emphasized that such
chemicals present at parts per bil-
lion (ppb) to parts per trillion
(ppt) levels can be harmless,
toxic, or carcinogenic. During
the past 50 years we have
learned, at great cost, that many
substances "generally regarded
as safe" can be extraordinarily
hazardous to humans, other life
forms, and to the total quality of
The proliferation of these xenobiotic
chemicals in the global environment
poses living problems for each of us
aboard "spaceship earth."
It has been estimated that every
year more than 500 new and
potentially toxic chemicals are
produced on a scale large enough
that traces of them enter the
environment through air, water,
and directly and indirectly into food.
Access/Use Info Resources Assess Health Risk Chem Expos '93
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the environment The ubiquitous
use of asbestos is a case in point!
Seven case studies are presented
here that illustrate the magnitude
of the problem that can result
from waiting to identify toxic
hazards until there have been dec-
ades of "human guinea pig"
exposure.
Tetraethyl Lead
Lead tetraethyl [(C2H5)4Pb] was
developed in 1922 by Midgley
and Boyd as an "antiknock" sub-
stance to prevent predetonation
in internal combustion engines.
The use of tetraethyl lead in the
United States increased propor-
tionately with the growth of the
automobile industry, and in
1970, approximately 360 million
pounds of tetraethyl lead was
consumed. At that time the aver-
age lead content of gasoline was
2.6 g/gal. Lead is released in
automobile exhausts primarily as
an aerosol of lead chlorobromide
(PbClBr) with a median particle
diameter of about 0.25|i. As a
result, atmospheric concentra-
tions of lead range from
0.3 mg/m in rural areas to
1.4 mg/m in average urban loca-
tions. Concentrations in areas
congested with heavy traffic are
much higher, e.g., Los Angeles
freeway areas containing as
much as 38 mg/m (Ewing and
Pearson 1974). The influence of
leaded fuel automobile exhausts
on lead in the environment is
enormous, as shown by investiga-
tions of lead content in the Green-
land ice cap, which rose about
fourfold in ice deposited over the
period of 1930 to 1950
(Murozumi et al. 1969).
Although lead has been known
as a toxic metal since antiquity,
"the lead from automobile
exhausts was widely perceived
as inconsequential" despite the
enormous amounts liberated to
the environment and the ease
with which the aerosol is
inhaled. Patterson (1965) was the
first to warn about the severity of
the toxic hazards of lead in the
environment. Relatively recent
investigations have shown that
lead inhibits the formation of the
blood pigment heme by inhibit-
ing the enzyme delta-
aminolevulinic acid synthetase.
For many years, it was widely
stated by the lead industry that
human blood lead levels of 100
jog per deciliter represented a
"safe level" with complete free-
dom from toxicological effects.
However, WHO (1977) in its
"environmental health criteria"
now considers much lower blood
lead levels to be associated with
a variety of human toxicoses as
shown in Table 1.
Thus, the liberation of lead from
automobile exhausts is now seen
to be a major health hazard in
areas of heavy traffic, particu-
larly to children in which low
levels of lead intoxication have
been shown to result in brain
damage associated with learning
Relatively recent investigations have
shown that lead inhibits the
formation of the blood pigment heme
by inhibiting the enzyme
delta-aminolevulinic acid synthetase.
Table 1. Relation of human lead levels to abnormal
physiological effects21
Blood lead |ig/dl Physiological effects
100
60-80
50-70
40-50
3(MO
20-35
>10
a Source
Original "safe level"
Lead encephalopathy
Brain dysfunction
Peripheral neuropathy, ALA excretion,
Erythrocyte ATP-ase inhibition
Free erythrocyte protoporphyria
Erythrocyte ALA-D inhibition
World Health Organization (1977).
anemia
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decrements. The EPA attempted
to reduce the use of lead alkyls
in gasoline for more than a dec-
ade before a schedule of com-
plete phase out was completed in
1982.
Poly chlorinated Biphenyls
(PCBs)
Chlorination of biphenyl (C6Hs-
CsHs) produces a range of chlo-
rinated isomers of which 224
distinct congeners are possible.
The commercial compounds con-
sist of a series of fractions identi-
fied by average chlorine content
(e.g., Aroclor 1242 is 42% chlo-
rine and averages 1% C^HpCl,
16% Ci2H8Cl2, 49% Ci2H7Cl3,
25% Cl2H6Cl4, 8% C12H5C15,
and 1% Ci2H4Cl6). These PCB
fractions are typically viscous
oils with very low vapor pres-
sures that, because of their high
chlorine content, are relatively
inert to chemical degradation.
Because of their stability and
lack of acute toxicity (rat oral
LDso for Aroclor 1242 is 8700
mg per kg), "the PCBs for many
years were generally considered
as safe."
PCBs were introduced commer-
cially in 1929, and annual pro-
duction in the United States was
20,786 tons in 1960 and
increased to 42,527 tons by 1970
(C&ENews). Approximately
400,000 tons was produced
between 1948 and 1973, and
these substances, used as fire-
proof hydraulic fluids, lubri-
cants, dielectrics, plasticizers,
adhesives, and printing products,
became ubiquitous.
Jensen (1966) first identified
PCBs as environmental pollut-
ants in marine fish and birds by
their characteristic gas-liquid
chromatographic patterns. Soon
it was apparent that PCB conge-
ners that have very high lipid/
water partition coefficients are
readily bioconcentrated in aqua-
tic organisms and biomagnified
through food chains (Table 2). In
Japan, PCB oils contaminated
the human diet and produced a
pathological condition called
Yusho or rice oil disease. The
symptomology involved dark-
ened skin; brownish pigmenta-
tion of nails, lips, and gums; and
severe acne (Goto and Higuchi
1969). PCBs are highly deleteri-
ous to mammalian reproduction;
mink, Mustela vison, are espe-
cially sensitive as shown in
Table 3 (Aulerich and Ringer
1977). PCBs were first detected
in Coho salmon from the Great
Lakes in 1969. Between 1972
and 1974, the average PCB
concentration in fish from Lake
Michigan was 10.2 ppm (range
2.1 to 18.9) (Simmons 1984).
Thus, the normal mink diet of
freshwater fishes is responsible
for widespread reproductive fail-
ures in mink farms. Speculation
Soon it was apparent that PCB
congeners that have very high lipid/
water partition coefficients are
readily bioconcentrated in aquatic
organisms and biomagnified
through food chains.
Table 2. Partition coefficients and biomagnification of PCB
congeners in laboratory model ecosystema
Biphenyls
4-Chloro
4,4'-Dichloro
2,5,2'-Trichloro
2,5,2',5'-Tetrachloro
2,4,5,2',5'-Pentachloro
n-Octanol/
H2O partition
390
5,700
7,800
8,100
16,600
2,4,5,2',4',5'-Hexachloro 29,900
Decachloro
aSource: Metcalf and Lu
189,300
(1978).
Biomagnification in
mosquito fish,
Gambusla affinis
480
1,200
6,400
12,000
12,100
42,000
97,000
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has suggested that the wide-
spread bioconcentration of PCBs
in fish poses a threat of extinc-
tion of all fish-eating mammals
(Marquenie 1990).
Table 3. Effects of dietary PCBs
on mink reproduction3
PCS in diet
(ppm)
0
1
2
5
10
15
Offspring per
female
6.0
4.3
0.3
0.0
0.0
0.0
aSource: Aulerich and Ringer
(1977).
The threat to human health from
dietary intake of PCBs is obvi-
ous. State health agencies of
Michigan, Indiana, Illinois, and
Wisconsin have issued a Lake
Michigan sport-fish advisory that
women and children should not
eat lake trout 20 to 23 in. in
length, Coho salmon over 26 in.
Chinook salmon 21 to 32 in., and
brook trout up to 23 in. Fish
larger than these limits should
not by eaten by anyone. PCB
contamination of Great Lakes
fish has destroyed a $500 million
commercial fishing industry.
PCB production was banned in
Sweden in 1972 and discontin-
ued in the United States in 1976.
However, it is estimated that
between 1930 and 1970 the total
loss of PCBs in North America
alone was about 500,000 tons,
with 30,000 tons dispersed in air,
60,000 tons discharged into
water and underlying sediments,
and 30,000 tons deposited in
landfills and dumps (Simmons
1984). Thus, PCB contamination
of the total environment will per-
sist for many years to come.
Dibromochloropropane
(DBCP)
1,2-Dibromo-3-chloropropane
(BrCH2CH2BrCH2Cl) bp 196° C
is a soil fumigant and nemato-
cide introduced in the United
States in about 1955 and found
especially useful for the control
of plant parasitic nematodes that
attack grapes, peaches, citrus,
pineapple, and soybeans. Unlike
other soil fumigants, DBCP
could be safely applied to soils
with growing perennial crops.
Because of its high boiling point
and comparatively low toxicity
(rat oral LDso: male 0.17 g/kg
and female 0.26 g/kg), "it was
considered as a very safe soil
fumigant." United States produc-
tion was 12 million pounds in
1976. Torkelsonetal. (1961)
found that laboratory rats, mice,
rabbits, and guinea pigs exposed
to 12 ppm DBCP vapors for 70
to 92 days exhibited severe atro-
phy and degeneration of the tes-
tes, which in rats was characteri-
zed as degenerative changes in
the seminiferous tubules, an
increase in sertoli cells, reduction
in the number of sperm cells, and
development of abnormal sperm
cells. Rats exposed to 5 ppm
DBCP had testicular weights
reduced by 50%. However, it
was concluded that if human
worker exposure were limited to
1 ppm, "there would be little like-
lihood of injury." This toxicologi-
cal data was submitted in 1961 to
the Food and Drug Administra-
tion (FDA) and U.S. Department
of Agriculture (USDA) by the
manufacturers of DBCP in a peti-
The threat to human health from
dietary intake of PCBs is obvious.
Rats exposed to 5 ppm DBCP had
testicular weights reduced by 50%.
However, it was concluded that if
human worker exposure were
limited to 1 ppm, "there would be
little likelihood of injury."
Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
tion to establish tolerances on 44
crops. The tolerances were
reviewed by FDA and USDA,
and tolerances were established
on food crops based on the belief
that DBCP degraded in soils to
produce inorganic bromide ions,
which were taken up by plants.
The tolerances granted ranged
from 5 ppm for apricots, nectar-
ines, and peaches to 130 ppm for
endive and lettuce.
Subsequently, the National Can-
cer Institute published carcino-
genicity studies with laboratory
rats and mice (Olson et al. 1973)
showing that rats and mice
exposed to DBCP developed a
very high incidence of gastric
and mammary tumors. Although
these studies were confirmed by
industry carcinogenesis studies,
for more than 4 years these
results were not communicated
to workers producing or using
DBCP (Pollack 1979).
Federal regulation to severely
limit the use of DBCP originated
only in 1977. In that year a group
of male agricultural chemical
plant workers who were con-
cerned about their inability to
father children contacted an inde-
pendent laboratory through their
union to analyze sperm samples,
after being refused help by their
employer. Test results showed
significant evidence of sterility.
The National Institutes for Occu-
pational Safety and Health
(NIOSH) evaluated working con-
ditions in the plant and eventu-
ally confirmed that exposure to
DBCP was causing oligospermia
or azoospermia. Subsequently,
the EPA and the Occupational
Safety and Health Association
(OSHA) conducted sperm counts
on several hundred male workers
in South Carolina, California,
and Texas exposed to DBCP.
These men were exposed in vari-
ous occupations from production
to sales to agricultural work.
There was a significant correla-
tion between extent of use and
exposure to DBCP (pound per
day) and quantitative sperm
count as summarized in Table 4
for the South Carolina cohort
(Pollack 1979).
At this point, production of
DBCP was stopped by one large
manufacturer, and EPA began the
Rebuttable Presumption Against
Reregistration (RPAR) process to
control the use of DBCP in agri-
culture. Following extensive
risk/benefit analysis and lengthy
hearings that lasted for nearly
4 years, the use of DBCP was
suspended on 19 vegetable crops
and 11 tree fruits. These suspen-
sions were challenged by the
manufacturer and the agricultural
industry. Subsequently, however,
substantial residues of intact
DBCP were found in edible
fruits and vegetables, and it was
further demonstrated that a large
percentage of well waters from
There was a significant correlation
between extent of use and exposure
to DBCP (poundper day) and
quantitative sperm count.
Table 4. Correlation between use index and sperm count for South
Carolina workers exposed to DBCPa
Occupation
Formulators (n = 8)
Custom applicators (n = 2)
Farmers (n= 18)
Farm workers (n = 12)
Researchers (n = 7)
Salesmen (n = 6)
Use index
(Ib/day)
5,000
345
710
240
10
450
Sperm count
(106/ml)
12.1
2.7
17.8
37.8
101.5
73.0
aSource: Pollack (1979).
Access/Use Info Resources Assess Health Risk Chem Expos '93
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the San Joaquin Valley of Califor-
nia had demonstrable residues of
DBCP. Therefore, EPA was com-
pelled to withdraw all registra-
tions of DBCP in 1982.
Leptophos
This organophosphorus insecti-
cide was patented in 1969 as a
replacement for DDT, especially
for the control of Lepidopterous
caterpillars, hence the name.
Approximately 17 million
pounds was sold in 50 countries
between 1971 and 1976. Egypt
received 6.67, Indonesia 2.08,
Japan 1.83, and Guatemala 0.56
million pounds. Leptophos, O-
methyl O-4-bromo-2,5-dichlo-
rophenyl phenylphosphonothio-
nate, is highly persistent and lipo-
philic (water solubility 9 ppb,
m-Octanol/H2O partition coeffi-
cient ca 2 x 10 ). This insecticide
was shown to produce organo-
phosphorus induced delayed
neurotoxicity (OPIDN) in the
hen in 1969, and these results
were confirmed by WHO in
1971. OPIDN results from selec-
tive inhibition of neurotoxic
esterase in the axons of the cen-
tral nervous system, and as a
result animals and humans
exposed develop irreversible
paralysis of the limbs together
with bizarre mental effects
(Metcalf 1982).
Massive applications of lepto-
phos to cotton in Egypt in 1971
to control the cotton leafworm
Spodoptera littoralis produced
ascending paralysis and death in
about 1300 water buffalo (Abou-
Donia et al. 1974). There was
also evidence of widespread
human poisoning with lassitude,
headache, muscarinic and epigas-
tric symptoms, and depressed
acetylcholinesterase (Hasson et
al. 1978).
Despite these warnings, the
effort to market leptophos on a
large worldwide scale continued,
and in 1974, EPA published its
intent to set tolerances for lepto-
phos of 10 ppm on lettuce and
2 ppm on tomatoes. These high
residue values attested to the per-
sistence of the insecticide.
From 1973 through 1975, a
series of unusual nervous system
complaints occurred among
employees of a leptophos manu-
facturing plant in Houston,
Texas. The symptoms included
tingling and weakness in arms
and legs, slurred speech, memory
lapses, hallucinations, and para-
plegia. The most severely
affected workers were diagnosed
by company physicians as suffer-
ing from schizophrenia, encepha-
litis, and multiple sclerosis
(Curtis 1978). Concerns that
developed among factory person-
nel and consulting physicians
resulted in an investigation by
NIOSH, and it was eventually
found that 63 of 155 workers dis-
played neurological and perform-
ance decrements. Because of the
many questions arising over con-
tinuing use of lephophos, EPA
appointed an advisory committee
that reported in October 1976
that leptophos was a delayed
neurotoxin, having potential haz-
ard to man from manufacturing,
use, and consumption of residues
on food. Before the committee
report was issued, the manufac-
turer withdrew its U.S. registra-
tion applications on August 18,
1976.
Leptophos was patented in 1969 as
a replacement for DDT, especially
for the control of Lepidopterous
caterpillars.
A series of unusual nervous system
complaints occurred among
employees of a leptophos
manufacturing plant in Houston,
Texas.
AccessA'sc Info Resources Assess Health Risk Chem Expos '93
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Pyriminil
This chemical, 4-(4-nitrophenyl)-
N'-3-pyridinylmethyl)urea, was
developed as a selective single-
dose rodenticide effective
against warfarin-resistant rats.
Peardon (1974) presented the fol-
lowing oral LDso values, purport-
ing to demonstrate the highly
selective rodenticidal qualities of
pyriminil.
Test animal LDso mg/kg
Mouse
Norway rat
Roof rat
Cotton rat
Rabbit
Dog
Chicken
Cat
Monkey
98
5
18
20-60
300
500
710
62
2,000^,000
"The very high toxicity to rats
and the low toxicity to nonhu-
man primates suggested that
pyriminil would be an effective
and safe rodenticide for home
use."
Pyriminil was registered as a,
rodenticide with EPA in 1975 as
a house mouse tracking powder
with 10% active ingredient (AI),
a commercial rat killer with 2%
AI, and a rat confection
(Vacor®) with 2% AI. Pyriminil
was test marketed in Korea in the
mid-1970s and the manufacturer
maintained that only a few inci-
dents of poisoning associated
with Vacor® treated grain had
occurred. However, Lee et al.
(1977) reported on 251 cases of
human poisoning and a number
of fatalities in Korea following
accidental or suicidal ingestion
of pyriminil. About 80% of the
patients evidenced diabetic
hyperglycemia, with massive
necrosis of the islets of Langer-
hans of the pancreas and abnor-
mal pathology of liver and
kidney. Human poisoning from
Vacor® ingestions developed in
California, including those from
ingestion of a new 0.5 pyriminil
formulation sold "over the
counter." It has become evident
that pyriminil has human toxicity
similar to that in the rat and can
cause permanent life-long diabe-
tes, intractable hypertension, and
severe autonomic neuropathy
(Pont et al. 1979). After consider-
able pressure from regulatory
agencies, pyriminil was with-
drawn from the market by the
manufacturer in 1979.
Toxaphene
The insecticide toxaphene is
made by photochlorinating the
bicyclic terpene camphene, from
old pine stumps, to contain 67 to
69% chlorine. The product is a
semicrystalline gum with an
empirical formula of CioHioClg.
Toxaphene was introduced as an
insecticide in 1947 and was
widely used for the control of the
cotton boll weevil, Anthonomus
grandis. When registrations of
DDT were discontinued in 1971,
toxaphene became its primary
replacement as the major cotton
insecticide. Cumulative produc-
tion and use by 1974 was esti-
mated at about 1 billion pounds.
Toxaphene was registered as an
insecticide with EPA under a
"grandfather clause" "with the
general supposition that it was
biodegradable and nonaccumula-
tive through food chains." Know-
ledge of chemical composition
and residue chemistry was nonex-
istent until modern GC-MS
investigation showed that it was
Pyriminil was developed as a
selective single-dose rodenticide
effective against warfarin-resistant
rats.
Toxaphene was introduced as an
insecticide in 1947 and was widely
used for the control of the cotton
boll weevil.
Access/Use Info Resources Assess Health Risk Chem Expos '93
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composed of at least 180 chlorin-
ated terpenes (Holmstead et al.
1974), of which the most toxic is
2,2,5-«wto-6-ex0-8,9,9,10-octa-
chlorobornane with a mouse
intraperitoneal LDso of 3.1
mg/kg. Toxaphene is extremely
toxic to fish, producing a crip-
pling collagen deformity at con-
centrations as low as 50 ppt, and
is also an animal carcinogen.
Following development of GC
methods for detecting toxaphene
congeners, toxaphene residues
were identified in Great Lakes
fishes in 1979, and subsequent
investigation has shown that lake
trout, Salvelinus namaycush,
from Lake Michigan contain as
much as 11 ppm of the toxa-
phene congeners. Toxaphene resi-
dues are now known to be
widespread in the Great Lakes
and to be bioaccumulated
through food chains (Rice and
Evans 1984). Toxaphene has
been widely used as an insecti-
cide in the United States in the
cotton-growing southern states,
and it is evident that much of its
dispersal into the northern Great
Lakes has resulted from atmos-
phere transport and deposition.
As a result of these findings, the
registration of toxaphene was
canceled by EPA in 1982.
Chlorofluorocarbons
(CFCs)
These relatively inert gas/liquids,
of which trichlorofluoromethane
(FCC13) bp 23TC (CFC 11) and
dichlorodifluoromethane
(FiCCli) bp 29.79°C (CFC 12)
are the best known, were
invented by Henne & Midgely in
1930 and found immediate use
as refrigerants. Their success as
propellants for aerosol sprays
invented by Goodhue & Sullivan
greatly accelerated usage and
U.S. production of CFCs (in met-
ric tons) rose over the years as
follows:
1942
1958
1962
1970
1974
4,500
60,000
100,000
150,000
200,000
In 1972, more than 2.7 billion
aerosol dispensers were pro-
duced in the United States. Pro-
duction in the rest of the world
equaled or surpassed U.S. pro-
duction by 1974. CFCs were
widely believed to be "so stable
that they are entirely harmless"
(Encyclopedia Britannica 9th
ed., 1956). However, in 1974
Molina and Rowland predicted
from computer modeling that
CFCs released into the atmos-
phere slowly diffuse into the
stratosphere where they undergo
the following reactions with
ozone, a gas that forms a barrier
around Earth which protects
against the passage of ultraviolet
radiation.
Cl + Os -> CIO + O2
CIO + O -> Cl + Oi
The CIO formed can regenerate
Cl by reacting with atomic oxy-
gen. Therefore, one atom of Cl
can degrade a large number of
molecules of Os. Although EPA
banned the further U.S. use of
CFCs as aerosol propellants in
1978, the slow diffusion rates
and relative stability of these
CFC molecules, together with
the large reservoirs of CFCs in
the stratosphere, formed the basis
for a prediction that ozone levels
would continue to decrease for
Molina and Rowland predicted from
computer modeling that CFCs
released into the atmosphere slowly
diffuse into the stratosphere where
they undergo reactions with ozone.
Although EPA banned the further
U.S. use of CFCs as aerosol
propellants in 1978, the slow
diffusion rates and relative
stability of these CFC mole-
cules, together with the large
reservoirs of CFCs in the
stratosphere, formed the basis for
a prediction that ozone levels
would continue to decrease for
another 7 to 8 years.
Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
another 7 to 8 years (Guttowsky
1976). The estimated atmos-
pheric lifetime of CFC-11 is
75 years, and its concentration is
2.3 x 10"4 ppm; and that of CFC-
12 is 110 years, with a concentra-
tion of 3.8 x 10"4 ppm (Hileman
1989).
Although the modeling predic-
tions were vigorously challenged
by the chemical industry, espe-
cially in developing countries,
the discovery in 1985 of a large
hole in the ozone layer above
Antarctica has been repeatedly
verified. Several international
congresses have called for a total
ban on the production of CFCs
as the only way to prevent sub-
stantial destruction of the ozone
layer. Nevertheless, by mid-
1990, 15 years after the initial
warning, there is still no con-
certed worldwide action.
It has been demonstrated that
exposure to ultraviolet light of
wavelengths from 280 to 320 nm
is responsible for initiation of
skin cancers: basal cell carci-
noma, squamous cell carcinoma,
and malignant melanoma. The
incidence of these neoplasms is
highest in areas of intense solari-
zation (e.g., Queensland, Austra-
lia, where it is 39.6 per 10
population annually and Norway
where it is 12 per 105). In both of
these areas, the incidence is dou-
bling every decade. In Arizona,
the incidence has quadrupled
over the past 10 years (Rook et
al. 1986). The American Cancer
Society estimates that 1 in 7
Americans, or more than
600,000 in 1990, will develop
skin cancers during their lives.
Although skin cancers usually
arise as much as 30 years after
ultraviolet exposure, 25% of
those currently diagnosed with
malignant melanoma were under
age 39. Increasing damage to the
ozone layer, which protects Earth
from this dangerous ultraviolet
radiation will inevitably be fol-
lowed by heightened incidence
of skin cancer in humans.
Summary and
Conclusions
Each of the seven case studies
presented here relates to syn-
thetic organic chemicals that
have had extensive use and have
contaminated various segments
of the human environment. Each
of these chemical contaminants
was developed and used widely
under the supposition that it was
"generally regarded as safe." In
every case, detailed investiga-
tions made after uses were estab-
lished and markets developed
have shown that these substances
were so lexicologically and envi-
ronmentally hazardous that they
had to be withdrawn from the
market place. The most sobering
lessons to be learned are (1) the
Seven case studies presented here
relate to synthetic organic
chemicals that have had extensive
use and have contaminated various
segments of the human environment.
Table 5. Time required after introduction of new chemicals for
warnings of hazards and for eventual regulation
Chemical
Tetraethyl lead
PCBs
DBCP
Leptophos
Pyriminil
Toxaphene
CFCs
Year introduced
1922
1929
1955
1969
1975
1947
1930
Warning of
hazard
1965
1966
1961
1971
1977
1979
1974
Decisive
regulatory
action
1982
1976
1982
1976
1979
1982
1990
Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
inordinate period of time
required after commercial intro-
duction of the new chemical
until the first warning of toxic
hazard occurred and (2) the even
more astonishing lengths of time
after the unmistakable warning
until decisive regulatory action
was taken. These dates are sum-
marized for the seven chemicals
in Table 5.
With increasing proliferation and
production of synthetic organic
chemicals and the exploding
human population, the human
inhabitants of our world can no
longer afford to wait for decades
to determine toxic hazards of
chemicals already in use and to
implement decisive regulatory
action. The importance of this
symposium on "Access and Use
of Information Resources in
Assessing Health Risks from
Chemical Exposure" lies in its
organization and support by the
Oak Ridge National Laboratory,
Biomedical and Environmental
Information Analysis Section,
and by the EPA Office of Health
and Environmental Assessment.
It must be evident that if we are
to better assess health risks from
chemical exposure, we need the
broadest possible use of informa-
tion on hazards, and if we are to
minimize these hazards at an
acceptable rate, we need decisive
regulatory action.
References
Abou-Donia, M. B., M. A. Othman,
G. Tantawy, A. Z. Khalil, and M. F.
Swawer. 1974. Neurotoxic effect of lep-
tophos. Experientia 30:63-4.
Aulerich, R., and R. Ringer. 1977. Cur-
rent status of PCB toxicity to mink, and
effect on their reproduction. Environ.
Contain. Toxicol. 6:279-92.
Curtis, T. 1978. Danger Men work-
ing. Texas Monthly, pp. 129-33, 182-
202.
Ewing, B. B., and J. E. Pearson. 1974.
Lead in the environment. ChapL 1. In:
Advances in Environmental Science and
Technology, Vol. 3. J. N. Pitts, Jr., and R.
L.Metcalf(eds.)
Goto, M., and K. Higuchi. 1969. The
symptomatology of Yusho (chloro-
biphenyls) poisoning in dermatology.
Fukuoka Acta Henl. 60:409.
Guttowsky, H. H. (Chairman). 1976.
Halocarbons: Effects on stratospheric
ozone. Panel on Atmospheric Chemistry,
National Academy of Sciences, Wash-
ington, D.C.
Hassan, A., F. B. Abdel-Hamid, A.
Abou-Zeid, D. A. Mokhtar, A. A. Abdel-
Pazek, and M. S. Ibrahain. 1978. Clini-
cal observations and biochemical studies
on humans exposed to leptophos. Che-
mosphere 7:283-90.
Hileman, B. 1989. Global warming.
Chem. Eng. News March 13, p. 25^4.
Holstead, R. L., S. Khalifa, and J. E.
Casida. 1976. Toxaphene composition
analyzed by combined gas chromatogra-
phy-chemical ionization mass spectrome-
try. Agric. Food Chem. 22:939^(4.
Jensen, S. 1966. A new chemical haz-
ard. New Sci. 32:612.
Lee, T-h., J-c. Kang, M-d. Han, J-s.
Kim, J-w. Rob, M-y. Chung, and B-j.
Choi. 1977. A clinical analysis of roden-
ticide "RH-787" intoxication in Korea.
J. Korean Diabetic Assoc. 4:43-51.
Marquenie, J. M. 1990. Assessing the
environmental impacts from contami-
nated sediments in the Netherlands. In:
Proceedings of the Technology Transfer
Symposium for Remediating Contami-
nated Sediments, Great Lakes Basin.
Metcalf, R. L. 1982. Historical per-
spective of organophosphorus ester-
induced delayed neurotoxicity.
Neurotoxicology 3:269-84.
Metcalf, R. L., and P.-Y. Lu. 1978. Par-
tition coefficients as measures of bioac-
cumulation potentials for organic
compounds. Final Report, U.S. Environ-
mental Protection Agency, Contract No.
68-014189, July 15.
Molina, M. J., and F. S. Rowland.
1974. Stratospheric sink for chlo-
rofluoromethanes chlorine atom cata-
lyzed destruction of ozone. Nature
249:810-12.
Murozumi, M., T. J. Chow, and C. C.
Patterson. 1969. Chemical concentra-
tions of pollutant lead aerosols, terres-
trial dust and sea salts in Greenland and
Antarctic snow strata. Geochim. Cosmo-
chim. Acta 33:1247-94.
Olson, W. A., R. T. Habermann, E. K.
Weisburger, J. M. Ward, and J. H. Weis-
burger. 1973. Induction of stomach can-
cer in rats and mice by halogenated
Human inhabitants of our world can
no longer afford to \vaitfor decades to
determine toxic hazards ofchemcials
already in use and to implement
decisive regulatory action.
10
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aliphatic fumigants. J. Nat. Cancer Inst.
51:1993-95.
Patterson, C. C. 1965. Contaminated
and natural lead environments of man.
Arch. Environ. Health 11:344-60.
Peardon, D. L. 1974. RH-787, a new
selective rodenticide. J. Pest Control 42
(Sept.): 14, 16, 18, 27.
Pollack, F. H. 1979. Federal regulation
of toxic substances. Report THA/CDT
79/3, Department of Technology and
Human Affairs, Washington University,
St. Louis, MO.
Pont, A., J. M. Rubino, D. Bishop, and
R. Peal. 1979. Diabetes mellitus and
neuropathy following vacor ingestion in
man. Arch. Intern. Med. 139:185-87.
Rice, C. P., and M. S. Evans. 1984.
Toxaphene in the Great Lakes. Chapt. 8.
In: Toxic Contaminants in the Great
Lakes, Advances in Environmental Sci-
ence and Technology, vol. 14, J. O.
Nriagu and M. S. Simmons (eds.)
Rook, A., D. S. Wilkinson, F. J. G.
Ebling, R. H. Champion, and J. L. Bar-
ton. 1986. Textbook of Dermatology, 4th
ed.,p.2445.
Simmons, M. S. 1984. PCB contami-
nation in the Great Lakes. Chapt. 13. In:
Toxic Contaminants in the Great Lakes,
Advances in Environmental Science and
Technology, vol. 14, J. O. Nriagu and M.
S. Simmons (eds.)
Torkelson, T. S., S. E. Sadek, V. K.
Rowe, J. K. Kodama, H. H. Anderson,
C. S. Loguvam, and C. H. Hine. 1961.
Toxicological investigations of 1,2-di-
bromo-3-chloropropane. Toxicol. Appl.
Pharmacol. 3:545-59.
World Health Organization (WHO).
1972. Health Hazards of the Human
Environment. Geneva, Switzerland.
Access/Use Info Resources Assess Health Risk Chem Expos '93
11
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Environmental Laws Regulating Chemicals: Uses
of Information in Decision Making Under
Environmental Statutes
Jeffrey M. Gaba, Southern Methodist University
Three areas are addressed in this paper: generic issues that arise simply in the process of decision-making under environmental
statutes; different decision-making standards under various environmental statutes; and efforts to legislate a "safe" or
"acceptable" risk from exposure to carcinogenic chemicals.
The scope of this paper is a
rather difficult assign-
ment — environmental
laws regulating chemicals. It is
roughly equivalent to being
asked to explain the biology of
toxic substances in half an hour.
I could provide a thumb-nail
sketch of a list of statutes and,
along the way, bore you with a
large number of acronyms that
you've probably all heard
before. However, I don't think
that would do you any good.
What I thought I would do is
give you some idea about the dif-
ferent ways information is used
under various statutes and some
different ways to think about
how the information you pro-
duce is used by government regu-
lators.
There are three main areas I will
address: generic issues that arise
simply in the process of decision-
making under environmental stat-
utes; different decision-making
standards under various environ-
mental statutes; and finally, some
issues I want to get off my chest
about efforts to legislate a "safe"
or "acceptable" risk from expo-
sure to carcinogenic chemicals.
Issues in the Decision-
Making Process
Several issues are involved in the
process of decision-making
under environmental statutes that
significantly affect the way infor-
mation is used by government
regulators.
1. Decisions must be made.
The first and most important
point to note is that when dealing
with the regulation of a chemical
under environmental statutes, a
decision must be made. Regula-
tors do not generally have the
luxury of sitting back and wait-
ing for more information or more
studies. It is absolutely critical
to remember that a decision to
wait for more information is in
itself a decision. In some cases,
waiting for more information pre-
vents the introduction of a new
chemical into the market. In
other cases, waiting may allow
continued human and environ-
mental exposure to a potentially
harmful chemical. Every deci-
sion, whether to act or not to act,
is a decision with important con-
sequences.
Several issues are involved in the
process of decision-making under
environmental statutes that
significantly affect the way
information is used by government
regulators.
Regulators do not generally have
the luxury of sitting back and
waiting for more information or
more studies.
Access/Use Info Resources Assess Health Risk Chem Expos '93
13
-------
2. Decisions are almost always
based on imperfect data.
Decisions involving the human
and environmental effects of
chemicals are almost always
based on imperfect data. Indeed,
a primary characteristic that
unites all of the many environ-
mental statutes, perhaps the fact
which defines environmental law
itself, is that decisions are made
under conditions of almost com-
plete uncertainty. Yet, this is
something that regulators, law-
yers, and the general public, have
to live with.
As a scientist, you may be accus-
tomed to rejecting a study
because it has a p- value of 0.1,
(i.e., a 10% chance that the out-
come can be attributed to
chance) and is therefore not sta-
tistically significant. It may be
somewhat difficult to accept the
fact that decisions are made and
conclusions are drawn based on
data that you might not feel com-
fortable with at all. None the
less, it must be done. You use
(he best data that is available,
and you go forward.
3. Decisions may be made using
various procedures.
In some cases, decisions are
made using "notice and com-
ment" rule making. The govern-
ment publishes a proposed
regulation, accepts comments
from the public, considers these
comments, and publishes a final
rule with an explanation that
responds to the comments and
explains the rationale for the
decision. This process involves
mostly written comments and
written explanations. In other
cases, there may be an obligation
to follow almost trial like proce-
dures that may include public
hearings and cross examination
of witnesses.
4. Adequacy of the data may
vary based on the allocation of
the burden of proof.
The "burden of proof varies
among regulatory decisions. In
assessing the adequacy of data
underlying a decision, the regula-
tors may be affected by the allo-
cation of the burden of proof. In
many cases, it is the government
that is required to document and
justify its action. In some situ-
ations, however, it is the people
affected by a decision who have
the burden of proof. At least
nominally, for example, if a per-
mit is being issued, it is the pro-
ponent of the permit, that is the
person seeking the permit, who
has the burden of proving that
the government's action was
improper.
5. Courts apply varying stand-
ards of review.
There are also differences in the
standards of review applied to
various regulatory decisions.
This means that there is some
variation in how carefully a court
will scrutinize a decision. In
most regulations adopted
through notice and comment rule-
making, the standard applied is
whether the decision is "arbitrary
and capricious." Under the Toxic
Substance Control Act (TSCA),
however, the statute specifically
states that the decision has to be
based on "substantial evidence."
At least theoretically, the "sub-
stantial evidence" standard
requires a greater burden of justi-
fication than does a standard of
"arbitrary and capricious."
It may be somewhat difficult to accept
the fact that decisions are made and
conclusions are drawn based on data
that you might not feel comfortable
with.
There are differences in the
standards of review applied to
various regulatory decisions.
14 Aecess/Use Info Resources Assess Health Risk Chem Expos '93
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6. There is no consistency or
rationality among various
statutes.
Finally, do not look for any con-
sistency or rationality among
various statutes in how these vari-
ous issues are parceled out. Each
statute is influenced by varying
political influences, and each has
its own history. It is very hard to
come up with explanations why,
under one statute, you go
through a trial-like hearing
whereas under another statute
you can adopt a rule by notice
and comment rulemaking. There
may be no rational explanation
for the difference other than the
evolutionary history of the par-
ticular statutes.
Varying Statutory
Standards
Another basic point is that envi-
ronmental statutes have different
statutory standards—different
goals—which means the informa-
tion is used in different ways. I
get uncomfortable when I see a
health assessment or a health
review document of a chemical
prepared in the abstract. Most of
the statutes are not designed to
generate information; they are
designed to produce action based
on information. Information on
health effects is used in different
ways under different statutes.
I will attempt to categorize some
of the different standards that are
used in environmental statutes.
Don't get an idea that these are
hard and fast categories—they're
not; they blend into one another.
It is, however, useful to have
some idea about the different
ways in which information might
be used.
1. Absolute safety
The simplest approach I will call
absolute safety. Perhaps the
clearest of the few examples of
such a standard is the Delaney
Clause in the Food, Drug and
Cosmetic Act. Under this stat-
ute, for example, a food additive
is classified as unsafe and prohib-
ited if it has been determined to
be a carcinogen. Statutory lan-
guage, at least for food additives,
is that it is unsafe if it is "found
to induce cancer when ingested
by man or animal or if it is found
after tests which are appropriate
for the evaluation of the safety of
food additives to induce cancer
in man or animal." This purports
to demand absolute safety; noth-
ing may be used as a food addi-
tive if it has been found, through
tests, to be a carcinogen.
You may be aware that there are
ways around this clause. The
FDA has tried to evade or mini-
mize the impact of the Delaney
Clause through a variety of tech-
niques. For example, they have
rules relating to the sensitivity of
method of the test procedures.
There was also an attempt by the
FDA to come up with a de mini-
mis rule, which said that "insig-
nificant" or de minimis levels of
carcinogens or de minimis risk
associated with carcinogens
would not violate the Delaney
Clause. This attempt was struck
down by a court that held that
Congress had specifically and
clearly stated that any level of
carcinogen would be considered
unsafe as food additive. Thus,
Delaney stands as essentially a
rule of absolute safety.
2. Unreasonable risk
Another approach used in stat-
utes requires a determination of
Do not look for any consistency or
rationality among various statutes in
how these various issues are
parceled out.
The simplest approach I will call
"absolute safety."
Access/Use Info Resources Assess Health Risk Chem Expos '93
15
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whether a risk is "unreasonable."
Where a statute allows considera-
tion of "reasonableness," it gener-
ally involves a balancing of
economic impact with health
effects. One good example is in
the Federal Insecticide, Fungi-
cide, Rodenticide Act (FEFRA),
which deals with the registration
of pesticides. Under FIFRA, the
EPA must consider whether the
use of a pesticide will cause
"unreasonable adverse effects on
the environment" The definition
of unreasonable risk to man or
the environment 'takes into
account the economic, social,
and environmental costs and
benefits of use of the pesticide."
This may involve something like
a cost-benefit assessment
although it is generally not a
strict cost-benefit analysis. It
does, however, give room to bal-
ance costs and benefits. This is in
stark contrast to the Delaney
Clause, which does not allow
such a balancing.
Another characteristic of statutes
that have some concept of reason-
able risk is that there is almost
never guidance on how to strike
the balance; the agency generally
has broad discretion in determin-
ing how to balance competing
interests. For example, in a case
involving establishing standards
for allowable pesticide residues
on raw agricultural products
under the Food, Drug and Cos-
metic Act, at one point, the
agency continued a tolerance for
ethylene dibromide (EDB) based
on the economic impact on for-
eign countries if the tolerance
were eliminated.
3. Environmental quality-based
decisions
Under a third type of standard,
decisions are made based on con-
sideration of the effects on envi-
ronmental quality or human
health. The primary ambient air
quality standards under the Clean
Air Act [National Ambient Air
Quality Standards (NAAQS)]
require that the agency determine
a standard based solely on the
effect on human health and the
environment. The statute says,
for example, that "a national
ambient air quality standard shall
be the ambient air quality stand-
ards, the attainment and mainte-
nance of which in the judgement
of the administrator based on
such criteria and allowing ade-
quate margin of safety, are requi-
site to protect the public health."
Under the Comprehensive Envi-
ronmental Response, Compensa-
tion, and Liability Act (CERCLA
or "Superfund"), the basic stand-
ard for establishing cleanup lev-
els at hazardous waste sites is
"protection of human health and
the environment." In most cases,
at least nominally, environmental
quality-based decisions are not
supposed to involve considera-
tion of economic impacts.
Implicitly, however, this is
always considered.
There are many familiar prob-
lems in defining an adequate,
acceptable number to reflect pro-
tection of human health and the
environment. This is particularly
difficult to do with possible car-
cinogens. How is a safe level, or
a level that has an ample margin
of safety for protection of the
environment, established? What
risk constitutes an acceptable
risk when you are operating on
the assumption that a chemical
carcinogen does not have an
effect threshold? What health
effects do you look at? Are you
just looking at carcinogenicity or
are you looking at reproductive
Where a statute allows consideration
of ' 'reasonableness,'' it generally
involves a balancing of economic
impact with health effects.
Decisions are made based on
consideration of the effects on
environmental quality or human
health.
16
Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
or behavioral impairments as
well?
4. Technology-based standards
In some statutes, standards are
established not on the health or
environmental impact of a chemi-
cal but on the technological and
economic ability of industry to
control the discharge of a chemi-
cal. This is a "technology-
based" standard, and such a
standard essentially ducks the dif-
ficult questions of defining a safe
level. Most discharge limits
established under the Clean
Water Act, for example, are tech-
nology based. You may have
heard of best available technol-
ogy (BAT) or best practicable
technology (BPT) limitations.
All industrial dischargers in the
United States are required to
meet these standards, which are
based on the availability and cost
of pollution control equipment.
The advantage of a technology-
based standard is that it allows
you to avoid the difficult deci-
sions and the uncertainties
involved in setting a health-
based or environmental quality-
based standard. The regulators
are generally working with data,
such as the costs and removal
efficiency of a biological treat-
ment system, which is more reli-
able and with which they are
more comfortable.
There are, however, serious criti-
cisms of technology-based stand-
ards. In general, the goal of
environmental statutes is not
simply the reduction of pollu-
tion, but protection of human
health and the environment.
Technology-based standards gen-
erally do not take into considera-
tion, in any direct way, the
impact on the environment of
controlling the pollutant. This
can lead to either overregulation
or underregulation. A
technology-based standard may
reduce pollutants well below
levels that will affect human
health. Critics would argue that
this is overregulation. In the
more likely case, however, a
technology-based standard may
not reduce pollution enough, and
people and the environment are
still exposed to risk.
5. Communications standards
Finally, there are statutes that do
not directly regulate conduct at
all but which rely on communica-
tion and the dissemination of
information. Perhaps the grand-
daddy of them all is the
National Environmental Policy
Act (NEPA) which requires the
collection and dissemination of
information through the environ-
mental impact statement process.
There is very little substance to
NEPA. The U.S. Supreme Court
has indicated that NEPA is
purely a procedural statute that
may not itself authorize the gov-
ernment to impose regulatory
controls or alter its substantive
decisions. What NEPA does do
is get information out to the pub-
lic and to the decision maker.
Other statutes usually provide
authority to take action.
There are other more current
examples in which providing
information is the basis for a
statutory scheme. The Occupa-
tional Safety and Health Admini-
stration (OSHA) has promul-
gated a communications regula-
tion that requires employers to
provide workers with informa-
tion about various chemicals to
which they may be exposed in
the workplace. The new, and
already infamous, Title III of
How is a safe level, or a level
that has an ample margin of
safety for protection of the
environment established?
There are serious criticisms of
technology-based standards.
Access/Use Info Resources Assess Health Risk Chem Expos '93
17
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CERCLA contains the "commu-
nity right-to-know" provision,
which, among other things,
requires industrial facilities to
develop information both about
the quantities of certain hazard-
ous substances they release into
the environment and to provide
information to local emergency
planning boards.
These statutes all have an inter-
esting common objective or
rationale, or at least we can pro-
vide a common rationale. Basi-
cally, it is the idea that the free
market can work in environ-
mental regulation the way it
works in the marketplace. The
statutes appear to assume that
there will be consequences from
the dissemination of information.
In other words, if you get infor-
mation out, action will flow.
Workers, for example, will bar-
gain for reduction of chemicals
in the workplace or bargain for
higher pay because of exposure.
Neighbors may sue a facility for
creating a nuisance.
Actually, the most important con-
sequence of the dissemination of
information under these statutes
may be that it triggers political
action. Congress is now in the
final stages of adopting amend-
ments to the Clean Air Act, and
there are significant provisions in
the proposed amendments deal-
ing with toxic emissions from
industrial facilities. One of the
driving factors has been recent
information about toxic emis-
sions that is based on informa-
tion required by statutes.
There is a quote relevant to these
information statutes and relevant
to the work a lot of you do. Jus-
tice Louis Brandeis thought that
the free exchange of ideas would
protect against private corrup-
tion. He wrote "sunlight is the
best disinfectant," and it seems
to me to be a nice quote for toxi-
cologists involved in information
dissemination.
Problems in establishing
"acceptable" levels of risk
Finally, let me leave you with
something that I have been want-
ing to get off my chest. There is
a lot of talk among agencies and
in Congress about coming up
with a magic number to define
negligible risks or acceptable
risks. The idea is that, through
risk assessments, we can come
up with fairly good estimates of
risks to human health and that
we can use this information to
define some safe or acceptable
level of risk. These days the com-
monly advocated "safe" levels
involve risks ranging from one in
ten thousand to one in a million.
I have some trouble with this
approach, and I just wanted to
share my concerns with you and
stimulate your thinking about it.
There are two reasons that I
think it may not be appropriate to
define "the" safe level of
exposure.
1. Not all risk assessments are
conservative.
The first of these involves the
common, and I believe, errone-
ous belief that all risk assess-
ments are based on conservative
assumptions and always over-
state risks. EPA has said this, and
certainly industry likes to point
out the conservative assumptions
that are used in the extrapola-
tions from mice to humans.
I don't know how many of you
believe this, but, if nothing else,
the history of establishing esti-
mates of safety for various
OSHA has promulgated a
communications regulation that
requires employers to provide
workers with information about
various chemicals to which they may
be exposed in the workplace.
The most important consequence of
the dissemination of information
under these statutes may be that it
triggers political action.
18
Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
chemicals should put you on
guard. Let me point out just two
areas in which the assumptions
may not be so conservative.
Risk assessments involve not
only judgements of the potency
or dose response for a chemical
but also exposure assessments.
In the Water Quality Criteria, for
example, exposure assessments
used to be, and I think still are,
based on an assumption of expo-
sure of a 70-kg human, drinking
21 of water and eating 2g of fish
per day over a 70-year lifetime.
I exceed the 70-kg standard, but
many other people do not. You
will note, for example, that
women and children are not par-
ticularly well represented.
Another problem that has trou-
bled me is that the exposure does
not include anything other than
oral exposure. I have not seen
many risk assessments that
include estimates of exposure by
dermal contact, and yet it is obvi-
ous that for some chemicals, der-
mal contact through a shower
can result in as much of a chemi-
cal entering the body as by drink-
ing the water.
Another "nonconservative"
assumption involves the end'
point of concern. For most of the
controversial chemicals, cancer
is the concern. Although there
may be questions about the ade-
quacy of the data on carcino-
genicity, frequently there is no
data on neurological or reproduc-
tive effects which may occur
over a broad exposure range.
This lack of data is frequently
lost in the shuffle when regula-
tory numbers are produced based
on potential carcinogenic effects.
Additionally, the assessment may
not be considering environ-
mental effects; be careful to iden-
tify what end point was observed
in a risk assessment.
2. Not all risks are equally
acceptable.
A second reason that I'm uncom-
fortable with using risk assess-
ment to establish a level of
"acceptable risk" is that I am sim-
ply not sure what having one spe-
cific number to indicate
acceptable risk means.
Some researchers have reviewed
the risks that are accepted by the
public in a range of activities to
define a single "acceptable" level
of risk. However, not all risks
are created equal. I may be will-
ing to accept a 10"4 risk to have
gasoline to drive my car. I may
not be willing to accept the same
risk in order to get a fluorocar-
bon to spray Pam on pans to stop
food from sticking. A one-in-a-
million risk may be very low, but
I may not be willing to accept
even that level if it is for an activ-
ity that I think is essentially frivo-
lous or not beneficial.
I think there is an allure in pick-
ing a specific number that
ignores the fact that almost every-
thing is going to involve a trade-
off. I worry that we lose some of
the appropriate information and
cut off the regulation process if
we define a specific risk level.
In fact, the only rationale that I
can think of for coming up with
a specific number is to eliminate
certain transaction costs. It
avoids the expense of acquiring
additional data about costs and
benefits. This may or may not be
an adequate justification. Keep
in the back of your mind,
though, that the issue of what is
an acceptable risk level is not in
any sense a factual question
about the risks we accept when
A troubling problem is that the
exposure does not include
anything other than oral
exposure.
Another ' 'nonconservative''
assumption involves the end point
of concern.
Access/Use Info Resources Assess Health Risk Chem Expos '93
19
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undertaking other activities, such
as driving a car. It is a question
about how much we are going to
pay to get more information
about the costs and benefits of
the activity being regulated. If
that is the case, it really requires
a case-by-case decision based on
the activity that is being regu-
lated.
Conclusion
Environmental statutes use infor-
mation about the environment in
a variety of ways, and the data
you generate are going to be
plugged in and distorted and
twisted and used in a variety of
different contexts. You should
recognize that after data leaves
your hands, there is a whole new
process, with its own constraints
and problems, that goes on
before final decisions are made.
Not all risks are created equal
20 Access/Use Info Resources Assess Health Risk Chem Expos '93
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Information Needs for Risk Assessment
Christopher T. DeRosa, * Harlal Choudhury, and Rita S. Schoeny,
U.S. Environmental Protection Agency
Risk assessment can be thought of as a conceptual approach to bridge the gap between the available data and the ultimate goal of
characterizing the risk or hazard associated with a particular environmental problem. To lend consistency to and to promote quality
in the process, the U.S. Environmental Protection Agency (EPA) published Guidelines for Risk Assessment of Cardnogenicity,
Developmental Toxicity, Germ Cell Mutagenicity and Exposure Assessment, and Risk Assessment of Chemical Mixtures. The guide-
lines provide a framework for organizing the information, evaluating data, and for carrying out the risk assessment in a scientifi-
cally plausible manner. In the absence of sufficient scientific information or when abundant data are available, the guidelines
provide alternative methodologies that can be employed in the risk assessment.
Introduction
The purpose of this paper
is to outline and describe
some of the information
needs of risk assessors within the
context of both the risk assess-
ment process and the EPA guide-
lines. Risk assessment can be
thought of as a process to bridge
the gap between the available
data and the ultimate goal of
characterizing the risk or hazard
associated with a particular envi-
ronmental problem. To lend con-
sistency to and to promote
quality in the process, the EPA
published Guidelines for Risk
Assessment of Carcinogenicity,
Developmental Toxicity, Germ
Cell Mutagenicity and Exposure
Assessment, and Risk Assess-
ment of Chemical Mixtures. The
guidelines are intended to be a
dynamic blueprint to guide the
risk assessment process from
experimental data to risk charac-
terization. The guidelines pro-
vide a means for directing the
thought process for organizing
the information, evaluating data,
and carrying out the risk assess-
ment. The guidelines also direct
presentation of a meaningful syn-
thesis of the information (risk
characterization) that clearly
calls out all of the limitations
associated with the risk assess-
ment process.
In assessing information needs
for any risk assessment, several
variables must be addressed. One
factor to be considered is the spe-
cific issue being addressed or the
goal of the risk assessment. Risk
assessment can have many appli-
cations such as risk screening
and setting time or resource-
based priorities, in addition to
more traditional approaches.
Typically, risk assessment
defines the basis for regulatory
action in terms of setting stand-
ards or defining criteria or reme-
dial action. It is obvious that the
latter goal can be met only with a
more data-intensive risk assess-
ment process than would be used
for priority setting. Another fac-
tor in defining information needs
is the time frame available for
completion of the assessment
process. A short time span will
certainly circumscribe the scope
of a risk assessment process and
the attendant data-gathering
Guidelines provide a means for
directing the thought process for
organizing the information,
evaluating data, and carrying out
the risk assessment.
Risk assessment defines the basis
for regulatory action in terms of
setting standards or defining
criteria or remedial action.
*Now affiliated with Agency for Toxic Substances and Disease Registry.
Access/Use Info Resources Assess Health Risk Chem Expos '93
21
-------
effort. It is not unusual to encoun-
ter circumstances in an EPA
regional or state office in which
an immediate turnaround is
needed. On the other hand, a
regulatory action can sometimes
span not just years but decades,
depending on the immediacy or
perceived immediacy of the
problem.
In a rather circular fashion, the
use of risk assessment method-
ologies or tools is limited by the
data available, and the informa-
tion needs are defined by the
choice of a risk assessment meth-
odology. Some methods are obvi-
ously much more data intensive
than others. For example, the
multistage model used for quanti-
tative risk estimates for nonthres-
hold responses (such as cancer
induction) requires the incidence
data. Many exposure assessment
tools and models require specific
types of data, such as population
size, location, food sources, and
so on. The key is to match mod-
els and methods to the data avail-
able. The EPA guidelines
facilitate that process by delineat-
ing procedures for data choice,
thereby defining what data can
be used for the specific type of
risk assessment (i.e., the kinds of
assays and data that are, in fact,
suitable for use).
Still another consideration is the
audience for the risk assessment
Although consideration of the tar-
get audience may not influence
the risk assessment process, it
should affect the presentation of
the information. In some cases,
especially when a nontechnical
group is to be the recipient of
information, it may not be neces-
sary to provide details of models,
lengthy descriptions of experi-
mental assays, and so forth. It is
important, however, to convey a
sense of the extent (or lack) of
data used in the estimate as well
as the assumptions used and
uncertainties involved. The Risk
Assessment Guidelines provide a
framework for defining uncer-
tainties in the process and spec-
ify the use of default values for
procedures to be used in the
absence of information. Risk
communication must be done so
that the audience is informed
rather than confused or misled.
An example of documents that
are aimed at both risk profession-
als and the general public are the
Agency for Toxic Substances
and Disease Registry (ATSDR)
lexicological profiles. These
documents begin with a general
public health summary, written
in jargon-free language, of health
effects that might be encountered
in exposed human populations.
This is followed by a more tech-
nical description of data and risk
assessment.
Risk Assessment Process
as a Determinant of
Information Needs
At this time, the EPA has guide-
lines only for risk assessment
regarding the identification and
characterization of adverse
health effects linked to human
exposure. As described by the
National Research Council (NRC
1983), risk assessment consists
of four interrelated components:
hazard identification, dose-
response assessment, exposure
assessment, and risk charac-
terization (Fig. 1). The first com-
ponent of the risk assessment
process is hazard identification,
which is a qualitative index of
the nature of the effects and their
biological significance. The
Use of risk assessment
methodologies or tools is limited by
the data available, and the
information needs are defined by the
choice of a risk assessment
methodology.
An example of documents that are
aimed at both risk professionals and
the general public are the Agency
for Toxic Substances and Disease
Registry (ATSDR) lexicological
profiles.
22 Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
major question to be answered in
the hazard identification step is
the likelihood that effects
observed in one population (usu-
ally experimental) could occur in
another population (usually
human). Several issues are
linked to hazard identification.
The first is the validity and the
meaning of the toxicity data. Not
all data are created equal, hence,
data should be evaluated for their
legitimacy in terms of the risk
assessment process. It's clear that
technology has become increas-
ingly sophisticated in its ability
to detect effects; what has not
kept pace is the risk assessor's
ability to interpret the biological
significance of those effects.
One process for organizing haz-
ard data and presenting conclu-
sions is the weight-of-evidence
(WOE) scheme. The most
widely used weight-of-evidence
classifications have been devel-
oped to assess the likelihood of a
material to be a human carcino-
gen. EPA currently uses a car-
cinogen classification process
similar to that developed by the
International Agency for
Research on Cancer (IARC). In
this system, human data and that
derived from animal bioassays
are evaluated on whether they
constitute sufficient, limited,
inadequate, or no evidence for
carcinogenicity. After a prelimi-
nary classification has been
established, data on metabolism,
genotoxicity, and other mechanis-
tic data are considered in arriv-
ing at final classification. The
EPA also employs WOE
schemes in the processes of haz-
ard identification of human germ
cell mutagens and developmental
toxicants. Criteria for all of the
WOE judgments are described in
the Risk Assessment Guidelines.
Dose-response
Assessment
\
Hazard
Identification
Risk
Characterization
Exposure
Assessment
The second component of risk
assessment is the dose-response
assessment.
Fig. 1. National Academy of Science/National Research Council
risk assessment paradigm.
All have procedures in common
for (1) evaluating data for its
appropriateness to the risk assess-
ment, (2) describing minimal
data requirements, and (3) organ-
izing the data.
The second component of risk
assessment is the dose-response
assessment, which is evaluation
between dose and some meas-
ured response. Usually, the only
data available to the risk assessor
are from animal assays using
relatively high doses or epidem-
iologic data from humans
exposed to high concentrations
in the work place or by some
accidental means. However, the
job of the assessor of environ-
mental risks is to estimate the
magnitude of expected health
consequences from ambient
exposures. Figure 2 illustrates
the chief difficulty in this task,
that of inferring the shape of a
dose-response curve at exposures
below the experimentally
Access/Use Info Resources Assess Health Risk Chem Expos '93
23
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observed range. Such inferences
are the source of significant
uncertainty. Information needs
are driven by the uncertainty rec-
ognized in the risk assessment
process. The most useful, and
least common, type of informa-
tion is incidence of observed
effects at doses approximating
the expected exposure to
humans. The EPA guidelines pro-
vide assistance in choosing mod-
els for extrapolation to low doses
for less-than-ideal data. This
includes judgments as to the actu-
ality (or at least to the statistical
significance) of an apparent dose-
response relationship and the use
of information regarding the
mechanism of toxicity in the
choice of a low-dose extrapola-
tion procedure. For example, the
guidelines support the use of an
extrapolation procedure that
incorporates low-dose linearity
for presumed carcinogens, based
on hypotheses wherein a carcino-
gen initiates the carcinogenic
process through an irreversible
change in the cellular DNA. This
hypothesis is supported in gen-
eral for a number of chemicals
by a large body of data; informa-
tion on the mechanism of car- .
cinogenicity for the chemical in
question removes more of the
uncertainty in the application of
a linear low-dose model. The
guidelines further specify that
unless data exist to recommend a
particular model, the linearized
multistage model be used. This
model, as any other, has specific
data requirements: there must be
numerical incidence data, a sin-
gle number (as opposed to a
range) must be used for dose,
and there must be at least two
dose groups (one of which must
be nonzero).
DOSE-RESPONSE CURVE
R
E
S
P
O
N
S
E
Range of inference -
Dose
Observation range
Fig. 2. Inferring the shape of a dose response curve at exposures below the
experimentally observed range.
The third component of the risk
assessment process is exposure
assessment. This step attempts to
determine whether the impact or
the target of the hazard could be
a population or a specific sub-
population. Exposure assessment
also addresses the pathway, or
pathways, by which the agent
reaches that target. The issues in
exposure assessment include the
most likely route of exposure
(dermal, inhalation, or oral); the
nature and identification of the
exposed population; and the mag-
nitude, duration, and frequency
of exposure. Built into this proc-
ess is consideration of the events
and the properties and charac-
teristics of the populations that
might potentiate or mitigate con-
cern about defined risks.
The risk characterization compo-
nent requires increasingly greater
attention in the risk assessment
The third component of the risk
assessment process is exposure
assessment.
24 Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
community. This component is
an attempt to integrate hazard
identification, dose response
assessment, and the exposure
assessment into qualitative or
quantitative assessment. A chal-
lenge in risk characterization is
that these different components
of the risk assessment process
are often carried out by distinctly
different groups of scientists or
disciplines, and very often the
uncertainties linked to each of
the components in the process
are lost as the conclusions are
carried forward to the risk charac-
terization stage. The challenge is
to tighten the linkage between
these components of the process
so that the risk characterization
is the most biologically plausible
characterization that can be
developed, while identifying the
uncertainties inherent in the
process.
Clearly, the use of animal data
raises the question of concor-
dance of effects among species,
especially in light of "negative"
epidemiologic studies. Concerns
about factors, links to epidemio-
logical studies, and the difficulty
in accurately quantifying the
exposures are often linked to
these studies. Extrapolation of
high to low dose and extrapola-
tion from animals to humans in a
quantitative sense are concerns
in the dose response assessment.
The degree of confidence
increases when the approach is
adjusted from modeling to ambi-
ent monitoring to biological
monitoring. The presentation of
the risk characterization presents
the opportunity for a comprehen-
sive discussion of the uncertain-
ties encountered and assump-
tions used in the risk assessment
process.
Examples of Effect of
Information Availability on
Risk Assessment
The degree to which the extent
and type of data available influ-
ences the methods and processes
of risk assessment is illustrated
in this section. It uses chronic
noncancer health risk assessment
as an example.
The Reference Dose (RfD) (for-
merly called the Acceptable
Daily Intake) continues to be the
foundation of risk assessment for
noncancer end points despite
occasional flurries of criticism.
RfD is defined as an estimate
spanning an order of magnitude
that is likely to be without
adverse health effects or signifi-
cant risks to human populations
over a lifetime of exposure. Pro-
cedurally, the development of
RfD is very straightforward:
RfD =
NOAEL
UFxMF
where
NOAEL = No-Observed-
Adverse-Effect Level
UF = Uncertainty Factor
MF = Modifying Factor
The NOAEL is generally derived
from experimental animal data
but may be based on human data.
The magnitude of the uncertainty
factor and the modifying factor
is inversely proportional to the
confidence in the database and
directly proportional to the need
for additional or better types of
information. "Better types of
information" does not necessar-
ily refer to value judgements
about the conduct of studies but
to studies that are most relevant
to the risk assessment process.
The degree to which the extent and
type of data available influences the
methods and processes of risk
assessment is illustrated.
The NOAEL is generally derived from
experimental animal data but may be
based on human data.
Access/Use Info Resources Assess Health Risk Chem Expos '93
25
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The risk assessment process
itself will determine what types
of data are sought and what types
of data are, in fact, most relevant
Although the development of an
RfD is operationally very
straightforward, some of the
deliberative factors linked to the
development of an RfD are not.
This is illustrated in Fig. 3,
which shows a family of dose-
response curves based on hypo-
thetical animal data for bio-
logical effects of a particular
agent Liver damage linked to a
NOAEL is an effect level but is
construed as being nonadverse.
The line representing decrease in
weight gain, which is judged to
be a No Observed Effect Level
(NOEL) is at the lower-most por-
tion of the curve. For the pur-
poses of risk assessment, the
point that represents a minimal
amount of liver damage, but not
sufficient damage to be con-
strued as adverse, would prob-
ably be selected. Once that
selection has been made, the
NOAEL is scaled by application
of the uncertainty factor and
modifying factor magnitudes,
which are a direct function of the
information needs.
Table 1 shows data for the criti-
cal effect of nitrate as an exam-
ple of a case in which data are
not abundant, but what data does
exist are very relevant. These
data are for the critical effect in a
sensitive subgroup—increased
levels of methemoglobinemia in
infants who were given formula
made from nitrate-contaminated
well water.
In this case, there is high confi-
dence that we have identified the
true population threshold for
adverse effects (i.e., 11 to
20 ppm), which is defined as a
RESPONSE
Decrease in
Weight Gain
Liver
Damage
NOEL
NOAEL
DOSE
(mg/kg/day)
NOEL - No observed effect level
NOAEL - No observed ADVERSE effect level
Fig. 3. Hypothetical dose-response relationships for a population.
NOEL. In this instance, the
uncertainty factor is equal to 1,
indicating that uncertainty
around the RfD is negligible.
Thus, for nitrate there exists very
relevant data for human risk
assessment and the information
needs here are considered largely
satisfied. A contrasting example
is the pesticide, mirex. Mirex at
one time was used in the eradica-
tion of fire ants. It was intro-
duced into the environment in
Table 1. RfD for Nitrate
Critical effect
Experimental
doses
UF MF RfD
Methemoglobinemia NOEL: 10 ppm
of drinking water
or 10 mg/L
converted to 1.0
mg/kg/day
Infant chronic
exposure to drinking
water
1 1E+0
mg/kg/day
26 Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
substantial quantities and there is
an abundance of animal data on
it. However these data are not as
relevant to human risk assess-
ment for a chronic exposure as
are the nitrate data. The majority
of the data were from studies of
relatively short duration for
which only frank effects were
observed. The current RfD meth-
odology requires a NOAEL, or
failing that, a Lowest Observed
Adverse Effect Level (LOAEL).
A Frank Effect Level in animals
is considered to be so far above
the theoretical human threshold
of effect that its use is contraindi-
cated. The only suitable data for
mirex are from a less-than-life-
time study wherein a Lowest
Effect Level (LEL) was deter-
mined. This is an instance in
which the information needs for
risk estimation were only mini-
mally met, thus enduring a large
degree of uncertainty in the
assessment, as seen in Table 2.
This is reflected in the composite
uncertainty factor of 10,000 —
10 each for protection of sensi-
tive human subpopulations and
animal-to-human extrapolation
and an additional 100 to account
for subchronic to chronic
extrapolation, use of an LEL in
the absence of a NOAEL, and
the insufficiency of the database
for determining the most sensi-
tive toxicologic end point.
In these two examples, the risk
assessment process was essen-
tially driven by information avail-
ability (or lack thereof). In both
cases, sufficient data existed to
allow application of the standard
RfD methodology and the provi-
sion of a risk assessment consid-
ered protective in terms of
human health. For mirex, the
information requirements were
barely met; for other environ-
mental agents even minimal rele-
vant data may not be available.
For example, the RfD Work
Group recently considered the
databases for several polycyclic
aromatic hydrocarbons (PAHs)
including acenaphthylene. This
PAH was the subject of a 90-day
gavage study in rats. Effects con-
sidered to be adverse were
observed at the lowest dose
tested (100 mg/kg/day). Because
high mortality was observed in
the female rats treated at this
dose, the data were considered
inappropriate for calculating an
RfD. The best one could do with
these data would be in prepara-
tion of a hazard screen or rank-
ing method.
By contrast, information is abun-
dant (approaching an embarrass-
ln the examples, the risk assessment
process was essentially driven by the
information availability (or lack
thereof).
Table 2. RfD for Mirex
Critical effect
Decreased pup survival in a
Multigeneration vole
reproduction study
Experimental doses UF MF
NOEL: None 10,000 1
LEL: 0.1 ppm (0.015 mg/kg/day)
RfD
2E-6
mg/kg/day
Source: Shannon (1976).
Access/Use Info Resources Assess Health Risk Chem Expos '93
27
-------
ment of riches) in terms of useful
data for risk assessment of lead.
The database, in general, is suffi-
ciently complete to the extent
that it dictates a departure from
the traditional reference dose
approach. Because the dose
response function extends to the
lowest blood levels of lead identi-
fied in study populations, a dis-
cernable threshold has not been
demonstrated. We also have the
situation of multimedia expo-
sures, which recognizes that the
primary source of lead exposure
from anthropogenic releases is
the air, but oral exposure pre-
dominates. Consequently, we
have to reflect multimedia expo-
sure, reference doses or reference
concentrations. In the case of
lead, a powerful predictive tool
is available to us, and the data
required is written for its
application. It has long been rec-
ognized that overt lead toxicity
was associated with blood levels
exceeding 30 (ig/dL; impaired
nervous system function, renal
dysfunction, and cardiovascular
system effects are all noted at
these levels. However, attention
is increasingly focused on subtle
biochemical and neurobehavioral
lesions that extend to the lowest
levels of blood lead tested, which
include indicators such as ele-
vated levels of aminolevulenic
acid. In adults, elevated blood
pressure can be a concern
because the doubling of blood
lead levels from 7 to 14 mg/dL is
associated with 2- to 3-mm
increases in blood pressure. The
question is, What is the signifi-
cance of a 2- to 3-mm increase in
blood pressure? Because of
lead's presence in food, water,
and soil, the predominant route
of exposure for environmental
lead is oral. The Biokinetic
Uptake model, developed by Har-
ley and Kneip at New York Uni-
versity and elaborated on by Jeff
Cohen, formerly of the Office of
Air Quality Planning and Stand-
ards, and others at Research Tri-
angle Park (EPA 1986),
describes the pharmacokinetics
of lead within the body. This
model has been integrated into a
software package that allows the
user to present health conse-
quences of lead exposure within
a context to make judgments
without resorting to a single
level of exposure. Using this
approach, the user can integrate
dose response assessment devel-
oped for health effects with the
exposure assessment in the Bioki-
netic Uptake model to define the
implications of blood lead in an
exposed sensitive population,
such as 2-year-old children, who
are especially vulnerable because
of their behavior. In this case,
rather than defining a single
level, one can define the popula-
tion that is above a prescribed
blood level. It is important to
remember that several assump-
tions are linked to these conclu-
sions. Most noteworthy in this
case is the presumed contribu-
tions of dietary lead to overall
lead exposures. The most recent
Food and Drug Administration
survey indicated that these blood
levels might be inflated. The
model now is being revised to
reflect this new information.
This discussion does not suggest
that the RfD is in error or has out-
lived its usefulness; it continues
to be a very useful risk assess-
ment tool or reference point in
decision making. However, it is
important to recognize that there
is no single correct method for
characterizing risk. Rather,
decision-analytic tiers made up
Information is abundant (approach-
ing an embarrassment of riches) in
terms of useful data for risk assess-
ment of lead.
In the case of lead, a powerful
predictive tool is available to us,
and the data required is written for
its application.
28 Access/Use Info Resources Assess Health Risk Cbem Expos '93
-------
of several methods are to be
invoked, depending on data avail-
ability and the actual purpose of
the assessment (i.e., for screen-
ing, ranking, prioritizing or for
providing effective [predictive]
estimates or conservative [protec-
tive] estimates of relative risks).
A goal of a wide range of meth-
ods development and research
efforts is to identify more predic-
tive methods. These methods
should represent integration of
exposure and effect and be able
to provide estimates of popula-
tion distribution linked to body
burdens and associated effects.
This is heavily dependent on the
aggregation of more data of
many sorts, including informa-
tion on mechanism of toxicity,
shapes of dose response curves,
toxicokinetics, and so on. This
suggests the need for more use-
ful insights regarding the
appropriate use of biomarkers
and of exposure, effect, and sus-
ceptibility data. Again, this
would have to be tied to the
development of selection criteria
for the goals of a particular
assessment effort, whether
screening, protective, or predic-
tive, and type of data and tools
available for the characterization
process. A final consideration
beyond the immediate informa-
tion needs already discussed
would be an examination of the
risk assessment process per se
and how information databases
might be used more effectively
to identify recurring patterns or
trends that, in turn, lend them-
selves to hypotheses and
hypothesis testing. In this way, a
new generation of risk assess-
ment tools may emerge that
extend beyond what is some-
times viewed as dichotomous
safe versus nonsafe charac-
terization of risk. It is by defin-
ing these types of issues more
fully in risk characterization that
we set the stage for more
informed risk management deci-
sions that incorporate social,
legal, economic, and political
concerns.
References
National Research Council. 1983.
Risk assessment in the federal govern-
ment: Managing the process. Committee
on the Institutional Means for Assess-
ment of Risks to Public Health, Commis-
sion on Life Sciences, NRC National
Academy Press, Washington, D.C.
Shannon, V. C. 1976. The effects of
mirex on the reproductive performance
arid behavioral development in the prai-
rie vole (Microtus ochrogaster). Ph.D.
Dissertation, Iowa State University,
Ames, Iowa. Diss. Abstr. B 37(6):2712-
13. .
U.S. Environmental Protection
Agency (EPA). 1986. Air quality criteria
document for lead. EPA-600/8-
83/028dF. Prepared by the Office of
Health and Environmental Assessment,
Environmental Criteria and Assessment
Office, Research Triangle Park, N.C. for
the Office of Air Quality Planning and
Standards.
Walton, G.' 1951. Survey of the litera-
ture relating to infant methemoglo-
binemia due to nitrate-contaminated
water. Am. J. Public Health 41:986-96.
A new generation of risk assessment
tools may emerge that extends beyond
what is sometimes viewed as
dichotomous safe versus nonsafe
characterization of risk.
Access/Use Info Resources Assess Health Risk Chem Expos '93
29
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Information Needs for Risk Management/
Communication
David A. Bennett, U.S. Environmental Protection Agency
The hazardous waste cleanup program under the Comprehensive Environmental Response, Compensation, and Liability Act
(Superfund) is delegated to the ten Regions of the U.S. Environmental Protection Agency (EPA) and has, to date, identified more than
33,000 sites for consideration. The size and complexity of the program places great demands on those who would provide
information to achieve national consistency in application of risk assessment while meeting site-specific needs for risk management
and risk communication.
Introduction
The topic to discuss in this
paper is extremely broad.
It can be narrowed some-
what by relying on the perspec-
tive of the Superfund program
for hazardous waste cleanup
under the Comprehensive Envi-
ronmental Response, Compensa-
tion, and Liability Act
(CERCLA). Superfund is a
regionally delegated program,
and the sites are found across the
country. That in itself is a risk
communications problem. Super-
fund is doing its share of risk
management. More than 31,000
sites have been looked at nation-
wide, and to date, about 1200 of
these have been determined to
need detailed assessment and a
formal risk management deci-
sion, a Record of Decision. Each
site presents unique management
and communication challenges.
A strength of the Superfund pro-
gram is that we treat each site
individually. At the same time,
we strive for consistency in man-
agement of the program across
the country.
The goals of this paper are to
review the Superfund process
and opportunities for applying
health risk information to man-
agement and communication. It
will look at some challenges and
intentions in using risk assess-
ment in a program such as Super-
fund. Finally, it will identify the
audiences to whom we must com-
municate and look a bit at the
information they may request.
Overview of the Superfund
Program
Since the passage of CERCLA
ten years ago, more than 33,000
sites that may need attention
under the Superfund program
have been identified and entered
into a data base, CERCLIS. The
preremedial program gives each
of these a Preliminary Assess-
ment based on existing informa-
tion. To date, we have looked at
about 31,000 of these sites and
have determined that about
17,000 need additional sampling,
additional assessment, and analy-
sis — the Site Inspection (SI).
The more than 13,000 Sis that
have been done have produced
the following results: almost
6000 sites required no further fed-
eral action, the decision process
is incomplete on about 5500
sites, and about 1200 sites were
Goals are to review the Superfund
process and opportunities for applying
health risk information to
management and communication.
Since the passage of CERCLA ten
years ago, more than 33,000 sites
have been identified that may need
attention under the Superfund
program.
Access/Use Info Resources Assess Health Risk Chem Expos '93
31
-------
placed on the National Priorities
List (NFL). The Hazard Ranking
System, a structured value model
using risk-based information,
determines which sites pose suffi-
cient threat to warrant further fed-
eral action and placement of the
site on the NPL.
Sites on the NPL move into the
remedial process for more thor-
ough characterization, baseline
risk assessment, evaluation for
cleanup alternatives, and the
Record of Decision. The baseline
risk assessment answers two
questions: How bad is this site?
and, How bad could it become if
we did nothing else? It considers
current uses of the site and possi-
ble future uses (e.g., what would
be the risk to people who moved
to the site?). Risk analysis
beyond the baseline may look at
the remedial alternatives to ask:
What will be the result of the
remedial action? How can we
decide 'how clean is clean' if we
decide to take action? Answers to
the questions must be meaningful
to both risk managers (federal
and state employees who are usu-
ally not risk assessors) and the
public.
CERCLA directs that we design
cleanup to meet standards set by
other state or federal laws,
so-called Applicable or Relevant
and Appropriate Requirements
(ARARs). Also, as a matter of
policy, EPA has chosen to use
risk assessment to evaluate pro-
tection of public health and the
environment. This is the
approach recommended by the
National Academy of Sciences in
1983. The challenge for Super-
fund, however, is to apply it to
sites that are heterogeneous, and
that may have several chemicals
and several pathways of exposure
to populations at or near the sites.
Data may be complete or some-
what incomplete, and we may not
have toxicity data of high quality
for all of the chemicals at the
site. What we are trying to do is
be responsibly, rationally conser-
vative in the application of risk
assessment to the site.
Some of the challenges or ten-
sions in using risk assessment
and risk information in the Super-
fund program include the
following:
1. There is a need to act now.
Congress and the public expect
expeditious cleanup of Super-
fund sites. We cannot wait a
long time for significantly bet-
ter science.
2. There is the tension between
doing a site-specific risk
assessment that is true to the
site and the perception that
national consistency requires a
single set of numbers or stand-
ards for cleanup levels. Super-
fund uses a standard process to
gain the benefits of charac-
terizing the risk and uncer-
tainty at each site.
3. There is a tension to provide
early cleanup targets to expe-
dite engineering evaluations vs
creating false expectations
about where we might finally
end up following baseline risk
assessment and setting cleanup
goals.
4. Finally, there is a tension
between setting goals in the Re-
cord of Decision and the
engineering realities of the site.
When we get out there and
start moving the dirt around or
pumping and treating the
water, realities may not quite
match with the expectations—
the goals. In the end, though,
As a matter of policy, EPA has
chosen to use risk assessment to
evaluate protection of public health
and the environment.
There are many challenges or
tensions in using risk assessment and
risk information in the Superfund
program.
32
Access/Use Into Resources Assess Health Risk Chem Expos '93
-------
risk analysis and comparison
with goals can show that you
have cleaned up the site. This
is the 'how clean is clean' deci-
sion.
Audiences
Who are our audiences in the
Superfund program? First, the
managers. At each site there is a
Remedial Project Manager
responsible for that site. (S)he
has to deal with the engineers, hy-
drogeologists, toxicologists, the
people around the site, and senior
management. (S)he wants to
have some specific risk informa-
tion to support decisions.
Another audience is the risk
assessors, the toxicologists who
must conduct the site-specific
risk assessment. To evaluate
exposures they need data that is
gathered on site. To support the
risk assessors' needs we have
educated the people who gather
data not just to look at dirt, air,
and water; we look at the activi-
ties of the individuals at the site.
People fish, and they eat the fish.
They grow crops. (Although it is
not a topic of this paper, we also
look for exposures that may pose
ecological risks.)
Risk assessors also need high
quality, consistent sources of
information on toxicity of con-
taminants. We take advantage of
what the EPA has already done in
evaluating the available lexico-
logical information. We refer to
the EPA's Integrated Risk
Information System (IRIS) as the
gold standard of the Superfund
program. To supplement IRIS
we've worked with'the Environ-
mental Criteria and Assessment
Office (ECAO) of the Office of
Research and Development to
develop the Health Effects
Assessment Summary Tables,
which are published quarterly.
Additional help comes from a
Superfund Technical Support
Center and hotline at ECAO to
provide information to risk asses-
sors when they have trouble find-
ing sufficient information or have
uncertainty about how to proceed
in the Superfund program.
Engineers constitute another audi-
ence. These typically are contrac-
tors to EPA or to Potentially
Responsible Parties.
The site decision-makers them-
selves, the managers in the
Regional EPA office, are an
audience.
Finally, the concerned public
around the site is an audience.
There is often more than one
type or group who represent the
concerns of the site. Many of
these sites have long histories.
People have been living with, on,
or near these areas for sometimes
many, many years. As Peter Sand-
man has said, many of these peo-
ple are outraged. Coming to them
and saying, "I'm from Washing-
ton, I'm here to help, and I've got
the answer to your problem"
does not deal with outrage. At
some of these locations there are
others who owe their jobs to the
potentially responsible parties.
What do those folks want in
terms of risk communication, in
terms of information? The
answer is "a lot of things," but
there are a couple, at least, that
ought to be kept in mind as we
think about information sources
and how they might be made
available, either directly or
through others, to these
individuals. First, very simply,
they want recognition and consid-
eration of their concerns. A
Who are our audiences in the
Superfund prog ram ?
What information is needed for risk
communication ?
Access/Use Info Resources Assess Health Risk Chem Expos '93
33
-------
group may have a strong, firm
belief that there is a very high
incidence of a particular adverse
effect in the community around
the site. To the toxicologist or epi-
demiologist there may seem that
there is no evidence for the ef-
fect, at least at first view, but it
can still be addressed and looked
at as we do the assessment. Out
of that we may find some things
that we can actually do during
our risk management actions,
and, if nothing else, we have rec-
ognized and given consideration
to the people's concerns.
The public also may want all
problems removed. This is the
NIMBY, not in my back yard,
phenomenon that so often
appears during discussion of sit-
ing a new incinerator or other
facility. Superfund sees the other
side of this argument: if you have
lived with a problem all this time,
you don't want it in your back-
yard any longer. However, when
we are successful in communicat-
ing and providing information
that is meaningful to all parties at
a site, we can often form a true
partnership in the
decision-making process and
decisions for effective treatment
of wastes to minimize risks can
be made.
Conclusions
For the future, I think we will see
more focus on the public around
sites and perhaps less on the tech-
nical details of what we do.
Appropriate decisions at Super-
fund sites can be achieved by
working with the concerned peo-
ple at the sites. One example is
that of EPA risk assessors and
EPA site managers working with
the public early in the process.
Also, the Agency for Toxic Sub-
stances and Disease Registry,
which must do a Health Assess-
ment at each Superfund site, is
visiting communities and state
and local health departments to
see what data may be available
and what concerns are expressed
by the people in the community.
Finally, I think we'll see more
information sharing among all
parties, working toward more of
a partnership in the program.
We need more focus on the public
around sites and perhaps less on
the technical details of what we do.
34 Access/Use Info Resources Assess Health Risk Chem Expos '93
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Evolution of Toxicology Information Systems
John S. Wassom and Po-Yung Lu, Oak Ridge National Laboratory
Society today is faced with new health risk situations that have been brought about by recent scientific and technical advances.
Federal and state governments are required to assess the many potential health risks to exposed populations from the products
(chemicals) and by-products (pollutants) of these advances. Because a sound analysis of any potential health risk should be based
on the use of relevant information, it behooves those individuals responsible for making the risk assessments to know where to
obtain needed information. This paper reviews the origins of toxicology information systems and explores the specialized
information center concept that was proposed in 1963 as a means of providing ready access to scientific and technical information.
As a means of illustrating this concept, the operation of one specialized information center (the Environmental Mutagen
Information Center at Oak Ridge National Laboratory) will be discussed. Insights into how toxicological information resources
came into being, their design and makeup, will be of value to those seeking to acquire information for risk assessment purposes.
Introduction
Scientific and technological
developments have
brought unprecedented
benefits to our standard of living,
but also have brought unprece-
dented problems. In an attempt
to stem the tide of environmental
degradation, federal and state
governments now are required to
provide hazard assessments
and/or health risk projections for
a variety of chemical agents that
may have serious far-reaching
consequences. To make sound
and efficient assessments, the
availability and use of reliable
data is an essential of the risk
assessment process.
The end product of scientific
research and development is new
data and information. In the field
of toxicology, new data and infor-
mation are being generated at a
phenomenal pace and are being
published at an exponential rate.
Much of the information publish-
ed is stored in computers in one
form or another for subsequent
use and analysis. This situation
provides both an invaluable
resource and an enormous chal-
lenge to those involved in assess-
ing health risks from chemical
exposure. With large amounts of
government funds being devoted
to health and environmental
research programs and with
maintenance of our living envi-
ronment at stake, the growth rate
of the toxicology literature is
expected to increase every year.
To cope with this growing body
of literature and to make it easily
accessible to users, different
types of information systems
have been created. Perceptions
vary about how information
should be handled or processed,
and these differences of opinion
have influenced the availability,.
accuracy, and use of toxicology
information. Many information
systems developed to serve the
field of toxicology have changed
significantly over the years. Sev-
eral factors have served as cata-
lysts for the changes in the
systems and in how toxicology
information is handled. Among
these factors are different view-
points on (1) how scientific infor-
mation should be packaged for
public use, (2) economic trends,
and (3) research emphasis. This
paper examines the evolution of
To make sound and efficient
assessments, the availability and use
of reliable data is an essential of the
risk assessment process.
Several factors have served as
catalysts for the changes in the
systems and in how toxicology
information is handled.
Access/Use Info Resources Assess Health Risk Chem Expos '93
35
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toxicology information systems
in relation to current needs for
ready access to reliable informa-
tion to be used to identify chemi-
cal hazards and make risk
characterizations.
Origins
In keeping with the evolutionary
theme, we would like to quote
the person who has had the most
profound effect on the way we
think about evolution. Charles
Darwin, in his provocative book
published in 1859, made a beauti-
ful and often-quoted statement at
the conclusion of his treatise
regarding the origin of species:
"There is grandeur in this view
of life .. . From so simple a
beginning, endless forms most
beautiful and most wonderful
have been and are being
evolved" (Darwin 1859).
In the context of toxicology infor-
mation centers, we have para-
phrased Mr. Darwin's classic
statement, "There is grandeur in
this view of information systems
.. From so simple a beginning,
endless forms to serve the toxi-
cology research area have
resulted—some most interesting
and some most useful have been
and are being evolved."
The first toxicology information
system was created the moment
someone filed an item of infor-
mation regarding some parame-
ter of toxicity for future
reference and use. When the
printing press revolutionized the
production and access of written
manuscripts, the volume of infor-
mation increased, and files of
documents were compiled and
stored for future use. This par-
ticular information collection
scenario was occurring in many
locations throughout the civi-
lized world as people enamored
with scholarly pursuits and curi-
osity increased attempts to deter-
mine the toxic properties of
agents of all kinds. Aside from
the filing of toxicology manu-
scripts in personal files, collec-
tions of these documents were
being housed in museums, later
called libraries. Because humans
have an innate need to communi-
cate and share knowledge, early
lexicologists were eager to share
information and discuss their
research. Investigators began to
communicate with each other
both in writing and in conversa-
tion, spawning the appearance of
journals and specialty books ori-
ented toward toxicological
sciences. It soon ensued that
among the priorities of an early
scientist was the acquisition,
application, and communication
of knowledge. As years passed
the number of scientists conduct-
ing toxicological research
increased as did publication of
more papers, books, documents,
etc.
A recent study (Lu and Wassom
1985) showed that the number of
papers published in the field of
toxicology (all disciplines) dou-
bled during the decades of the
1970s and 1980s. As a result, the
task of acquiring, using, and com-
municating toxicology informa-
tion has become more difficult.
Decades ago access to toxicol-
ogy information was not a major
problem because it could be
obtained through the "invisible
college" of communication with
colleagues, attendance at scien-
tific meetings, and the reading of
a few key journals. However, as
the art of toxicology became
more sophisticated and research
more important, investigators
found their ability to acquire
Early toxicologists were eager to
share information and discuss their
research.
The number of papers published in
the field of toxicology doubled during
the decades of the 1970s and 1980s.
36 Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
information and keep up with
new developments diminished
significantly.
Toxicology Information
Systems
About 20 years ago two separate
President's Science Advisory
Committees reviewed, in depth,
issues concerning technical infor-
mation. One of these reports was
issued under the auspices of the
President's Commission on Sci-
ence and Information (1963),
headed by Alvin C. Weinberg,
who at that time was also Direc-
tor of the Oak Ridge National
Laboratory (ORNL). This report,
entitled "Science, Government,
and Information," stated "the
technical community must recog-
nize that handling technical infor-
mation is a worthy and integral
part of science." This report,
above all others, was the first to
call for the producers of informa-
tion (scientists/researchers) to be
actively involved in the manage-
ment (access/use) of information.
A later report (President's Com-
mission on Science and Techni-
cal Information 1966), entitled
"Handling of Toxicological
Information," defined toxicology
information as "all information
descriptive of the effects of
chemicals on living organisms or
their component subsystems"
and further indicated the neces-
sity of "a computer-based com-
prehensive and exhaustive
system for storage and retrieval
of valid information on the inter-
action between chemicals and
biological systems." The recom-
mendations set forth in these two
reports have clearly influenced
the direction of most information
systems development over the
past two decades. Also, during
this time, the availability and
application of computer technol-
ogy in information processing
and management have evolved
to the point that use of computers
for data/information manage-
ment has become routine. In
1970, for instance, there were
only around 70 computer-
readable databases, with an esti-
mated fewer than 10 million
records available; by 1981 this
number had increased to 750
databases with over 250 million
records, and on-line searches of
these databases (information
files) in the United States and
Canada reached 6 million.
The phenomenal growth in the
creation of databases/informa-
tion files has also carried over
into the development of periph-
eral software systems for more
efficient access and management
of the information contained in
these files or databases. Overall,
this rapid growth of hardware
and software has been focused
for the most part on making the
information retrieval process
faster, more flexible, comprehen-
sive, and cost effective.
The basic concept that should
form the foundation of any toxi-
cology information system,
whether it is a database, file,
computer network, or some other
type, is that the system should be
designed, developed, and main-
tained for the end user. .Unfortu-
nately, far too many of the
toxicology information systems
in operation have either forgotten
this root concept or never gave it,
serious consideration in the first
place. Proof of this can be easily
obtained through conversations
with active or practicing
researchers in any of the toxicol-
ogy disciplines. A majority, if
questioned, will respond that
The technical community must
recognize that handling technical
information is a worthy and
integral part of science.
The recommendations of the 1966
President's, Commission on Scientific
and Technical Information clearly
influenced the direction of most
information systems development over
the past two decades.
Access/Use Info Resources Assess Health Risk Chem Expos '93
37
-------
they do not use a particular data-
base, file, or computer system
because the specific type of infor-
mation needed cannot be easily
obtained. Unless the system is
user-friendly and information for-
matted so that a query can be
initiated using scientific terminol-
ogy of the day, direct use by
researchers will not occur. In my
opinion, systems structured with-
out these characteristics are des-
tined to obtain a user frequency
among practicing lexicologists
of only 10 to 15%. This leaves
an estimated 85 to 90% would-
be users to obtain information
via the 'Invisible college."
The production of information in
the lexicological sciences fol-
lows the same pathway evident
for almost any other area that
strives to produce and use knowl-
edge. This information pathway,
illustrated in Fig. 1, is very sim-
ple and perhaps therein lies the
problem. It is so simple that,
unfortunately, a number of those
responsible for development or
maintenance of information sys-
tems forgot it or assumed
wrongly that it is an intrinsic part
of the system. As evident in the
title of this symposium, "Access
and Use of Information
Resources in Assessing Health
Risks From Chemical Expo-
sure," the keyword is "informa-
tion." Unless information
systems designed to provide
access to lexicological knowl-
edge pay attention to the needs
of the end user, they are worth-
less.
The Specialized Informa-
tion Center Concept
Most of us know that the risk
assessment process is composed
of four steps: (1) hazard identifi-
Literature g
t c
I Research I
ta^^n^mum* I , 1
(Knowledge I
III. Ill - -.LJLIILM,- || ,|J| I
Fig. 1. The Information Cycle.
cation, (2) dose-response assess-
ment, (3) exposure assessment,
and (4) risk characterization.
To carry out or implement the
conditions of these four steps,
good reliable data/information
must be available. Consider this
issue: do you, as someone who
has responsibility in risk assess-
ment, have access to reliable and
complete data/information? We
would wager that if a survey
were taken, 85 to 90% of you
would say "No." In ihe mililary,
information is equaled with intel-
ligence and, militarily speaking,
we have not properly handled
our intelligence. Mosl of ihe wis-
dom from ihe Presidential Com-
mission on Science and
Information in 1963 and 1966
remained locked between the
covers of these two reports. The
most significant pearls of wis-
dom from these reports is the
idea for the specialized informa-
tion center and the plea that
those involved in the technical
aspect of a science should
become involved with the collec-
tion and use of the information
Those involved in the technical
aspect of a science should became
involved with the collection and use
of the information generated by
that science.
Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
generated by that science. We are
proud to say that these axioms
have been followed with the
origination, development, and
maintenance of the toxicology
databases/information files here
at ORNL. Because of limitations
in time and because most ORNL
databases/information files have
been elegantly presented in the
poster sessions, this paper will
focus on only one of these, the
Environmental Mutagen Informa-
tion Center (EMIC), to illustrate
how the specialized information
center concept was implemented
at ORNL.
The Environmental
Mutagen Information
Center (EMIC)
In the late 1960s, the need for
information accessibility in the
area of mutation research was
recognized by the newly formed
Environmental Mutagen Society
(EMS), which initiated action to
provide access to the literature
on mutagenicity and related sub-
jects. As a result of the action
taken by the EMS, EMIC was
officially organized at ORNL in
the fall of 1969, following the
.concept of the specialized infor-
mation center as proposed in the
Weinberg report. EMICs reason
for being is to establish a means
by which researchers and others
could have ready access to the lit-
erature of genetic toxicology. A
staff of dedicated people was
assembled along with all possi-
ble methods and equipment to
carry out this mandate. Prior to
1969, the genetic toxicology lit-
erature was in a state of disarray,
and publication frequency was
increasing each year (Table 1).
Records reveal that documents
currently collected and indexed
at EMIC were published in over
3800 different sources. This fact
more than any other illustrates
the futility of individual efforts
Table 1. Yearly publication
frequencies for genetic
toxicology literature
Year of
publication
Number of
documents
1967 and
prior years
1968
1969
1970
1971
1972
1973
1974
1975
1976
1977
1978
1979
1980
1981
1982
1983
1984
1985
1986
1987
1988
1989
1990a
1991
1992a
1993a
2527
982
1410
1949
2421
2611
2787
2396
2713
2903
3232
3866
3895
4146
4467
4981
4603
4004
*3857
3523
3030
2992
3046
>4000
3508
4000
4000
aLiterature collections for these years
are incomplete; numbers shown are
projections.
EMIC's reason for being is to
establish a means by which
researchers and others could have
ready access to the literature of
genetic toxicology.
Access/Use Info Resources Assess Health Risk Chem Expos '93
39
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to access the genetic toxicology
literature. Interestingly enough,
as of May 1991 almost half of
the over 78,000 EMIC papers
surveyed were published in
about 30 key journals (Table 2).
For this reason, it is recom-
mended that libraries located at
institutions actively engaged in
genetic toxicology research pro-
vide easy access to these key
journals, particularly Mutation
Research, Environmental and
Molecular Mutagenesis, and
Mutagenesis.
Publications selected to become
a part of the EMIC information
file are indexed by a group of
skilled staff members. EMIC's
document selection and indexing
procedures are thoroughly
explained in Wassom (1973,
1980) and Wassom and Mailing
(1978). These procedures are
briefly reviewed here to explain
how the EMIC file is constructed
and how it may be used to access
the genetic toxicology literature.
After a document is selected for
entry into the EMIC file, a copy
is obtained and index terms
describing the bibliographic data,
agent/organism, keywords, and,
Chemical Abstracts Service
(CAS) Registry Numbers are
recorded and entered in the com-
puter. Table 3 shows an example
of this type of entry.
The next step in the indexing
scheme focuses on the indexing
of information pertinent to assay
systems and/or genotoxic end-
points. Only papers containing
original experimental data are
indexed: indexing terms note
the assay system used or geno-
toxic endpoint that is either
looked for or observed. Excep-
tions to this policy include
reviews, symposia, book chap-
Table 2. Key journal sources used by the Environmental
Mutagen Information Center
Biochemical Pharmacology
Biochimica etBiophysia Acta
Biochemistry and Biophysics
Canadian Journal of Genetics and Cytology
Cancer Letters
Cancer Research
Carcinogenesis
Cell Biology and Toxicology
Chemico-Biological Interactions
Cytology and Genetics (USSR)
Environmental and Molecular Mutagenesis
Environmental Health Perspectives
Experientia
Experimental Cell Research
Federation Proceedings
Genetics
Hereditas
Human Genetics
Japanese Journal of Genetics
Journal of Bacteriology
Journal of the National Cancer Institute
Molecular and General Genetics
Mutagenesis
Mutagenesis, Carcino genesis and Teratogenesis
Mutation Research
Proceedings of the American Association of Cancer Research
Proceedings of the National Academy of Sciences USA
Radiation Research
Science
Soviet Genetics (USSR)
Toxicology
Toxicology and Applied Pharmacology
Toxicology Letters
ters, and abstracts considered
pertinent by an EMIC staff mem-
ber. All papers to be indexed
with these parameters are first
judged on content and are
grouped into one or more of the
eight general categories shown in
Table 4. On completion of this
general grouping, the more spe-
cific index terms are then
assigned where appropriate (e.g.,
40 "Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
GM, HGPRT assay or EC, chro-
mosome aberrations).
The information indexed by
EMIC can be accessed via com-
puter in a variety of ways: com-
pound, organism, assay system,
or end point. The fields indexed
can be queried individually or in
combination with information in
other fields. This capability pro-
vides a powerful tool for the
researcher, particularly in docu-
ment selection and subject evalu-
ation. Because it is not possible
to provide illustrations for the
many genetic toxicology assay
systems, users may contact
EMIC directly for further infor-
mation on particular systems of
interest. The EMIC file can be
accessed directly via the
National Library of Medicine
TOXLINF/TOXNET* computer
systems.
Conclusion
The illustration using EMIC as
an example of the specialized
information center concept
clearly shows how a file can be
developed for use by a specific
toxicology discipline in concert
with researchers of that discir
pline. The process is not easy but
with perseverance it can be done.
Kathy Deck of the Agency for
Toxic Substances and Disease
Registry** put together a listing
of some of the available sources
of computerized information on
toxicology and environmental
health. These listings, although
not inclusive of all the various
files, databases, books, etc., avail-
able for these subject areas, are
Table 3. Example of the scheme used by EMIC during its first phase
of document indexing
Accession number
Authors
Title
Publication source
Publication date
Literature type
Test object, common
classification
Test object, specific
classification
Tissue culture
Agents and Chemical
Abstracts Service
Registry Number
(CASRN)
077618
Warr, Tracey J.;Parry, J.M.; Callander, R.D.;
Ashby, J.
Methyl vinyl sulfone: A new class of
Michael-type genotoxin
Mutation Research 245:191-199
1990
Journal article with original data
Bacteria; Mammal, Chinese hamster cell
culture
SALMONELLA TYPHIMURIUM.TA98,
SALMONELLA TYPHIMURIUM.TAIOO,
SALMONELLA TYPHIMURIUM,TA1535,
SALMONELLA TYPHIMURIUM,TA1537,
SALMONELLA TYPHIMURIUM,TA1538;
CRICETULUS GRISEUS
Don-WG3H Cells; LUC2 Lung cells
Methyl vinyl sulfone (3680-02-2);
Acrylamide (79-06-1); Micfosomes,rat,S9
(NO CASRN)
Table 4. Major EMIC categories used for the classification of assay
systems and/or biological end points
Effects on nucleic acids (EN)
Gene mutations (GM)
Effects on chromosomes (EC)
Cytological effects (CE)
Mitotic or meiotic effects (MM)
Plant pigment mutation (PM)
Fertility and sterility studies (FS)
Miscellaneous studies and/or effects (MS)
*For further information about Toxline or Toxnet, interested individuals may contact Specialized Information Services, National
Library of Medicine, 8600 Rockville Pike, Bethesda, MD 20894.
**For further details about the listing of sources for computerized information on toxicology and environmental health, please
contact Kathryn S. Deck, Information Resources Management Group, Center for Environmental Health and Injury Control, Cham-
blee 27 ¥-29, Centers for Disease Control, Atlanta, GA 30333.
Access/Use Info Resources Assess Health Risk Chem Expos '93
41
-------
valuable compendiums that show
the vast nature and divergent
types of systems and books avail-
able to the toxicology informa-
tion consumer. Which of these
offer the best means of accessing
the literature? You, as users,
should study each of them well,
keeping in mind the admonitions
expressed by the Presidential
Commission on Science and
Information of 1963 and 1966.
Make your selections wisely so
that you can have confidence that
your future decisions, research,
or risk assessments have been
based on the best information/
data available. In closing, we ask
that as representatives of both
state and federal agencies you
remember these points:
• You must accept or share with
others the responsibility for
information activities con-
nected with the various scien-
tific and technical areas
associated with fulfillment of
your mission.
• Short-comings, deficiencies,
etc., that are noticed in infor-
mation activities should be
voiced and demands for
improvement made through
and with the support of the
appropriate scientific and/or
technical society.
• Federal and state agencies
must devote an appreciable
portion of their talents and
funds to support information
activities.
• Information should become a
highly placed focal point for
all government agencies.
• Information activities should
be maintained in the research
and development environment
of an agency, laboratory, etc.,
and not as an administrative
function.
If these guidelines are followed,
the information activities for the
toxicology sciences can and will
evolve to a more usable state
rather than become extinct
through nonuse.
References
Darwin, Charles D. 1859. The Origin
of Species. A facsimile of the sixth edi-
tion with an introduction by Sir Julian
Huxley, NAL Penguin, Inc., New York,
1958.
Lu, P. Y., and J. S. Wassom. 1985.
'Information Science in Toxicology,"
Proceedings of the National Science
Council, ROC, Taipei, Taiwan, Republic
of China, March 24-April 2.
President's Commission on Science
and Technical Information. 1963. Sci-
ence, government and information, Gov-
ernment Printing Office, Washington,
D.C.
President's Commission on Science
and Technical Information. 1966. Han-
dling of toxicology information, Govern-
ment Printing Office, Washington, D.C.
Wassom, J. S. 1973. The literature of
chemical mutagenesis. pp. 271-87. In:
Chemical Mutagens, Vol. IH, Alexander
Hollaender (ed.), Plenum Press, New
York, Chapter 34.
Wassom, J. S. 1980. The storage and
retrieval of chemical mutagenesis infor-
mation, pp. 313-30. In: Progress in
Environmental Mutagenesis, M.
Alacevic (ed.), Elsevier/North-Holland
Biomedical Press, North Holland.
Wassom, J. S., and H. V. Mailing.
1978. Specialized information centers in
toxicology. I. Environmental Mutagen
Information Center (EMC), pp. 351-85.
In: Advances in Modern Toxicology, W.
G. Flamm, and M. A. Mehlman (eds.),
Hemisphere Publishing Co., Washing-
ton, D.C.
42
Access/Use Info Resources Assess Health Risk Chem Expos '93
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Information and Technology: A Coexistence
Without Limits, A Beginning With No Apparent
Ending
i
David J. Reisman, U.S. Environmental Protection Agency
A variety of issues must be addressed in development of software for information resources. One is accessibility and use of
information. Another is that to properly design, abstract, index, and do quality control on a database requires the effort of
well-trained and knowledgeable personnel as well as substantial financial resources. Transferring data to other locations has
inherent difficulties, including those related to incompatibility. The main issue in developing health risk assessment databases is the
needs of.the user.
To those of you who have
come not knowing what
to expect at this sympo-
sium,, one good description
might be that this is the first
attempt to really view the ways
in which information and tech-
nology are used to advance the
health risk assessment process.
This morning, the information
needs of the risk assessors and
the risk managers were reviewed.
I am a database manager and
have worked in the health and
environmental risk area within
the Environmental Protection
Agency (EPA) in Cincinnati for
12 years. I have written and
reviewed many different types of
health assessment documentation
and methodology, including
ambient and drinking water crite-
ria documents, health advisories,
and environmental health docu-
ments, plus the various EPA
health risk assessment method-
ologies. I have experience as a
risk assessor, but not a risk man-
ager. Through all of these work
experiences, I have observed that
technology has been providing
information at a faster pace in
recent years. Yet, with each step
in growth, demand for more data
"at your fingertips" creates the
need for more advanced technol-
ogy. The coexistence will always
improve, but the indefinite limits
of this growth depend on many
other variables. The automated
databases created over the last 30
years are still only the beginning.
A glimpse at artificial intelli-
gence and its possibilities illus-
trates how much immediate, as
well as long-term, growth can
occur.
In preparation for this talk, I
began to retrace the steps that
brought me to information sci-
ence. When I was just starting
college, I frequently went
between our computer science
department and our computer
room, which was a quarter mile,
walk. I always carried boxes of
computer cards because that's
how we did databases in "those"
days. The programming watch-
word was "always number your
computer cards." One day I stum-
bled down a few steps, only to
catch my balance but not my
now-mixed cards. Today, we
don't carry cards, and we don't
Automated databases created over
the last 30 years are only the
beginning.
The programming watchword was
' 'always number your computer
cards.''
Access/Use Info Resources Assess Health Risk Chem Expos '93
43
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walk; we telecommunicate!
Technology has had a tremen-
dous impact on information flow.
Although beneficial in many
ways, this impact has affected
health risk assessment scientists
because they can be over-
whelmed by the sheer quantity of
information. Even with the infor-
mation and data, without appro-
priate science and methodology,
it is still a challenge for risk man-
agers and decision-makers to pro-
vide the best risk-based decision.
Risk assessors often provide the
research data with their best
analysis, along with those data
provided by other interested
groups; but then the risk man-
ager is "caught in the middle" of
all these different parties and
their respective scientific analy-
ses and conclusions with, in most
cases, no previous experience
upon which to base a decision.
Generally, it is still better to have
conflicting data than to have
none at all. The capability to pro-
vide that information quickly has
made risk analysis much more
meaningful, and hopefully, more
scientifically valid than it was
previously.
One of the purposes of this sym-
posium is to look at accessibility
and use of information resources
in health risk assessment. The
first slide states, "research yields
information which provides bet-
ter technology to conduct more
research." This little statement
defines a large aspect of risk
assessment research. It is a con-
tinual process, almost like a loop
or a real Catch 22. More research
yields more information, and
along with additional informa-
tion are advances in technology
that allow us to conduct better
research, which again comes
back to providing more informa-
tion. Statisticians sometimes say
that one can never have enough
data, because more data can
make assessments both precise
and accurate. In this process,
technology appears to be a pro-
moter of the whole information
process, and as technology is
improved there is a seemingly
endless promotion of the proc-
ess. The following is a discus-
sion of parts of the information
process and its technology, along
with some of the problems and
pitfalls inherent in it.
To properly design, abstract,
index, and do quality control on
a database requires the effort of
well-trained and knowledgeable
personnel, as well as substantial
financial resources. Most data-
bases in the health risk assess-
ment area are being developed
by the government. Obviously,
because of the substantial finan-
cial requirement, private industry
would have to be assured of
return on that investment before
becoming involved. Thus, the
transfer of information is highly
dependent on the transfer of dol-
lars, either for purchasing of
equipment or developing infor-
mation tools.
In planning an information tool
the creators sometimes have an
idea of what they want, and
know what technological tools
are available to them, but do not
have a total view of who or why
people would use products out-
side their limited immediate
arena. In an attempt to go beyond
this immediate arena, the EPA's
Chemical Unit Record Estimates
(CURE) database was planned
over nine months. Much of this
time was used to analyze avail-
able data and the different types
of documentation that the EPA
It is a continual process, almost like a
loop or a real Catch 22.
To properly design, abstract, index,
and do quality control on a
database requires the effort of
well-trained and knowledgeable
personnel.
44
Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
Office of Heath and Environ-
mental Assessment (OHEA) pro-
duces. From this review, the
needed data fields were deter-
mined, and then the actual build-
ing of the database was begun.
However, many times an infor-
mation tool is an outgrowth of a
smaller "pilot" project. Then,
another group slightly alters the
original to fit a new or expanded
need, or older databases are
made more useful because of bet-
ter computer software and hard-
ware. But in the development
stage, it seems that efforts con-
stantly have to be repeated.
Again, the circular motion is cre-
ated because as data are
abstracted, indexed, and then
reviewed, the need to change cer-
tain fields tbecomes obvious. In
most databases, the ever-evolving
process of updating and upgrad-
ing never stops. One thing to try
to avoid in building databases, is
the dilemmas. With luck, the
dilemmas won't become the last
stage, disaster, which usually
marks the end of the database.
This phase follows funding cuts
and loss of involved personnel.
Even with a great database staff,
things are sometimes over-
looked. For example, once the
prototype is built and sent to
many of your user groups, the
telephone rings and you get a per-
son on the other line who says,
"Why doesn't this work?" One
common experience is the prob-
lem of the novice user. Some-
times the problem is simply that
the user has a low density drive
on his computer and has been
sent a high density disk. Often a
simple problem can be over-
looked because the users come in
all experience categories.
Transferring data to other loca-
tions always creates dilemmas.
For example, I once sent a pro-
gram to somebody in a Washing-
ton, D.C. office for review. The
person at the other end called
me, and after almost an hour and
a half, we still couldn't under-
stand why the program wasn't
working. I sent a batch of new
diskettes, and the same thing hap-
pened again. After about two
days, I found that while I was
using color monitors, this person
was still using a black and white.
When the program translated
down to the black and white
monitor, the highlight bar could
not be seen because it was stay-
ing in the background. This also
happened when running some of
our programs on the laptops with
plasma displays. These are some
of the unexpected technology pit-
falls. Technological advances ,
can also mean that you must
reverse or retrace your previous
efforts to insure accuracy and
precision.
The main issue we must examine
in developing health risk assess-
ment databases is the needs of
the user. Technology has
changed and developed, allow-
ing us to store large amounts of
data on smaller, portable
machines. The risk assessor can
now carry a machine to a site
and have quite a bit of relevant
data at hand, but the question
remains, "Does he have the abil-
ity and training to make these
decisions immediately?" If sev-
eral computer systems contain
large amounts of data, the end
user could purchase an expensive
laptop that has a large hard disk,
but would all this information
help or would it make the job
even more difficult? Information
personnel in the health risk
Some older databases can now be
made more useful.
Transferring data to other locations
always creates dilemmas.
Access /Use Info Resources Assess Health Risk Chem Expos '93
45
-------
assessment field have the ability
to develop worthwhile and sensi-
ble tools. However, they must
make sure that these tools are of
good quality, not just great quan-
tity, and must be useful and avail-
able. If cost is the limiting factor,
then resources should be used
wisely.
The development of different
databases on different software
creates another technological dif-
ficulty: incompatibility. This
term can cover a wide variety of
areas. For example, on one side
of PC-development are the 'Inde-
pendent Banana Merchants", and
on the other side we have the
"Apple sellers"; two commonly
used company machines that
can't talk well to each other.
What good are databases if they
are limited only to a certain type
of user or certain type of
machine? It may seem to the non-
computerized risk assessor that a
lot of information is available
and can be transferred at will, but
the transfer process is not easy,
takes too much valuable time,
and therefore frequently is not
worth the effort. Incompatibility
also is not just in the equipment
or the software. There is also the
incompatibility of database man-
agers who do not talk to each
other because of the "my turf
attitude.
New software is constantly
appearing on the market, or cur-
rent versions are changed or
updated so that even persons
using the "same" software may
not be compatible. A prime
example is the little message
'Incorrect DOS version" which
is displayed when work done on
one machine is transferred to a
machine with a lower version of
DOS which consequently won't
run. An inexperienced user may
keep trying to no avail, but
although the program will not
run, it is not damaged. The user
then calls the person in his office
that he/she needs the most: the
resident "chiphead" who under-
stands hardware and software. It
reminds me of the salesman who
sold me my first PC after I had
only a few weeks of PC experi-
ence. I didn't know what he was
talking about, so I just said,
"Well, I don't understand, so I'll
take that one. It looks nice, has
good features, and it's got a nice
color monitor."
Previously, people carried calcu-
lators; now they carry laptops or
computerized workbooks to
meetings. The real question now
is, can we manage all of this? As
a person who works in both the
information science area and
with health effects documenta-
tion, I think it's very difficult.
We have a big job ahead of us,
but we shouldn't get dismayed
because today we have better
information than ever to do our
assessments.
In connection with this is one of
my other chief points — prolif-
eration. When I was in graduate
school, some of our experiments
were on planarian regeneration.
You cut away a piece of the pla-
naria and it regenerates that
piece. You do the same thing to a
hard disk on a PC. You remove 3
MB of data so that you will have
room for another program, but, 2
weeks later you are back where
you started. It seems that infor-
mation on a hard disk constantly
regenerates or replaces itself.
Two years ago, I got a 300 MB
hard disk as a solution. Today I
need a 600 MB hard disk! At this
point, what we really have to
The main issue that we must
examine is the needs of the user.
The transfer process is not easy,
takes too much valuable time, and
therefore frequently is not done.
46 Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
look at is the possibility of infor-
mation overloading brought on
by expanding technology. Every
office needs a good information
manager.
Risk assessors must inform the
information personnel and the
researchers exactly what type of
data is needed in order for a true
"applied" research project to be
conducted. By achieving this
level of communication, we will
be able to get the proper type of
information and data on which to
base our risk management deci-
sions. The technological tools
are available, but the current
communication among various
associated risk assessment sec-
tors is still in its infancy.
My final point is that of accessi-
bility represented by this figure
of a gentleman standing in front
of a bookshelf that is over 10
feet high. Naturally, the book
that he wants to read is on the
INFORMATION
MUST BE
ACCESSIBLE
TO BE OF
ANY VALUE
top shelf with no ladder in sight.
Information must be accessible
to be of any value.
We have the information and the
technology is available; friendly
and usable systems must be
developed to make the data
accessible to all who need it.
Can we manage all of this?
Access/Use Info Resources Assess Health Risk Chem Expos '93
47
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The Challenge of Information Access
Linda A. Trovers, U.S. Environmental Protection Agency
Traditional methods of risk communication may not work for large quantities of information. Federal databases are being created
to meet the public's right-to-know.
The "public right-to-know"
about the business of gov-
ernment is a fundamental
principle of our democratic gov-
ernment and open society. As the
public becomes more interested
in environmental issues, they
expect to receive information
and get answers from federal and
state officials. A local citizens'
action group may want to gather
information to gain support for
or against local landfills or
municipal waste incinerators.
Traditional methods of risk com-
munication may not work for
such large quantities of informa-
tion; as a consequence, federal
databases are being created to
meet the public's right-to-know.
Over the past two decades, the
federal government has system-
atically exploited computer and
communications technology to
conduct its business more effec-
tively, efficiently, and economi-
cally. The government has
learned it must also answer the
public's questions.
In the process, federal agencies
have converted public informa-
tion from paper documents and
data files into electronic database
systems. Federal agencies rou-
tinely manipulate this computer
data to fulfill agency missions
ranging from determining the
risk of a potentially hazardous
substance to ascertaining where
the next enforcement inspection
should be conducted. A growing
number of agencies require busi-
nesses to provide data collected
for regulatory purposes in elec-
tronic formats and in turn the
government fulfills its informa-
tion disclosure responsibilities
by disseminating public informa-
tion through government, com-
mercial, and nonprofit interactive
computer and communications
networks.
This fundamental transformation
of public information and public
decision making into computer-
ized data processes occurred
without serious public policy
attention being paid to how it
may affect the public's right-to-
know. Moreover, little public pol-
icy debate or concerted effort has
been initiated to resolve elec-
tronic information policy issues,
citizen access rights being a core
concern.
I suggest that the debate has
begun. You can expect to hear
more about the government's
responsibility and obligation to
share information with the pub-
lic. Public action groups are
beginning to form with the very
specific purpose of seeking out
and analyzing information that
the government collects from
industry.
Federal databases are being
created to meet the public's
right-to-know.
This fundamental transformation of
public information and public
decision- making into computerized
data processes occurred without
serious public policy attention being
paid to how it may affect the public's
right-to-know.
Access/Use Info Resources Assess Health Risk Chem Expos '93
49
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Senator Jeff Bingaman (D-NM)
has written the Federal Informa-
tion Resources Management Act
of 1989 (S. 1772) to reauthorize
the Paperwork Reduction Act.
The legislation was introduced in
a series of hearings in 1989 in
the Subcommittee on Govern-
ment Information and Regula-
tion. Subsequent hearings on the
bill by the full Committee on
Government Affairs were held in
February 1990. S. 1772 promotes
availability and public access to
information in several ways,
including:
"Agencies, not Office of Manage-
ment and Budget (OMB), have
the primary responsibility for
decisions about dissemination
activities, and those agencies are
required for the first time to
establish a sound information dis-
semination management pro-
gram." According to this bill,
public access must be equitable
and equal.
Another example of this new
public access debate can be
found in the House of Repre-
sentatives bill to create the
Department of Environmental
Protection (H.R. 3847). Unlike .
the Senate version, this bill's-pub-
lic access provisions are far
reaching. This bill would require
the newly created department to
write a guide to environmental
information services, products,
and systems; develop methods
for cross-linking and integrating
environmental data; create a
study, incorporating pilot pro-
jects, to show ways to use com-
puters to disseminate informa-
tion; and set up an advisory com-
mittee to recommend improve-
ments in public access. No new
appropriation of funds is linked
to this proposed responsibility.
The real-time example this paper
will discuss is the Environmental
Protection Agency's (EPA) large
precedent-setting sharing of envi-
ronmental data. We have respon-
sibility for designing and imple-
menting an environmental data-
base—the Toxic Release Inven-
tory (TRI), which Congress
directed the EPA to create specifi-
cally to be shared with the pub-
lic. We began collecting data
from industries in 1988 and now
have 2 years of experience with
the system and the public's use
of the database. Today, informa-
tion on the estimated annual
releases of 320 chemicals or mix-
tures from over 20,000 emitters
resides on a user-friendly com-
puter at the National Library of
Medicine for all the world to use.
During the first year of opera-
tion, nearly 170,000 searches of
the database were made.
These searches were not just
done out of curiosity. The infor-
mation is being used in a variety
of ways. Companies are compar-
ing their performances to those
of their competitors and deciding
to make dramatic voluntary
reductions in their toxic releases.
Citizens are studying the releases
in their communities and
demanding information to assist
them in their public policy
debates. The release of this infor-
mation creates a strong demand
for more information to be col-
lected and consolidated by EPA
and state environmental
agencies.
Not everyone feels comfortable
using computers, so the EPA is
also providing information from
the TRI in many traditional
nonelectronic ways. These
include a National Report, which
is an easy to understand sum-
We have responsibility for
designing and implementing an
environmental database—the
Toxic Release Inventory (TRI).
The information is being used in a
variety of ways.
50 Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
mary of the database. The
database is also on microfiche at
over 3300 county libraries in the
country. Diskettes of each state's
emission reports have been dis-
tributed to each State Health or
Environmental Department, and
more than 500 Depository Librar-
ies have the database on CD-
ROM. All of these products are
for sale to the general public
from either the Government
Printing Office or the National
Technical Information Service.
I hope that talking about our
experience at EPA with TRI
helps convince you that the
debate on the principle of Right-
To-Know and Public Access to
government information is of
critical importance today. I think
this point is best summed up by a
quote of Senator Bingaman. He
said: Our nation's information
strategy must also include an
affirmative responsibility for pub-
lic access to government informa-
tion. Unfortunately, our laws
governing information policy
have not yet enabled our society
to benefit fully from the advan-
tages offered by the "information
age."
By now you must be saying to
yourself, "What does this have to
do with me and the information I
manage or use?" The new 1990s
challenge to environmental scien-
tists and managers will be public
access to information, informa-
tion which in the past we have
kept for our exclusive use to sup-
port activities such as research
and development or government '
rule making.
With that challenge facing us, a
number of actions can be taken
to enhance our ability to accept
that challenge and improve our
use of environmental data in gov-
ernment decision making.- It is
important that risk communica-
tion mechanisms evolve at the
same pace as the improvements
to our environmental data. We
must continue to foster outreach
efforts so that our data is accu-
rately communicated in an under-
standable manner and is made
available to all citizens.
Many "how to" guidance docu-
ments are available to help you
develop traditional informational
brochures and other materials for
the public's use. I encourage all
of you to work with your staff
and with risk communication spe-
cialists to create easy to under-
stand public information.
As we move towards computer
access, we are faced with unique
challenges. The following are
three major information manage-
ment principles that we set for
ourselves in creating the TRI
database that can help meet ac-
cess goals now and in the future.
• Standardization of Data Fields;
• Integration of Data Bases,
where appropriate; and
• Data Quality/Data Control
Processes.
Based on the experience we
gained from making TRI pub-
licly available, these three princi-
ples are the most important
issues for government informa-
tion managers to focus on in the
next few years.
Government managers and data-
base developers should be sensi-
tive to the need to standardize
data fields across databases. Two
such fields that lend themselves
to such an approach are location
data and facility identification
data. Both of these data fields are
important when doing any sort of
Actions can be taken to enhance our
ability to accept the challenge and
improve the use of environ-
mental data in government
decision-making.
There are three major information
management principles that we set for
ourselves in creating TRI.
Access/Use Info Resources Assess Health Risk Chem Expos '93 51
-------
trends or geographic exposure
analysis. Efforts should be made
by database developers to stand-
ardize as many of these types of
data fields as possible. Such an
effort will help increase the abil-
ity of users to integrate informa-
tion across databases, which is
the second principle to highlight.
As we move into cross-media
risk and exposure assessments,
the ability to integrate informa-
tion across databases becomes
more important. Database devel-
opers should think about how
their data will be used by others
in the government as well as out-
side the government. We must
move away from databases that
are for the exclusive use of a few
people and move toward data-
bases that will be searched by a
broad spectrum of users.
I work at EPA, so I know it is no
simple matter to start thinking
and working with our informa-
tion in this very different way.
We have very tight budgets for
information purposes. This may
indeed be called the "information
age," but you couldn't tell it
from the way we are forced to
budget. Information is still seen
as a frill—a convenience, not a
necessity. However, this attitude
is changing, and in the competi-
tion for resources nothing sells a
budget better than to tell those in
charge of resources that you have
a highly vocal set of users who
are clamoring for enhancements.
Strong indications that the data
are wanted and are being used to
protect the environment (for
example) should help kill the
myth that information is merely
a frill that can be budgeted for
only in good years, and cut back
in lean years. Integration of data
across data bases can help rein-
force the argument for appropri-
ate resources.
States are also coming into the
'Information Age." Many more
opportunities exist to share infor-
mation and enter into partner-
ships between the federal and
state levels of governments.
The final point is the need for a
good quality assurance and qual-
ity control (QA/QC) process for
your data collection. This is the
most important lesson learned in
collecting the TRI data. The
original policy decision, because
of resource constraints, was to
enter the data collected exactly
as provided by the submitter. As
you can imagine, this caused
many problems with the quality
of the database and reliability of
the information that users
retrieved. Now, EPA is fully
applying appropriate QA/QC
process to the TRI database.
TRI is evolving as users find-
new ways to analyze the data and
as we learn how to make this
public right-to-know experiment
work better. Congress directed us
to build this system for the peo-
ple, and we are still learning the
best techniques to make TRI
work for everyone.
Move away from databases that are
for the exclusive use of a few
people and move toward databases
that will be searched by a broad
spectrum of users.
TRI is evolving as users find new
ways to analyze the data and as we
learn how to make this public
right-to-know experiment work
better.
52 Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
Structure Activity Relationships to Assess New
Chemicals Under TSCA
Angela E. Auletta, U.S. Environmental Protection Agency
Under Section 5 of the Toxic Substances Control Act (TSCA), manufacturers must notify the U.S. Environmental Protection Agency
(EPA) 90 days before manufacturing, processing, or importing a new chemical substance. This is referred to as a premanufacture
notice (PMN). The PMN must contain certain information including chemical identity, production volume, proposed uses, estimates
of exposure and release, and any health or environmental test data that are available to the submitter. Because there is no explicit
statutory authority that requires testing of new chemicals prior to their entry into the market, most PMNs are submitted with little or
no data. As a result, EPA has developed special techniques for hazard assessment of PMN chemicals. These include (1) evaluation
of available data on the chemical itself, (2) evaluation of data on analogues of the PMN, or evaluation of data on metabolites or
analogues of metabolites of the PMN, (3) use of quantitative structure activity relationships (QSARs), and (4) knowledge and judge-
ment of scientific assessors in the interpretation and integration of the information developed in the course of the assessment. This
approach to evaluating potential hazards of new chemicals is used to identify those that are most in need of additional review or fur-
ther testing. It should not be viewed as a replacement for testing.
Introduction
TSCA was enacted and
signed into law by Presi-
dent Gerald Ford on Octo-
ber 11, 1976. It went into effect
on January 1,1977. Simply
stated, TSCA provides EPA with
the authority "to regulate com-
merce and protect human health
and the environment by requir-
ing testing and necessary use
restrictions on certain chemical
substances..."
TSCA has two main regulatory
features: (1) acquisition of suffi-
cient information by EPA to iden-
tify and evaluate potential
hazards from chemical sub-
stances and (2) regulation of the
production, use, distribution, and
disposal of such substances
where necessary. Although
TSCA consists of 31 sections,
principal provisions of the act
are described in Sects. 4 (Testing
of Existing Chemical Sub-
stances), 5 (Premanufacturing
Notices for New Chemicals), 6
(Regulation of Hazardous Chemi-
cal Substances), 7 (Imminent
Hazards), and 8 (Reporting and
Retention of Information).
This paper will deal with the use
of quantitative structure activity
relationships (QSAR) to assess
new chemicals submitted under
Sect. 5. Particular reference will
be made to the use of mutagenic-
ity data in this context.
Premanufacture Notice
Under Sect. 5 of TSCA, a manu-
facturer must notify EPA 90 days
before manufacturing, process-
ing, or importing a new chemical
substance. A "chemical" may be
any of a wide variety of organic
or inorganic substances manufac-
tured or imported by the chemi-
cal industry for uses such as
dyes, pigments, lubricant addi-
tives, chemical intermediates,
synthetic fibers, structural poly-
mers, or coatings. Essentially, it
includes any commercial chemi-
cal except those used as drugs,
pesticides, food additives, cos-
Quantitative structure activity
relationships (QSAR) are used to
assess new chemicals submitted
under Section 5 of TSCA.
Access/Use Info Resources Assess Health Risk Chem Expos '93
53
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metics, and certain other uses
that are controlled by other
statutes.
"New" is defined as any chemi-
cal not listed on the Inventory of
Existing Commercial Chemicals.
The inventory was first compiled
in 1977 and included those
chemicals that were being manu-
factured or imported for use at
that time. Since then, PMN
chemicals for which EPA has
received a Notice of Commence-
ment (NOC) have been added to
the inventory, which now
includes over 60,000 entries.
Since 1979, EPA has received
over 7000 PMNs. Of these,
approximately 60% were dis-
crete chemicals and approxi-
mately 40% were polymers.
TSCA requires that certain infor-
mation be provided in the new
chemical notification. This
includes chemical identity, pro-
duction volume, proposed uses,
estimates of exposure and
release, and any health or envi-
ronmental test data that are avail-
able to the submitter at the time
of submission.
Section 5 contains no explicit
statutory authority requiring
manufacturers, processors, or im-
porters to conduct testing of new
chemicals prior to their entry
into the market. Therefore,
approximately 50% of all PMNs
received contain little or no test
data. The types of data received
and the distribution of this data
between nonpolymer and poly-
mer chemicals are shown in
Table 1. Although the data
shown in the table are for the
years from 1979 - 1985, figures
should be regarded as substan-
tially accurate because the rate of
Table 1. Percentage of data by type submitted with premanufacture
notices, 1979 -1985
Type of data
All
Nonpolymers Polymers
None
Toxicity
Acute toxicity
Oral
Dermal
Inhalation
Skin/eye irritation
Sensitization
Mutagenicity
Other
Ecotoxicology
Environmental fate
51
40
40
23
11
38
11
15
11
10
9
38
53
53
29
13
48
17
23
16
15
13
68
24
24
14
7
21
5
6
4
4
4
Section 5 contains no explicit statutory
authority requiring manufacturers,
processors, or importers to conduct
testing of new chemicals prior to their
entry into the market.
54 Access/Use Info Resources Assess Health Risk Chem Expos '93
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data submission with PMNs has
not changed appreciably in the
period from 1985= 1990. Note
that data received are associated
primarily with nonpolymer sub-
missions. Most of the data
received are acute oral toxicity
data. Mutagenicity data, primar-
ily the results of testing in the
Salmonella/mammalian microso-
mal assay, are received with 5%
of all PMNs.
Because of the paucity of data
associated with PMN submis-
sions, the assessment of potential
toxicity of new chemicals is con-
ducted using special techniques
developed for this purpose.
These include (1) evaluation of
available data on the chemical
itself, (2) evaluation of data on
analogues of the PMN chemical,
on its metabolites or their ana-
logues, (3) use of QSARs, and
(4) knowledge and judgement of
scientific assessors in the inter-
pretation and integration of the
information developed in the
course of the assessment. The
use of QSARs is limited to the
estimation of (1) physical chemi-
cal properties such as water solu-
bility, log P, and vapor pressure,
and (2) acute aquatic toxicity and
bioconcentration factors, which
can be estimated on the basis of
log P. Currently, EPA does not
use QSARs for health effects
because too few endpoints and
too few classes of chemicals
have been studied to permit rou-
tine use of such methodology in
PMN assessments.
Evaluation of PMN
Chemicals
In evaluating chemicals under
Sect. 5, EPA must distinguish
between those that may present a
"reasonable" risk to health or the
environment and those that pre-
sent an "unreasonable" risk. Risk
is defined as a function of haz-
ard, which includes a determina-
tion of both toxicity and
exposure; unreasonable risk also
includes a consideration of expo-
sure. EPA has 90 days from the
receipt of submission of a PMN
to make this determination. The
schedule for the assessment proc-
ess is shown in Table 2.
During the first week after a-
PMN is received, it is presented
before a Structure Activity Team
(SAT) composed of chemists,
lexicologists and environmental
scientists. Using professional
judgment based on knowledge of
relevant structural analogues, the
SAT expresses concern for poten-
tial environmental effects or for
health effects, which may
include cancer, mutagenicity,
teratogenicity, neurotoxicity, or
other chronic or acute effects.
Concern is not expressed for all
chemicals. Likewise, when con-
cern is expressed for a particular
PMN chemical, it is not necessar-
ily expressed for all effects.
Within 1 week of the SAT meet-
ing, a second meeting is held at
which the SAT concerns, the use
scenario, and expected exposure
are considered together and a
decision is made on whether or
not to continue the review proc-
ess (Detailed Review).
Once a chemical enters into the
Detailed Review Process, a team
of health and/or environmental
experts is convened. Each expert,
examines the PMN from the per-
spective of his or her area of
expertise and makes a case using
direct or supportive evidence.
Direct evidence includes data
dealing specifically with the
PMN chemical. Such data may
EPA must distinguish between those
chemicals that may present a
"reasonable" risk to health or the
,r environment and those that present
an "unreasonable" risk.
The SAT expresses concern for
potential environmental effects or for
health effects, which may include
cancer, mutagenicity, teratogenicity,
neurotoxicity, or other chronic or
acute effects.
Access/Use Info Resources Assess Health Risk Chem Expos '93
55
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Table 2. Premanufacture notice (PMN) hazard assessment process
Day Activity
0 Receipt of notice
2-9 Determine chemical nature
Review submitted test data
Identify suitable analogues including analogous PMN chemicals
Perform preliminary literature searches on the PMN chemical and relevant analogues
Obtain in-house data on analogues, if available
10 Chemistry team meets
11 Structure activity team (SAT) meets to discuss fate and health and ecotoxicology hazards
14 Exposure analysis team meets to discuss occupational, consumer and environmental exposure
15 Preliminary risk decision is made
Low risk cases are dropped from further review. Others enter into a detailed review for analysis of
risks
16-60 Detailed review
Analogue identification continues, literature searches are performed, and relevant literature is
identified and acquired
Available data, including any available on the PMN chemical, are reviewed and evaluated
The PMN is evaluated to determine such factors as absorption, metabolism, and the potential for
activation/deactivation in the body
A written hazard assessment is prepared utilizing the data developed and relating the data on the
analogue to the PMN chemical
65 Internal peer review of hazard/risk conclusions and development of testing recommendations
80 Final risk decision
Cases that do not appear to present an "Unreasonable risk of Injury" are dropped
Chemicals that "may present an unreasonable risk" are subject to regulatory action (e.g., exposure
controls may be specified, restrictions may be placed on use, or testing requirements may be
specified)
56 Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
have been submitted with the
PMN or may have been found in
the scientific literature.
Supportive evidence may include
data on a potential metabolite of
the PMN or data on a close struc-
tural analogue of the PMN or on
analogues of a potential metabo-
lite. Because data oh the PMN
itself is generally not available,
most evidence is supportive in
nature. To be useful as suppor-
tive evidence, analogues selected
must fulfill two requirements:
(1) they must resemble the PMN
or its potential metabolites struc-
turally, functionally, in physio-
chemical properties, electronic
potential, or some combination
of these factors, and (2) they
must offer .the promise of a pro-
ductive literature search.
After the completion of the
detailed review, several courses
of action may be taken by the
agency.
1. The agency may determine
that the chemical poses no
unreasonable risk to health or
the environment. In that case,
manufacture of the chemical
may begin following the expi-
ration of the 90-day period. On
receipt of an NOC from the
submitter, the chemical is
added to the inventory of exist-
ing chemicals and is no longer
considered a "new" chemical.
2. If it is determined that there is
enough information on which
to base a judgement that a
chemical presents an unreason-
able risk, the agency may issue
a proposed rule that will initi-
ate some type of direct control
of the chemical. If it is deter-
mined that a total ban is
required, the agency may issue
a proposed order to prohibit
manufacture under Sect. 5(f)
ofTSCA.
3. If it is determined that there is
insufficient information on
which to base an evaluation of
the chemical, that it may pre-
sent an unreasonable risk of
injury to health or the environ-
ment or may be manufactured
in sufficient quantities to cause
significant environmental or
human exposures, the agency
may issue a proposed order to
prohibit or limit the production
of the substance under
Sect. 5(e) ofTSCA. As a result
of a Sect. 5(e) order, the com-
pany may be required to sub-
mit data following specific
testing of the PMN or it may
be required to control expo-
sure levels by the use of protec-
tive clothing or equipment.
Section 5(e) orders may also
limit manufacture for desig-
nated uses only.
Use of Mutagenicity Data
In general, mutagenicity data are
used for three purposes under
Sect. 5: (1) as part of exposure-
based testing, (2) to assess the
potential of the PMN chemical to
induce heritable genetic effects,
and (3) as part of the weight of
evidence that a chemical may be
a potential oncogen.
The criteria for exposure-based
testing and the tests required
when such triggers are met are .
shown in Tables 3 and 4. Not all
tests are necessarily performed
on all chemicals that satisfy the
conditions for exposure-based
testing. When mutagenicity test-
ing is required, the agency asks
for a two-test battery of the Sal-
monella assay and a mouse
micronucleus assay. Because the
intraperitoneal route is
After completion of detailed review,
several courses of action may be
taken by the agency.
Mutagenicity data are used for three
purposes.
Access/Use Info Resources Assess Health Risk Chem Expos '93
57
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Table 3. TSCA Section 5 criteria for exposure-based testing
1. > 1000 workers exposed
2. > 100 workers exposed by inhalation to 10 mg/kg/day
3. > 100 workers exposed by inhalation to 1 10 mg/kg/day for
100 days/year
4. > 250 workers exposed by routine dermal contact for 100
days/year
5. Presence of the chemical in any consumer product where the
physical state of the chemical in the product and the manner
of use would make exposures likely
6. > 70 mg/year exposure via surface water
7. > 70 mg/year exposure via air
8. > 70 mg/year exposure via groundwater
9. > 10,000 kg/year release to environmental media
10. > 1000 kg/year release to surface water after calculated
estimates of removal by treatment
Table 4. TSCA Section 5 testing requirements
for high-volume chemicals
1. Acute oral toxicity test in rats
2. 28-day repeated dose oral study in rats (may include
developmental, reproductive, or neurotoxicity testing)
3. Salmonella assay and in vivo micronucleus assay
4. LCso in Daphnia, LCso in fish, and bioassay in algae
considered most sensitive by
agency scientists, it is required
for the micronucleus assay. At
this stage of testing, the empha-
sis is on determining intrinsic
mutagenic potential and not on a
determination of risk. If risk
were a prime consideration at
this point, then routes of admini-
stration that are more relevant to
human exposure might be chosen
for testing.
Because of the nature of the
PMN assessment process, which
relies heavily on the use of ana-
logue data, and because of limita-
tions in the size of the data base
of chemicals tested for heritable
genetic effects, concern for a
chemical's ability to induce heri-
table gene or chromosomal muta-
Concemfor a chemical's ability
to induce heritable gene or
chromosomal mutations is rarely
supportable under Section 5.
58 Access/Use Info Resources Assess Health Risk Chem Expos '93
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tions is rarely supportable under
Sect. 5. In the few instances in
which such a concern has been
supported, required testing has
included the dominant lethal
assay and assays for chromoso-
mal aberrations in testicular
cells. It is understood when such
testing is required, that if posi-
tive, additional tests (e.g., a heri-
table translocation assay) may be
required for risk assessment pur-
poses.
The principal use of mutagenic-
ity data under Sect. 5 has been as
part of the weight-of-evidence
that a chemical may be
oricogenic.
In supporting a concern for
potential oncogenicity of a PMN
chemical, the agency will gener-
ally cite data on an analogue that
is known to be oncogenic (i.e.,
demonstrated tumor-forming
ability in one or more animal
studies). In such instances,
mutagenicity data on the PMN
chemical or on the analogues are
used to lend support to the case
for potential oncogenicity. In
cases in which no analogue of
the PMN chemical has been
tested for oncogenicity,
mutagenicity data alone are gen-
erally not considered sufficient
to support a concern for potential
oncogenicity. Regulatory action
is seldom, if ever, taken on the
basis of mutagenicity data alone,
especially on the basis of in vitro
mutagenicity data.
Mutagenicity data have been
required as part of several Sect.
5(e) notices. Initially, these
requirements were primarily for
Salmonella test data. For certain
classes of chemicals, the require-
ment was for in vitro gene muta-
tion data, specifically, for data
from the mouse lymphoma
L5178Y TK +A system. More
recently, the agency has begun
requiring certain manufacturers
to submit data from a battery of
tests that has included the Salmo-
nella assay and an in vivo assay
for chromosomal effects, espe-
cially the micronucleus assay.
Where an appropriate oncogenic
analogue has been tested in the
same assays as those required for
the PMN chemical, this agent is
generally included in the test as a
positive control chemical. In
some cases, where activity of the
analogue chemical in short-term
tests was not known, the agency
has required the simultaneous
testing of both the PMN chemi-
cal and the analogue. Positive
results for both the PMN chemi-
cal and the analogue are used to
support the weight-of-evidence
that the PMN chemical may be
an oncogen. In these instances, a
2-year bioassay of the PMN
chemical or the use of protective
equipment to limit exposure is
generally required.
Negative results for the PMN
chemical, in the face of positive
results for the analogue, are
taken as an indication that the
PMN chemical is probably
nononcogenic or, in cases in
which the analogy may have
been doubtful, that the analogue
was not appropriate. In either
case, concern for potential onco-
genicity is lessened as a result of
mutagenicity data and a 2-year
bioassay is generally not consid-
ered necessary.
In those instances in which the
analogue chemical is inactive in
short-term tests for mutagenicity,
negative results for the PMN
chemical do not alleviate con-
cern for potential oncogenicity.
When an appropriate oncogenic
analogue has been tested in the
same assays as those required for
the PMN chemical, this agent is
generally included in the test as a
positive control chemical.
Negative results for the PMN
chemical, in the face of positive
results for the analogue, are taken
as an indication that the PMN
chemical is probably nononcogenic.
Access/Use Info Resources Assess Health Risk Chem Expos '93
59
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Because of the cost of conduct-
ing a long-term bioassay, such a
requirement is often interpreted
by the regulated industry asade
facto ban. Chemicals subjected
to the requirement for a long-
term bioassay are often with-
drawn by the submitter because
they cannot support the cost of
testing. The agency hopes that
judicious and reasonable use of
short-term testing will increase
in the Sect. 5 process and that
this increase in the use of short-
term testing will reduce the num-
ber of chemicals subject to a
bioassay.
Chemicals subjected to the
requirement for a long-term bioassay
are often withdrawn by the submitter
because they cannot support the cost
of testing.
60
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Quantitative Genetic Activity Graphical Profiles
for Use in Chemical Evaluation
19 9 2
Michael D. Waters, H. Frank Stack, Neil E. Garrett, and Marcus A. Jackson,
U.S. Environmental Protection Agency
Environmental Health Research and Testing, Inc.
A graphic approach, termed a Genetic Activity Profile (GAP), was developed to display a matrix of data on the genetic and related
effects of selected chemical agents. The profiles provide a visual overview of the quantitative (doses) and qualitative (test results)
data for each chemical Either the lowest effective dose or highest ineffective dose is recorded for each agent and bioassay. Up to
200 different test systems are represented across the GAP. Bioassay systems are organized according to the phytogeny of the test
organisms and the end points of genetic activity. The methodology for producing and evaluating genetic activity profiles was
developed in collaboration with the International Agency for Research on Cancer (IARC). Data on individual chemicals were
compiled by IARC and by the U.S. Environmental Protection Agency (EPA). Data are available on 343 compounds selected from
volumes 1-53 of the IARC Monographs and on 115 compounds identified as Superfund Priority Substances. Software^ to display the
GAPs on an IBM-compatible personal computer is available from the authors. Structurally similar compounds frequently display
qualitatively and quantitatively similar profiles of genetic activity. Through examination of the patterns of GAPs of pairs and groups
of chemicals, it is possible to make more informed decisions regarding the selection of test batteries to be used in evaluation of
chemical analogs. GAPs provided useful data for development ofweight-of-evidence hazard ranking schemes. Also, some
knowledge of-the potential genetic activity of complex environmental mixtures may be gained from an assessment of the genetic
activity profiles of component chemicals. The fundamental techniques and computer programs devised for the GAP database may
be used to develop similar databases in other disciplines.
Introduction
Data derived from short-
term tests are usually
interpreted according to
the phylogenetic category of the
test and the end point detected.
Commonly studied end points
include DNA damage, gene
mutation, sister-chromatid
exchange, micronuclei, chromo-
somal aberrations, aneuploidy,
and cell transformation. Few
short-term bioassays monitor
more than one or two of these
end points. Therefore, data from
a variety of short-term tests are
required to properly define the
response profile of a given
chemical agent.
Garrett et al. (1984) developed a
technique for presenting the
quantitative genetic toxicology
data for a chemical compound as
a bar graph (genetic activity pro-
file) in which test systems (identi-
fied by three-letter code words)
are displayed along the x-axis
and values corresponding to the
doses employed in the tests are
shown on the y-axis. The total
data available from up to 200 dif-
ferent short-term bioassays for a
compound are thus presented in
a standardized format that allows
rapid visualization of the genetic
(or related) effects induced. The
technique facilitates qualitative
as well as quantitative assess-
ments of genetic toxicity. Cur-
rent procedures for the prepara-
tion and evaluation of genetic
activity profiles (GAPs) are
described by Waters et al.
(1988a) in the context of their
use by the International Agency
for Research on Cancer (IARC).
Data from a variety of short-term
tests are required to properly
define the response profile of a
given chemical agent.
Few short-term bioassays
monitor more than one or two of
these end points.
Access/Use Info Resources Assess Health Risk Chem Expos '93
61
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Methodology
The data set for a given chemi-
cal, consisting of a discrete set of
tests and the doses required to
induce responses in those tests,
are presented in a bar graph as
illustrated in Fig. 1.
The bar (profile lines) originat-
ing on the x-axis represent the
tests plotted in either a phyloge-
netic or end point sequence. A
three-letter code is used to iden-
tify the test system represented
by each bar. Values on the y-axis
are the logarithmically trans-
formed lowest effective doses
(LED) and highest ineffective
doses (HID) tested. The term
"dose," as used in this report,
does not take into consideration
length of treatment or exposure
and may therefore be considered
synonymous with concentration.
The doses or concentrations used
for all in vitro tests were con-
verted to M£/ml, and those for in
vivo tests to mg/kg bw per day.
Because dose units are plotted on
a log scale, differences in
molecular weights of compounds
do not greatly influence compari-
sons of GAPs.
Profile-line height (the magni-
tude of each bar) is a function of
the LED or HID, which is associ-
ated with the characteristics of
each individual test system, such
as population size, cell-cycle
kinetics, and metabolic compe-
tence. These characteristics and
other factors make the detection
limit of each test system differ-
ent, therefore responses across
the GAP will vary substantially.
No attempt is made to adjust or
relate responses in one test sys-
tem to those of another.
Line-heights are derived as fol-
lows: For negative test results,
Lowest Effective Dose
(yg/ml or mg/kg bw/da)
0.001
.01
OH
.u
in
inn
KM")
IflAfin.
innnnn «
10
1U*J
lUUU
ifwvift
inoorio
Highest Ineffective Dose
(^g/ml or mg/kg bw/da)
Log Do
Units
~
7_j
6_
4_
— -3
c -
se POSITIVE RESULTS
,_ E
Q Test system code
- W
- y/s^ Study with activation
- - — Study without activation
i
>-- -
— i
_ i
•
~ /\
NEGATIVE RESULTS
Fig. 1. A schematic representation of a Genetic Activity Profile (GAP) showing
four studies for the test ECW (2 positive and 2 negative). The average LED of the
majority call is indicated by a solid vertical bar. A dashed vertical bar indicates con-
flicting test results for the study. Note in cases where there are an equal number of
positive and negative studies as here, the majority call is positive.
the highest dose tested without
excessive toxicity is defined as
the HID. If there is evidence of
extreme toxicity, the next lower
dose is used. A single dose yield-
ing a negative result is consid-
ered equivalent to the HID. For
positive results, the LED is
recorded. If the original data
have been analyzed statistically
by the author, the dose recorded
is that at which the response was
significant (p < 0.05). If the data
were not analyzed statistically,
the dose required to produce an
effect is estimated as follows:
When a dose-related positive
response is observed with two or
more doses, the lower of the
doses is taken as the LED; a sin-
gle dose resulting in a positive
response is considered equiva-
lent to the LED.
To accommodate both positive
and negative responses on a con-
tinuous scale, doses are trans-
formed logarithmically so that
effective (LED) and ineffective
The term ' 'dose,'' as used in this
report, does not take into •
consideration length of treatment
or exposure and may therefore be
considered synonymous with
concentration.
62 ' Access/Use Mo Resources Assess Health Risk Chem Expos '93
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(HID) doses are represented by
positive and negative numbers,
respectively. The logarithmic
dose unit [LDU(ij)] for a given
test system i and chemical j is
represented by the expressions:
LDU(ij) = - logio(dose), for HID
values; LDU<0
LDU(ij) = 5 -logio(dose), for
LED values; LDU>0
These simple relationships
define a dose range of 0 to -5
logarithmic units for ineffective
doses (1 to 100,000 pg/ml or
mg/kg bw/day) and 0 to +9 loga-
rithmic units for effective doses
(100,000 to 0.0001 ng/ml or
mg/kg bw/day). A scale illustrat-
ing the LDU values is shown in
Fig. 1. Negative responses at
doses <1 (ig/ml (mg/kg bw/day)
were set equal to 1. Effectively,
an LED value >100,000 or an
HID value <1 produces an LDU
= 0; no quantitative information
is gained from such extreme val-
ues. Levels of log dose units
between 1 and -1 define a "zone
of uncertainty" in which positive
results are reported at very high
doses (10,000 to 100,000 p.g/ml
or mg/kg bw/day), and negative
results are reported at relatively
low dose levels (1 to 10 jig/ml or
mg/kg bw/day).
All dose values are plotted for
each assay using either a bar (-)
for results obtained in the
absence of an exogenous metabo-
lic system or a caret (A) for those
obtained in the presence of an
exogenous metabolic system.
When all results for a given
assay are either positive or nega-
tive, the geometric 'mean of the
responses is plotted as a solid
line; when conflicting data are
reported for the same assay (i.e.,
both positive and negative
results) the majority data are
shown with a solid line and the
minority data with a dashed line
(drawn to the extreme response).
In the few cases in which the
numbers of positive and negative
results are equal, the solid line is
drawn in the positive direction
and the negative response is indi-
cated with a dashed line, drawn
from the origin to the extreme
negative LDU (Fig. 1).
The three-letter code words rep-
resenting the commonly used
tests were originally defined by
the GENE-TOX program of the
U.S. Environmental Protection
Agency (EPA) (Waters 1979;
Waters and Auletta 1981). These
codes have been systematically
redefined and expanded to facili-
tate inclusion of additional tests
in the future (Waters et al. 1988).
Evaluation of Genetic and
Related Effects
IARC has employed the GAP
methodology (Waters et al.
1988) in evaluating genetic and
related effects of suspected
human carcinogens in IARC
Monographs Supplement 6
(IARC 1987a) and in vols. 36,
39,41, 44 (IARC 1985a, 1985b,
1986,1988b), and 46-53 (IARC
1989b, 1989c, 1990a, 1990b,
1990c, 1991a, 1991b, 1991c).
Figure 2 illustrates the procedure
currently employed by the IARC
as it relates to the GAP data base.
Nesnow (personal communica-
tion) has recently completed a
personal computer (PC) dBase •
version of the data on carcino-
genicity contained in IARC
Monographs Supplement 7
(IARC 1987b) and IARC Nlono-
graph Vols. 43^9 (IARC 1988a,
1988b, 1989a, 1989b, 1989c,
1990a, 1990b, 1991a, 199Ib,
Three-letter code words
representing the commonly used
tests were originally defined by the
GENE-TOX program.
The International Agency for
Research on Cancer employs the
GAP methodology in evaluating
genetic and related effects of
suspected human carcinogens in
IARC Monographs.
Access/Use Info Resources Assess Health Risk Chem Expos '93
63
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PRIOR TO THE IARC MONOGRAPH WORKING GROUP MEETING
1. IARC selects compounds and completes literature search
2. Working subgroup members review literature for individual compound(s)
3. Subgroup member prepares
(a) Written summary
(b) Summary table
(c) Data listing
4. Drafts of data and summaries are sent to IARC
DURING THE IARC MONOGRAPH WORKING GROUP MEETING
5. Genetic and related effects subgroup convenes
6. Data summaries and tests are verified for each compound
7. Final drafts are submitted to Working Group for review
8. Data tables and summaries are sent to EPA/GTD for dose verification
9. Genetic activity profiles and data listings are prepared and sent to IARC
Fig. 2. The current process of chemical selection and review of data on genetic and related effects used
in the preparation of genetic activity profiles for IARC Monographs.
1991c). Most of these agents are
included in the GAP data base
[derived from IARC Monographs
Supplement 6 (IARC 1987) and
Monograph Vols. 46-49 (IARC
1989b, 1989c, 1990a, 1990b)].
Therefore, these two databases
can be used to examine retrospec-
tively the usefulness of short-
term tests for the prediction of
carcinogenicity and the relation-
ship between specific genetic
end points or assays and carcino-
genicity.
PC Version of the GAP
Data Base - Version 3.0
Copies of software for IBM-
compatible PCs to display and
search GAPs are available from
the authors. Computer programs
require the following minimum
configuration: PC using Intel
8086 chip (PC XT) with 640-kb
memory, a hard-disc drive, an
enhanced graphics card (EGA or
VGA), a high-resolution color
monitor, and DOS Version 3.2 or
higher.
Generally, an Intel 80286 (PC
AT) computer is preferred
because data processing and
graphics display are faster than
with the 8086 computer.
Optional devices used for data
and graphic output include a line
printer and plotter. Alternatively,
a laser printer or equivalent can
be used to print the Hewlett
Packard (HPGL) plotter files
using additional software.
The GAP software is distributed
on a single high density, 5.25 in.
floppy disk containing the pro-
grams, data, and GAP
bibliography.
Executable programs are
archived on the program disk
and are compiled from programs
Copies of software for
IBM-compatible PCs to display and
search GAPs are available from
the authors.
64
Access/Use Info Resources Assess Health Risk Chem Expos '93
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written in Turbo Pascal. During
installation of the programs, the
necessary directory and subdirec-
tories are created. The installed
programs and data use approxi-
mately 1.2 Mb of disk space.
The bibliography of the GAP
data is also in an archived file.
The file requires 0.7 Mb of disk
space; however, the bibliography
is not necessary to operate the
GAP programs, and it may be
deleted and reinstalled as
needed.
The database consists of two
data sets, "IARC" and 'EPA."
The IARC data set contains data
on 343 agents published in Sup-
plement 6 (IARC 1987) and in
Volumes 46-53 of the IARC
Monographs (IARC 1989b,
1989c, 1990a, 1990b, 1990c,
1991a, 1991b, 1991c). The EPA
data set contains data on 115
agents assembled for the Genetic
Toxicology Division of EPA
(Waters.et al. 1990a). A list of
the individual projects included
in each data set may be viewed
using the GAP computer pro-
gram. A data subdirectory is pro-
vided for users to enter their own
data. s
The main program menu of GAP
Version 3.0 offers the following
selections: agents, profiles, data
listings, modify data, short cita-
tions, and additional information,
"Agents" provides options to list
the available projects, CAS num-
bers and agent names. Another
menu allows ordering of the list
by any of the three options.
'Profiles" provides graphic dis-
play of the short-term test data
on selected agents. A menu is
used to select the sequence of
test codes, either in phylogenetic
order of organisms (i.e.,
prokaryotes, lower eukaryotes,
etc.) or in test end-point order
(i.e., DNA damage, gene muta-
tion, etc.). Individual test codes
may be examined to determine
the source citations by using the
GAP program zoom-in features.
"Listings" produces a listing of
the data in either phylogenetic or
end-point order and may be
directed to the PC screen, a
printer, or a data file.
"Modify data" is used to add,
change, or delete agents or test
results (e.g., test codes, results,
doses, and reference numbers).
"Short citations" permits search-
ing the literature citation informa-
tion for approximately 6000
short citations contained in the
GAP database. The citation infor-
mation includes the citation num-
ber (LITNR), the Environmental
Mutagen Information Center
(EMIC) accession number, and a
short citation (consisting of the
last names of up to three authors,
the first page number, and the
year of the publication). The cita-
tion information may be
searched by author or by EMIC
number to determine if a citation
is present. Short citations also
may be added to the file and are
automatically assigned citation
numbers.
"Additional information"
includes three-letter test code
definitions, the scale of log-dose
units used in the profiles, infor-
mation on the dose conversions,
and tables listing projects for
both the EPA and IARC data
sets.
The bibliography of the GAP data
is also in an archived file.
The citation information may be
searched by author or by EMIC
number.
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65
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Some Applications of the
GAP DataBase
1. Comparative Evaluation of
Genetic Activity Profiles
Using Computer-Based Profile
Matching Techniques.
Where an adequate number of
the same test has been used to
evaluate two or more chemicals,
it is possible to use the main-
frame computer to select match-
ing "pairs" of GAPs. This
computer-based pairwise match-
ing process may be extended to
all chemicals in the database.
The pilot applications of this pro-
cedure to EPA databases on
known or suspected human car-
cinogens (Garrett et al. 1984)
and on pesticide chemicals (Gar-
rett et al. 1986) have demon-
strated that structurally similar
compounds frequently display
qualitatively and quantitatively
similar profiles of genetic activ-
ity. This implies that the GAP
database should be of consider-
able utility in structure activity
relationship (SAR) investigations
and in selecting tests and batter-
ies of tests to be applied to
chemicals that have not been
fully evaluated (Waters et al.
1988b).
Through the examination of the
patterns of GAPs of pairs and
groups of chemicals, it is possi-
ble to make informed decisions
regarding the selection of test bat-
teries to be used in the sub-
sequent evaluation of structurally
similar chemicals. The approach
draws on the information in the
entire database and may be
linked to computer systems that
model the molecular properties
of the chemicals under evalu-
ation (Richard et al. 1989). This
comparative information can
enhance our understanding of the
relationships between genetic
and related activity in short-term
tests and molecular properties of
structurally related chemicals
and thus contribute to our knowl-
edge of the mechanisms of com-
plex processes such as
carcinogenesis.
2. Testing and Evaluation of
Complex Mixtures
A recent application of GAPs is
in the testing and evaluation of
complex mixtures (Waters et al.
1990b). Some knowledge of the
potential genetic activity of a
complex environmental mixture
may be gained from an assess-
ment of the genetic activity of its
component chemicals. This
requires information on the
chemical components and com-
position of the mixture. For
example, the Atmospheric
Chemical Compound database
developed by Graedel et al.
(1986) contains information on
chemical structures, properties,
detection methods, and sources
of chemicals found in ambient
air. The GAP database provides a
computer-generated graphic rep-
resentation of genetic bioassay
data as a function of dose. Using
the two databases together, infor-
mation on the quantity of an indi-
vidual chemical present within a
mixture may be related to the
quantity (LED) of the chemical
required to demonstrate a posi-
tive response in one or more
genetic bioassays. Quantitative
information on the carcinogenic
potency of each individual com-
pound [toxicity dose for 50% of
a population (TDso) value] may
also be related to the quantity pre-
sent in the mixture or mixture
fraction. In turn, the quantity of
the chemical in the complex mix-
// is possible to make informed
decisions regarding the selection of
test batteries to be used in the
subsequent evaluation of structurally
similar chemicals.
The GAP database provides a
computer-generated graphic
representation of genetic bioassay
data as a function of dose.
66
Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
ture to which humans are
exposed may be estimated and
used to calculate the percent
human exposure dose/rodent
potency dose (HERP) for the
chemical (Gold et al. 1984,
1987; Gold 1991). By using an
additivity assumption, for exam-
ple, an estimate of potential car-
cinogenic hazard for the mixture
may be calculated based on the
HERP indices for the known
chemical components. This con-
ceptual approach is limited by
the relatively small number of
chemicals identified in complex
mixtures for which genetic toxi-
cology and animal cancer data
exist.
3. Weight-of-Evidence Ranking
Schemes
Committee I of the International
Commission for Protection
Against Environmental
Mutagens and Carcinogens
(ICPEMC) has been involved for
several years in the development
of a computer-based methodol-
ogy to assess the evidence from
short-term genetic tests that a
chemical is a mutagen (Lohman
et al. 1990). The evaluative
approach selected by ICPEMC
Committee I is based on a
"weighted test" scoring system
that provides a relative ranking
of genotoxic potential. Input data
for this ranking methodology
have been obtained from the
GAP database (Brusick 1991).
The results of the application of
the Committee I ranking scheme
are to be compared by ICPEMC
with results obtained by applying
the carcinogenicity ranking
scheme of Nesnow (1984,1991).
4. Development of Other Data-
Bases „.
The fundamental techniques and
computer programs devised for
the GAP database may be used
to develop similar databases in
genetic toxicology and in other
disciplines. Dearfleld et al.
(1991) have described the appli-
cation of the GAP methodology
to the data base being con-
structed by the EPA Office of
Pesticide Programs. Kavlocket
al. (1991) have successfully used
the approach and modified com-
puter programs to assemble
graphic activity profiles and cor-
responding data listings for sev-
eral developmental toxicants.
Future Directions
A useful application of the GAP
database in the future will
involve computer-based profile
matching techniques (see 2.
above) with weight-of-evidence
ranking schemes (see 4. above)
to subset chemicals that act simi-
larly (i.e., have Similar GAPs).
Correlative structure-activity
approaches can then be used
more effectively to identify the
substructural elements of chemi-
cals that are responsible for par-
ticular biological responses to
suggest biologically plausible
mechanisms of action (Waters
1990).
References
Brusick, D. 1991. A proposed method
for assembly and interpretation of short-
term test data. Environ. Health Perspect.
96:101-11.
Dearfield, K.L, J.A.Quest, R.J. Whit-
ing, H.F. Stack, and M.D. Waters. 1991.
Characteristics of the U.S. EPA's Office
of Pesticide Programs' toxicity informa-
tion databases. Environ. Health Per-
spect. 96:53-6.
Garrett, N. E., H. F. Stack, M. R.
Gross, and M.D. Waters. 1984. An analy-
sis of the spectra of genetic activity pro-
Correlative structure-activity
approaches can be used to identify
the substructural elements of
chemicals responsible for particular
biological responses so as to
suggest biologically plausible
mechanisms of action.
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duced by known or suspected human car-
cinogens. Mut. Res. 134:89-111.
Ganett, N. E., H. F. Stack, and M. D.
Waters. 1986. Evaluation of the genedc
activity profiles of 65 pesticides. MuL
Res. 168:301-25.
Gold, L.S., T.H. Slone, N.B. Manley,
G.B. Garfmkel, E.S. Hudes, L.
Rohrbach, and B.N. Ames. 1991. The
carcinogenic potency database: Analy-
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Institute/National Toxicology Program.
Environ. Health Perspect 96:11-15.
Gold, L. S., G. Backman, K. Hooper,
and R. Peto. 1987. Ranking the potential
carcinogenic hazards to workers from
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genic in rodents. Environ. Health Per-
spect 76:211-20.
Gold, L. S., C. B. Sawyer, R. Magaw,
G. M. Backman, M. de Veciana, R.
Levinson, N. K. Hooper, W. R. Haven-
der, L. Bernstein, R. Peto, M. C. Pike,
and B. N. Ames. 1984. A carcinogenic
potency database of the standardized
results of animal bioassays. Environ.
Health Perspect. 58:9-319.
Graedel, T. E., D. T. Hawkins, and L.
D. Claxton. 1986. Atmospheric Chemi-
cal Compounds: Sources, Occurrence,
and Bioassay. Academic Press, Orlando,
Fla.
IARC. 1985a. Appendix: Activity pro-
files for short-term tests, pp. 325-45. In:
IARC Monographs on the Evaluation of
Carcinogenic Risks of Chemicals to
Humans, Vol. 36. Some Allyl and
Allylic Compounds, Aldehydes, Epox-
ides and Peroxides. International
Agency for Research on Cancer, Lyon,
France.
IARC. 1985b. IARC Monographs on
the Evaluation of Carcinogenic Risks of
Chemicals to Humans, Vol. 39. Some
Chemicals Used in Plastics and Elastom-
ers. International Agency for Research
on Cancer, Lyon, France.
IARC. 1986. IARC Monographs on
the Evaluation of Carcinogenic Risks of
Chemicals to Humans, Vol. 41. Some
Halogenated Hydrocarbons and Pesti-
cide Exposures. International Agency
for Research on Cancer, Lyon, France.
IARC. 1987a. IARC Monographs on
the Evaluation of Carcinogenic Risks to
Humans - Genetic and Related Effects:
An Update of Selected IARC Mono-
graphs from Volumes 1 to 42, Suppl. 6.
International Agency for Research on
Cancer, Lyon, France. 729 pp.
IARC. 1987b. IARC Monographs on
the Evaluation of Carcinogenic Risks to
Humans: Carcinogeniciry: An Update of
Selected IARC Monographs from Vols. 1
to 42, Suppl. 7. International Agency for
Research on Cancer, Lyon, France.
IARC. 1988a. IARC Monographs on
the Evaluation of Carcinogenic Risks to
Humans, Vol. 43. Man-made Mineral
Fibers and Radon. International Agency
for Research on Cancer, Lyon, France.
IARC. 1988b. IARC Monographs on
the Evaluation of Carcinogenic Risks to
Humans, Vol. 44. Alcohol Drinking.
International Agency for Research on
Cancer, Lyon, France.
IARC. 1989a. IARC Monographs on
the Evaluation of Carcinogenic Risks to
Humans, Vol. 45. Occupational Expo-
sures in Petroleum Refining: Crude Oil
and Major Petroleum Fuels. Interna-
tional Agency for Research on Cancer,
Lyon, France.
IARC. 1989b. IARC Monographs on
the Evaluation of Carcinogenic Risks to
Humans, Vol. 46. Diesel and Gasoline
Engine Exhaust and Some Nitroarenes.
International Agency for Research on
Cancer, Lyon, France. 458 pp.
IARC. 1989c. IARC Monographs on
the Evaluation of Carcinogenic Risks to
Humans, Vol. 47. Some Organic Sol-
vents, Resin Monomers and Related
Compounds, Pigments and Occupational
Exposures in Paint Manufacture and
Painting. International Agency for
Research on Cancer, Lyon, France. 535
pp.
IARC. 1990a. IARC Monographs on
the Evaluation of Carcinogenic Risks to
Humans, Vol. 48. Some Flame Retar-
dants and Textile Chemicals, and Expo-
sures in the Textile Manufacturing
Industry. International Agency for
Research on Cancer, Lyon, France. 345
PP-
IARC. 1990b. IARC Monographs on
the Evaluation of Carcinogenic Risks to
Humans, Vol. 49. Chromium, Nickel,
and Welding. International Agency for
Research on Cancer, Lyon, France.
677 pp.
IARC. 1990c. IARC Monographs on
the Evaluation of Carcinogenic Risks to
Humans, Vol. 50. Some Pharmaceutical
Chemicals. International Agency for
Research on Cancer, Lyon, France.
415 pp.
IARC. 199 la. IARC Monographs on
the Evaluation of Carcinogenic Risks to
Humans, Vol. 51. Coffee, tea, mate,
methylxanthines, and methylglyoxal.
International Agency for Research on
Cancer, Lyon, France. 513 pp.
IARC. 19§lb.ZA«CMonographs on
the Evaluation of Carcinogenic Risks to
Humans, Vol. 52. Chlorinated drinking
water, chlorination by-products; some
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other halogenated compounds; cobalt
and cobalt compounds. International
Agency for Research on Cancer, Lyon,
France. 544 pp.
IARC. 1991c. IARC Monographs on
the Evaluation of Carcinogenic Risks to
Humans, Vol. 53. Some pesticide com-
pounds. International Agency for
Research on Cancer, Lyon, France.
612pp.
Kavlock, R.J., J.A. Greene, G.L. Kim-
mel, R.E. Morrissey, E. Owens,
JM Rogers, T.W. Sadler, H.F. Stack,
M.D. Waters, and F. Welsch. 1991.
Activity profiles of developmental toxic-
ity: Design considerations and pilot
implementation. Teratology. 43:159-85.
Lohman, P.H.M., M.L. Mendelsohn,
D.H. Moore H, M.D. Waters, and D.J.
Brusick. 1991. The assembly and analy-
sis of short-term genotoxicity test data—
An ICPEMC Committee 1 working
paper, pp. 283-94. In: Mutation and the
Environment, Part D, M.L. Mendelsohn
and R.J. Albertini (eds.), Wiley-Liss,
New York.
Nesnow, S. 1984. A multi-factor rank-
ing schemedbr comparing the carcino-
genic activity of chemicals. Mutation
Res. 134:89-111.
Nesnow, S. 1991. Multifactor potency
scheme for comparing the carcinogenic
activity of chemicals. Environ. Health
PerspecL 96:17-21.
Richard, A. M., J. R. Rabinowitz, and
M. D. Waters. 1989. Strategies for the
use of computational S AR methods in
assessing genotoxicity. Mutat. Res.
221:181-96.
Waters, M. D. 1979. The GENE-TOX
program, pp. 449-67. In: Banbury
Report 2, A. W. Hsie, J. P. O'Neill, and
V. K. McElheny (eds.), Cold Spring Har-
bor, Cold Spring Harbor Laboratory,
Maine.
Waters, M. D., and A. Auletta. 1981.
The GENE-TOX program: Genetic
activity evaluation. J. Chem. Inf. Corn-
put. Sci. 21:35-38.
Waters, M. D., L. D. Claxton, H. F.
Stack, A. L. Brady, and T.E. Graedel.
1990b. Genetic activity profiles in the
testing and evaluation of chemical mix-
tures. Teratog. Carcinog. Mutag. 10:147-
64.
Waters, M.D., A.M. Richard, J.R.
Rabinowitz, H.F. Stack, N.E. Garrett,
P.H.M. Lohman, and H.S. Rosenkranz.
1992. Structure-activity relationships—
computerized systems.In: Proceedings
of the Scientific Group on Methodolo-
gies for the Safety Evaluation of Chemi-
cals (SGOMSEQ-8 Workshop on
Cross-Species Differences in DNA Dam-
age and its Consequences, Research Tri-
angle Park, NC, March 1990.
Waters, M. D., H. F. Stack, A. L.
Brady, P.H.M. Lohman, L. Haroun, and
H. Vainio. 1988a. Use of computerized
data listings and activity profiles of
genetic and related effects in the review
of 195 compounds. Mut. Res. 205:295-
312.
Waters, M. D., H.F. Stack, and M. A.
Jackson. 1990a. Genetic activity profiles
on hazardous substances listed under
SARA, Sect. 110—The first 100 Super-
fund Priority Substances. U.S. Environ-
mental Protection Agency Internal
Report, Washington, D.C.
Waters, M. D., H. F. Stack, J. R. Rabi-
nowitz, and N. E. Garrett. 1988b.
Genetic activity profiles and pattern rec-
ognition in test battery selection.
Mutat. Res. 205:119-38.
Access/Use Info Resources Assess Health Risk Chem Expos '93
69
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The TSCA Inter agency Testing Committee's
Approaches to Screening and Scoring Chemicals
and Chemical Groups: 1977-1983
JohnD. Walker, U.S. Environmental Protection Agency
This paper describes the TSCA Interagency Testing Committee's (ITC) approaches to screening and scoring chemicals and chemi-
cal groups between 1977 and 1983. During this time the ITC conducted five scoring exercises to select chemicals and chemical
groups for detailed review and to determine which of these chemicals and chemical groups should be added to the TSCA Section
4(e) Priority Testing.List.
Introduction
The TSCA Interagency Testing
Committee (ITC) was created
under Section 4(e) of the Toxic
Substances Control Act (TSCA)
after six years of intense Con-
gressional debate over proposed
toxic substances control legisla-
tion. Congress directed 8 U.S.
government organizations to
appoint members to the ITC for
4-year terms and established spe-
cific qualifications for member-
ship. Congress mandated that
one member each shall be
appointed by the:
Administrator of the U.S. Envi-
ronmental Protection Agency
(EPA),
Secretary of Labor (the Occupa-
tional Safety and Health
Administration, OSHA),
Chairman of the Council on Envi-
ronmental Quality (CEQ),
Director of the National Institute
for Occupational Safety and
Health (NIOSH),
Director of the National Institute
of Environmental Health Sci-
ences (NIEHS),
Director of the National Cancer
Institute (NCI),
Director of the National Science
Foundation (NSF),'and
Secretary of the Department of
Commerce (DOC).
Since the ITC's first meeting on
February 5,1977,10 U.S. gov-
ernment organizations with expe-
rience in chemical testing have
participated as Liaison Members:
Department of Defense (DOD),
Department of the Interior (DOI),
Food and Drug Administration
(FDA),
Consumer Product Safety Com-
mission (CPSC),
Department of Agriculture
(USDA),
National Toxicology Program
(NTP),
National Library of Medicine
(NLM),
Agency for Toxic Substances and
Disease Registry (ATSDR),
Department of Transportation
(DOT), and the
Six years of intense Congressional
debate led to creation of the TSCA
Interagency Testing Committee.
Access/Use Info Resources Assess Health Risk Chem Expos '93
71
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U.S. International Trade Commis-
sion (USITC).
Congress directed the ITC to:
1) develop the TSCA Section
4(e) Priority Testing List within
9 months of TSCA's effective
date, 2) use 8 statutory criteria to
prioritize testing for about
60,000 existing chemicals,
3) determine the order in which
the Administrator of the EPA
should implement the testing rec-
ommendations for chemicals and
chemical groups on the TSCA
Section 4(e) Priority Testing
List, 4) revise the TSCA Section
4(e) Priority Testing List at least
every six months and 5) facilitate
coordination of chemical testing
among the U.S. Government
organizations represented on the
ITC.
Developing Initial Lists
Initial Lists of chemicals and
chemical groups were developed
from lists of chemicals referred
to the ITC by Statutory and Liai-
son organizations (Table 1).
These chemicals and chemical
groups were referred to the ITC
because of concerns about the
adequacy of test data. Develop-
ing the Initial List was the first
stage of selecting chemicals by
the ITC (Fig. 1).
The ITC's First Scoring Exercise
was conducted in 1977. At that
time, there was no TSCA Inven-
tory of commercially-available
existing chemicals and chemical
Chemicals were included in the ITC's
Initial Lists because U.S. regulatory
agencies had concerns about test data
adequacy.
Duplicates
Non-TSCA
Regulated Chemicals,
Non-Commercial
Chemicals,
Regulated Substances
Polymers, Poorly-
characterized
Mixtures and
Inert Substances,
Well-Characterized
Chemicals
Chemicals with
Low Exposure
Chemicals with
Sufficient data
or Low Adverse
Effects Potential
Chemicals added to
TSCA Section 4(e)
Priority Testing List
sent to
Administrator, US EPA
Testing
Modified
Deferrals
Fig. 1. The TSCA Section 4(e) Interagency Testing Committee process for screening, scoring and
selecting chemicals and chemical groups: 1977-1983.
72 Access/Use Info Resources Assess Health Risk Chem Expos '93
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Table 1.
DOI
EPA
EPA
EPA
EPA
FDA
NCI
NIOSH
NIOSH
NSF
OSHA
ACGIH
CANADA
Sources of Chemicals and Chemical Groups for the ITC's
Source
Fish and Wildlife Hazards
Priority Pollutants
Air Contaminants
Estuarine Pollutants
Office of Toxic Substance Priority Chemicals
Potential Carcinogens
Substances for Cancer Bioassays
Criteria Document Substances
Substances with Potential Occupational Exposure
Environmental Contaminants
Suspected Carcinogens
Threshold Limit Value Substances
Environmental Contaminants of Concern to Canada
First Scoring Exercise
Chemicals
174
129
337
9
162
88
372
127
500
80
116
570
160
groups. Estimates of the number
of chemicals and mixtures sub-
ject to TSCA ranged from
10,000 to 100,000. All of these
were within the statutory pur-
view of the ITC. TSCA listed a
number of factors related to
chemicals and chemical groups
that the ITC had to consider
before recommending testing:
1) quantities manufactured, 2)
quantities released to the environ-
ment, 3) numbers of individuals
exposed and duration of expo-
sure, 4) extent of human expo-
sure, 5) structural relationships
to known toxic substances,
6) available toxicity data, 7) reli-
ability of test data to. predict haz-
ard and 8) availability of testing
facilities. The ITC used these fac-
tors and some nonstatutory fac-
tors such as concerns for
adequacy of data to develop a
tiered process for selecting
chemicals and chemical groups
for testing consideration. The
first step in this process involved
developing an Initial List of
chemicals for consideration
(Walker and Brink 1989).
To develop the Initial List, the
ITC focused its attention on sub-
stances that satisfied the TSCA
Section 4(e) statutory factors and
some nonstatutory factors such
as concerns for adequacy of data.
The ITC chose to limit its Initial
List to chemicals or groups
which had been identified in pre-
vious reviews by ITC's Statutory
or Liaison organizations as being
of concern because of potential
adverse effects on human health
or the environment or as having
large production volumes and a
potential for substantial human
exposure or environmental
release.
In addition to referrals from
Statutory and Liaison organiza-
tions, the Initial List also
included 570 chemicals and
Attention was focused on chemicals
that have potential adverse effects on
human health or the environment.
Access/Use Info Resources Assess Health Risk Chem Expos '93
73
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chemical groups for which the
American Conference of Govern-
ment Industrial Hygienists
(ACGIH) had established Thresh-
old Limit Values and 160 chemi-
cals and chemical groups of
concern to the Canadian govern-
ment. After removing duplicates,
the Initial List contained approxi-
mately 3,600 chemicals and
chemical groups (Table 2).
The ITC's Second Scoring Exer-
cise was conducted in 1978. At
that time, there was still no
TSCA Inventory. The chemicals
for consideration included those
described above (the sources of
which are listed in Table 1) plus
chemicals included in the Envi-
ronmental Mutagen Information ,
Center (EMIC) and the Environ-
mental Teratology Information
Center (ETIC) databases. This
list was screened against the list
of synthetic organic chemicals
compiled annually by the
USITC. This screening produced
an Initial List of 1571 chemicals
(Table 2).
The ITC's Third Scoring Exer-
cise was conducted in 1980. The
TSCA Inventory was available
for the first time and was used as
the sole source of chemicals for
the Third Scoring Exercise.
Chemicals in the public portion
of the Inventory with minimum
aggregate production volumes
equal to or greater than 2 million
pounds were included in an
The Initial List contained about 3600
chemicals and chemical groups of
concern to FTC's Statutory and Liaison
organizations.
Table 2. Sources and Numbers of Chemicals Processed Through the ITC's First, Second, Third, Fourth,
Scoring
Exercise Year
1 1977
2 1978
3 1980
4 1981
5 1983
Includes about
and Fifth Scoring Exercises
Number of Chemicals
0 .„. . , Initial Master Preliminary Biological
Sources of Chemicals T. T. T . . J „ .
List List List Scoring
Listed io Table 1 3600 170Q 33Qa 45J
Table 1, EMIC and ETIC databases and 1571 252
USITC list of synthetic organic chemicals
TSCA Inventory chemicals with annual i Q'7'7 91^
production volumes >2 million pounds
TSCA Inventory chemicals with annual 2755 213
production volumes >1 million pounds,
STORET, FDA fish contaminants, CPSC
database and mixtures removed from 3rd
Scoring Exercise
TSCA Confidential Business Information 3370 4-71 714.'' 714,
Inventory and Public Inventory chemicals
>1 million pounds and not in previous
scoring exercises, 820 previously scored
chemicals, 257 previously deferred
chemicals, 46 analogs of known
carcinogens, 6 chemicals from Canada's
Environmental Protection Service, 5
chemicals from CPSC, 4 chemicals from
DOI/FWS, and 11 chemicals from EPA
290 chemicals and 40 chemical groups.
Detailed
Review
80
107
75
82
bAlso referred to as a Working List.
74 Access/Use Info Resources Assess Health Risk Chem Expos '93
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Initial List of 1877 chemicals
(Table 2).
The ITC's Fourth Scoring Exer-
cise was conducted in 1981.
Chemicals in the public portion
of the TSCA Inventory with
minimum aggregate production
yomnies equal to or greater than
1 million pounds were selected
for consideration as were chemi-
cals from several other sources
including cumulative supple-
ments to the TSCA Inventory,
EPA's STORET database (75
chemicals), FDA's list of food
(fish) contaminants (38 chemi-
cals), the Auerbach Consumer
Product Database from CPSC
(1.320 chemicals) and chemical
mixtures removed from consid-
eration during the Third Scoring
Exercise (52 chemical mixtures).
Combining these lists and remov-
ing 1877 chemicals considered
during the Third Scoring Exer-
cise and 244 duplicates produced
an Initial List of 2755 chemicals
(Table 2).
The ITC's Fifth Scoring Exercise
was conducted in 1983. The con-
fidential business information
(CBI) portion of the TSCA
Inventory was used for the first
time. Chemicals in the public
and CBI portions of the TSCA
Inventory with minimum aggre-
gate production volumes equal to
or greater than 1 million pounds
that were not considered during
previous scoring exercises (1765
chemicals) were selected for con-
sideration as were chemicals
from several other sources
including 820 previously scored
chemicals that were not studied
in detail, 257 previously deferred
chemicals, 46 analogs of known
carcinogens, 6 chemicals of con-
cern to Canada's Environmental
Protection Service, 5 chemicals
recommended by CPSC, 4
chemicals recommended by the
DOI's Fish and Wildlife Service,
and 11 chemicals recommended
by the EPA's Office of Toxic Sub-
stances. This Initial List con-
tained 3370 chemicals (Table 2).
Developing Master Lists
Master Lists of chemicals and
chemical groups were generated
from Initial Lists by deferring
chemicals that were considered
to be non-TSCA regulable or. not
commercially significant. This
was the second stage of selecting
chemicals by the ITC (Fig. 1).
The Master List was developed
from the Initial List from the
First Scoring Exercise by defer-
ring a number of substances hav-
ing pesticide, food additive, or
drug uses, all of which are regu-
lated under other Federal statutes
and are exempted from regula-
tion under TSCA. To identify
them, the Initial List was com-
pared with lists of pesticides pre-
pared by the EPA and lists of
food additives and drugs pre-
pared by the FDA, using Chemi-
cal Abstracts Service (CAS)
Registry Numbers. Since some
entries on source lists did not
include CAS numbers, manual
purging was done. Consideration
was also given to the fact that a
substance used as a pesticide,
food additive or drug may also
have other uses that are subject
to the authority of TSCA. Since
pesticides, food additives, and
drugs are generally produced in
limited quantities, substances
identified as such but having
annual production volumes over
10 million pounds were consid-
ered likely to have TSCA uses as
well and were retained on the
Master List for further review of
Chemicals were added from such
sources as the FDA's list of food
contaminants and Canada's
Environmental Protection Service.
The Initial List was compared with
lists of pesticides prepared by the EPA
and lists of food additives and drugs
prepared by the FDA.
Access/Use Info Resources Assess Health Risk Chem Expos '93
75
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their uses. Substances identified
as pesticides, food additives, or
drugs but known to have TSCA
uses were also retained.
The resulting Master List was
reduced further by the elimina-
tion of chemicals which were
judged not likely to be in com-
mercial production. This was
accomplished by comparing the
file against EPA's Candidate List
of Chemical Substances, pre-
pared by the Office of Toxic Sub-
stances (dated April 1977). The
basis of comparison for this
purge was also an assigned CAS
number. Consequently, this purge
did not affect those chemicals on
source lists for which no CAS
number was given. In an attempt
to eliminate substances which
were not in commercial produc-
tion, the following rule was
adopted: any substance not iden-
tified by a CAS number which
appeared on the NIOSH Registry
and on none of the other source
lists was judged not likely to be
in commercial production. This
decision was based on the fact
that the NIOSH Registry lists
any substance for which toxic
effects have been reported,
including research chemicals. A
scan of the substances eliminated
by the application of this rule
demonstrated its usefulness: few
of the purged substances were
recognized to be in commercial
production. As a result of the
purges described above, about
230 pesticides, 40 food additives,
270 drugs, 450 non-commercial
chemicals with CAS numbers
and 960 non-commercial chemi-
cals without CAS numbers were
removed from the Initial List, cre-
ating a Master List of approxi-
mately 1700 substances (Table 2).
Historical records on the develop-
ment of Master Lists during the
second, third and fourth scoring
exercises could not be located.
The Master List prepared from
the Fifth Scoring Exercise Initial
List was reduced to 2914 chemi-
cals by eliminating duplicates.
The list of 2914 chemicals was
further reduced to 471 chemicals
by removing 329 well-studied
chemicals, 102 polymers from
innocuous monomers, 950
poorly-characterized mixtures of
variable indefinite or unknown
structure, 387 chemicals under
review elsewhere, 316 inorganic
and organic chemicals of known
or suspected low hazard poten-
tial, 189 chemicals produced in
less than 100,000 pounds per
year, and 170 chemicals of low
lexicological concern (Table 2).
Exposure Scoring of
Chemicals
Details of exposure scoring as
they were developed for the First
Scoring Exercise are available in
Appendix A.
The ITC initially considered
applying all 8 statutory factors to
the chemicals and chemical
groups in the Master List, but
concluded that it would be impos-
sible to collect and review all
this information considering the
limitations of the available infor-
mation systems, the number of
professional judgements to be
made and the statutory time lim-
its for submitting the ITC's First
Report to the EPA Administrator.
The ITC eliminated considera-
tion of factors 5-7 (structural rela-
tionships to known toxic
substances, available toxicity
data, and reliability of test data to
predict hazard) because it would
be time consuming to consider
The Master List was reduced by
eliminating chemicals judged not
likely to be in commercial production.
It would be impossible for the ITC to
collect and review all statutory-
mandated information considering
resource limits, limitations of available
information systems, and the statutory
time limits for submitting reports to the
EPA Administrator.
76 Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
factors which to a certain extent
had been used to select sub-
stances for the Initial List. The
ITC reviewed surveys conducted
by the Society of Toxicology and
the Department of Health Educa-
tion and Welfare and the plans of
FDA's National Center for Toxi-
cological Research and decided
that statutory factor number 8
(availability of testing facilities)
was adequate for chemicals
likely to be added to the ITC's
Fkst Report (ITC 1977). In their
2nd and 3rd Reports, the ITC rec-
ommended conducting a more
comprehensive survey of avail-
able facilities for conducting
health and environmental tests
(ITC 1978 a,b).
Based on these considerations,
the ITC used statutory factors
1-4 (quantities manufactured,
quantities released to the environ-
ment, numbers of individuals
exposed, duration and extent of
human exposure) to score chemi-
cals on the Master List. Using a
combination of published data
and professional judgement, the
ITC attempted to score each of
the chemicals and chemical
groups in the Master List for
each of these factors. Informa-
tion on chemical uses was criti-
cal for the development of scores
for environmental release and
general population exposure.
This information was available
for only about 700 of the 1700
chemicals and chemical groups
on the Master List.
Historical records on exposure
scoring of chemicals on Master
Lists during the second, third and
fourth scoring exercises could
not be located.
Exposure scoring of the chemi-
cals in the Master List from the
Fifth Scoring Exercise used
methods similar to those
described for ITC's First Scoring
Exercise (ITC 1977).
Developing Preliminary
Lists
Preliminary Lists of chemicals
and chemical groups were gener-
ated from Master Lists by expo-
sure scoring and were the third
stage of selecting chemicals by
the ITC (Fig. 1).
Exposure scoring reduced the
Master List from the First Scor-
ing Exercise to a Preliminary
List that contained approxi-
mately 290 chemicals and 40
chemical groups (Table 2).
These chemicals and chemical
groups as well as examples of
chemicals in these chemical
groups were made publicly avail-
able by the ITC in two Federal
Register notices that were pub-
lished June 17,1977 (42 FR
30531) and August 11,1977 (42
FR 40756).
In selecting the approximately
330 chemicals and chemical
groups included on the Prelimi-
nary List, the ITC considered all
of the scored substances and
eliminated from consideration a
number of them which in the
ITC's professional judgment
were found to be:
a. Under stringent regulation or
of lower priority for the ITC's
purposes because their hazard
was reasonably well charac-
terized (e.g., vinyl chloride
and mercury);
b. Essentially inert materials (e.g.
certain polymers) or sub-
stances reasonably well charac-
terized as having low toxicity
(e.g., methane);
Information on chemical uses was
critical for developing scores for
environmental release and general
population exposure.
Exposure scoring reduced the Master
List to a Preliminary List containing
about 290 chemicals and 40 chemical
groups.
Access/Use Info Resources Assess Health Risk Chem Expos '93
77
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c. Covered by testing require-
ments under food, drug and
cosmetic or pesticide legisla-
tion (e.g., citric acid); or
d. Certain natural products (e.g.,
asphalt) whose consideration
should be deferred pending bet-
ter characterization for testing
purposes.
In addition to the scored sub-
stances on the Preliminary List,
the ITC also considered the un-
scored substances from the Mas-
ter List and a number of
additional substances recom-
mended by ITC Members.
In reviewing substances for pos-
sible inclusion on the Prelimi-
nary List, the ITC also
considered the desirability of
grouping substances into catego-
ries. In several cases the ITC
grouped chemically-related sub-
stances from the Master List
while in other cases the ITC
retained groups which had
already appeared in one of the
source lists. About 15% of the
entries on the Preliminary List
were substances categories.
Historical records on the develop-
ment of Preliminary Lists during
the second, third and fourth scor-
ing exercises could not be
located.
Exposure scoring of the 471
chemicals in the Master List
from the Fifth Scoring Exercise
produced a Preliminary List of
214 chemicals (Table 2).
Biological Scoring of
Chemicals on Preliminary
Lists
Details of the criteria that were
used to score chemicals for bio-
logical effects are available in
Appendix B. Biological scores
were developed by experts. The
number of chemicals that were
scored for biological effects dur-
ing each scoring exercise is listed
in Table 2.
The ITC used these biological
scores as part of the effort to
rank chemicals for consideration.
The ITC also reviewed a list of
those substances evaluated by
the scorers which were known or
might be anticipated to have addi-
tional adverse health or environ-
mental effects as a result of
contaminants appearing in the
commercial product or degrada-
tion products of the substance
under consideration.
The ITC's selection of sub-
stances for more detailed review
also reflected the effect of con-
cerns by the Statutory or Liaison
organization that referred the sub-
stance to the ITC (Table 2).
In keeping with the statutory
guidance provided the ITC in
Section 4(e)(l)(A) of TSCA, the
ITC focused attention on sub-
stances suspected of causing can-
cer, gene mutations, or birth
defects. This emphasis was
reflected not only in the ITC's
consideration of individual sub-
stances and categories, but also
in its structuring of the review
process, since these effects were
scored individually and, in
effect, received greater attention
than did other effects scored in
groups (e.g., other toxic effects
or ecological effects).
Selecting Chemicals for
ITC Consideration and
Public Comment
The ITC provides many opportu-
nities for the public to comment
on ITC procedures and the
chemicals and chemical groups
The Committee also considered the
desirability of grouping substances
into categories.
The ITC used biological scores as pan
of the effort to rank chemicals for
consideration.
78 Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
that are selected for review by all
Statutory and Liaison organiza-
tions (Fig. 1). For example, all
30 (as of May 1992) ITC Reports
to the EPA Administrator have
been published in the Federal
Register and public comments
on the testing recommended in
these Reports have been solicited
and considered.
Before the ITC added any chemi-
cals or chemical groups to the
Priority Testing List, the Prelimi-
nary List from the First Scoring
Exercise and a background docu-
ment describing its development,
was published by the ITC in
July, 1977. The ITC published 2
notices in the Federal Register
(42 FR 30531 and 42 FR 40756)
announcing the availability of
the List and'background docu-
ment and requesting public com-
ment. Comments were
specifically requested on:
a. Methodology used by the ITC
in developing the Preliminary
List;
b. Substances not appearing on
the Preliminary List which
commentors might recom-
mend for consideration by the
ITC and the commentor's rea-
sons for the recommendation;
c. Substances appearing on the
Preliminary List which com-
mentors might recommend
that the ITC not consider fur-
ther and the reasons for that
recommendation; and
d. Need for and relative priority
of testing of the substances
being considered by the ITC.
Comments on the Preliminary
List were received from about 65
industrial firms, trade associa-
tions, environmental organiza-
tions, government agencies, and
individuals. About two-thirds of
the commentors recommended
deletion of one or more subT
stances or categories appearing
on the Preliminary List, while
four commentors recommended
additional substances for the
ITC's consideration. About one-
fifth of the comments focused on
the methodology employed by
the ITC in developing the Pre-
liminary List and about one-third
included comments on other
issues related to the ITC's activi-
ties. Such issues were: the use of
categories in the ITC's recom-
mendations to EPA, documenta-
tion of the ITC's reasons for its
decisions with respect to specific
substances, and provision of
opportunity for public comment
on the ITC's action.
Public comments on the Prelimi-
nary List were reviewed by the
ITC and considered in the devel-
opment of the ITC's initial rec-
ommendations. Four of the
seven additional substances rec-
ommended by commentors were
added to the Preliminary List for
consideration in selecting sub-
stances and categories for
detailed review. Because of the
large number of comments rec-
ommending deletions of sub-
stances from the ITC's
consideration and the limited
time available under the statutory
deadline, pertinent comments
were considered on a substance-
by-substance or category-by-
category basis during the ITC's
review of preliminary dossiers
and consideration of reasons for
and against recommending test-
ing. Comments on the ITC's
methodology were reviewed and
considered in subsequent activi-
ties of the ITC. In the ITC's judg-
ment, the recommended changes
in methodology would not, if
Focus was on substances suspected of
causing cancer, gene mutations, or
birth defects.
Many opportunities were provided for
the public to comment on procedures
and chemicals.
Access/Use Info Resources Assess Health Risk Chem Expos '93
79
-------
implemented, alter its initial rec-
ommendations. Comments deal-
ing with use of categories,
documentation of the ITC's rea-
sons for actions, and other
more general issues were also
reviewed and considered in the
development of the ITC's recom-
mendations.
During the First Scoring Exer-
cise, public comments were solic-
ited on 80 chemicals that were
selected for detailed review
(Table 2).
During the Second Scoring Exer-
cise, public comments were solic-
ited on the 451 chemicals that
were scored for biological effects
(Table 2).
During the Third Scoring Exer-
cise, the 215 chemicals that were
scored for biological effects were
reduced to a list of 107 chemi-
cals that were published in the
October 7, 1980 Federal Regis-
ter (43 FR 66506) for public
comments (Table 2).
During the Fourth Scoring Exer-
cise, the 213 chemicals that were
scored for biological effects were
reduced to a list of 75 chemicals
that were published in the Febru-
ary 25,1982 Federal Register
(47 FR 8244) for public com-
ments (Table 2).
During the Fifth Scoring Exer-
cise, the 214 chemicals that were
scored for biological effects were
reduced to a list of 82 chemicals
that were published in the
November 9, 1983 Federal Reg-
ister (48 FR 51519) for public
comments (Table 2).
Developing And Revising
The TSCA Section 4(e)
Priority Testing List
Developing and revising the
TSCA Section 4(e) Priority Test-
ing List has been previously
described by Walker (1993a).
All the ITC Reports containing
the original as well as revisions
to the Priority Testing List as a
result of selecting chemicals
from the First through Fifth Scor-
ing Exercises are listed below in
the references. Most of the
chemical fate, bioconcentration
and ecological effects testing has
been previously described
(Walker 1990a,b, 1991b, 1993b).
References
ITC. TSCA Interagency Testing Com-
mittee Report to the Administrator;
Receipt of Report and Request for Com-
ments Regarding Priority Testing List of
Chemicals:
1977 Initial Report. Federal Register
42:55026-80, October 12,1977.
1978a. Second Report. Federal Regis-
ter 43:16684-88, April 19, 1978.
1978b. Third Report. Federal Register
43:50630-35, October 10, 1978.
1979a. Fourth Report. Federal Regis-
ter 44:31866-99, June 1, 1979.
1979b. Fifth Report. Federal Register
44:70664-74, December 7, 1979.
1980a. Sixth Report. Federal Register
45:35897-910, May 28, 1980.
1980b. Seventh Report. Federal Regis-
ter 45:78432-46, November 25, 1980.
198 la. Eighth Report. Federal .Regis-
ter 46:28138-44, May 22,1981.
1981b. Ninth Report. Federal Register
47:5456-63, February 5, 1982.
1982a. Tenth Report. Federal Register
47:22585-96, May 25, 1982.
1982b. Eleventh Report Federal Reg-
ister 47:54625-44, Decembers, 1982.
1983a. Twelfth Report. Federal Regis-
ter 4S-.24441-52, June 1,1983.
1983b. Thirteenth Report. Federal
Register 48:55674-84, December 14,
1983.
1984a. Fourteenth Report. Federal
Register 49:22389-407, May 1984.
Comments dealing with use of
categories, documentation of the ITC's
reasons for actions, and other more
general issues were also reviewed and
considered in the development of the
ITC's recommendations.
80
Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
1984b. Fifteenth Report. Federal Reg-
ister 49:46931-49, November 29,1984.
1985a. Sixteenth Report. Federal Reg-
ister 50:20930-39, May 21,1985.
1985b. Seventeenth Report. Federal
Register 50:47603-12, November 19,
1985.
1986a. Eighteenth Report. Federal
/tester 51:18368-75, May 19,1986.
1986b. Nineteenth Report Federal
Register 51:41411-32, November 14,
1986.
I987a. Twentieth Report Federal Reg-
ister 52:19020-26, May 20, 1987.
1987b. Twenty-first Report. Federal
Register 52:44830-37, November 20,
1987.
1988. Twenty-second Report Federal
Register 53:18196-210, May 2,1988.
Walker, J.D. and R.H. Brink. 1989.
New cost-effective, computerized
approaches to selecting chemicals for
priority testing consideration, pp. 507-
36. In: G. W. SuterH and M. A. Lewis,
Eds., Aquatic Toxicology and Environ-
mental Fate: Eleventh Volume, ASTM
STP 1007. American Society for Test-
ing and Materials, Philadelphia, PA.
Walker, J.D. 1990a. Bioconcentration,
chemical fate and environmental effects
testing under Section 4 of the Toxic Sub-
stances Control Act. Toxicity Assess-
ment An International Journal 5:61-75.
Walker, J.D. 1990b. Review of chemi-
cal fate testing conducted under Section
4 of the Toxic Substances Control Act:
chemicals, tests, and methods, pp. 77-
90. In: W. G. Landis and W. H. vander-
Schalie, Eds., Aquatic Toxicology and
Risk Assessment Thirteenth Volume,
ASTM STP 1096, American Society for
Testing and Materials, Philadelphia) PA.
Walker, J.D. 199 la. Chemical Selec-
tion by the Interagency Testing Commit-
tee: Use of Computerized Substructure
Searching to Identify Chemical Groups
for Health Effects, Chemical Fate and
Ecological Effects Testing. Science of
the Total Environment 109/110:691-700.
Walker, J.D. 1991b. Ecological effects
testing under the Toxic Substances Con-
trol Act: Acrylamide. Environmental
Toxicology and Water Quality: An Inter-
national Journal 6:363-69.
Walker, J.D. 1993a. The TSCA Inter-
agency Testing Committee, 1977 to
1991: Creation, Structure, Functions,
and Contributions. In: J.,Gorsuch, J.
Dwyer, C. Ingersoll, and T. LaPoint,
Eds., Environmental Toxicology and
Risk Assessment, ASTM STP 1173,
American Society for Testing and Mate-
rials, Philadelphia, PA, in press.
Walker, J.D. 1993b. Review of Eco-
logical Effects and Bioconcentration
Testing Recommended by the TSCA
Interagency Testing. Committee and
Implemented by EPA: Chemicals, Tests
and Methods. In: W. G. Landis, J. S.
Hughes, and M. A. Lewis, Eds., Environ-
mental Toxicology and Risk Assess-
ment, ASTM STP 1179, American
Society for Testing and Materials, Phila-
delphia, PA, in press.
Appendix A—
Exposure Scoring
Exposure scoring was similar for
the ITC's first, second, third,
fourth and fifth scoring exer-
cises. The factors used to score
chemicals for exposure during
the first scoring exercise are
described below.
Factor 1: Production
Annual production data were col-
lected from a number of sources:
a. EPA's Air contaminants
(Table 1)
b. EPA study of industrial data on
650 candidate chemicals for
testing
c. EPA Office of Research and
Development's chemical pro-
duction data on about 140
chemicals
d. Synthetic Organic Chemicals,
United States Production and
Sales. 1975. United States
International Trade
Commission
e. Stanford Research Institute.
1975 Chemical Economics
Handbook
f. Chemical and Engineering
News: Vol. 52, No. 51,
12/23/74; Vol. 55, No. 18,
5/2/77; Vol. 55, No. 24, 6/13/77
The Factor 1 score assigned to a
chemical was the common loga-
rithm of the highest annual pro-
All ITC reports containing the original
as well as revisions to the list are in
the references for this paper.
Access/Use Info Resources Assess Health Risk Chem Expos '93
81
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duction value (in millions Ibs/yr)
found in any of the above
sources. If an annual production
value was not available for a
chemical in any of these sources,
a Factor 1 score of-0.5229 (cor-
responding to an assumed annual
production of 300,000 pounds)
was assigned.
Score
Release Rate
Factor 2: Quantity Released to
the Environment
The quantity of chemical
released to the environment was
scored on a scale from 0 to 3 as
follows:
Estimate Based on Uses
3 >30 percent
2 3 to 30 percent
1 0.3 to 3 percent
0 <0.3 percent
Mostly dispersive uses
Some dispersive uses
Few dispersive uses; or primarily
industrial chemical with propensity for
leaks
Well contained industrial chemical
Estimates of release rates for a
number of chemicals were listed
in EPA's study of industrial data
on 650 candidate chemicals for
testing. For those chemicals for
which no release rates were
given, an estimate was made on
Score
Lifetime
the basis of the dispersive nature
of the chemical's uses.
An estimate was also made of
the chemical's persistence
according to the following table:
Example
3
2
1
0
Infinite (years or greater)
Order of 1 year
Order of a few days
Hours or less
Compounds of metals
Tetrachloroethylene
SO2
Reactive compounds
The sum of the scores of the two
subfactors, release quantity and
persistence, was taken as an indi-
cation of the environmental bur-
den posed by the chemical.
Factor 3: Occupational Exposure
The source of data on occupa-
tional exposure to chemicals was
the National Occupational Haz-
ard Survey (NOHS) conducted
by NIOSH.
In this survey, approximately
7000 of the most common haz-
ards occurring in the working
place were rank ordered. To
achieve an occupational expo-
sure score with a range and direc-
tion similar to those of the other
factors, the Factor 3 score
assigned to a chemical was
3.8451 minus the common loga-
rithm of its rank on the NOHS
list. (3.8451 is the logarithm of
7000.) Chemicals which did not
appear on the NOHS list were
given a score of zero, equivalent
Release quantity and persistence, were
taken as an indication of the
environmental burden posed by the
chemical.
Approximately 7000 of the most
common hazards occurring in the
working place were rank ordered.
82 Access/Use Info Resources Assess Health Risk Chem Expos '93
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to having been ranked number
7000 on the survey.
Factor 4: Extent to Which the
General Population is Exposed
Four individual subfactors were
scored and then summed to meas-
ure the general population expo-
Score
No. of people
sure. The four subfactors were
scored as follows:
Subfactor 1: Number of people
exposed to the chemical
(exclusive of a workplace envi-
ronment)
Example
>20 x 10 Widely used household products (e.g.,
wearing apparel, shoe polish, certain
surface coatings, common paints and
their solvents, common plastics and
their additives, detergents, furnishings
and carpets, wood cleaning products,
refrigerants, natural gas, nonfood
packaging materials, flameproofers)
General air, food and water
contaminants
Automotive products (e.g., gasoline
and additives, rubber, surface
coatings, plasticizers, flameproofers)
Products used widely in commercial
buildings (mostly same as household,
including commercial cleaners,
disinfectants)
2-20 x 106 Less widely used household products
(e.g., uncommon paints, specialty
apparel such as baby wear, hobby
uses, arts and crafts, tools)
«
Regional air and water pollutants,
farm chemicals (exclusive of
pesticides)
0.2-2 x 106 Specialty hobbies (e.g., photography),
specialty products
Neighborhood air and water
pollutants from local industries
<2 x 10 Chemical intermediates rarely found
outside the workplace
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Subfactor 2: Frequency of
Exposure (to the typical person
Score
Frequency
in ranking number of people
exposed under Subfactor 1)
Examples
3 Daily or more often
Weekly
Monthly
Yearly or less
frequently
General air, food and water
contaminants, household products in
regular use, material used inside
automobiles, clothing
Hobby crafts, household products
used intermittently (e.g., certain
cleansers), bleaches, gardening
products
Dry cleaning, certain solvents, house
maintenance (e.g., polishes, certain
cleaning agents), automobile
maintenance
Application of household paints,
specialty products
Subfactor 3: Exposure intensity.
This is intended to reflect the
total amount of material that
comes into contact with the aver-
age or typical person whose
exposure has been scored under
subfactors 1 and 2. Scoring of
this factor considered the number
of grams of the material that
makes contact with the average
person in the course of one expo-
sure (daily, weekly, monthly, or
Score Frequency
yearly as scored in subfactor 2).
Thus, for example, a trace pollut-
ant may lead to exposure to a
typical person of the order of
micrograms per day every day;
use of a specialty solvent might
lead to exposure of a typical per-
son of the order of grams per day
once a year; these would be
scored 3,0 and 0,0 respectively
on subfactors 2 and 3.
Examples
High (10;1 or
more grams per
exposure)
Medium (10"1 to
10"2 g per
exposure)
Low(10"3to
exposure)
0 Very low (less
than 10"5gper
exposure)
Plastics, fabrics, surface coatings, volatile
solvents in closed spaces, liquids
contacting skin, high concentration gases
Fabric additives, solvents in open spaces
or outdoors, dusts, solutes, transitory
exposures to vapors or aerosols
Low level indoor exposure, volatile
substances from home furnishings and
building materials (e.g., plasticizers,
flameproofers), low volatility solvents,
pigments
Environmental contaminants (low level
air, food, and water contaminants),
monomers in polymers
Exposure intensity is intended to
reflect the total amount of material
that comes into contact with the
average or typical person whose
exposure has been scored under
subfactors 1 and 2.
84 Access/Use Info Resources Assess Health Risk Chem Expos '93
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Subfactor 4: Penetrability. This
is a measure of the material that
comes into contact with a person
(whether by dermal, inhalation,
or ingestion exposure) and that is
Score Penetrability
expected to be absorbed into the
body (even transitorily) with
potential for interaction with
cells.
Examples
High (10 to 100%
absorption)
Medium (1 to 10%
absorption)
Low (0.01 to 1%
absorption)
Negligible (less than
0.01% absorption)
Organic solvents in liquid, mist, or
aerosol form, vapors and gases if
likely to be soluble in body fluids,
respirable-sized particles, surface
active agents, materials known to
have high dermal systemic toxicity
Solvents with low volatility and/or
larger molecules, organic materials
in water solution, waxes and
polishes, coarse dusts
Certain solids, dermal exposure to
most inorganic materials in water
solution
Polymers, metals
In making the judgements called
for in scoring Subfactors 2 and 4
above, knowledge of the chemi-
cal's uses was necessary. Use
information was collected form
the following sources:
1. The Condensed Chemical Dic-
tionary, Ninth Edition,
Hawley, Van Nostrand Rein-
hold Company, New York,
1977.
2. The Merck Index, Ninth Edi-
tion, Merck and Company,
Inc., Rahway, N.J., 1976.
3. Faith, Keyes, and Clark's
Industrial Chemicals, Lowen-
heim and Moran, Fourth Edi-
tion, J. Wiley and sons, Inc.,
New York, 1975.
4. Chemical Marketing Reporter,
Schnell Publishing Company,
Inc., New York.
5. Encyclopedia of Chemical
Technology, Kirk-Othmer,
Inter-Science Publishing Com-
pany, New York, 1972.
Ranking chemicals based on pro-
duction, environmental release
and occupational exposure
A linear weighting scheme was
used to rank order the chemicals.
The rank of the jl chemical, rj,
was computed by the formula:
i=\
where w; is the weight assigned
to the ith factor,
fij is the ith factor score of the jl
chemical, and
si is a scaling factor chosen to
normalize the assigned scores.
Access/Use Info Resources Assess Health Risk Chem Expos '93
85
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The four scaling factors
employed were:
si = log 20,850 - 4.33191; 20,850
million Ib/yr being the maxi-
mum of all Factor 1 chemical
production quantities.
S2 = 6; 6 being the maximum of
all Factor 2 environmental
release scores.
s = 3.8451 log 3 = 3.3680; third
being the highest NOHS rank
among the scored chemicals.
(Ranked first and second on
the NOHS list were continuous
noise and mineral oil, the for-
mer not being a chemical
hazard and the latter not being
among the scored chemicals.)
54 = 12; 12 being the maximum
of all Factor 4 general popula-
tion exposure scores.
This choice of si, S2, S3, 54,
guaranteed that
<1
Si
for all i and j, and furthermore,
that for each i,
I -^ I = 1 for at least one
Si
chemical j.
Appendix B —
Biological Scoring
This step of the ITC's procedure
extended the scoring of the sub-
stances under consideration to
statutory factors 5-7 (structural
relationships to known toxic sub-
stances, available toxicity data,
and reliability of test data to pre-
dict hazard) of TSCA Section
To accomplish this, each sub-
stance on the Preliminary List
was scored for each of seven bio-
logical activity factors by a num-
ber of experts. The factors were:
carcinogenicity, mutagenicity,
teratogenicity, acute toxicity,
other toxic effects such as repro-
ductive effects or organ-specific
toxicity, bioaccumulation, and
ecological effects. After review-
ing a summary of information on
the biological activity of the sub-
stance, each of the experts
assigned a score to the substance
for the effect(s) for which that
expert was responsible.
At least nine experts were used,
with two or three experts sepa-
rately evaluating each effect.
Each expert considered both the
summary information and his
personal knowledge of the sub-
stance and chemically-related
substances in assigning scores.
Any substantial discrepancies
among individual experts were
identified, discussed among
them, and a consensus reached;
in the case of minor discrepan-
cies in the scores for any factor,
the scores of the several scores
were averaged.
In addition, three of the effects
(carcinogenicity, mutagenicity,
and ecological effects) were sepa-
rately scored by government
experts from the National Cancer
Institute, National Center for
Toxicological Research, and
Department of Interior, respec-
tively. These scores were aver-
aged with those of other experts.
Scores assigned for the various
effects took the form of a posi-
tive or negative numerical score
(generally 0, 1, 2, or 3). Assign-
ment of a positive score indi-
cated a judgment that further
testing of the substance is not
needed for the effect under con-
sideration, while the magnitude
of the score indicated the degree
to which the effect had been con-
Each substance on the Preliminary
List was scored for each of seven
biological activity factors by a
number of experts.
Three of the effects (carcinogenicity,
mutagenicity, and ecological effects)
were separately scored by
government experts from the
National Cancer Institute, National
Center for Toxicological Research,
and Department of Interior.
86
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-------
firmed or the dose level at which
it had been found. Assignment of
a negative score, on the other
hand, indicated a judgment that
further testing should be con-
ducted, with the magnitude of
the score reflecting a judgment
as to the level of numerical score
that might be anticipated after
testing. For example, in scoring a
substance for carcinogenicity a
score of +3 meant that the sub-
stance is well established as a car-
cinogen in humans or experi-
mental animals, while a score of
-3 meant that the substance is
strongly suspected of carcino-
genic activity but has not been
adequately tested. In averaging
the scores assigned to a sub-
stance by the several scorers for
a given factor, no mixing of posi-
tive and negative scores was per-
mitted. Any discrepancies
between scorers in choosing
scores were discussed among the
experts and resolved. The crite-
ria applied by the experts in
. assigning scores for the various
factors are described below.
Categories of substances appear-
ing on the Preliminary List were
not generally scored as entities,
but rather, scores were assigned
separately for each of the exam-
ple substances listed under the
category heading in the list.
Biological and environmental
scores
A. The five human health effect
factors and two environmental
effect factors were scored as
follows:
Factor 1: Carcinogenicity
a. Positive Scores Assigned:
+3 Established carcinogen in
humans or in 2 animal spe-
cies, or in one animal spe-
cies in well-replicated
experiments
+2 Established carcinogen in 1
animal species
+1 Insufficient or inadequate
experimental data for defi-
nite conclusions, but either
(a) no experimental or struc-
tural reason for suspicion,
or (b) good negative
mutagenicity tests, or (c)
low biological activity.
(Note: some inert com-
pounds—examples, argon,
nitrogen—were given a
score of-zero on this factor
despite not having been
tested.)
0 Adequately tested in ani-
mals with negative results
in each of two species
b. Negative Scores Assigned*:
-3 Needs testing, strongly sus-
pect (close structural rela-
tionship to known
carcinogen, positive result
in validated in vitro test,
inconclusive but suspicious
positive animal test, etc.)
-2 Needs testing, suspect
(structural resemblance to
known carcinogen, etc.)
-1 Needs testing, some reason
for suspicion (potent organ-
specific toxin, enzyme
indiicer, suspect co-
carcinogen, etc.)
* Chemicals presently undergo-
ing testing for carcinogenicity
in the framework of the NCI
bioassay program were scored
as suspect carcinogens. Their
special status was documented
for the members of the ITC.
c. Criteria for Accepting Positive
Test Results (scores 2 or 3)
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87
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Validated positive findings in ani-
mal studies consisted of any test
results which clearly indicated
treatment-related carcinogenicity
or tumorigenic effects. This was
based on the criteria set out in
the report of the National Cancer
Advisory Board, Subcommittee
on Environmental Carciriogenic-
ity, "General Criteria for Assess-
ing the Evidence for Carcino-
genicity of Chemical Sub-
stances" (1976).
d. Criteria for Accepting Nega-
tive Test Results (including
zero scores)
In general, the protocol of the
test conformed to, or was reason-
ably consistent with the current
NCI Guidelines (J.M. Sontag et
al., Guidelines for Carcinogen
Bioassay in Small Rodents,
DHEW 76-801). It was recog-
nized that many older tests do
not conform to these guidelines.
Therefore, good scientific judg-
ment was applied to the evalu-
ation of these tests in order to
determine whether differences in
protocols significantly weakened
confidence in the reported nega-
tive results. In assigning a zero
score, the guiding principle was
the judgment that further testing
was unnecessary.
Factor!: Mutagenicity
a. Positive Scores Assigned:
+2 Mutagen in two or more test
systems**
+1 Mutagen in one test system
0 Tested in more than one sys-
tem with negative results
and no reason for suspicion
(similar to inactive com-
pounds, etc.)
** These and other scores were
normalized to the 0-3 scale for
all factors involved.
b. Negative Scores Assigned:
-3 Needs testing, strong reason
for suspicion (structural
similarity to known
mutagen, reported carcino-
genicity, teratogenicity, or
other cellular toxicity)
-2 Needs testing, some reason
for suspicion (structural
similarity to known
mutagens and/or
carcinogens)
-1 Needs testing, no reason to
assign high priority
c. Examples of Short-Term Sys-
tems Considered for Scoring
Were:
The Salmonella/micTosome. test,
(Ames), E. coli WP2 uvr A, etc.
test (Bridges, Witkin), B. subtilis
M45 Rec-, etc. test (Kada), E.
coli pol A+/pol Al- test (Rosen-
kranz), Yeast test (Zimmerman),
Neurospora test (de Serres) and
Drosophila test (Vogel). Mam-
malian cells in culture and in
vitro transformations were also
considered.
Factor 3: Teratogenicity
a. Positive Scores Assigned:
+3 Confirmed teratogen in
humans or in two appropri-
ate animal species
+2 Confirmed teratogen in 1
animal species
+1 Insufficient or inadequate
experimental data for defi-
nite conclusions, but either
(a) no experimental or struc-
tural reason for suspicion,
or (b) low biological activity
Scientific judgment was applied to
the evaluation of these tests in order
to determine -whether differences in
protocols significantly weakened
confidence in the reported negative
results
Access/Use Info Resources Assess Health Risk Chem Expos '93
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0 Adequately tested in two
suitable animal species with
negative findings for terato-
genic activity
b. Negative Scores Assigned:
-3 Needs testing, strongly sus-
pect (close structural rela-
tionship to known
teratogen, inconclusive but
suspicious positive animal
tests, etc.)
-2 Needs testing, suspect
(equivocal result in animal
test, etc.)
-1 Needs testing, some reason
for suspicion
c. Criteria for Acceptance of
Teratogenicity Tests
Accepted teratogenicity tests con-
formed reasonably to the recom-
mendations and principles
outlined in 'Principles for Evalu-
ating Chemicals in the Environ-
ment," National Academy of
Sciences, pp. 173-182, 1975; and
"The Testing of Chemicals for
Carcinogenicity, Mutagenicity,
Teratogenicity," Department of
Health and Welfare, Canada, pp.
137-176, March 1973.
Factor 4: Acute Toxicity
a. Positive Scores Assigned:
+3 extremely toxic: < 50
mg/kg
+2 very toxic: 50-500 mg/kg
+1 moderately toxic: 0.5-5
0 very slightly toxic: > 5 g/kg
b. Negative Scores Assigned:
-2 not tested, but suspected to
be 50-500 mg/kg
-1 not tested, but suspected to
be 500-5000 mg/kg •
c. Criteria for Quantitation of
Acute Toxicity
Standard systems of toxicity rat-
ing based on Probably Lethal
Dose in humans were used when
available. Lowest Lethal Doses
and LDso values in various ani-
mal systems were also widely
used.
Factor 5: Other Toxic Effects
a. Positive Scores Assigned:
+3 Effects at low doses (<1
mg/kg/day)
+2 Effects at moderate doses
(1-10 mg/kg/day)
+1 Effects at high doses (> 10
mg/kg/day)
0 Very low or negligible bio-
logical activity (e.g., nitro-
gen, argon, etc.)
b. Negative Scores Assigned:
-3 Needs testing (structural
similarity to another chemi-
cal which rates +2 or +3;
.questionable reports of
effects which need confir-
mation, etc.)
-2 Needs testing, some reasons
for suspicion
-1 Needs testing, inadequate
information available to
give high priority
c. Criteria for Scoring
This factor includes both revers-
ible and irreversible effects,
delayed or cumulative toxicity,
organ-specific effects, effects on
reproduction, behavior, etc. The
score entered reflects the toxic
effects noted in animals (or in
humans if data were available) at
the lowest dose-range. If the
chemical was reported or sus-
pected to have more than one
toxic effect, negative scores for
Access/Use Info Resources Assess Health Risk Chem Expos '93
89
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one type of toxic effect super-
seded any positive scores for
another. In many cases, reports
of one type of effect at low doses
engendered suspicion of the like-
lihood of others; in such cases
the chemical was scored with the
appropriate negative score,
unless thoroughly tested.
Factor 6: Bioaccumulation
a. Positive Scores Assigned:
+3 High (MO4)***
+2 Appreciable (102 to 104)
+1 Low(<102)
0 Experimental evidence for
non-accumulation (<1);
water soluble compounds
***The degree of bioaccumula-
tion (more precisely, the tissue-
specific storage factor) is defined
as the concentration of the chemi-
cal in the tissues (at "steady
state" or after prolonged expo-
sure) divided by the concentra-
tion of the chemical in the
ambient medium.
b. Negative Scores Assigned:
-3 Testing important, judged
likely to be high
-2 Testing important, judged
not likely to be high, but
likely to be appreciable
-1 Needs testing, little or no
experimental data
c. Criteria for Scoring
Bioaccumulation is used here in
its broad sense of the accumula-
tion of a chemical in one or more
tissues of an animal (or plant) to
levels higher than those in the
ambient medium. For purposes
of screening chemicals, it was
considered significant primarily
in cases in which the accumula-
tion in tissues represented an
enhanced probability of effects,
either on the organ in which the
chemical was concentrated, or on
animals which feed on the organ-
ism which accumulated the
chemical. A high degree of
bioaccumulation is usually found
only in aquatic organisms. For
these organisms, bioaccumula-
tion is known to be dependent
primarily on water solubility and
it is empirically predicted by the
octanol/water partition coeffi-
cient. Zero scores were assigned
to completely water soluble
organic chemicals.
Substances which are easily
metabolized will not be bioaccu-
mulated even if they have a high
partition coefficient (example,
chloroform). Thus ease of meta-
bolism was a factor considered in
evaluating the potential for bioac-
cumulation.
Factor?: Ecological Effects
a. Positive Scores Assigned:
+3 Effects at low concentra-
tions (10" or less in air or
water)****
+2 Effects at moderate concen-
trations (1(T7 to 10"9 in air
or water)
+1 Effects at high concentra-
tions (10" or greater in air
or water)
****Inair for gases or vapors: 1
part of chemical per billion parts
air by volume (ppb). In water
for liquids and solids: 10"9 gram
per cubic meter (ng/m3)
b. Negative Scores Assigned:
-2 Testing needed, possibility
of major or widespread
effects
-1 Testing needed, possibility
of minor or local effects
90 "Access/Use Info Resources Assess Health Risk Chem Expos '93
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c. Criteria for Scoring:
Ecological effects considered
toxic effects on non-human ani-
mals and plants, ecosystem
effects, effects on atmosphere
and climate, ozone depletion,
etc. Generally, positive scores
(established hazard) were
assigned only to a limited num-
ber of thoroughly tested chemi-
cals (e.g., pesticides, some metal
containing compounds, or some
specific chemicals). In other
cases, the potential for ecological
effects was judged according to
availability of data on toxicity in
particular, published information
on specific tests, structural simi-
larity to compounds of better
known ecotoxicity, published
data on depletion potential for
stratospheric ozone. Zero scores
were assigned only to com-
pounds with low biological activ-
ity (LD50 > 1 g/kg or AQTR >
100 ppm).
Factor 8: Contaminants and Envi-
ronmental Degradation or Con-
version Products
a. Positive Scores Assigned:
+1 .Contaminants, etc., known
to be important
0 Contaminants, etc., not sus-
pected of being important,
or known to be of no impor-
tance.
b. Negative Scores Assigned:
-1 Contaminants, etc., suspect,
needs testing
c. Criteria for Scoring:
The scores for this factor were
not averaged. A negative score
took priority over a positive
score at any time; if no negative
score was assigned to a chemi-
cal, the positive score +1 was
overriding. A zero score was
assigned only if it was scored
unanimously by all scorers. The
score for this factor was not
added: (1) if the principal break-
down product was the major
problem and it was the basis for
scores on other criteria such as
persistence and toxicity (exam-
ples: DDE, PAN); (2) for in vivo
metabolism of carcinogens to
active forms (e.g., arene oxides,
activated nitrosamines, etc.).
The following literature sources
were extensively used by the
scorers:
References of general
interest
NI'OSH Registry of Toxic Effects of
Chemical Substances. 1976.
Kirk-Othmer Encyclopedia of Chemi-
cal Technology. Edited by A. Standen,
Interscience Publishers, New York.
1963,1972.
The Condensed Chemical Dictionary,
9th ed. Van Nostrand Reinhold Co.,
New York. 1977.
The Merck Index, 9th ed. Merck and
Co., Inc., Rahway, N.J. 1976.
Chemical Consumer Hazard Informa-
tion System. Consumer Product Safety
Commission, Washington, D.C. 1977.
A Study of Industrial Data on Candi-
date Chemicals for Testing. Stanford
Research Institute, Palo Alto, California.
1976.
Brown, S.L., et al. Research Program
on Hazard Priority Ranking of Manufac-
tured Chemicals, Phase II- Final Report
to National Science Foundation. Stan-
ford Research Institute Menlo Park, Cali-
fornia. 1975.
Dorigan, J., et al. Scoring of Organic
Air Pollutants, Chemistry, Production
and Toxicity of Selected Synthetic
Organic Chemicals, MITRE, MTR-
6248.1976.
The Encyclopedia of Chemistry. Han-
pel and Hawley, 3rd ed. Van Nostrand
Reinhold Co., New York . 1973.
1. References on Carcinogenicity
Survey of Compounds Which Have
Been Tested for Carcinogenic Activity
Through 1972-1973. DHEW Publication
No. NIH 73-453, National Cancer Insti-
tute, Bethesda, Maryland.
Suspected Carcinogens - A subfile of
the NIOSH Toxic Substances List.
Access/Use Info Resources Assess Health Risk Chem Expos '93
91
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IARC Monographs on the Evaluation
of Carcinogenic Risk of Chemicals to
Man. WHO, International Agency for
Research on Cancer. Lyon, France.
Chemicals Being Tested for Carcino-
genicity by the Bioassay Program,
DCCP. National Cancer Institute. 1977.
Information Bulletin on the Survey of
Chemicals Being Tested for Carcino-
genicity, No. 6. WHO, Lyon, France.
1976.
2, 3. References on Mutagenicity
and Teratogenicity
Shepard, T.H. Catalog of Teratogenic
Agents. Johns Hopkins University Press,
Baltimore. 1973.
EMIC/Environmental Mutagen
Information Center File, Oak Ridge
National Laboratory, Oak Ridge,
Tennessee.
4, 5. References on Acute Toxic-
ity and Other Toxic Effects
Thienes, C.L. and T. J. Haley. Clinical
Toxicology. Lea and Febiger, Philadel-
phia. 1972.
Gosselin, Hodge, Smith and Gleason.
Clinical Toxicology of Commercial
Products, 4th ed. The Williams and
Wilkins Company, Baltimore. 1976.
Casarett, J.J. and J. Doull. Toxicology,
the Basic Science of Poisons. McMillan
Publishing Co., Inc., New York.
Debruin, A. Biochemical Toxicology
of Environmental Agents. Elsevier/
North Holland, Inc., New York. 1976.
Threshold Limit Values for Chemical
Substances and Physical Agents in the
Workroom Environment with Intended
Changes for 1976. American Confer-
ence of Government Industrial Hygien-
ists.
Criteria for a Recommended Standard
- Occupational Exposure to..., prepared
by NIOSH.
Browning, E. Toxicity and Metabo-
lism of Industrial Solvents. Elsevier,
Amsterdam. 1969.
Browning, E. Toxicity of Industrial
Metals, 2nd ed. Appleton-Century-
Crofts, New York. 1969.
Fairhall, L.T. Industrial Toxicology,
2nd. ed. Williams and Wilkins Co., Balti-
more, Maryland. 1969.
Sax, N.I. Dangerous Properties of
Industrial Materials, 3rd ed. Reinhold
Publishing Corp., New York. 1975.
Chemical Safety Data Sheets. Manu-
facturing Chemists Association, Wash-
ington, D.C.
Industrial Safety Data Sheets.
National Safety Council, Chicago,
Illinois.
6,7. References on Bioaccumula-
tion and Ecological Effects
Applegate, V.C., J.H. Howell, A.E.
Hall, Jr. and M.A. Smith, 1957. Toxicity
of 4,346 Chemicals to Larval Lampreys
and Fishes. U.S. Dept Interior, Fish and
Wildlife Service. Special Scientific
Report-Fisheries No. 207. Washington,
D.C.
Battelle Columbus Laboratories.
1971. Effects of Chemicals on Aquatic
Life: Selected Data from the Literature
through 1968. Vol. 3 of Water Quality
Criteria Data Book. U.S. Environmental
Protection Agency, Washington, D.C.
Hahn, W, and P. Jensen. Water Qual-
ity Characteristics of Hazardous Materi-
als; Texas A and M University (1974).
(Taken from the NIOSH Registry of
Toxic Effects of Chemical Substances
1976.)
Kemp, H.T., R.L. Little, V.L.
Holoman, and R.L. Darby. 1973.
Effects of Chemicals on Aquatic Life
(Compilation Dated 1968-1972). Water
Quality Data Book - Vol. 5 U.S. Environ-
mental Protection Agency, Duluth, Minn.
Leo, A., C. Hansch, and D. Elkins.
1971. Partition Coefficients and Their
Uses. Chem. Rev. 71:525-616.
Lincer, J.L., M.E. Haynes, and M.L.
Klein. 1976. The Ecological Impact of
Synthetic Organic Compds. on Estuarine
Ecosystems. U.S. Environmental Protec-
tion Agency, Gulf Breeze, Florida, EPA-
600/3-76-075.
Metcalf, R.L., P.Y. Lu, and I.P.
Kapoor. 1973. Environmental Distribu-
tion and Metabolic Fate of Key Indus-
trial Pollutants and Pesticides in a Model
Ecosystem. Illinois University, Water Re-
sources Center, Research Report 69,
Urbana, Illinois.
Pimentel, D. 1971. Ecological Effects
of Pesticides on Non-target Species.
Executive Office of the President, Office
of Science and Technology, Washington,
D.C.
Sauter, S., K.S. Buxton, K.J. Malek,
and S.R. Petrocelli. 1976. Effects'of
Exposure to Heavy Metals on Selected
Freshwater Fish. Toxicity of Copper,
Cadmium, Chromium, and Lead to Eggs
of Seven Fish Species. Environmental
Protection Agency, Duluth, Minnesota.
EPA-600/3-76-105.
National Academy of Sciences. 1973.
Water Quality Criteria, 1972. U.S. Envi-
ronmental Protection Agency, Ecologi-
cal Research Series No. EPA-R3-73-033.
McKee, J.E., and H.W. Wolf (eds.).
1963. Water Quality Criteria, 2nd Edi-
tion. State Water Quality Control Board,
Sacramento, California.
92 "Access/Use Info Resources Assess Health Risk Chem Expos '93
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U.S. Environmental Protection
Agency. 1976. Criteria Document
PCBs. Washington, D.C.
National Institute of Environmental
Health Sciences. 1973. Symposium on
Phthalate Ester Plasticizers. Environ-
mental Health Perspectives, Experimen-
tal Line 3.
National Academy of Sciences.
1975a. Principles for Evaluating Chemi-
cals in the Environment. Washington,
D.C.
National Academy of Sciences.
1975b. Assessing Potential Ocean Pol-
lutants. Washington, D.C.
U.S. Environmental Protection .
Agency. 1975. Quality Criteria for Water
(preliminary draft). Washington, D.C.
National Academy of Sciences. 1976.
Halocarbons: Effects on Stratospheric
Ozone, Washington, D.C.
Access/Use Info Resources Assess Health Risk Chem Expos '93 93
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EPA's Risk Assessment Guidelines: Overview
Dorothy E. Patton, U.S. Environmental Protection Agency
The U.S. Environmental Protection Agency (EPA) risk assessment guidelines for cancer, quantification, and exposure Issues are
discussed.
The U.S. Environmental
Protection Agency (EPA)
risk assessment guide-
lines provide principles, con-
cepts, and standards for
evaluating risks to human health
from exposure to environmental
toxicants. There are separate
guidelines for different assess-
ment topics, for example, cancer,
reproductive effects, exposure,
and mixtures. Each guideline
offers information on risk assess-
ment methodology and gives pol-
icy guidance on certain difficult
or controversial issues.
Five guidelines were published in
1986. Proposals for new guide-
lines and proposals to amend
some of the 1986 guidance have
been published during the last 2
years. This second generation of
guidelines not only expands ,
EPA's risk assessment guidance
to new subject matter areas, but
also introduces new methods and
concepts into EPA's formal guid-
ance. Most important, new devel-
opments in cancer classification,
quantification of risk, and expo-
sure are expected to improve the
risk assessment process.
Cancer Classification Issues. A
number of classification systems
have been invented over the
years by various organizations.
Some are derived from others.
Each has different objectives and
results. EPA is considering revi-
sion of its own system. EPA has
gathered views of scientists out-
side and inside the agency on
what goals such a system should
serve, what information it should
seek to summarize, and how vari-
ous kinds of information should
weigh in classification. Since
classification systems attempt to
characterize the likelihood of car-
cinogenic effects from human
exposure, any discussion of clas-
sification soon turns to issues
where there is lack of scientific
consensus. A few of these are
human relevancy of animal bioas-
say results, questions of mecha-
nisms, and the theoretical issue
of the intrinsic vs situational haz-
ards of a chemical. These kinds
of issues and potential ways of
building a classification system
to accommodate them are
presented.
Quantification Issues. The refer-
ence dose (RfD) model, which is
derived from the acceptable daily
intakes (ADI) approach, has been
extensively used by EPA for pre-
dicting exposure levels that are
likely to be without significant
risk of adverse effects for human
health effects other than cancer.
The RfD can be improved
through a critical analysis of its
subcomponents, the no-observed-
adverse-effect level (NOAEL),
and uncertainty factors. More-
over, additional published dose-
response methods are gaining
favorable review as improve-
Each guideline offers information on
risk assessment methodology and gives
policy guidance on certain difficult or
controversial issues.
New developments in cancer
classification, quantification of risk,
and exposure are expected to improve
the risk assessment process.
Access/Use Info Resources Assess Health Risk Chem Expos '93
95
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ments to the existing RfD, or as
enhancements when the regula-
tory goal is to estimate the likely
human exposure. One of these
approaches, the benchmark
method, is under discussion as an
option for quantification.
Exposure Issues. Exposure assess-
ment faces at least three tough
issues in the next few years. First,
the terminology used by assessors
must be standardized. Currently,
there are several different
schemes used to define exposure
and dose, not to mention terms
such as reasonable worst case
exposure. Second, the potential
positive impact of computer tech-
nology on data collection, inter-
pretation, and availability is vast,
but so are the potential drawbacks
of invalidated, ad-hoc computer
modeling. How this issue plays
out should not be left to chance.
Third, the almost universal use of
time-weighted average in expo-
sure assessment will face a seri-
ous challenge as new toxicologi-
cal methods such as biological-
based dose-response models are
developed which need more
detailed information than time-
weighted average. This may
become the largest issue for expo-
sure assessment in the late 1990s.
96
Access/Use Info Resources Assess Health Risk Chem Expos '93
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EPA's Program for Risk Assessment Guidelines:
Cancer Classification Issues
Jeanette Wiltse, U.S. Environmental Protection Agency
Issues presented are related to classification of weight of evidence in cancer risk assessments. The focus in this paper is on lines of
evidence used in constructing a conclusion about potential human carcinogenicity. The paper also discusses issues that are
mistakenly addressed as classification issues but are really part of the risk assessment process.
The Environmental Protec-
tion Agency (EPA) has
been working toward
revising its cancer risk assess-
ment guidelines that were pub-
lished in 1986. The effort started
about 2 years ago; at that time,
we were in a "maybe so",
"maybe not" mood about it.
Given the time and effort it
takes, inertia has to be overcome
before actually revising the
guideline, because in all of these
situations, there is a lot of contro-
versy. In 1989 the EPA Risk
Assessment Forum sponsored a
workshop during which experts
from several places were brought
together and asked to address
several issues about cancer risk
assessment. One of these is the
subject of my discussion—classi-
fication of weight of evidence.
Now, that is very arcane. The
classification scheme is that
small nutshell summary that is
the conclusion of a risk assess-
ment on cancer that says do we
or don't we think the agent may
be carcinogenic to human beings
and at what level of confidence
we can say so. It's usually a prob-
abilistic statement, "probably
yes" or "possibly yes." Some-
times, we know the answer is
yes, and that's the end of the
statement. The thing that keeps it
from being an academic exercise
in which scientists sit around try-
ing to see if they can agree on
what they would say about an
agent, is that as soon as EPA
makes a statement, it hits the
newspaper. Then my boss has to
go on television to explain why
it is and what it is because a lot
of the industry will get upset
when one of the chemicals they
market is characterized as being
probably, possibly, or known to
be carcinogenic to people.
Because we use a classification
scheme to communicate to risk
managers, we communicate the
same thing to the public and to
industry. It becomes a center of
controversy, whether we are
ready for it or not. That's why
classification schemes are
controversial.
Any discussion of classification
schemes is really a discussion of
how cancer risk assessment is
done, bottom to top. Classifica-
tion schemes are expressions of a
risk assessment that may be sev-
eral hundred pages long, cover
15 topics, and present lines of
evidence from several different
scientific disciplines. This paper
is limited to the lines of evidence
that we use in constructing a con-
It becomes a center of controversy,
whether we are ready for it or not.
Any discussion of classification
schemes is really a discussion of how
cancer risk assessment is done.
Access/Use Info Resources Assess Health Risk Chem Expos '93 97
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elusion about potential human
carcinogenicity—how they're
put together—and to identifying
some of the major issues that are
mistakenly addressed as classifi-
cation issues but are really just
part of the risk assessment proc-
ess. The elements used in our cur-
rent guidelines are lines of
evidence, or bodies of evidence.
Two directly address carcino-
genicity: human evidence of car-
cinogenicity and long-term
animal studies of carcinogenic-
ity. The remainder are sources of
indirect evidence. None of the
sources of indirect evidence
answer the question of whether
an agent causes a cancer, a
tumor, in an animal or a human
being. Structure activity doesn't
answer the question "Is this car-
cinogenic?" or "Has this agent
caused a tumor anywhere?" Like-
wise, pharmacokinetics and meta-
bolism can tell you a lot about
how the agent is processed in the
body, which may be relevant to
its potential for carcinogenicity,
but it doesn't tell you whether it
is or it isn't a carcinogen.
What I will call genome toxicity,
a broader term than genetic toxic-
ity, is any kind of an effect on the
information a cell contains that
helps run its own machinery.
Genome toxicity is relevant in
considering the potential for car-
cinogenicity, but it doesn't tell
whether the agent is going to
cause tumors.
The term I will use for basically
everything about toxicity is gen-
eral toxicity. Is there any other
kind of adverse effect that this
chemical causes? We use this
kind of information to learn
more about what happens to the
chemical in the body. Does it
have a target tissue? Does it have
targets in common with those of
other agents that we know to be
carcinogenic? Does it impact the
immune system, for instance,
which helps in general with resis-
tance to cancer-causing agents.
Specialized short-term tests con-
stitute another line of evidence. I
don't quite know how to describe
all of the tests that exist now
(that probably didn't exist 5
years ago) that have to do with
mechanisms of carcinogenesis.
They are not standardized. There
are a lot of them, but many of
them have to do with manipulat-
ing oncogenes and tumor sup-
pressor genes and putting them
in systems with agents and see-
ing what happens; they can tell
us quite a lot about mechanisms,
if we know how to interpret the
results.
All of the schemes and most of
the risk assessments for carcino-
gens have been built on the two
direct lines of evidence—on
whether an agent is a carcinogen
or not. If however, you look at
the relevant factors to be
included as evidence for carcino-
genicity, most of the advances in
the experimental sciences are not
in those two direct areas. It is the
other elements that raise a chal-
lenge to classification schemes
and risk assessment methods that
primarily rely on direct lines of
evidence. In my opinion, all of
the indirect lines have become
increasingly useable and power-
ful in predicting risk or in putting
together a story of the structure
of the chemical: how it is likely
to behave in a biological system,
and the likelihood of its carcino-
genicity. In the future, I think the
long-hoped-for substitutes for
long-term animal bioassays,
which take so long and cost so
Genome toxicity is any effect on the
information a cell contains that
helps it run its own machinery.
All of the schemes and most of the
risk assessments have been built on
whether an agent is a carcinogen or
not.
98
Access/Use Info Resources Assess Health Risk Chem Expos '93
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much, will arise put of these
other lines of evidence. The chal-
lenge to our classification system
at EPA comes, in part, from that.
It is very heavily reliant, as are
our other systems, on direct evi-
dence of carcinogenicity. That is
still appropriate. We are not yet
at the stage of being able to walk
around that. The question is
whether any system, EPA's
included, allows enough space
for growth for the remaining
kinds of information and for
their power to tell about the
potential carcinogenicity of an
agent
Some existing classification
schemes include EPA's in 1986,
the International Agency for
Research on Cancer (IARC) revi-
sion to its 1987 scheme, and
something called the Tripartite
scheme, which, I think, was pub-
lished by Canadian, U.S., and
European scientists. I believe
that the European communities
use it for guidance. A paper that
is to be published soon by the
American Industrial Health
Council (AIHC) that creates still
another kind of classification sys-
tem addresses the question, How
do you deal with questions of ani-
mal bioassay data that may not
be relevant to predicting
human carcinogenicity for one
reason or another?
Table 1 shows one classification
scheme. These are the "boxes"
into which the predications and
the risk assessments are sorted.
Behind each of these is a com-
plete risk assessment. Obviously,
this is a terrible way to portray
any kind of scientific risk assess-
ment because it boils it all down
to one or two words. Neverthe-
less, the public and our risk man-
agers need to know what we
Table 1. EPA Cancer Classification Scheme: Weight of evidence
based on human and animal evidence
Human evidence
Sufficient
Limited
Inadequate
No data
No evidence
Animal Evidence
Sufficient
A
Bl
B2
B2
B2
Limited
A
Bl
C
C
C
Inadequate
A
Bl
D
D
D
No data
A
Bl
D
D
D
No
evidence
A
Bl
D
E
E
There may be instances in the classification of both human and animal data indicat-
ing that different categorizations than those given in the table should be assigned.
Assignments are tentative and may be modified by ancillary evidence. All relevant
information is evaluated to determine if the designation of the over-all weight of evi-
dence needs to be modified. Relevant factors to be included along with the tumor
data from human and animal studies include structure-activity relationships, short-
term test findings, results of appropriate physiological, biochemical, and toxicologi-
cal observations, and comparative metabolism and kinetic studies. The nature of
these findings may cause an adjustment of the overall categorization of the weight
of evidence.
A = HUMAN CARCINOGEN
Bl = PROBABLE HUMAN CARCINOGEN
Limited evidence in human studies
B2 = PROBABLE HUMAN CARCINOGEN
Sufficient evidence from animal studies, inadequate
evidence or no data from human studies
C = POSSIBLE HUMAN CARCINOGEN
D = NOT CLASSIFIABLE AS TO HUMAN CARCINO-
GENICITY
E = NO EVIDENCE
Fig. 1. EPA carcinogenicity classification scheme.
Access/Use Info Resources Assess Health Risk Chem Expos '93 , 99
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really think of the potential of an
agent to cause these effects. So,
in one way or another we are
going to be boiling it down for
that purpose.
What is hoped is that a classifica-
tion scheme will allow us to be
consistent in the way we boil it
down from one data set to the
next. If it is kept simple, people
will be able to understand it. Fig-
ure 1 shows the EPA cancer cate-
gories. All the way from
"known" to be a human carcino-
gen down to "not carcinogenic."
The IARC classification system,
Fig. 2 is very similar. As a matter
of fact, our EPA system derives
from the IARC system. But the
IARC has often relied on the two
direct lines of evidence, the
human data and the animal data
(long-term animal studies). They
don't really have a place in their
scheme for using all other hazard
elements. They wouldn't use
structure-activity, I don't think.
They are beginning to look at
other things, but so far their
scheme is not designed to fully
accommodate lines of indirect
evidence. So, although these
look very similar, EPA has tried
to use more of the indirect evi-'
dence in its decisions than the
IARC has.
One of the criticisms of weight-
ing schemes is that in EPA's
work (and possibly lARC's,
although I'm not sure), one line
of evidence can drive the deci-
sion. For instance, a couple of
positive animal bioassays and
you're already way up the scale.
Other kinds of data won't have
much impact on this even if
other lines of evidence make it
extremely doubtful that those
two animal bioassays can be rele-
vant to humans. In such cases
A = CARCINOGENIC TO HUMANS
2A = PROBABLY CARCINOGENIC TO HUMANS
Limited evidence of carcinogenicity in humans and
sufficient evidence of carcinogenicity in animals
2B = PROBABLY CARCINOGENIC TO HUMANS
Limited evidence of carcinogenicity in humans in
the absence of sufficient evidence in experimental
animals. Also when there is inadequate or non-
existent evidence of carcinogenicity in humans but
sufficient evidence in experimental animals.
3 = NOT CLASSIFIABLE AS TO CARCINOGENI-
CITY IN HUMANS
4 = PROBABLY NOT CARCINOGENIC TO HUMANS
Fig. 2. IARC carcinogenicity classification scheme.
you have to undo the initial clas-
sification—sort of climb down
out of it. That's the criticism—
that the initial decision about
how to rank the chemical is more
driven by one side of the evi-
dence than it is the other side of
evidence. A true weight of evi-
dence scheme would not work
that way. It is a characteristic of
the schemes up to now that they
have put overriding weight on
the direct evidence. I'm not criti-
cizing that — we have to do that.
What I'm saying is that this
approach tends to muscle out the
potential growth and strength of
some of the other data.
Finally, another criticism—that
people tend to pigeon-hole data
sets by the numbers. The use of
numerical schemes tends to pro-
mote routine activity—we don't
think about how we do things or
analyze them as well as we
should. For these reasons we
might consider changing our
classification and weight of evi-
dence schemes. The experimen-
tal database around which things
What is hoped is that a
classification scheme will allow us
to be consistent in the way we boil
risk assessment down from one
data set to the next.
People tend to pigeon-hole data sets
by the numbers.
100 Access/Use Info Resources Assess Health Risk Chem Expos '93
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were originally designed has
changed drastically. To
accommodate this change, we
may need to be more explicit
about using newer research data
in our classification schemes. We
don't actually make it impossible
to use that data now, but we
could be more explicit about
how those data are weighed with
direct data to arrive at conclu-
sions. One criticism is that we
don't classify potential carcino-
genicity of an agent differently
by route of exposure. If it's
known to be a human carcinogen
by the oral route it is tagged as a
known human carcinogen. We
don't emphasize the fact that
data may also show that by the
dermal route it's really not
expected to be a carcinogen haz-
ard. In the future we might be
able to say that it is a known
human carcinogen by the oral
route and something else by the
dermal route.
Over the last few years one of
the biggest controversies dealing
with cancer risk assessment has
to do with questioning the rele-
vance of animal carcinogen bio-
assays to human carcinogenesis.
This issue increasingly confronts
anybody dealing with long-term
animal bioassays. There are cer-
tain tumor types that instantly
.cause people to say "Oh that's
not relevant in considering
human carcinogens." I don't
think current schemes deal with
this issue particularly well and I
don't know whether they need
to. One reason we find it hard to
deal with some of these ques-
tions is that some of the issues
go back to indirect evidence and
the possibility of weighing the
evidence differently. That's why
I am not sure that relevance
deserves special treatment. Nev-
ertheless it is something that
causes people to question the cur-
rent scheme.
Among people in EPA who are
looking at revising the guide-
lines, a lot of discussion has to
do with the relevance of animal
data. How do you discuss things
like that? Where do you make a
place in your classification
scheme to show how you
weighed that kind of issue? How
do we accommodate this fact to
make classification schemes
accommodate what I think is
going to be an exploding data-
base of mechanisms research in
the next 10 or 15 years? I think
we are going to be doing
research in the future for strictly
mechanistic information.
The numbers and letters of classi-
fication schemes are a problem.
This is a personal question for
me; I look down all these lists of
alphanumeric schemes for class-
ifying and I get lost. I can't trans-
late between systems. Numbers
and letters are beginning to get to
me a little bit. I hope we can find
a way to use words for these clas-
sifications. The question of class-
ifying by route of exposure is
under discussion, so that's a pos-
sibility. Another issue is whether
the potency of a carcinogen
should be part of the weight of
evidence. That is, when we say
it's a probable human carcino-
gen, is it at a high dose or at a
low dose? Is it somewhere in the
middle? The question has been
raised about whether those kinds
of issues belong in weight of evi-
dence for the classification
schemes.
In answering these questions
(these are more my statements
than EPA's), I think we will have
to provide more explicit rules
One of the biggest controversies
dealing with cancer risk assessment
has to do with questioning the
relevance of animal carcinogen
bioassays to human carcinogenesis.
The numbers and letters of classifi-
cation schemes are a problem.
Access/Use Info Resources Assess Health Risk Chem Expos '93
101
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and a greater weight for indirect
evidence aside from human stud-
ies and animal bioassays. The
time has come to start classifying
by route of exposure.
I sat down and tried to picture a
matrix that would bring potency
into discussions of whether some-
thing is a potential carcinogen,
given the trouble we have figur-
ing out what the potency is. I
couldn't figure out how to do
that without bogging down.
Some people are trying to push
for a view that something like a
promoter that may have some
kind of threshold is not really a
carcinogen. It is set aside in a
category by itself. A lot of peo-
ple tend to think that carcinogens
are strictly agents that are geno-
toxic and that those are the ones
that should be classified, not pro-
moters. I don't now expect the
agency to categorize differently
according to mechanisms that
may be at work. The means by
which something causes or might
cause cancer is not necessarily
part of the classification. It cer-
tainly would be a limitation, a
part of the hazard charac-
terization, but not necessarily a
part of whether saying something
is or is not potentially carcino-
genic.
We may be able to propose some-
thing next year; I hope we can.
We have not really come to clo-
sure even within our work
groups about how to deal with
many of the issues. We are in the
midst of a sea of data that didn't
exist when the very first guide-
lines came out. A lot of the data
around now—mechanisms is an
example—weren't there; now we
are afloat in it. We will get out
the new guidelines if it's at all
possible, but we probably won't
finish until next year.
The means by which something
causes or might cause cancer is not
necessarily part of the classification.
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EPA's Program for Risk Assessment Guidelines:
Quantification Issues
Michael L. Dour son, U.S. Environmental Protection Agency
The quantitative procedures associated with noncancer risk assessment include reference dose (RfD), benchmark dose, and severity
modeling. The RfD, which is part of the EPA risk assessment guidelines, is an estimate of a level that is likely to be without any
health risk to sensitive individuals. The RfD requires two major judgments: the first is choice of a critical effect(s) and its No
Observed Adverse Effect Level (NOAEL); the second judgment is choice of an uncertainty factor. This paper discusses major
assumptions and limitations of the RfD model
Work on the noncancer
quantitative guide-
lines started in 1984.
After a year of inconclusive dis-
cussion, the technical panel dis-
banded and was replaced by an
Acceptable Daily Intake (ADI)
work group. The point was to get
colleagues together from various
agency offices to look at non-
cancer assessments prepared by
the individual offices. After two
years of ADI work group experi-
ence, the agency restarted its
guideline development for non-
cancer.
This paper will discuss some of
the quantitative procedures asso-
ciated with noncancer risk assess-
ment. The first is reference dose
(RfD). Two other quantitative
procedures exist that are quite
new. One is referred to as a
benchmark dose and the second
is loosely classified as severity
modeling. A fourth procedure
exists called decision analytic
approach, which the Office of
Air Radiation uses with it's air
pollutants, but this will not be
discussed here.
An RfD is an estimate of a level
that is likely to be without any
health risk to sensitive individu-
als. Some think of an RfD as
being below a threshold dose.
This, however, is not necessarily
universally accepted.
The RfD requires two major
judgments, the first of which
after looking at all the data is to
choose a critical effect(s) and its
No Observed Adverse Effect
Level (NOAEL). The second
judgment is the choice of an
uncertainty factor after looking
at the entire data base and deter-
mining the status of missing data.
The first assumption of the RfD
model is that a threshold exists
for toxic effects. Obviously, for
some chemicals thresholds are
thought not to exist. Where a
threshold does not exist for a
toxic endpoint, calculating an
RfD is not appropriate. We also
assume that the RfD represents a
subthreshold dose and that if we
protect against a critical effect,
we protect against all adverse
effects. A major limitation is that
although the choice of the
NOAEL for the critical effect
uses all of the data, in the RfD
model only the NOAEL dose is
used quantitatively. Also, if we
use only a particular NOAEL,
we are losing information in the
Estimating RfD requires choosing a
critical effect(s) and its NOAEL It
also requires choosing a composite
uncerta inty factor.
The first assumption of the RfD
model Is that a threshold exists for
toxic effects. Obviously, for some
chemicals, thresholds are thought not
to exist. Where a threshold does not
exist for the toxic endpoint,
calculating an RfD is not appropriate.
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study on which you have chosen
to focus. Another limitation is
that uncertainty factors are impre-
cise and the RfD model cannot
estimate risks above the RfD.
Regarding the quantitative issues
of the RfD, we have focused dur-
ing the last couple of years on
the statistical variability of a
NOAEL. A paper was published
by Brown and Erdreich in 1988
discussing this effort. The
authors did not focus just on the
value of a NOAEL but also con-
sidered its limitations or variabil-
ity. It is thought that if NOAELs
are based on larger numbers of
animals per dose group, the
NOAELs will tend to decrease
because by looking at more ani-
mals an effect is more likely to
be apparent. Such latter
NOAELs are likely to have a
tighter variability.
Another aspect to this area of
research is looking at data that
fall behind various uncertainty
factors. A publication by Hattis,
Erdreich, and Ballew (1987)
focused on the uncertainty factor
for within-human variability. It
characterized the statistical distri-
bution of the uncertainty factor
on the basis of human pharma-
cokenetic modeling or human
pharmacogenetic parameters.
The authors showed that for
healthy individuals, an uncer-
tainty factor of 10 covered about
96% of the variability. This sup-
ports the notion that tenfold
uncertainty factors are conserva-
tive and that values less than 10
are actually more likely to occur.
Other published work yields
similar distributions. For exam-
ple, EPA often uses a tenfold
uncertainty factor to extrapolate
from a subchronic to a chronic
exposure, as do other federal
agencies. This factor accounts
for about 96% of the compari-
sons of subchronic to chronic
extrapolation; the average factor
is about 2 or 3. One area of our
research is focused on trying to
get a better quantification of
NOAELs, uncertainty, and modi-
fying factors, with the end result
of trying to characterize the prob-
ability distribution of a reference
dose.
Another area of research is the
benchmark dose. Several investi-
gators are looking at this and a
number of papers have been pub-
lished. The first was by Crump
(1984), followed by Dourson et
al., (1985). The idea behind
benchmark dose is to use all of
the data on a particular end point.
A mathematical model is applied
to that data and then an estimate
is made of upper confidence lim-
its, perhaps 95%. Depending
upon how many animals were
used per dose level and how
good the data fit along the slope,
one might get tight 95% confi-
dence limits or you might get
confidence limits that were less
tight. The idea of a benchmark
dose, then, is to focus on a par-
ticular point along this curve. In
the 1984 and 1985 publications,
10% was used, but only as an
example. The lower 95% confi-
dence limit on the dose associ-
ated with a 10% response level
would be the benchmark dose,
and for the rest of the toxicity
database one uses different uncer-
tainty factors. Reasons for differ-
ent uncertainty factors might
include disparate severity of
effects and slopes of dose-
response curves. Again, the
benchmark dose is one way of
using more of the information to
get a reference dose. Other issues
regarding the benchmark dose
Our research is focused on trying to
get a better quantification of NOAELs,
uncertainty factors, and modifying
factors, with the end result of trying to
characterize the probability
distribution of a reference dose.
The idea behind benchmark dose is to
use all of the data on a particular end
point. A mathematical model is
applied to that data and then an
estimate is made of upper confidence
limits, perhaps 95%.
104 Access/Use Info Resources Assess Health Risk Chem Expos '93
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approach include deciding which
end point to choose as the bench-
mark. Several published exam-
ples used 10%, but 1%, 5%, or
other values could be chosen.
With these various benchmarks,
which type of uncertainty factor
should be applied? Several statis-
tical issues exist as well, but
these will not be discussed.
Another idea is to plot what is
called the severity of the toxic
effect. Even before the idea of
severity of toxic effect can be
broached, there are a host of
issues associated with adversity
and severity of effect that are not
well worked out even within the
Agency. For a particular organ
system, it might be very easy to
say some effects are clearly not
adverse and that some effects are
clearly adverse. For example, an
increase in smooth endoplas-
matic reticulum in the liver,
clearly caused by the chemical,
may not be an adverse effect. In
fact, it might be protective;
whereas infiltration of liver cells
with fat is clearly a sign of dis-
functioning liver cells and is con-
sidered adverse. However, for
developmental toxicity the ques-
tion of what is adverse may not
be as clearly defined. In some
areas, such as immunotoxicol-
ogy, what constitutes an adverse
effect is only now being dis-
cussed. Let us assume for the
moment that we have a good han-
dle on the differences. Then, for
any particular chemical it is pos-
sible to plot the probability of a
No Observed Effect Level, the
probability of a NOAEL, and the.
probability of other categories of
toxicity with increasing dose.
One can then take several dose
scales for different chemicals,
normalize them, and compare the
various risks of different chemi-
cals above the RfD based on plot-
ting the severity data for each
individual chemical. On the basis
of this analysis, the risk manager
might choose to regulate chemi-
cal B differently than chemical C
if they were both over the RfD
by a tenfold factor. As with
benchmark dose, many issues
also exist with severity model-
ing. For example, what consti-
tutes an adverse effect? What
does the severity of effect mean?
The mathematical model cur-
rently used is just one of many
that could be used, and there is a
discontinuity in the curve that
hasn't been solved yet.
In summary, EPA uses reference
doses for noncancer risk assess-
ment. This method is part of our
developing risk assessment
guidelines. In addition to the
RfD, other quantitative
approaches exist such as the
benchmark dose, and the severity
of toxic effect. More publica-
tions on these quantitative proce-
dures may find their way into the
literature in the near future.
Even before the idea of severity of
toxic effect can be broached, there are
a host of issues associated with
adversity and severity of effect that
are not well worked out even within
the agency.
One can then take several dose
scales for different chemicals,
normalize them, and compare the
various risks of different chemicals
above the RfD based on plotting the
severity data for each individual
chemical.
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EPA's Program for Risk Assessment Guidelines:
Exposure Issues
Michael A. Callahan, U.S. Environmental Protection Agency
Three major issues to be dealt with over the next ten years in the exposure assessment field are: consistency in terminology, the
impact of computer technology on the choice of data and modeling, and conceptual issues such as the use of time-weighted
averages.
The first exposure assess-
ment issue, terminology,
needs to be dealt with
immediately. The definition of
exposure itself has been contro-
versial. There is general agree-
ment that exposure to a chemical
substance means contact of that
substance with a person or other
organism, and that exposure
assessment is the qualitative or
quantitative description of that
contact: intensity, duration, fre-
quency, and route. Other aspects
of the terminology, however, are
not standardized. These include
differences in how the terms
'exposure' and 'dose' are used,
units for each, and differentiation
of different types of dose: for
example administered dose,
applied dose, and absorbed dose.
the U.S. Environmental Protec-
tion Agency (EPA) expects that
its Guidelines for Exposure
Assessment [57 FR 22888],
which includes a glossary of
terms, should be the major vehi-
cle in assuring consistency in ter-
minology both within the
Agency and with the outside sci-
entific community.
The second issue which must be
dealt with in the next few years,
is the potential impact of com-
puter technology on data collec-
tion, interpretation and avail-
ability. The technology exists to
put enormous data storage and
retrieval capabilities in the hands
of assessors through personal
computers with CD-ROMs. EPA
has begun investigations of the
usefulness of a risk assessment
library on CD-ROM [EPA/600/9-
91/045 a] and a collection of mod-
els with their documentation on
CD-ROM [EPA/600/C-92/002].
These have enormous potential
for positive impact on the expo-
sure assessment field. However,
without validation of models, the
availability of large amounts of
data and models might raise the
question of validity of the assess-
ments, which would be a nega-
tive impact on the field. We are
at a crossroads today and it is up
to the exposure assessment com-
munity to make a wise choice of
paths.
The third issue which must be
dealt with in the next three to ten
years, has to do with the basic
way in which carcinogen expo-
sure assessments are done. The
almost universal use of time-
weighted averages for these
types of assessments will face a
serious challenge as new toxico-
logical models such as biologi-
cally-based dose-response
models are developed. These
Aspects of terminology, however,
are not standardized. These
include differences in how the
terms 'exposure' and 'dose' are
used, units for each, and
differentiation of different types of
dose:
The technology exists to put
enormous data storage and
retrieval capabilities in the hands
of assessors through personal
computers with CD-ROMs.
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new models will require more
detail from the exposure assess-
ment than just a time-weighted
average exposure or dose. In
some cases, a detailed time-
intensity profile will be required
as input to the dose-response
model. This is a challenge for the
exposure assessment community
that must be addressed and met
soon. Only then will we be ready
for the types of risk assessments
we can expect in the latter part of
the 1990s.
This is a challenge for the
exposure assessment community
that must be addressed and met
108
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Information Applications: Rapporteur Summary
Sidney Siegel, National Library of Medicine
An increased level of mathematical sophistication will be needed in the future to be able to handle the spectrum of information as it
comes from a broad array of biological systems and other sources. Classification will be an increasingly complex and difficult
issue. Several projects that are discussed are being developed by the U.S. Department of Health and Human Services (DHHS),
including a directory of risk assessment projects and a directory of exposure information resources.
As rapporteur to this
group, I will quickly
identity what I believe
has been said and what was not
said. Also, I may comment on
what could be. Through discus-
sions, we can hopefully generate
within the symposium partici-
pants a sense of quo vadis: where
are we going and why? Efforts to
put this symposium together
were obviously very intense. I
have put conferences together
myself, and it can be described
as pure aggravation. Throughout
the discussions, I had the impres-
sion that many presentations
could be characterized as preach-
ing to the converted. I think
many of the folks here don't
have to be converted or need to
have identified again what the
problems are that we face; we
need now to say which way we
are going. We need to address
issues relevant not only to which
way we should go but also why.
Session A covered chemicals,
health effects, and information
needs. The titles were The Prob-
lem of Living in a World Con-
taminated With Chemicals,
Environmental Laws Regulating
Chemicals, Information Needs
for Risk Assessment, and Infor-
mation Needs for Risk Manage-
ment Communication—all not
only interesting but very difficult
and ill-defined subject areas. The
history and development of an
awareness of the impact of
chemical agents on humans and
on the other compartments of the
environment were outlined.
Laws relevant to this symposium
were identified. However, we
should be sensitive to the fact
that there are at least 18 major
pieces of federal legislation that
impact the development, produc-
tion, distribution, use, and even-
tual disposal of chemical agents.
This listing does not include
laws that have been promulgated
by the 50 states. This session
also addressed some of the com-
plexities associated with identify-
ing and utilizing data and
information that could be suppor-
tive of the assessment and man-
agement of risk. Problems
associated with coordinating risk
management across federal
and/or state agency lines, espe-
cially when Superfund sites are
involved, were discussed. These
problems are not trivial.
Session B, Toxicology Informa-
tion Resources, Challenges, and
Needs, described the evolution
of systems and reminded me
some of discussions on the the-
ory of chaos. It is also apparent
that Session B chaos can be
ordered through the appropriate
There are at least 18 pieces of major
federal legislation that impact the
development, production,
distribution, use, and eventual
disposal of chemical agents.
Problems associated with
coordinating risk management
across federal and/or state agency
lines, especially when Superfund
sites are involved, are not trivial.
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109
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and imaginative application of
computer-based technology.
Session C dealt with the applica-
tion of toxicology information in
establishing priorities, chemical
testing, hazard ranking, and risk
assessment In this regard, Struc-
ture Activity Relationships
(SAR) was addressed as one of
means to assess issues relevant to
new chemical substances under
TSCA, as was the use of Quanti-
tative Genetic Activity Graphical
Profiles (GAP) for Use in Chemi-
cal Evaluations. The Interagency
Testing Committee Chemical
Nomination and Selection Proc-
ess was discussed. (During my
time at the National Cancer Insti-
tute [NCI] I had $250,000 to sup-
port activities relevant to QSAR,
but I couldn't get other branch
chiefs involved because they felt
QSAR was too close to the prac-
tice of witchcraft.)
We heard a discussion of the
GAP information profiles that
identify the start of accumulating
the intelligence base that will be
a new means to help us under-
stand the relationships in and
among a broad spectrum of dif-
ferent kinds of data. I think this,
is going to be one of the more
interesting and intriguing areas
of the future. An increased level
of mathematical sophistication
will be needed to handle informa-
tion derived from a broad array
of biological systems and other
sources. We have just started to
address the potential of those
kinds of multidimensional infor-
mation processing resources.
In Session D, Guidelines Used to
Assess Toxicological Hazards,
the titles included were Overview
of t lie EPA Programs for Risk
Assessment Guideline
Development, Cancer Classifica-
tion Issues, Quantification
Issues, and Exposure Issues. Sci-
entific issues were discussed that
in and of themselves are diffi-
cult; these issues are further con-
founded by the fact that they are
required to be precisely defined
in order to be implemented under
law. Such definitions will require
involvement of all our communi-
ties and interested citizens includ-
ing the federal and state
organizations responsible for
their application. Especially high-
lighted during this session was a
concept that goes back beyond
Linnaeus to the time when we
had witchdoctors and shamans
guiding us through our daily
lives. That is the concept of the
classification of toxic substances.
These witchdoctors and shamans
were able indeed to roughly sort
out some of the classifications of
substances that they dealt with.
This was done by setting up cap-
tured prisoners of war into three
groups—one group got the
unknown substance, a second
group a known agent, the third
group nothing. So, they quickly
could do LDsos concerning the
substances, and the shamans
could further build their own trea-
tise on poisons useful for man-
agement. Thus, classification has
been around for some time. Clas-
sification is not a trivial issue
because once you put a tag on
something, you are stuck with it,
especially if you are part of a
regulatory function of govern-
ment. By misclassification you
may hang yourself as well as
other federal and state agencies
out to dry. Of course, in addition,
there are significant impacts on
private-sector organizations that
must respond under law to such
classifications.
An increased level of mathematical
sophistication will be needed to
handle this information from a broad
array of biological systems and
other sources.
Classification is not a trivial issue
because once you put a tag on
something you are stuck with It If
you are pan of a regulatory function
of government.
110 Access/Use Info Resources Assess Health Risk Cliem Expos '93
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Some of the things coming in the
near future are projects, that I
think will be useful to all the
organizations represented here.
First, in the DHHS we are trying
to put together a Directory of
Risk Assessment Projects. Risk
assessment activities are costly
projects and people need to be
aware of what has been paid for
with public funds. I thought
when I got the money for the
effort it was going to be a techni-
cal piece of cake; technically, it
is a piece of cake. Then we ran
into the political issues — trying
to get the heads of the various
DHHS agencies to identify the
risk assessment projects in their
organizations. Things are mov-
ing forward, however. We have
had excellent cooperation from
one of our organizations in
DHHS, the National Center of
Toxicologic Research (NCTR)
represented at this meeting by
Angelo Turturro. It has been pos-
sible to work together to sort out
which of their projects would be
relevant for such a directory.
Another activity, which in its
own way is going to be politi-
cally even more difficult, has got-
ten support from the Interagency
Task Force on Cancer, Heart, and
Lung disease. It is a directory of
exposure information resources
developed across the federal
establishment; we hope to extend
it to include state environmental
and health agencies. So far, a 20-
page questionnaire is now being
tested by a limited number of
organizations. Of all the informa-
tion needs concerning risk assess-
ment and management and the
effects of chemical agents on
humans and other compartments
of the environment, the greatest
need is for information on expo-
sure that is scientifically timely,
complete, and credible.
Yesterday, we heard about the
many prioritization schemes out
there. Federal agencies have put
together between 36 and 40
major prioritization schemes
over the years, of which I have
been involved in about half.
These are variations on a basic
theme—What is the substance,
how much is produced, and
where and how is it distributed
and used? Details of such
schemes are driven by the needs
of the particular organization
compiling it. We need much
more sophistication in the vari-
ous models that are used to sup-
port the assessment and manage-
ment of risk. The sophistication
or applicability of models needs
to be increased. In communicat-
ing with users and affected com-
munities, we need to explain the
capabilities and limitations of a
particular model.
This symposium understandably
focused only on chemical agents.
However, humans and other com-
partments of the environment are
also concomitantly exposed to
biological and physical agents,
making the overall picture of
exposure even more interesting
and complex. Looking at only
one dimension of exposure is
naive and will not serve us well.
To address exposure overall will
require a significant effort in
communication and coordination
among federal and state agencies
and into the private sector. The
problems we face in this effort
can be best described as nontriv-
ial, and solutions will require the
best input we can get.
Finally, I leave you with a quote
that was translated into Latin by
We are trying to put together a
Directory of Risk Assessment
Projects.
Of all the Information needs
concerning risk assessment and
management and the effects of
chemical agents on humans and other
compartments of the environment, the
greatest need Is for Information on
exposure that Is scientifically timely,
complete, and credible.
Access/Use Info Resources Assess Health Risk Chem Expos '93
111
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the daughter of one of the people
in my office who is quite a
scholar. It's a takeoff on Rene'
Descartes and simply says "If I
think a system, it can be built."
As you see what your needs are,
imagination should be the least
limiting factor in determining
how to efficiently and effectively
meet them. "Si Rationem Puto,
Potest, Achficari!"
We need much more sophistication in
the various models used to support the
assessment and management of risk.
112 * Access/Use Info Resources Assess Health Risk Chem Expos '93
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How Information Resources are Used by Federal
Agencies in Risk Assessment Applications
William E. Legg, U.S. Army Environmental Hygiene Agency
This paper discusses the structure and responsibilities of the U.S. Army Toxic and Hazardous Materials Agency.
In the mid-1970s an agency
was established within the
Department of Defense,
known as the U.S. Army Toxic
and Hazardous Materials Agency
(USATHAMA). The primary
reason for starting this organiza-
tion was the Rocky Mountain
Arsenal in Denver, Colorado.
Those of you familiar with
Rocky Mountain Arsenal know
that there are about 165 func-
tional hazardous waste sites at
the arsenal. They are contami-
nated with such things as diiso-
propylmethyl phosphinate, other
chemicals associated with the
production of nerve and blister-
ing chemical warfare agents, and
several general-category indus-
trial chemicals. Since the incep-
tion of USATHAMA, the ,
number of problem installations
has risen, and thus, Rocky Moun-
tain Arsenal is no longer our sole
problem. For example, 34 Army
installations have been identified
with 36 functional sites that are
either on the National Priority
List (Superfund) or are proposed
for Superfund listing. In
Resource Conservation and
Recovery Act (RCRA) facility
investigations alone, there are
some 3500 installations that deal
with roughly 5000 functional
sites. It's a target-rich environ-
ment for any risk assessor.
Approximately 18 months ago,
the Surgeon General of the Army
recognized the need for medical
review of the health risk assess-
ments. Inherent in this review
process is the tenet that the Sur-
geon General of the Army is
responsible for the health and
well-being of all military and
civilian personnel working on
Army installations. Further, the
Surgeon General has assigned
the U.S. Army Environmental
Hygiene Agency (USAEHA) the
task of serving as his executing
agent for review and perform-
ance of health risk assessments.
Therefore, Program 39, of which
I am the chief, was created.
At USAEHA, we have what I
refer to as the "olive drab" ver-
sion of the Environmental Protec-
tion Agency (EPA). We
continuously interact with EPA
headquarters. Currently, we are
assisting Mr. Chet Osmond from
the Office of Solid Waste in con-
ducting energetic compound tech-
nology transfer information
seminars throughout the United
States. The military has several
sites that perform open burn-
ing/open detonation of explo-
sives and propellants in above-
ground and below-ground dis-
posal operations. Many things
can go wrong in these opera-
tions, and we are trying to assist
the permit writers in determining
Thirty-four Army installations have
been identified with 36 functional
sites that are either on the National
Priority List (Superfund) or are
proposed for Superfund listing.
The Surgeon General of the Army
recognized the need for medical
review of health risk assessments.
Access/Use Info Resources Assess Health Risk Chem Expos '93 113
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the associated environmental and
health concerns.
I have 8 individuals, including
myself, executing the health risk
assessment mission. I have
approval to fill 32 positions to
accomplish the mission.
Our agency has a matrix struc-
ture. We are staffed in director-
ates and divisions that
incorporate the disciplines of
toxicology, air pollution engi-
neering, surface-water and
groundwater sciences, health
physics, laser and microwave
technology, entomology, occupa-
tional and environmental medi-
cine, and so on. I draw from the
expertise in these directorates/
divisions to form the risk assess-
ment review or on-site risk
assessment teams.
What problems do I see in this
arena? For reasons similar to
those already discussed this
morning, there is a need to con-
solidate and integrate the numer-
ous databases for ease of use.
The 30 or 40 databases available
are extremely difficult to use
because of differences in the pro-
gramming language/hierarchal
structure of the programs. Simi-
larly, some commonality of use
of program type is needed across
the board, not only from the user
and contractor's perspective, but
also from the EPA regional
perspective.
Finally, I believe that we are not
adversaries in this endeavor; we
must be partners. The result
should be a clean environment
that is protective to human
health. We must accomplish our
tasks as partners, not as
adversaries.
We need to consolidate and integrate
the numerous databases for ease of
use.
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Tactical Approach to Maneuvering Within the
Chemical Contamination Labyrinth
Timothy W. Joseph, Department of Energy
The Department of Energy (DOE) recognized the need and accepts the responsibility for understanding the reality and mitigating
the consequence of the complex chemical contamination legacy It Inherited as well as controlling, reducing, and eliminating extant
emissions and effluents. The key to maneuvering through this complicated and muUifaceted labyrinth of concerns, from which a
meaningful, high quality, and cost-effective restoration/mitigation machine is then set in motion, is the ability to perform accurate,
factual, and explicit health and environmental/ecological risk assessments. Likewise, the common denominator for carrying out this
essential task is to have access to comprehensive and reliable data of known quality with which to perform those analyses. DOE is
committed to identify the data universe; to technically scrutinize and ensure the quality of that data; to develop efficient and cost-
effective means to maximize the handling, utilization, and sharing of that universe; and to undertake those assessments. DOE views
this as an effort that can only be accomplished through a merging of the technical excellence that exists within federal and state
agencies, academia, and industry. The task at hand is so large that only by integrating that intelligence base can we hope to
accomplish the goals of establishing meaningful standards, developing functional and effective solutions, and providing quality
guidance at a national scale.
No matter how good our
models are, no matter
how applicable the
assessment techniques are, and
no matter how proficient the
experts are in dealing with these
problems, the ability to perform
environmental, ecological, and
human health risk assessments
relies entirely on the universe of
data. It is perhaps the most per-
plexing and complicated part of
our assessment. Models can be
adjusted and verified, techniques
can be improved, and more can
be learned. However, we cannot
merely acquire all the data we
need.
Historical data, that abyss we
find ourselves so often trying to
analyze, is finite; it's all we have.
We must deal with its integrity
and its relevance. We must know
how to .best utilize the historical
data that we have. New data,
especially chemical data, is very
costly to collect and analyze.
Laboratory toxicological data
and environmental and ecologi-
cal effects data can make the
chemical data cost look cheap in
comparison. It is the access and
use of that data universe that we
rely on to carry out our analysis.
In performing assessments, we
start with historical data. We
look at all past operational data
that we can find, such as what
the facilities did, how long they
were in use, what materials were
used or must have been used,
and any operating parameters/
specifics we can determine. We
look at operational history and
any records we can find, such as
old manifest or disposal records;
we talk to past employees. We
then try to correlate what hard
information we find with what
we believe should have been tak-
ing place in that facility if they
were doing what we know or
believe they were supposed to.
We then attempt to determine
actual disposal methods or what
logic tells us would have been
their disposal methods at the
time. We look closely at the envi-
ronmental setting, old photos,
In performing assessment, we look at
past operational data, such as what
the facilities did, how long they were
in use, what materials were used or
must have been used, and any
operating parameters/specifics we can
determine. We look at operational
history and any records we can find,
such as old manifest or disposal
records; we talk to past employees.
Access/Use Info Resources Assess Health Risk Chem Expos '93 115
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old maps, how the area has
changed since that time, what
areas were used for disposal, and
what areas would probably have
been used for disposal. We look
at the natural setting, the soils,
the geochemistry, the geology
and hydrology—subsurface and
surface. We look at climatic and
meteorological data to address
transport and fate. It is impera-
tive that we fully understand the
transport and fate mechanisms
for the facilities that have been
operating for more then 45 years.
We then determine the contami-
nants on which we will concen-
trate. Critical, of course, is the
quality of the data. Are they
valid? How were they collected?
If data exist on volatiles, were
samples collected in a bucket and
then dumped in a sampling jar?
If so, those data are useless. We
look at the analytical aspects —
did the sample preparation intro-
duce contaminants? How accu-
rate and precise was the instru-
mentation vs the detection limit?
Was the detection limit influ-
enced by moisture content? We
need to understand the multitude
of aspects associated with the
quality of the data, which is
sometimes very difficult to deter-
mine and more often than not,
cannot be determined.
Next, we establish a list of tenta-
tively identified compounds. We
look at it, and compare it with
our knowledge of the facility. We
then may be forced to go back
because things don't correlate.
We attempt to determine back-
ground. It is preferable, however,
to use the word "reference"
rather than "background."
"Background" is an uncertain cri-
terion. Is it 100, 150, or 500
years ago, or is it some number
of years BC? Unless we can
beam up to the Starship Enter-
prise and use its sophisticated
sensors, we don't know what
background is or should be.
Where do we see the compound
or chemical? Where would we
expect to see it naturally and at
what levels? We have experi-
enced 150 years of industrializa-
tion with an extreme variety of
effluent and emissions; we have
more lead in our environment, as
identified to us yesterday, from
our automobiles than from indus-
try. From agriculture we have
complex of insecticides, herbi-
cides, etc. How do they change?
What about synergy? How long
have they been there? This com-
plicates determination of back-
ground. Background implies
"before man's influence, com-
pletely natural," whereas refer-
ence suggests "normal, expected,
prior to any influence from the
subject facility."
We then try to correlate the con-
taminants and concentrations
with locations, factor what we
believe the "reference" concen-
trations should be, sample
selected environmental and eco-
logical parameters and organ-
isms, and perform selected
toxicity studies when warranted.
We also use biological sampling
in an attempt to back-calculate
environmental contaminant lev-
els. This is an extensive, very
complicated, and expensive pro-
cedure. Without reliable data of
known quality, we are signifi-
cantly restricted in what we can
do. With good data, we can deter-
mine or reconstruct sources and
doses.
Having what we consider to be
good data, we must then be able
to accurately determine the
We need to understand the multitude
of aspects associated with the quality
of the data, which sometimes is very
difficult to determine and more often
than not, cannot be determined.
We try to correlate the contaminants
and concentrations with locations,
factor what we believe the
"reference" concentrations should be,
sample selected environmental and
ecological parameters and organisms,
and perform selected toxicity studies
when warranted.
116 Access/Use Info Resources Assess Health Risk Chem Expos '93
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actual risks and project with
some precision the potential
risks. How we do that is impor-
tant. The best minds in govern-
ment, industry, and academia are
working on just that. New qual-
ity guidance from Environmental
Protection Agency (EPA) and the
universities is available and
growing. Recent documents
from EPA are quite impressive.
It is a complicated yet very excit-
ing field. With our severely lim-
ited budgets, greater scrutiny
from congress, and the public,
we can only keep our heads
above water and progress toward
solutions to these complex and
very "expensive" problems by
combining our respective intelli-
gence to achieve solutions. The
best tactical maneuver we can
make is to join forces, combine
that intelligence base, and
become an efficient and effective
technical team. Together, we can
become both the model of techni-
cal excellence, as well as the
model for approaching and
accomplishing quality, verifiable,
and reiteratable risk analysis.
One positive consequence of the
pressures placed on our agencies
as a result of these limited budg-
ets is that.it has brought us
together as partners in solving
these problems, in contrast to
working in our own respective
closets, emerging once in a while
to merely state positions or make
criticisms. The cooperation
between our agencies, the states,
industry, and academia, has been
Outstanding. The number of guid-
ance documents generated, tech-
nical publications developed and
written through joint reviews,
planning efforts made, and the
close technical collaboration
achieved between us, has pro-
duced a genuine technical and
professional regard and fellow-
ship.
This complex and enigmatic
national concern—health and
environmental risks of chemical
exposure—requires an even
greater team effort. Again, the
best tactical measure we can take
is to combine that joint intelli-
gence. In a very real sense, we
simply can't solve the problems
by ourselves or merely wish
them away. DOE is steadfastly
committed to do all it can toward
assessing the problems and reach-
ing solutions. It will continue to
provide the most accurate and
complete data base possible and
engage the best scientists to do
the best research to achieve this
goal.
The best tactical maneuver we can
make is to join forces, combine that
intelligence base, and become an
efficient and effective technical team.
One positive consequence of the
pressures placed on our agencies as
a result of these limited budgets is
that it has brought us together as
partners in solving these problems,
in contrast to working in our own
respective closets, emerging once in
a while to merely state positions or
make criticisms.
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Information Resource Use and Need In Risk
Assessment
Angela Turturro, U.S. Food and Drug Administration
The manner in which the Food and Drug Administration (FDA) uses information resources comprises an interesting illustration of
federal agency information use. A description of the context in which risk assessment occurs within FDA is followed by a discussion
of information access and use, as well as a practical example.
FDA has six Centers, three
of which address regula-
tion of drugs, biologies
(e.g. vaccines) and devices (e.g.,
pacemakers), and radiation
health. The evaluation of risk of
drugs and biologies is a process
incorporating judgement and
involving risk comparison. The
agents are being considered
because they solve some therapeu-
tic problem; judgement of their
safety and efficacy must weigh in
as considerations the results of
not using them as well as the
existence of alternatives.
These factors with the addition of
engineering considerations are
also important to making evalu-
ations about medical devices. Not
only does the chronic toxicity of a
device, such as an artificial heart
have to be considered, as does its
capability to do the job, there also
has to be a judicious evaluation of
factors such as the possible fail-
ure of the device. In many ways
the requirements for an assess-
ment for a device are more simi-
lar to the kind of assessment
being done by the Nuclear Regu-
latory Commission for possibili-
ties of a nuclear plant failure than
to the kind of assessments an
agency like the U.S. Environ-
mental Protection Agency (EPA)
does on agents. Thus, these
responsibilities are performed by
using a risk assessment methodol-
ogy that is oriented toward their
risk-balancing procedures.
Risk assessment stresses other
considerations in the remaining
three FDA Centers. Risk assess-
ment in the Center that deals with
veterinary drugs is most often
directed at the risks associated
with the residues of drugs given
to animals when they are used for
food. When considering this spe-
cialized area, the efforts are simi-
lar to those conducted by the
Center that addresses the safety of
the food supply, which, oddly
enough, also evaluates the risks
of cosmetics. Risk assessments
similar to these are performed at
the National Center for Toxico-
logical Research, which also con-
ducts research into general
questions related to risk
assessment.
These differences emphasize the
point that risk assessment is part
of risk management (Turturro and
Hart 1987). Nobody does a risk
assessment unless it is for a regu-
latory reason, and the reason for
the assessment impacts on the
assessment itself. If the purpose
of an assessment is to weigh
The evaluation of risk of drugs and
biologies is a process incorporating
judgement and involving risk
comparison.
Risk assessment is part of risk
management.
Access/Use Info Resources Assess Health Risk Chem Expos '93
119
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alternatives for a necessary proce-
dure, it will be conducted differ-
ently than if the purpose is to set
limits for unwanted contamina-
tion. Using chronic feeding toxic-
ity studies is problematic for
estimating the toxicity of a drug
given over a short period of time,
although germane to the assess-
ment of a food contaminant
Information Resource Use
Deriving good exposure informa-
tion is much simpler for a drug
or biologic than for many other
agents. Drugs are usually given
under strictly controlled regimes.
In addition, the companies mak-
ing these products are required to
perform studies on humans,
reducing the problems associated
with animal-to-man extrapola-
tion. However, drugs are given
to sick people, and often to very
limited numbers with limited
representation of sensitive sub-
populations. In addition, drug
toxicity studies are almost
always of short duration, and
considerations of toxicity are lim-
ited to a few years of follow-up.
For drugs and biologies, there-
fore, simple evaluation of clini-
cal testing protocols is needed to
estimate exposure. Toxicity infor-
mation is estimated from human
studies, complemented by a com-
prehensive program of post-
market surveillance to supple-
ment information on toxicity.
Animal and short-term toxicity
information is used as a guide-
line to help define the limits of
the human exposures.
For devices, in addition to the
necessity to consider the conse-
quences of not using the device,
there are special considerations
of engineering aspects. Thus, the
Devices Center utilizes informa-
tion from materials science and
physics to estimate the prob-
ability of failure. Much of this is
proprietary data derived from
studies performed by the compa-
nies attempting to sell the device.
The major focus of the assess-
ment of risk associated with ani-
mal drugs concerns the residues
of drugs in animal products and
the risk to humans. Conceptually,
they are treated similar to
unwanted contaminants in food,
thus the information needs are
similar to those for the risks asso-
ciated with food.
In considering the risks associ-
ated with foods, it is useful to
appreciate that most of the FDA
effort is traditionally concen-
trated on the handling and con-
taminants of foods. The natural
constituents of food are consid-
ered safe by definition. This
assumption is maintained despite
the evidence of comparative
epidemiology that approximately
35% of all preventable cancer in
the United States is a result of
natural food constituents (Doll
and Peto 1981), and more recent
evidence that calorie intake is the
most significant factor in the
modulation of induced and
chronic toxicity, as well as spon-
taneous disease (Turturro and
Hart 1991).
Example
To illustrate the information
required for a risk assessment,
consider one performed for a cos-
metic color used mostly in lip-
stick (Hart et al. 1986). Risk
assessment has two major com-
ponents: exposure and toxicity.
For cosmetic skin exposure,
there are a number of factors to
consider: for example, applica-
Ifthe purpose of an assessment is to
weigh alternatives for a necessary
procedure, it will be conducted
differently than if the purpose is to
set limits for unwanted
contamination.
The major focus of the assessment of
risk associated with animal drugs
concerns the residues of drugs in
animal products and the risk to
humans.
120
Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
tion, penetration, and both local
skin effects and systemic effects.
The keys to skin exposure to cos-
metics are behavior and concen-
tration. To evaluate the exposure
to a compound in lipstick, such
questions as how and how often
it is applied and when it is used
need to be answered. In evaluat-
ing these factors, we found little
if any information on how many
times lipstick is reapplied, its
ingestion, or its absorption
through the lips. The concentra-
tions of the substances in the
dyes used in the lipsticks were
dependent on the particular lip-
stick being considered.
For toxicity, there was informa-
tion on pure color, but very little
on the complex formulations
used in real life. This was ironic
since the goal of risk assessment
is to determine the risk of toxic
agents under practical conditions
of use and exposure. The infor-
mation available was almost
never on practical combinations
of colors, or practical conditions
of exposure.
When Is There
Enough Data?
One important question in using
information resources is the ques-
tion of when there is enough data
to make a decision. In trying to
determine when there is enough
data, it is important to under-
stand that risk assessment is
often not four steps in a hierarchi-
cal process but actually a compi-
lation of information. One puts
all that is known into a box and
tries to organize the information.
That's why there will never be
enough data for a risk assessor;
the more data there is available,
the more data is used. An
attempt is made to identify data
gaps: glaring problems in mak-
ing the extrapolations necessary
to come to a conclusion.
An irony is that closing data gaps
does not always result in a per-
ceived increase in certainty. In
the past, one was not necessarily
aware of the many tacit assump-
tions about important factors
used in risk assessment due to a
lack of data and understanding.
Often, questions related to phar-
macokinetic and susceptibility
differences in species and indi-
viduals, or problems in the
response of a cell to an agent,
were not even considered. Now
as we are developing more infor-
mation about the effect of an
agent at the cell membrane, we
become more and more aware of
our lack of understanding. For
example, there was an assump-
tion that if a compound was car-
cinogenic in a rodent bioassay, it
was carcinogenic in people. This
assumption is now changing.
What should be understood is
that any current problem with
certainty is actually a problem in
perception of uncertainty. In the
past, risk assessors did not appre-
ciate how uncertain they actually
were. As we come to grips with
the quantitation of risk and incor-
porate current information, we
will be able to achieve a much
more accurate representation of
risk.
Conclusions
Information on exposure to com-
pounds, with the exception of
drugs and biological agents, is
hard and expensive to attain;
however, it is critical to efforts of
understanding toxicity under
practical conditions of use and
exposure. Information allowing
valid estimation of variability of
The information available was almost
never on practical combinations of
colors, or practical conditions of
exposure.
Information on exposure to
compounds, with the exception of
drugs and biological agents, is hard
and expensive to attain.
Access/Use Info Resources Assess Health Risk Chem Expos '93
121
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"contaminants" is often missing,
and, while extremely valuable, is
expensive to obtain. Toxicity
information in animals is often
available for pure compounds,
but people are almost never
exposed to pure compounds and
the effects of combinations of
agents are relatively unknown.
It can be seen that there are obvi-
ous needs for comprehensive
databases in a number of areas to
assist risk assessment, especially
in quantitating human exposure.
Efforts to improve these relevant
information sources will be very
useful in improving accuracy and
increasing the ability to conduct
risk assessments.
References
Doll, R. and R. Peto. 1981. The causes
of cancer Quantitative estimates of
avoidable risks of cancer in the United
States today. J Natl. Cancer Inst
66:1193-1308.
Hart, R.W., S.C. Freni, D.W. Gaylor,
J.R. Gillette, L.K. Lowry, JM. Ward, E.
K. Weisburger, P. Lepore, and A. Tur-
turro. 1986. Final report of the color
additive scientific review panel. Risk
Analysis 6(2):117-54.
Turturro, A. and R. Hart. 1987. Quanti-
fying risk and accuracy in risk assess-
ment: The process and its role in risk
management problem solving. Med.
Oncol. and Tumor Pharmaco. Ther.
4:125-32.
Turturro, A. and R.W. Hart. 1991. Lon-
gevity-assurance mechanisms and
caloric restriction. Annals New York
Academy of Sciences 621:363-72.
It can be seen that there are obvious
needs for comprehensive databases in
a number of areas to assist risk
assessment, especially in quantitating
human exposure.
122 Access/Use Info Resources Assess Health Risk Chem Expos '93
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Risk Assessment Activities at NIOSH:
Information Resources and Needs
Leslie T. Stayner, Theodore Meinhardt, Bryan Hardin,
National Institute for Occupational Safety and Health
Under the Occupational Safety and Health, and Mine Safety and Health Acts, the National Institute for Occupational Safety and
Health (NIOSH) is charged with development of recommended occupational safety and health standards, and with conducting
research to support the development of these standards. Thus, NIOSH has been actively involved in the analysis of risk associated
with occupational exposures, and in the development of research information that is critical for the risk assessment process. NIOSH
research programs and other information resources relevant to the risk assessment process are described in this paper.
Future needs for information resources are also discussed.
Under both the Occupa-
tional Safety and Health
Act (Public Law 91-596)
and the Mine Safety and Health
Act (Public Law 95-164), the
National Institute for Occupa-
tional Safety and Health
(NIOSH) is charged with devel-
oping recommended occupa-
tional safety and health stan-
dards, and conducting research
to support development of those
recommended standards.
NIOSH regards risk assessment
as a critical element in its deci-
sion logic for making recommen-
dations for standards when suit-
able data is available. Although
NIOSH has only limited regula-
tory authority (pertaining to the
testing and certification of respi-
rators and coal mine dust sam-
plers), the Institute's research,
recommendations and risk analy-
sis have had a substantial impact
on the regulatory actions of a
number of agencies such as the
Occupational Safety and Health
Administration (OSHA), the
Mine Safety and Health Admini-
stration (MSHA), and the Envi-
ronmental Protection Agency,
Occupational safety and health
hazards are evaluated on a case-
by-case basis. To develop a rec-
ommended standard, NIOSH
performs a comprehensive assess-
ment of all relevant research
information and, when possible,
a quantitative risk assessment.
The Institute's recommendations
with the accompanying detailed
analysis are published as Criteria
Documents and Current Intelli-
gence Bulletins. Less detailed
analyses, focused on specific
injury or disease occurrences,
may be published as Alerts or in
other publications. These publica-
tions are formally transmitted to
OSHA and MSHA in accordance
with requirements of the
Occupational Safety and Health
Act and the Mine Safety and
Health Act.
The purpose of the Occupational
Safety and Health Act is "... to
assure so far as possible every
working man and woman in the
Nation safe and healthful work-
ing conditions..." (Section
2(b)). The Act further charges
NIOSH, acting for the Secretary
of Health and Human Services,
NIOSH regards risk assessment as a
critical element in its decision logic
for making recommendations for
standards.
The Institute's recommendations are
published as Criteria Documents and
Current Intelligence Bulletins.
Access/Use Info Resources Assess Health Risk Chem Expos '93
123
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to "... describe exposure levels
that are safe for various periods
of employment, including but
not limited to the exposure levels
at which no employee will suffer
impaired health or functional
capacities or diminished life
expectancy as a result of his
work experience." (Section
20(a)(3)). Similar language is
contained in the Mine Safety and
Health Act NIOSH regards these
statements as legislatively man-
dated policy that guides its
assessment of risk.
Much of the data generated by
NIOSH research activities is rele-
vant for risk assessment pur-
poses. Generally these research
efforts address one of the compo-
nents of the risk assessment proc-
ess: hazard identification,
exposure assessment, dose-
response assessment, or risk char-
acterization.
NIOSH consists of three offices
and seven divisions. The Divi-
sion of Surveillance, Hazard
Evaluations, and Field Studies
(DSHEFS), the Division of Res-
piratory Disease Studies
(DRDS), and the Division of
Safety Research (DSR) are
responsible for major surveil-
lance and epidemiologic efforts
to identify work-related safety
and health problems and the asso-
ciated risk factors. The Division
of Biomedical and Behavioral
Sciences (DBBS) participates in
these investigations by assisting
with biological monitoring and
by developing and applying
improved techniques for charac-
terizing other biological
(neurobehavioral, immunologi-
cal, psychological) indicators of
exposure or effect. DBBS also
conducts worksite investigations
when physical agents, psycho-
logical stress, or ergonomic prob-
lems are the primary concern.
DSR conducts worksite investiga-
tions of selected traumatic occu-
pational fatalities, including
those resulting from exposures to
toxic substances in confined
spaces such as tanks and man-
holes. This investigative activity
is known as the Fatal Accident
Circumstance and Epidemiology
(FACE) project In addition to
being a hazard identification
activity, FACE enables the study
of factors that may contribute to
worker risk, and the develop-
ment and communication of risk
management options for control-
ling those factors. Information
on risk and risk management is
communicated to safety and
health professionals, and other
managers of workplace risk.
DSHEFS has primary responsi-
bility, with the collaboration of
DRDS, DSR, DBBS, and the
Division of Physical Sciences
and Engineering (DPSE), for a
research and service program
that provides a health hazard
evaluation (HHE) in any work-
place when requested by any
employer, employee repre-
sentative, or group of 3 or more
employees. In an HHE, a team
of NIOSH scientists investigates
suspected safety or health haz-
ards in the workplace. Upon com-
pletion of the investigation, both
the employer and the employees
are provided with a written
report in which any hazards iden-
tified are discussed and remedial
actions are recommended. If vio-
lations of OSHA standards are
revealed by the HHE, the written
report is also provided to the
OSHA Regional Office, often
resulting in a follow-up inspec-
tion by OSHA. DSHEFS also
These research efforts address one of
the components of the risk
assessment process: hazard
identification, exposure assessment,
dose-response assessment, or risk
characterization.
DSR conducts worksite investiga-
tions of selected traumatic
occupational fatalities, including
those resulting from exposures to
toxic substances in confined spaces
such as tanks and manholes.
124 Access/Use Info Resources Assess Health Risk Chem Expos '93
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has primary responsibility for the
conduct of industry-wide studies
which are in-depth epidemio-
logic studies of the association
between occupational exposures
and disease. These studies gener-
ally attempt to relate exposure
information with health out-
comes, and are thus an invalu-
able source of dose-response
information in addition to provid-
ing information for hazard identi-
fication.
DBBS and DRDS also conduct
laboratory research programs
that contribute to hazard identifi-
cation and develop exposure-
response data from in vitro and
in vivo research in mammalian
or sub-mammalian systems.
These programs also investigate
underlying mechanisms of dis-
ease and injury causation.
Human responses in limited, con-
trolled laboratory studies are also
undertaken, for example, to
evaluate the adequacy of current
exposure limits for chemicals or
margins of safety in controlling
for pre-clinical signs of potential
problems.
DPSE conducts substantial labo-
ratory and field research relating
to sampling and analytical tech-
niques and engineering control
technology. These activities con-
tribute primarily to risk manage-
ment by improving existing and
developing new options for expo-
sure measurement and control.
Other information ultimately con-
tributing to risk management is
developed by research programs
in DSR on personal protective
equipment, including respirators,
protective clothing, gloves, and
safety devices.
DSHEFS, DRDS, and DSR are
involved in several surveillance
activities that are aimed at the
detection and monitoring of dis-
ease and injury trends, as well as
the efficaciousness of regulatory
activities to control these hazards.
The Division of Training and
Manpower Development
(DTMD) is primarily involved in
activities related to the training
of professionals in occupational
health and safety through courses
that it offers and through the Edu-
cational Resource Centers (ERC)
program. However, DTMD has
recently developed a research
effort to evaluate the effective-
ness of training programs as a
prevention strategy.
The Division of Standards Devel-
opment and Technology Transfer
(DSDTT) is responsible for pro-
ducing the Institute policy recom-
mendations and regulatory
responses. In fulfilling these
tasks, DSDTT serves as the
bridge connecting the Institute
and its research divisions with
the regulatory agencies and the
public. DSDTT is responsible for
integrating all of these internal
sources of information and exper-
tise with external sources to
develop comprehensive analyses
of risk as the basis for policy rec-
ommendations. When suitable
data are available, the DSDTT
risk assessment unit performs a
quantitative risk assessment.
This may be a part of the compre-
hensive analysis of a Criteria
Document, or may be developed
in response to OSHA or MSHA
proposed rulemaking.
These analyses and recommenda^
tions are set forth in NIOSH pol-
icy documents, usually in the
format of a Criteria Document or
a Current Intelligence Bulletin.
DSDTT is currently involved in
conducting assessments of the
lung cancer risks associated with
DSHEFS has primary responsibility
for the conduct of industry-wide
studies which are in-depth
epidemiologic studies of the
association between occupational
exposures and disease.
Several surveillance activities are
aimed at the detection and
monitoring of disease and injury
trends.
Access/Use Info Resources Assess Health Risk Chem Expos '93
125
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exposure to diesel exhaust in
mines, and to cadmium. DSDTT
has also been involved in the
development of physiologically-
based and pharmacodynamic risk
assessment models for cancer
and noncancer outcomes through
a collaborative agreement with
researchers at the Massachusetts
Institute of Technology (MIT).
NIOSH technical reports and
journal publications produced
from the research efforts pre-
viously described are an
extremely useful source of infor-
mation for risk assessment
efforts and have been used exten-
sively by NIOSH and other agen-
cies for this purpose. These
journal articles may be obtained
by contacting the NIOSH
research divisions involved, and
the technical reports may be
obtained by contacting the publi-
cations office (513-533-8287).
DSDTT maintains three major
data bases: 1) RTECS is the
world's largest registry of toxic
chemicals covering over 100,000
chemicals; 2) NIOSHTIC is an
on-line bibliographic system con-
taining over 160,000 abstracts,
emphasizing occupational, envi-
ronmental, and historical litera-
ture; and 3) the Document
Information Directory System
(DIDS) is a directory of all
NIOSH-generated publications
and reports.
DSHEFS maintains the National
Occupational Exposure Survey
(NOES) data base and related
files derived from a representa-
tive sampling of the characteris-
tics of workplaces throughout the
country. DSHEFS has also cre-
ated an Occupational Mortality
Surveillance Data Base (OMSD)
which contains occupational and
cause of death information coded
from death certificates from 23
states between 1979-1987. The
OMSD may be a useful source of
information for hazard identifica-
tion, although more refined
epidemiologic studies will gener-
ally be needed to confirm the
hypotheses generated from this
data base. DSR maintains the
National Traumatic Occupational
Fatality (NTOF) data base and
FACE data bases. The NTOF
data base is a national census of
occupational fatalities developed
using death certificate informa-
tion obtained from the entire
United States population. NTOF
data are currently available for
the years 1980-1986. The FACE
data base is a compilation of data
from over 300 worksite investiga-
tions of selected occupational
fatalities. DRDS maintains two
data bases that consist of the
National Occupational Exposure
Survey in Mines (NOESM),
which is the equivalent of NOES
for mining environments, and the
X-ray Surveillance Program data
base, which is a collection of X-
ray and occupational data on
underground coal miners.
Clearly, epidemiologic informa-
tion provides the best basis for
estimating the risks for health
effects among human popula-
tions exposed to hazardous condi-
tions at work and elsewhere.
Unfortunately, suitable informa-
tion from human studies is often
unavailable and risk assessors
must rely on animal bioassay
information to estimate human
risks. Better exposure informa-
tion for estimating dose-response
relationships in epidemiologic
studies and for estimating the
extent of exposure among work-
ing populations is also sorely
needed. NIOSH is actively
involved in the development of
DSDTT serves as the bridge
connecting the Institute and its
research divisions with the
regulatory agencies and the public.
DSDTT maintains three major data
bases.
126 Access/Use Info Resources Assess Health Risk Chem Expos'93
-------
biologic markers which should
provide a better understanding of
the relationship between deliv-
ered dose (exposure) and the
dose at the target organ (biologic
dose). Finally, the development
of pharmacodynamic and
physiologically-based models
offer great potential for improv-
ing interspecies extrapolations.
However, there is clearly a great
need for additional information
on the basic kinetic and physi-
ological data that are used in
these models, particularly for
humans..
Summary
NIOSH views quantitative risk
assessment as an important ele-
ment in the development of rec-
ommendations for occupational
health standards. The Institute is
involved in a wide range of
research activities that provide
information relevant to all of the
components of the risk assess-
ment process.
Through these research efforts
NIOSH has developed an exten-
sive data base, which of course is
available to other agencies and
the public. Future risk assess-
ment activities at NIOSH will be
focused on developing better
methods for risk characterization
through improvements of expo-
sure characterization in
epidemiologic studies, and
through the incorporation of bio-
logic markers, and physiologic
and pharmacodynamic informa-
tion in the risk assessment
process.
Suitable information from human
studies is often unavailable and risk
assessors must rely on animal
bioassay information to estimate
human risks.
Access/Use Info Resources Assess Health Risk Chem Expos '93
127
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National Toxicology Program Chemical
Nomination and Selection Process
James K. Selkirk, National Institute of Environmental Health Sciences
The National Toxicology Program (NTP) was organized to support national public health programs by initiating research designed
to understand the physiological, metabolic, and genetic basis for chemical toxicity. The primary mandated responsibilities of NTP
were in vivo and in vitro toxicity testing of potentially hazardous chemicals; broadening the spectrum of lexicological information
on known hazardous chemicals; validating current toxicological assay systems as well as developing new and innovative toxicity
testing technology; and rapidly communicating test results to government agencies with regulatory responsibilities and to the medi-
cal and scientific communities.
During the 1970s, several
federal government agen-
cies independently
engaged in toxicity testing. It
became clear that a unified pro-
gram was necessary to avoid
duplication and to respond to (1)
the need for standardized toxicol^
ogy testing methods and (2) the
broadening range of diagnostic
assays used in the evaluation of
chemicals suspected of being
hazardous to humans. In 1978
the Secretary of the Department
of Health, Education, and Wel-
fare (HEW) responded to this
need by forming the NTP which
is composed of specially desig-
nated sections of several federal
agencies. Members included the
National Institute of Environ-
mental Health Sciences
(NIEHS), the Center for Disease
Control's National Institute for
Occupational Safety and Health,
and the Food and Drug Admini-
stration's National Center for
Toxicological Research. The
NTP was organized to support
national public health programs
by initiating research designed to
understand the physiological,
metabolic, and genetic basis for
chemical toxicity.
The primary mandated responsi-
bilities of NTP were in vivo and
in vitro toxicity testing of poten-
tially hazardous chemicals;
broadening the spectrum of toxi-
cological information on known
hazardous chemicals; validating
current toxicological assay sys-
tems as well as developing new
and innovative toxicity testing
technology; and rapidly commu-
nicating test results to govern-
ment agencies with regulatory
responsibilities and to the medi-
cal and scientific communities.
These important duties are still
the driving principles of NTP.
In 1981, Dr. David Rail, director
of the NIEHS became the direc-
tor of NTP, and management of
the program moved from the
National Cancer Institute in
Bethesda, Maryland, to Research
Triangle Park, North Carolina.
Although studies in the early
years of the program were
primarily designed as straightfor-
ward tumor bioassays, the last
decade has seen the NTP
program grow in range, scope,
and sophistication, along with
advances in basic toxicologic
knowledge. In addition, NIEHS
scientists are readily available to
A unified program was necessary to
avoid duplication.
The last decade has seen the NTP
program grow in range, scope, and
sophistication, along with
advances in basic toxicologic
knowledge.
Access/Use Info Resources Assess Health Risk Chem Expos '93
129
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assist regulatory agencies by
maintaining direct communica-
tion with regulatory agency staff
for consultation. NTP scientists
routinely confer on study designs
that will aid in risk assessment
and in decision making toward
the development of federal regu-
lations for controlling chemical
exposures in the workplace and
the general environment.
Because NTP is a consortium of
several federal agencies, the
administrative infrastructure is
designed to interact with, as well
as seek advice from all federal
agencies that are actively
engaged in or require knowledge
of chemical toxicity. Figure 1 out-
lines the way in which NTP man-
agement is coordinated through
several interagency committees.
The two NTP governing bodies
are the Executive Committee,
whose members are the senior
administrators of major federal
government public health agen-
cies, and a Board of Scientific
Counselors (BSC), which is com-
posed of nongovernment experts
in various fields of toxicology.
These two committees meet sev-
eral times a year to hear progress
reports of research programs of.
the various components of NTP
and to discuss individual agency
needs. The Steering Committee
is composed of senior staff mem-
bers of NTP agencies and meets
regularly to review ongoing toxi-
cology studies at the various
NTP research facilities.
In addition, special committees
function to support various
aspects of the NTP program.
The Chemical Evaluation Com-
mittee (CEC) receives and
reviews nominations of chemi-
cals for testing and makes recom-
mendations to the NTP Execu-
tive Committee.
The Annual Reports on Carcino-
gens working group is mandated
by Public Law 95-622 to publish
a list of substances (1) that may
be reasonably anticipated to be
carcinogens, (2) to which a sig-
nificant number of persons resid-
ing in the United States are
exposed, and (3) for which no
exposure standard is established.
The subcommittee on Data
Audits is composed of NTP
member agency staff and has a
more ad hoc function since it
meets only by special request
Reproductive studies are
reviewed by a special subcom-
mittee of experts that report
directly to the BSC.
The final product of NTP toxic-
ity studies is a comprehensive
summary of all lexicological
assays performed on a given
NTP, a consortium of several federal
agencies, is designed to interact with,
as well as seek advice from all federal
agencies that are actively engaged in
or require knowledge of chemical
toxicity.
Assistant Secretary for Health,
DHHS
""sr- ' sss. "™p
Fig. 1. Organizational management of the National Toxicology Program.
130 "Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
chemical. The Technical Reports
Sub-Committee consists of mem-
bers of the BSC as well as
nongovernment experts in vari-
ous toxicology disciplines. The
technical report meetings are
announced in the Federal Regis-
ter and are held in open public
session. Comments are invited
from all interested parties. The
technical report then becomes a
permanent record and is avail-
able through the National Techni-
cal Information Service.
Figure 2 summarizes the NTP
chemical nomination and selec-
tion process. Although the major
source of nominations histori-
cally has been government agen-
cies, chemicals can be
recommended for testing by any
individual who suspects that a
chemical may be a health hazard.
The NTP Chemical Selection
Coordinator receives nomina-
tions and is responsible for pre-
paring an information package
(Executive Summary) on the
nominated chemical for review
by CEC. If the committee
decides that current information
is insufficient to determine the
degree of potential hazard to
humans and accepts the chemi-
cal for testing, a Federal Regis-
ter notice is published, and any
individual (or organization) who
may have information not avail-
able in the open literature is
invited to submit it for NTP con-
sideration. Alternatively, CEC
may decide the available toxi-
cologic information is suggestive
of a hazard but insufficient to
draw a conclusion. It may recom-
mend some preliminary testing
such as in vitro genetic toxicol-
ogy to help in the preliminary
hazard assessment. Once com-
pleted, the results cycle back to
the recommending agency for
Fig. 2. Pathway for nomination and selection of chemicals for testing in the
National Toxicology Program.
review and a committee decision
is made whether to continue
toward full toxicological analysis
of the chemical. The amended
Executive Summary, along with
the rationale for deciding to
undergo more extensive testing
of the chemical, is reviewed by
both the Executive Committee
and the BSC. If all agree to pro-
ceed to the testing phase, the
Steering Committee decides
which NTP agency will be
responsible for developing the
test protocol. The final test pro-
tocol is subject to review by the
Toxicology Design Review Com-
mittee, which is composed of
NTP staff scientists, for confir-
mation that the planned assays
meet all the needs of the NTP
member agencies. Once the pro-
tocol is approved, the chemical
enters the in-depth evaluation
phase.
If the committee decides that
current information is insufficient
to determine the degree of potential
hazard to humans and accepts the
chemical for testing, a Federal
Register notice is published, and
any individual (or organization)
who may have information not
available in the open literature is
invited to submit it for NTP
consideration.
Access/Use Info Resources Assess Health Risk Chem Expos '93 131
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In most cases, short-term in vivo
tests are performed first to deter-
mine the metabolism and disposi-
tion of the chemical, locate target
organs, and develop a suitable
dosing regime to complete a
chronic 2-year bioassay. Usually,
2 weeks or 90 day, short-term
assays are conducted, the latter
being followed up with extensive
tissue and organ histopathology
to localize damaging chemical
effects. This 90-day tissue analy-
sis sets the stage for the chronic
study because it usually yields
clues about where the chemical
will probably exhibit its toxicity.
Clinical chemistries are also per-
formed at key times during the
short-term assays to assess the
metabolic effect of the chemical
on the animals' intermediary
metabolism, kidney, and liver
function. The chronic study lasts
104 weeks and is followed by an
extensive review of all the data
and a determination of carcino-
genicity of the chemical. The
conclusions are peer reviewed by
a panel of outside experts in pub-
lic session, and a final Technical
Report is published and made
available through the Govern-
ment Printing Office.
Ninety-day tissue analysis sets the
stage for the chronic study because
it usually yields clues about where
the chemical will probably exhibit
its toxicity.
132 »Access/Use Info Resources Assess Health Risk Chem Expos ' 93
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Assessing Human Health Risk in the USDA Forest
Service
Dennis R. Hamel, U.S. Department of Agriculture—Forest Service
This paper identifies the kinds of risk assessments being done by or for the, U.S. Department of Agriculture (USDA) Forest Service.
Summaries of data sources currently in use and the pesticide risk assessments completed by the agency or its contractors are
discussed. An overview is provided of the agency's standard operating procedures for the conduct of toxicological, ecological,
environmental fate, and human health risk assessments.
Since the beginning of man-
kind, men and women
have struggled to feed,
clothe, and house themselves.
The first tools used were manual;
however, through time, alterna-
tives including the use of chemi-
cals, began to emerge. In
agriculture and forestry, a new
era ensued, and as the use of
chemicals increased, so did ques-
tions about their effects on
human health and the environ-
ment. In time, a process of risk
assessment was developed to
deal with these questions.
Risk assessment takes many
forms. Practitioners use varying
definitions to describe the com-
ponents of risk assessment. In
the USDA Forest Service, we
sometimes use the terms risk
analysis and risk assessment
interchangeably, but for the most
part, we use risk analysis to
describe the process and risk
assessment to describe the docu-
mentation.
Most USDA Forest Service risk
assessment documents have been
prepared in compliance with the
National Environmental Policy
Act (NEPA). They relate to the
use of pesticides in forestry.
This use is minor, accounting for
less than 1% of all the pesticide
use in the United States. All pes-
ticide use must comply with the
Federal Insecticide, Fungicide,
and Rodenticide Act, as
amended, which is administered
by the U.S. Environmental Pro-
tection Agency (EPA).
The USDA Forest Service pesti-
cide policy is covered in Forest
Service Manual (FSM) 2150,
Pesticide Use, Management, and
Coordination. In addition to this
policy document, the agency has
compiled companion guidelines
in a handbook that has the same
title. The contents of the chapter
on risk analysis procedures
includes components of risk
analysis, hazard analysis, expo-
sure analysis, and risk charac-
terization. That of Hazard
Analysis includes Hazard Analy-
sis, Sources of Toxicity Informa-
tion, Types of Human Toxicity
Studies, and Types of Other
Organism Toxicity Studies. The
sections under Exposure Analy-
sis include Exposure Analysis,
Factors Affecting Human and
Environmental Exposure, Poten-
tial Routes of Exposure, Expo-
sure to Workers, Exposure to the
Public, and Exposure Scenarios.
Most USDA Forest Service risk
assessment documents relate to the
use of pesticides in forestry.
The USDA Forest Service pesticide
policy is covered in FSM 2150,
Pesticide Use, Management, and
Coordination.
Access/Use Info Resources Assess Health Risk Chem Expos '93
133
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In addition, the former Council
on Environmental Quality (CEQ)
regulations required that if infor-
mation was incomplete or
unavailable, federal agencies
must do a worst-case analysis.
This is no longer a requirement
of CEQ, but the Forest Service
continues to do them under the
proposed name of catastrophic
event scenarios. Their purpose is
to:
• determine if information is
missing and if it is relevant to
making a reasoned choice
among alternatives,
• identify the cost of obtaining
the missing information,
• determine if alternative scenar-
ios are generally acknow-
ledged as scientifically
reasonable,
• evaluate the state of the art to
collect the missing data, and
• indicate the probability of
occurrence.
Finally, we conduct risk charac-
terization that includes dose esti-
mation, evaluation, and
documentation.
You may be asking, "where does
the Forest Service obtain infor-
mation to assess health risks?"
The answer is that, primarily, we
obtain information from the EPA
using their reregistration stand-
ards, science chapters, Tox One
Liners, fact sheets, etc. The For-
est Service reformats this infor-
mation to fit forestry-use
situations and documents it in
risk assessments.
The agency also contracts with
independent sources who use
databases such as MEDLINE,
EMBASE (Excerpta Medica),
TOXLINE, the Hazardous Sub-
stances Data Bank, the Registry
of Toxic Effects of Chemical
Substances, the International
Pharmaceutical Abstract Data-
base, and the Chemical Carcino-
genesis Research and Informa-
tion System to collect, collate,
and interpret data for assessing
human health risk.
In summary, Gifford Pinchot,
first Chief of the Forest Service
said, "Conservation is the fore-
sighted utilization, preservation,
and/or renewal of forest, waters,
lands, and minerals for the great-
est good of the greatest number
for the longest time." To accom-
plish this mission, the Forest
Service has determined that
chemicals, including pesticides,
play a minor but important role
and that we have a responsibility
to use all available data to assess
the potential impacts of their use
on human health.
If information is incomplete or
unavailable, the forest service does a
worst-case analysis.
Primarily, we obtain information
from the EPA using their
reregistration standards, science
chapters, Tox One Liners, fact sheets,
etc.
134 • Access/Use Info Resources Assess Health Risk Chetn Expos ' 93
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Access and Use of Information Resources in
Assessing Health Risks from Chemicals in Food
Wesley A. Johnson, U.S. Department of Agriculture
The Food Safety and Inspection Service (FSIS) is responsible for the wholesomeness,. safety, and adulteration-free status of meat and
poultry. The agency developed the National Residue Program (NRP) to monitor these products for residue of drugs, pesticides, and
environmental contaminants. Today, few chemical residues are detected in meat and poultry because of the success of the NRP.
The National Residue Pro-
gram (NRP) Plan is
developed yearly to moni-
tor for chemical residues in both
domestically produced and
imported meat and poultry. The
randomly selected samples are
analyzed at one of the FSIS or
contract chemistry laboratories.
The laboratory testing results
along with other information are
used by FSIS for exposure assess-
ment to characterize and manage
the risks of adverse effects to
human health from consumption
of meat or poultry.
FSIS uses all available informa-
tion resources for its risk assess-
ment and risk management
decisions at points such as the
following:
1. Compound identification,
2. Compound Evaluation System
(CES) rank,
3. Compounds included in the
NRP, and
4. Detection method develop-
ment recommendations.
Each chemical has a time line or
history of use and regulatory
activity. (See Fig. 1.) A com-
pound's time line depicts the
sequence of decisions (in boxes)
that require FSIS (above line) to
use information resources to
make assessments for residue
occurrence in meat and poultry.
Each of the steps in the sequence
will be discussed as to how infor-
mation resources are used. Regu-
latory activity by other agencies
(below line), such as tolerance
setting and banning, are indi-
cated on the time line.
Databases, journal articles, gen-
eral reference materials, and
reports are used by FSIS to iden-
tify compounds that are of con-
cern. Compound tolerance-
setting reports from the U.S.
Environmental Protection
Laboratory testing results are used by
FSIS for exposure assessment to
characterize and manage the risks of
adverse effects to human health from
consumption of meat or poultry.
Actions/Decisions
by FSIS
Timeline
Actions by
Other Agencies
(e,g. EPA or FDA)
Compound
Identification
CES
CES Yearly
Review
Tolerance set
Recommend
Detection
Methods
Development
National
Residue
Plan
NRP
Yearly
Review
Ban
Fig. 1. Compound history .time line.
Access/Use Info Resources Assess Health Risk Chem Expos '93 135
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Agency (EPA) and the Food and
Drug Administration (FDA) are
the primary sources of informa-
tion for identification of com-
pounds of concern. The setting
of a tolerance for a compound in
animal tissues occurs after con-
siderable evaluation activity by
EPA or FDA and triggers FSIS
actions. A compound that pro-
duces a residue in meat or poul-
try and has adverse effects on
human health is a compound of
concern for further evaluation.
Minimum health safety regula-
tions were required for the use of
many drugs and pesticides in the
past. Some compounds are no
longer used but persist in the
environment, while others are
still in use. FSIS is actively inves-
tigating both of these classes of
compounds. Dibutyltin dilaurate
is an example of a compound
that has been in use but has had
little regulatory activity. During
the past 3 years, FSIS evaluated
and developed chemical detec-
tion methods and successfully
controlled residues from this
drug. This is an exciting example
of excellent work done by FSIS.
There are also examples of com-
pounds that produce residues arid
have been banned because of
their risk characterization.
FSIS, along with producers, the
Extension Service, and other fed-
eral agencies, has been instru-
mental in lowering the residue
violation rate by a factor of ten
over the past 20 years. Conse-
quently, FSIS is changing its
strategy to identify and sample
remaining populations of ani-
mals with significant concentra-
tions of chemical residue. FSIS
is identifying variables that are
common to populations of ani-
mals with drug or pesticide resi-
dues. Once the variables are iden-
tified, the animal populations
associated with these variables
will be targeted for appropriate
residue surveillance.
Compound Evaluation
System Rank
FSIS uses the CES as its risk
assessment procedure. Informa-
tion about the first two steps in
this risk assessment, hazard iden-
tification and dose response
assessment, is available from
FDA and EPA if a tolerance for
the compound in meat and poul-
try has been set. FSIS is able to
identify drugs and pesticides that
are of concern by using the
results of these two steps. FSIS
divides exposure assessment into
two parts. First, the approved
uses of drugs and pesticides of
concern are evaluated for poten-
tial animal exposure. Positive ani-
mal exposure assessment dictates
the use of pharmacokinetics to
predict whether the compound
produces a residue in meat or
poultry. A compound with posi-
tive animal exposure that also
produces a residue in meat and
poultry is evaluated for potential
exposure to humans. These data
are used to characterize the risk
of an adverse effect to human
health from consumption of meat
or poultry. In addition, the yearly
results from the NRP sampling
and testing are used to update the
exposure assessment and risk
characterization for each animal
slaughter class-compound pair.
The CES rank of compounds is
based on the severity of human
effects and the frequency at
which humans may be exposed.
A two-tiered hierarchical system
is used. Roughly, hazard is
ranked as follows: A = high
FSIS is changing its strategy to
identify and sample remaining
populations of animals with
significant concentrations of chemical
residue.
The CES rank of compounds is based
on the severity of human effects and
the frequency at which humans may be
exposed.
136 * Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
human health hazard, B. =
medium human health hazard, £
= low human hazard, D = negli-
gible effect, and Z = unknown.
The rank for frequency of expo-
sure to these compounds in meat
or poultry is based on the likeli-
hood of a person consuming a
toxic dose in meat or poultry.
These ranks are: 1 = high prob-
ability, 2 = medium probability,
3. = low probability, 4 = negli-
gible probability, and Z =
unknown.
The following is a quote from
the Compound Evaluation
System,
"There are more than 300 pesti-
cides approved for use in the
United States, with varying
potential for their occurrence as
residues in meat and poultry.
There are many others that may
also occur as a result of environ-
mental contamination or in
imported foods from significant
use in other countries. The num-
ber of potential residues from ani-
mal drugs and biologies is
equally impressive, again with
the foreign use of compounds
adding to the total number of
residues that may occur in meat
and poultry. The potent biologi-
cal activity of many of these
compounds raises concern
regarding the potential hazard to
human health associated with the
ingestion of meat and poultry
containing residues from pesti-
cides, drugs, or other chemicals.
"Clearly, it is neither feasible nor
necessary to monitor for residues
of all chemicals that could con-
taminate meat and poultry. How-
ever, in deciding which available
resources and monitoring efforts
should be assigned, it is impera-
tive that FSIS can assess relative
concerns for those residues most
Residue Produced?
No Yes
STOPl CONTINUE CES
1
Health Effects
C,D,orZ !
STOP |
Exception 1C !
AorB
CONTINUE CES
Exposure Frequency
3,4,orZ j
STOP i
Exception 3A j
I
1 or 2
lf1A,2A,3A,1B,2B,or1C
RECOMMEND for
Chemical Method Development.
Note 3A and 1C included
I
Method Development
T
NATIONAL RESIDUE PROGRAM PLAN
Fig. 2. The CES risk assessment process.
likely to have the greatest impact
on public health. To assist the
agency in the effective manage-
ment of its resources and residue
program activities, a compound
evaluation system was devel-
oped."
The following are some of the
databases searched for comple-
tion of a risk assessment under
CES.
Agricola 79 +
Agris
Agrochem Handbook
Biosis 1969 +
Access/Use Info Resources Assess Health Risk Chem Expos '93 137
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CAB Abstracts
Cancerlit
CA Search
Chem Industry Notes
Chemical Exposure
Chemname
Compendex Plus
Conf Papers Index
CRIS/USDA
Embase
Enviroline
Enviro Perio Bib
Federal Research In Progress
Food adlibra
Food Sci & Tech Abstracts
GPO Monthly Cat
HSDB
IRIS
Kirk Othmer Online
Life Sciences Coll
Medline
NTIS
NTP Chemtrack
Pollution Abs
Toxline
TSCA Inventory
Compounds Included in
the National Residue
Program Plan
The NRP is designed to ran-
domly sample the national herd
and test for residues by animal
slaughter class and compound
pair. The national herd is divided
into 19 animal slaughter classes
for residue testing. Compounds
are added to the NRP based on
the following:
1. the compound must produce a
residue in meat or poultry;
2. the compound must be ranked
according to the CES as Al,
A2.A3, B1.B2, orCl;and
3. a regulatory method for detec-
tion must be in the FSIS
laboratory.
Uj
IB
I i
||
£ 5
\\ \\
*Z N
D -
= Compounds for
National Residue Plan
= Review Yearly
= Review As Indicated
Z 4 3 2 1
Exposure Frequency Ranking
1 = High Exposure Probability
Z = Unknown
Fig. 3. Compound criteria for national residue plan.
The residue testing of the 19
slaughter classes is divided into
the following:
1. Monitoring phase - The moni-
toring phase is designed to ran-
domly sample and test for the
presence of concentrations
above tolerance for com-
pounds of concern in the
national herd on a yearly basis.
2. Surveillance phase - In this
phase biased sampling is used
to investigate and control the
movement of potentially adul-
terated product.
3. Exploratory phase - Regula-
tory actions are not used in this
phase. Information gathering
is one reason for including an
animal class-compound pair
under this phase. The recom-
mendations for development
of detection methods for
dibutyltin dilaurate were made
based on information from this
phase.
The National Residue Program Plan is
designed to randomly sample the
national herd and test for residues by
animal slaughter class and compound
pair.
138 Access/Use Info Resources Assess Health Risk Chem Expos'93
-------
Detection Method
Development Recommen-
dations
The Residue Evaluation and
Planning Division recommends
methods development for com-
pounds satisfying the NRP
requirements. This activity con-
tinues throughout the year. FSIS
uses practical analytical methods
for detecting chemical residues
in concentrations greater than tol-
erance in meat and poultry. Mul-
tiple sources of information are
required to satisfy the criteria
used as guidelines for methods
suitable for regulatory use.
Summary
The Food Safety and Inspection
Service randomly samples the
national herd for the presence of
drug, pesticide, and environ-
mental contaminant residues.
The animal slaughter class-
compound pair samples are
selected because of an assessed
risk of adverse human health
effect from consumption of this
slaughter class with residues of
the compound. The analytical
results from these samples repre-
sent a considerable amount of
data for exposure assessment;
these results and other new infor-
mation update the risk charac-
terizations of compounds in the
FSIS risk assessment process.
The animal slaughter class- compound
pair samples are selected because of
an assessed risk of adverse human
health effect from consumption of this
slaughter class with residues of the
compound.
Access/Use Info Resources Assess Health Risk Chem Expos '93 139
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How Information Resources are Used by Federal
Agencies in Risk Assessment Application:
Rapporteur Summary
Penelope Fenner-Crisp, U.S. Environmental Protection Agency
The application of information available for risk assessment from the federal perspective is described. Different federal agencies
conduct varying degrees of hazard evaluation, and some also generate empirical data. The role of the Agency for Toxic Substances
and Disease Registry in hazard assessments of potential public health impacts ofSuperfund sites includes identification of the 275
most significant substances. ATSDR is responsible for preparing toxicological profiles. ATSDR also identifies data gaps and needs
critical to adequately assessing human health impacts.
There are those who for
some time have been pre-
dicting the demise of the
concept of risk assessment as we
know and define it today. They
cite as evidence the trend toward
development of legislation that
dictates the use of technology-
based rather than risk-based regu-
latory solutions and/or prescrip-
tive elements to risk assessment
methodology. We have examples
of this on both the federal and
state levels. On the state level, an
example is California's Proposi-
tion 65 and Big Green, the Envi-
ronmental Protection Act of
1990. On the federal level,
aspects of this occur in the Clean
Air Act and in ongoing discus-
sions about food safety legisla-
tion that would impact both EPA
and the Food and Drug Admini-
stration. If this prediction is on
target, participants in this confer-
ence are either ignorant of the
forecast, are choosing to ignore
it, or know something is false
about the assertion. Several repre-
sentatives from federal and state
agencies earlier described how
they use information on hazard,
exposure, and risk in their own
work. The presenters' intention
apparently is to continue using
this kind of information because
they have practical applications
for it. The presenters said that
the roles of the federal agencies
in the risk assessment process
varied. Jim Selkirk at the
National Toxicology Program
(NTP), Leslie Stayner at the
National Institute for Occupa-
tional Safety & Health (NIOSH),
and Angelo Turturro repre-
senting the National Center for
Toxicological Research (NCTR),
all are from agencies that gener-
ate empirical data primarily for
other organizations to use.. Other
agencies have active risk assess-
ment roles although perhaps not
in the regulatory sense. An exam-
ple of this is the way the U.S.
Forest Service, as described by
Dennis Hamel, uses information
on pesticides when choosing
them for application in the field.
As previously mentioned,
NIOSH generates empirical data
and does some risk assessments.
Also, over the years it has done
hazard assessment in developing
criteria documents and bulletins
Some predict the demise of the
concept of risk assessment as we
know it.
Other agencies have active risk
assessment roles although perhaps
not in the regulatory sense.
Access/Use Info Resources Assess Health Risk Chem Expos '93
141
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for use by the Occupational
Safety and Health Administra-
tion (OSHA), and other organiza-
tions with respect to the occupa-
tional setting. The Agency for
Toxic Substances and Disease
Registry (ATSDR) Toxicology
Division's responsibilities
include the gathering of hazard,
dose response, exposure, and
epidemiologic data for the devel-
opment of lexicological profiles
in support of EPA's Superfund
Program. Some agencies' respon-
sibilities include cleanup of haz-
ardous waste sites. The Army
and Department of Energy pres-
entations noted that each has
responsibilities for assessing and
cleaning up hazardous waste
sites on federal properties. There-
fore, they too conduct their own
risk assessments, making use of
the various types of hazard
assessment and risk assessment
information available. In fact,
Major Legg called the Army the
"olive-drab EPA."
Additionally, some agencies
have enforcement responsibili-
ties. For instance, Dr. Turturro
spoke of the centers within the
FDA that are responsible for
food, drugs, cosmetics, medical
devices, biologies, etc., each cen-
ter having its own set of regula-
tory responsibilities. The Food
Safety and Inspection Service of
the U.S. Dept. of Agriculture
(USDA) is responsible for moni-
toring our meat, milk, and poul-
try for excess or unsanctioned
residues of pesticides or drugs.
Lastly, EPA has several environ-
mental laws to enforce. Many
EPA regulations were developed
using the risk assessment process.
Each presenter stressed the need
for good databases (good in the
sense of having adequate and
quality-assured data) containing
as much data as possible, and
having mechanisms by which
these data may be accessed eas-
ily by potential users. With 50
states and a number of federal
agencies generating these data
and storing them in a variety of
databases, it is easy to see why
there may be no common basis
for access. We in the federal gov-
ernment, and I assume those in
state government too, are often
castigated about redundancy:
that we have multiple avenues
for generating and storing essen-
tially the same information is not
a particularly efficient expendi-
ture of monies. The processes
that we have been talking about
at this conference suggest that
some of that redundancy can be
excised and that we can be more
efficient in the ways we gather
and communicate information.
ATSDR provides public health
assessments that address the
health impacts of Superfund sites
to EPA's Office of Emergency
and Remedial Response.
As a part of this process, Title I,
Section 110, of the Superfund
Amendments of 1986 directs the
ATSDR to develop programs in
three areas: listing of hazardous
substances, preparation of toxico-
logical profiles, and identifica-
tion of data gaps and the
implementation of necessary
research to fill priority data
needs. The first of these areas is
the listing of the 275 most "sig-
nificant" substances occurring at
Superfund sites based upon their
frequency of occurrence, inher-
ent toxicity, and potential for
human exposure. ATSDR is
responsible for preparing lexico-
logical profiles, in which the
information necessary to assess
The need for good databases is
stressed.
ASTDR is responsible for preparing
lexicological profiles in which the
information necessary to assess the
public health consequences of the
listed chemicals is collected and
summarized.
142
Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
the public health consequences
of the listed chemicals is col-
lected and summarized.
ATSDR also identifies data gaps
that should be filled for a thor-
ough assessment of the human
health impact of these chemicals.
Secondary to this is identifica-
tion of priority data needs that
are critical to adequately assess
human health impacts. To date
117 priority data needs have
been identified for 38 chemical
substances.
As anticipated, questions arose
regarding the funding and sched-
uling of testing. A directive in
the law addresses this situation,
particularly with respect to test-
ing requirements in negotiated
testing agreements with affected
industry or other funding
sources. It also addresses the use
of National Institute of Environ-
mental Health Sciences
(NIEHS), NTP, or other federal
agencies to fill research needs
that do not easily lend them-
selves to the use of testing
authorities such as the Toxic Sub-
stances Control Act or the Fed-
eral Insecticide Fungicide and
Rodenticide Act;
We have a lot of hazard-related
data that is used for hazard identi-
fication and dose-response
assessment. We haven't talked
about it much here, but quite
often when using the same
hazard-related data, various agen-
cies come to different conclu-
sions. One would expect
differences to occur with respect
to the exposure data because we
usually are focusing on a particu-
lar exposure scenario for which
we are developing a risk assess-
ment. However, one can ask
whether the hazard assessment
should be different. Efforts are
under way on the federal level to
evaluate this situation and work
toward harmonization, but I am
not certain about the degree to
which states are involved. For
some time now there have been
efforts among several federal
agencies to reach consensus on
the assumptions employed in haz-
ard assessment. An example of
this relates to the Food Safety
Initiative, which involves
USDA, FDA, and EPA. It is
apparent that the three agencies
often have distinct philosophies
and differences of opinion on
how hazard assessment should
be conducted. These differences
do not necessarily serve the pur-
pose well. Yesterday, another
example was alluded to that
acknowledged differences in
opinions among agencies. I
assume this was in reference to
dioxin, a chemical for which
there are not only differing U.S.
federal agency approaches to haz-
ard assessment, but also differ-
ences from and between govern-
ments internationally. A wide
range of opinion also exists
regarding the potential risk from
exposure to dioxin. We also
would find differences of opin-
ion if we took a different chemi-
cal and asked these agencies to
conduct risk assessments. I think
that in the future, access to and
sharing of hazard assessment
data and additional conferences
like this will become increas-
ingly important. Let's focus on
building a consensus on how
best to evaluate and use the data
and move forward from there.
EPA is not the only agency that
does risk assessment. Virtually
There have been efforts among
several federal agencies to reach
consensus on the assumptions
employed in hazard assessment.
Redundancy in the generation
and storing of information by
federal and state governments is
discussed.
Access/Use Info Resources Assess Health Risk Chem Expos '93
143
-------
every federal agency that has some risk assessment, either
some interest in the environment from the human health or the
(in the broadest sense), does environmental aspect.
144 * Access/Use Info Resources Assess Health Risk Chem Expos '93
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Information Resources in State Regulatory
Agencies—A California Perspective
Stephen M. DiZio, California Environmental Protection Agency
Various state regulatory agencies have expressed a need for networking with information gatherers/researchers to produce a
concise compilation of primary information so that the basis for regulatory standards can be scientifically referenced. California
has instituted several programs to retrieve primary information, generate primary information through research, and generate
unique regulatory standards by integrating the primary literature and the products of research. This paper describes these
programs.
Introduction
Our speakers today from
Massachusetts, New Jer-
sey, Tennessee, Illinois,
Louisiana, and Connecticut have
touched on a number of recur-
ring themes. These consist of a
reliance on federal sources, such
as the Oak Ridge National Labo-
ratory; the Agency for Toxic
Substances and Disease Registry
(ATSDR); and the U.S. Environ-.
mental Protection Agency
(EPA), especially the Integrated
Risk Information System (IRIS)
as available electronically
through the National Library of
Medicine, for risk assessment
information. The primary needs
identified are for networking
with those information gather-
ers/researchers to produce a con-
cise compilation of primary
information so that the basis for
regulatory standards can be scien-
tifically referenced.
The State of California shares
these needs, and has instituted
several programs to retrieve pri-
mary information, generate pri-
mary information through
research, and generate unique
regulatory standards by integrat-
ing the primary literature and the
products of research.
Retrieval of Primary
Information
Primary information, meaning
that available in the literature on
the toxicity, environmental fate,
and exposure assessment of
chemicals is essential to the regu-
latory decision-making process
utilized by the California Depart-
ment of Health Services (DHS),
Department of Toxic Substances
Control (DTSC), Department of
Pesticide Regulation (DPR),
Office of Environmental Health
Hazard Assessment (OEHHA),
and Office of Emergency Serv-
ices. This information is made
available to these groups through
several sources, including the
libraries of the University of Cali-
fornia (UC), on-line electronic
data services, and the National
Laboratories managed by UC.
1. Library services
Information resources made
available through the UC librar-
ies are funded by a large contract
with the UC Berkeley public
health library. Historically, the
DHS has maintained this fund-
ing, although with the recent
The State of California has instituted
several programs to retrieve primary
information, generate primary
information through research, and
generate unique regulatory standards
by integrating the primary literature
and the products of research.
This information is made available
through several sources, including
the libraries of the University of
California, on-line electronic data
services, and the National
Laboratories managed by UC.
Access/Use Info Resources Assess Health Risk Chem Expos '93
145
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creation of the California Envi-
ronmental Protection Agency
(Cal EPA) the various groups
within Cal EPA such as OEHHA,
DTSC, and DPR have assumed
authority over this funding and
have centralized management of
the contract within OEHHA. The
contract provides access to all
the information resources within
the entire UC system; thus, litera-
ture unavailable at Berkeley is
easily obtained through other
campuses, primarily those at UC
Davis and UC Los Angeles
(UCLA). This vehicle has pro-
vided the primary source of pub-
lished literature for state scien-
tists in the development of regu-
latory standards.
Recently, specialty libraries at
some of the UC campuses were
contracted separately for litera-
ture search and retrieval services
because of the unique capabili-
ties of a specialty library to
quickly and concisely summarize
the relevant information within a
particular field. One important
example has been the Environ-
mental Toxicology Information
Center within the Environmental
Toxicology Department at UC
Davis. This group provided valu-
able service to DTSC and DPR.
The library and its personnel are
dedicated to storage and retrieval
of textbooks, journals, and arti-
cles on the toxicity, fate and
transport, and environmental
exposure of pesticides and other
major environmental pollutants.
Consequently, the library may
serve as an essential arm of the
DTSC and DPR when this infor-
mation is needed quickly for
regulatory decision making. Dur-
ing the Loma Prieta earthquake
of 1989, the library installed
dedicated telephone equipment
for quick data retrieval and com-
munication, whereas San Fran-
cisco bay area facilities were
handicapped as a result of disrup-
tions in essential services caused
by the temblor.
Government libraries, particu-
larly the EPA Region IX library
in San Francisco, also serve as
sources of primary information
not easily obtainable through the
academic system. In particular,
the DTSC has made extensive
use of this facility for examina-
tion and retrieval of various EPA
Fact Sheets dealing with a wide
range of issues such as the pro-
posal of new maximum contami-
nant levels (MCLs) or the
permitting of landfills.
2. Electronic data retrieval
Many state agencies, particularly
the Office of Emergency Ser-
vices and DTSC maintain size-
able contracts with services such
as Lockheed Information Sys-
tems (DIALOG) and the
National Library of Medicine
(MEDLARS) for quick access to
literature abstracts and on-line
databases, particularly IRIS and
the Hazardous Substances Data
Bank (HSDB) as available
through TOXNET. In addition,
on-line bulletin board systems,
such as those operated by the
EPA Office of Solid Waste and
Emergency Response are often
utilized as supplemental sources
of information, particularly for
U.S. government publications,
which are often not stored in the
UC library system.
Use of the information available
on-line is varied. In emergencies
such as evaluation of public
health hazard of a rail spill, the
availability of HSDB through a
modem contained on a portable
computer has made quick access
Speciality libraries of the UC
campuses are contracted separately
for search and retrieval because of
the unique capabilities of a specialty
library to quickly and concisely
summarize the relevant information
within a particular field.
Use of the information available
on line is varied.
146 « Access/Use Info Resources Assess Health Risk Chern Expos '93
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to-relevant information possible
for DTSC and DHS. In regula-
tory standards development, lit-
erature searches form the basis
for the assessment of both
resource allocation and time
requirements for project comple-
tion by DPR and DTSC. For
research, data gaps in the avail-
able literature are first identified
by on-line searches so that pro-
ject priorities may be developed.
Thus, California governmental
agencies use a wide range of elec-
tronic information resources to
answer specific needs relating to
risks from chemical exposure.
3. National laboratories
Primary information retrieval
from the national laboratories
managed by UC, Lawrence
Berkeley Laboratory (LBL), and
Lawrence Livermore National
Laboratory (LLNL), is necessary
because of their respective sys-
tems of excellent in-house publi-
cations. Projects conducted for
various governmental agencies,
as well as original research con-
ducted by each national labora-
tory, are often first published
in-house prior to publication in
the public literature. Therefore,
for state agencies to maintain
state-of-the-art knowledge of the
fields of exposure assessment
and environmental risk assess-
ment, access to these publica-
tions through contract or
collaborative effort is essential.
Two examples of this, by no
means unique, are the models of
showering exposure and prob-
abilistic uncertainty analysis con-
ducted by Thomas McKone and
Kenneth Bogen of LLNL, which
were first available as LLNL
UCRL publications. Advance
knowledge of these efforts were
necessary for California to
develop modern drinking water
standards as well as to make
responsible regulatory decisions
in cases where uncertainties
existed in public exposure esti-
mates.
Generation of Information
through Research
Both the DTSC and the DHS
have funded original research
designed to provide information
necessary for the development of
regulatory guidance, regulatory
standards, and risk-management
decision making. This research
was conducted by major con-
tracts between DHS and DTSC
with the Regents of UC, allow-
ing access to all campuses within
the UC system as well as the
national laboratories. Some of
the projects are described below.
1. Research on assessment of
exposure resulting from
showering
The Environmental Sciences
Division of LLNL conducted
research in a home purchased by
the laboratory on the showering
exposure to trichloroethylene
(TCE). This project was funded
by DTSC. Bathroom plumbing
was modified to add measured
amounts of TCE to shower
water, and analyses were made
of the release of TCE into vari-
ous bathroom "compartments"
(e.g., shower walls, wet towels,
and bathroom air) so that model-
ing of inhalation exposure could
be developed from information
gathered in an actual home. In
addition, the dermal permeability
of TCE at environmentally rele-
vant concentrations in water
(parts-per-million levels) was
measured in laboratory animals
under controlled conditions to
Both the DTSC and the DHS have
funded original research designed
to provide information necessary
for the development of regulatory
guidance, regulatory standards,
and risk-management decision
making.
The Environmental Sciences Division
of LLNL conducted research in a
home purchased by the laboratory on
the showering exposure to
trichloroethylene (TCE).
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147
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better estimate dermal exposures
during swimming or showering.
2. Research on particle inhala-
tion by children
UC Irvine was funded to provide
experimental data on the inhala-
tion of fugitive dust particles by
humans by studying both the
nose as a selective sampling
device as well as the influence of
body size. Wind-tunnel experi-
ments with particles delivered in
a laminar flow were designed,
and mannequins with laser
devices embedded in the noses
were used to identify subsets of
populations exposed to dust parti-
cles dispersed from hazardous
waste sites by wind erosion. Chil-
dren, because of small body size,
were identified as the group with
the greatest exposure to inhalable
particles. This project was
funded by DTSC.
3. Research on dermal absorp-
tion of soil contaminants
The Department of Dermatology
at UC San Francisco was funded
by DTSC to provide information
on the dermal absorption of con-
taminants from soil. In vitro
experiments were conducted on
selected chemical groups, includ-
ing pesticides (chlordane, DDT,
and pentachlorophenol), metals
(cadmium and arsenic), and other
environmental contaminants
(e.g., benzo-a-pyrene) to evalu-
ate their penetration through
human skin. Some of these com-
pounds were also tested in vivo
in validation experiments in
which dermal absorption was
measured from soil applied to
the skin of rhesus monkeys. This
research has been singularly fruit-
ful, with regulatory impact where
soil exposure and cleanup is at
issue.
4. Research on exposure
modelling
LLNL was requested to construct
theoretical multipathway risk
assessment modeling experi-
ments to both integrate original
experimental results and to pro-
vide an evaluation of secondary
source contributions to exposure
and risk. The resulting effort has
integrated experimental results,
critical evaluation and selection
of relevant physicochemical
parameters, and professional
peer-reviewed modeling into an
unique multipathway tool
designed to provide remedial
objectives for selected environ-
mental media, such as soil. Its
use will be described in the fol-
lowing item.
5. Research on non aqueous
phase liquid transport in
vadose zone soil
LBL has been funded by DTSC
to provide original research on
transport of nonaqueous phase
liquids (NAPLs) through soil to
the water table. This project, now
in it's third year, will be used to
generate the information needed
for DTSC guidance on the evalu-
ation of the movement of NAPLs
at hazardous waste sites or facili-
ties.
Generation of Guidance
and Standards
Guidance for exposure assess-
ment and risk assessment, regula-
tory standards for acceptable
pesticide residues on crops, and
the development of regulatory
drinking water standards are but
some of the uses that California
agencies made of information
derived from information serv-
ices and that gathered through
original research. The following
The Department of Dermatology at
UC San Francisco was funded by
DTSC to provide information on the
dermal absorption of contaminants
from soil
LBL has been funded by DTSC to
provide original research on
transport of nonaqueous phase liquids
(NAPLs) through soil to the water
table.
148 Access/Use Info Resources Assess Health Risk Chem Expos '93
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examples are by no means all-
inclusive of the use of these serv-
ices by California agencies.
1. Development of California
drinking water standards
The state legislature authorized
DHS to develop 36 California
drinking water standards (MCLs)
to supplement those being devel-
oped by the federal government.
Chemical risk assessments, used
as the basis for the selection of
MCLs by the Sanitary Engineer-
ing Branch of the DHS, were
written by various groups within
the UC campus system, primar-
ily UC Davis, and the LLNL.
These documents were subjected
to national peer review and were
used to identify a range of scien-
tifically acceptable concentra-
tions for acceptable risk or
hazard of the individual agent.
2. Development of technical
guidance and standards
Technical guidance was deemed
necessary for the implementation
of the DTSC Integrated Site Miti-
gation process, with key guid-
ance promulgated as regulation.
Regulation development was
restricted to the department.
Guidance document develop-
ment, in terms of exposure mod-
eling, exposure pathway selec-
tion, use of multimedia models
in a back-calculation of soil
remediation levels as mentioned
in the preceding, and prob-
abilistic analysis of uncertainty
was contracted by DTSC to
LLNL. These were designed to
integrate the information
resources developed and utilized
by all state agencies with those
research projects mentioned in
the preceding, and provide work-
able tools for environmental
remediation to be used by both
the public and private sectors.
Conclusions: Future
Needs
One of the goals of this confer-
ence was to identify current and
future needs in the field of infor-
mation resources. From the state
perspective, several major items
were identified as necessary and
appropriate goals for those sup-
plying information resources to
the state agencies.
1. Better information exchange
among states
Several of the speakers expres-
sed the desire for some form of
directory and formal information
exchange system so that unique
resources developed by an
agency in one state would be
accessible to agencies in other
states. The existence or develop-
ment of air, water, and soil crite-
ria has been mentioned by
several state representatives, pro-
voking great interest from their
counterparts in other state and
federal agencies.
Currently, the most effective tool
for this sort of exchange has
been the telephone. However, as
this resource database grows, a
more systematic and readily
accessible vehicle will be neces-
sary to achieve maximum utiliza-
tion of these products and to
avoid unnecessary duplication of
effort. The experience in Califor-
nia has been that, even within a
state, the growth of various agen-
cies with risk assessment respon-
sibilities has resulted in a loss of
effective communication, result-
ing in duplication of effort.
The State legislature authorized
DHS to develop 36 California water
standards to supplement those
being developed by the federal
government.
Technical guidance was deemed
necessary for the implementation of
the DTSC Integrated Site Mitigation
process, with key guidance
promulgated as regulation.
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2. Better information exchange
about local problems that
occur nationwide
Certain items requiring risk
assessment support occur nation-
ally but are not systematically
addressed by either the federal
RCRA or CERCLA programs.
One such case that immediately
comes to mind is that of the
manufactured gas facilities.
Before natural gas was widely
distributed, coal and diesel gassi-
fication plants flourished in
many urban settings. The buried
waste derived from the operation
of these plants occurs from coast
to coast across the United States.
Although many of the problems
associated with these facilities
are similar, they are dealt with at
state and local levels. Conse-
quently, there is a need for better
exchange of information
between the states about how
risks are assessed and managed
at these facilities. An archival
system for such information
would improve the efficient han-
dling of these and similar
problems.
3. Epidemiological support
Dr. David Brown of the Connecti-
cut Department of Health spoke
of the critical need for exchange
between states about how rapid,
end-point specific information is
used to arrive at a decision when
human health risk is immediately
apparent. His experience consult-
ing with his counterparts in Cali-
fornia illustrates the need for a
more systematic, possibly cen-
tralized system whereby epidemi-
ologists and other health
professionals can be identified
and information sources can be
quickly accessed when problems
arise.
Certain items requiring risk
assessment support occur but are not
systematically addressed by either the
federal RCRA or CERCLA programs.
150 Access/Use Info Resources Assess Health Risk Chem Expos '93
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How Information Resources Are Used by State
Agencies in Risk Assessment Applications—
Illinois
Clark S. Olson, Illinois Environmental Protection Agency
The Environmental Protection Agency of the Stale of Illinois (Illinois EPA) has programs in water, air, and land pollution and water
supplies paralleling those of the U.S. Environmental Protection Agency (EPA). The organization is part of a tripartite arrangement
in which the Pollution Control Board is the judicial arm, the Department of Energy and Natural Resources is the research arm, and
the Illinois EPA is the enforcement arm. Other state agencies are also concerned with various aspects of the environment and may
do risk assessments for chemicals. Although there are various risk assessment activities, both formal and informal, in our agency
and in others, this paper will discuss only recent initiatives in water quality criteria.
Water quality criteria
are similar to water
quality standards for
acceptable environmental levels
of substances, except that the
legal force is not as great. Stand-
ards include consideration of eco-
nomic, technical, and social
impact of the regulation, whereas
criteria are intended to be com-
pletely "scientific." In other
words, standards can contain an
element of risk management,
whereas criterion determination
is more purely risk assessment.
Basically, we can calculate a cri-
terion and implement it ad hoc
whereas the Pollution Control
Board sets standards that apply
more uniformly and widely. Our
criteria are calculated for setting
effluent limits, for cleanup levels
in spills and as general goals for
nonpoint pollution.
In this new initiative of control-
ling "toxics"in water, the states
were given a choice of adopting
whatever national numbers were
available, adopting a procedure
for obtaining numbers, or a com-
bination of the two. Illinois
adopted the approach of setting a
procedure and calculating num-
bers as needed. If the number is
used in a legal document, which
will most likely be the permit,
the public can challenge the
number.
We have a methodology for cal-
culating criteria for acute and
chronic effects in aquatic life and
to protect wildlife and human
health. The latter criteria are for
chronic exposure. The procedure
for calculating criteria for aqua-
tic life is much more explicit and
detailed than that for calculating
criteria for wildlife and human
health. Criteria, or at least crite-
ria documents, have been pub-
lished for the so-called "priority
pollutants" and for a small num-
ber of other substances. How-
ever, no wildlife criteria are
included in that program.
We are using the new regulations
to calculate criteria for aquatic
life. We are not sure when or
how criteria for wildlife or
human health will be implemen-
ted, but some of the same princi-
ples and concerns related to
Our criteria are calculated for
setting effluent limits, for cleanup
levels in spills, and as general
goals for nonpoint pollution.
We have a methodology for
calculating criteria for acute and
chronic effects in aquatic life and to
protect wildlife and human health.
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calculating criteria for aquatic
life will apply. However, it is evi-
dent that the sources of data and
kinds of end points will be differ-
ent.
In calculating criteria, the imme-
diate information needs are for
simple end points for acute and
chronic effects — LCso and no-
effect levels. In addition, we con-
sider information on bioconcen-
tration, log P, quantitative struc-
ture activity relationship (QSAR)
studies, sublethal effects, ecosys-
tem level effects, metabolism,
and environmental fate.
There are several functions
involved in developing a crite-
rion: (1) finding and identifying
the necessary data; (2) getting
the data, preferably from the
original document; (3) selecting
and evaluating the data to make
the calculation according to set
procedures; and (4) considering
any other kinds of information
necessary to make a final evalu-
ation or validation of the
numbers.
To go about these various tasks,
our physical and personnel
resources include a technical
library within the agency that is
supervised by an experienced ref-
erence librarian. The library staff
is capable of searching in Nation-
al Library of Medicine (NLM)
and Lockheed data bases. The
library contains 18,000 books,
350 journals, and 25,000 other
documents and has interlibrary
loan services. We also have a
separate group of toxicology and
environmental chemistry special-
ists, one of whom is capable of
searching EPA data bases. Also
available in Springfield, where
we are located, are the main state
library and two university
libraries.
With regard to the above items
(1) and (2), search and retrieval,
two principles are written into
our regulations. One is that the
literature search should be com-
plete, and the other that we
should try to get the original
document.
The first task is of course impos-
sible, but we interpret it to mean
that we should look beyond the
relevant EPA data bases. In con-
trast, I think there are agencies
and consultants that would con-
sider a search on AQUIRE to be
sufficient, for instance, in doing
a criterion calculation for aquatic
life. We would like to define or
outline what might be considered
an adequate literature search, but
that probably will not be possible
for some time.
The most likely starting place for
us is the water quality criteria
documents published by EPA,
along with some water quality
"advisories" for some additional
chemicals. The reason for start-
ing with the priority pollutant
water quality criteria documents
is that our chemists are mainly
looking for "priority pollutants."
We need to search beyond these
documents because they are gen-
erally out of date, because we
need to get data relevant to our
state, and because in many cases
a calculated criterion is not actu-
ally given anyway. Also, we
have found a few instances in
which data were not included.
Second, we often will do a
search on AQUIRE. We may get
to the point at which we might
consider this obligatory. Another
source is the June literature
review issue of the Journal of the
Water Pollution Control
Federation. This resource some-
times gives the actual toxicity
Several functions are involved in
developing a criterion.
Two principles are written into our
regulations. One is that the literature
search should be complete; the other
is that we should try to get the original
document.
152 Access/Use Info Resources Assess Health Risk Cliem Expos '93
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data and at least has bibliog-
raphic information. Finally, we
think that manual searching is
still necessary; that is, checking
through the bibliographies of
more recent papers to see if they
contain any references to earlier
papers not yet identified.
Computerized data bases offer
many advantages but may also
have some drawbacks if they are
used uncritically. The main
advantage is that they are a fast
way of identifying all references,
including "gray," foreign, and
older literature, original copies
of which are hard to get. How-
ever, we are not sure whether we
can use these sources anyway. In
addition, computerized data
bases may contain some data
evaluation to assist with func-
tions (3) and (4) of developing
criteria, and an evaluated data
base may present the experimen-
tal details of toxicity tests in a
systematic way. The difficulties
with computerized data bases are
redundancy (i.e., data may be
incorporated more, than once
because it was published in more
than one place), incompleteness,
inaccuracy, and currentness.
To adhere to the second principle
built into our regulations, that
the original document should be
obtained and used, takes time
and costs money for interlibrary
services when we do not have
the original document in our
library. It also means that we are
going to have to build up a
reprint file, but the library may
be able to do that.
In summary, our efforts with cal-
culation of aquatic criteria have
presented some problems, but
the challenge of selecting data
sources and mathematical mod-
els with which to set wildlife and
human criteria appears to be
even more daunting for the
future.
Computerized databases offer many
advantages but may also have some
drawbacks If they are used
uncritically.
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Information Resources: How They Are Utilized
by Louisiana
Suzanne Gardner, Louisiana Department of Environmental Quality
Louisiana, now in a developmental stage of policy and planning, has completed a project aimed at reducing hazardous releases of
air toxics in the state. The state is also conducting a Comparative Risk Project and is using risk assessment practices to develop its
water quality standards.
In developing an air toxic list, Louisiana incorporated four major criteria into the ranking: emission levels, human health effects,
potential population exposure,, and persistence or accumulation in the environment. For the human health effects criterion, data for
each substance was gathered from numerous sources, although the Integrated Risk Information System (IRIS) database was used as
a primary source for toxicological information.
Following guidelines established by the Environmental Protection Agency (EPA), the Office of Water Resources, Water Pollution
Control Division, has developed numerical criteria for human health protection based on risk assessment procedures in the 1989
Water Quality Standards Revision. Currently over 30 toxic substances have risk-based criteria for the protection of human health in
the standards. Numerical criteria were calculated for carcinogenic substances having an EPA Classification of A, Bl, B2, or C.
Cancer class designations along with cancer potency slopes and reference doses were extracted from the IRIS database, with the
exception of those chemicals that had not been assessed in IRIS as of December 1, 1988. The parameters-necessary for calculating
human health criteria for the missing chemicals were taken from 1980, 1984, and 1985 ambient water quality criteria documents;
data on bioconcentration factors were included.
Currently, Louisiana is working on a Comparative Risk Project, a ranking of the environmental issues in the state relative to
potential risk to the public, which is the basis for a widespread 1991 public outreach effort.
The Louisiana Department
of Environmental Quality
(LaDEQ), utilized infor-
mation resources as a vital tool
in developing planning strategy.
The department recently com-
pleted a project aimed at ranking
air toxics based on toxicological
data. The state used risk assess-
ment analyses to develop water
quality criteria. Currently, the
Office of Policy Analysis and
Planning is conducting the Lou-
isiana Comparative Risk Project,
a project that compares risk
across various environmental
issues. This labor intensive pro-
ject requires the use of informa-
tion resources over a broad
spectrum of issues.'
In an attempt to reduce state-
wide air emissions, Louisiana
passed the Comprehensive Toxic
Air Pollution Control Program,
Act 184, in June of 1989. A list
of not more than 100 toxic air
pollutants was to be regulated in
accordance with Act 184. To
rank these pollutant compounds,
several information resources
were needed. Various criteria
have been used by other states.
Most use the pounds discharged
and the potential population
exposed. Louisiana established
four criteria for ranking air pol-
lutants: amount discharged,
potential population exposed,
human health effects, and persist-
ence in the environment.
The first step was to identify the
chemicals to be included. The
Superfund Amendment
Reauthorization Act (SARA),
Title III, provided the basis for
the list. Of a total of 319 chemi-
cals, 178 were reported to be
emitted into the air in Louisiana.
Louisiana uses a variety of
information resources in developing
environmental planning strategies.
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155
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Calculations of the pounds dis-
charged were based on the 1987
SARA Toxic Chemical Release
Inventory Database. The data-
base consists of mandated com-
pany reports of intentional and
nonintentional releases. Point
and nonpoint emissions were
totaled for each chemical emitted
in Louisiana.
Calculations of potential popula-
tion exposure were based on U.S.
Census track data, utilized with
the help of the geographic infor-
mation service laboratory at Lou-
isiana State University Campus
Laboratory. A 10-km radius for
each emitting facility was estab-
lished and the Geographical
Information System (CIS) esti-
mated population within each
10-km area. The assumption was
made that the population within
each designated area was evenly
distributed. For human health
effects, the Integrated Risk Infor-
mation System (IRIS) database
was used.
IRIS was selected for its risk
assessment and risk management
information. The qualitative and
quantitative risk assessments
served as guidelines to evaluate
the potential hazard of chemi-
cals. Quantitative risk assess-
ment included potency factors,
unit risk, and air concentrations
at designated risk levels. For
accumulation and persistence in
the environment, the information
was harder to find. Data needed
included atmospheric half-lives,
evaporation rates, vapor pres-
sures, and reaction rates. Missing
lexicological data were calcu-
lated using reference doses
(RfDs), where applicable, taking
into account uncertainty factors.
Inhalation studies were given
preference over other studies.
One of the problems was the vast
amount of information needed
for each chemical. For several
chemicals, such as benzene,
abundance of lexicological data
was found, whereas in other
cases, such as picric acid, very lit-
tle information was found.
Once the data were collected, a
ranking for each criteria was per-
formed by designating a positive
integer for each criteria: the
higher the integer, the higher the
hazard. By this process, each
chemical was assigned a set of
numbers corresponding to the
severity of each criteria. These
numbers were then loaded into a
Hasse computer-ranking pro-
gram, developed by Dr. Ephram
Helfin of Canada, which estab-
lishes binary relationships
between chemicals by comparing
one data point with another. The
result is displayed graphically as
diagrams that resemble branch-
like structures, much like a
genealogical tree.
In developing the water quality
standards, the Office of Water
Quality Resources, Water Pollu-
tion Control Division, developed
human health protection stand-
ards based on risk assessment
analyses. Risk-based values have
been established for over 30
toxic substances. Numerical crite-
ria were developed for those sub-
stances with an EPA carcino-
genic classification of A, Bl, B2,
or C. Cancer potency slopes and
RfDs were taken from IRIS.
Data unavailable from these
sources, including bioconcentra-
tion factors, were taken from
1980, 1984, and 1985 ambient
air and water criteria documents.
A number of assumptions had to
be made: the use of 2 L for water
consumption, the use of 70 kg
Louisiana's comprehensive Toxic Air
Pollution Control Program utilizes
IRIS for its risk assessment and risk
management information.
In developing water quality standards,
the Office of Water Quality Resources,
Water Pollution Control Division,
developed human health protection
standards based on risk assessment
analyses.
156 Access/Use Info Resources Assess Health Risk Cbem Expos '93
-------
for the average adult body
weight, and a one-in-a-million
health risk for carcinogens. An
incidental ingestion rate (89 mL/
day) was calculated with the help
of the Department of Health and
Hospitals.
In our criteria, the water quality
standard for each chemical is pro-
portional to the product of the
risk level and the average adult
body weight, divided by the
slope factor, and the ingestion
rate, the average water consump-
tion, the bioconcentration factor,
and a fish consumption rate
(0.02 kg/day).
Average adult body weight x
Selected risk level
Slope factor [Avg. water consumption +
Incidental ingestion rate +
Fish consumption rate
(Unit conversion factor)(BCF)]
For noncarcinogens, RfDs were
substituted for the risk levels of
10"6. We utilized this calculation
for both public and nonpublic
water supplies.
Currently, LaDEQ is working on
the Louisiana Comparative Risk
Project, which ranks the environ-
mental issues in Louisiana rela-
tive to the risk to the public. This
follows a similar 1987 investiga-
tion by EPA called "Unfinished
Business," a comparative assess-
ment of an environmental issue.
For each issue, scenarios will be
developed that represent the
importance and magnitude of
each issue. Each issue will be put
through three levels of analysis:
health effects, ecological effects,
and welfare effects. The health
effects assessment will assess the
health risk associated with each
issue. The assessment of ecologi-
cal effects will include effects on
the economy. Welfare effects
include those effects that affect
quality of life. The second level
of analysis will be to rank the
problem areas within each effect
category. The third level of analy-
sis will be to rank the issues
across effect categories.
This process includes multidisci-
plinary involvement across vari-
ous agencies around our state.
Information resources and data
will be collected statewide for
this project. Louisiana is one of
the few states currently to start a
comparative risk project. The
comparative risk project will
redirect up to 30% of state
monies, so each agency has a
stake in this project.
LaDEQ is working on the Louisiana
Comparative Risk Project, which
ranks the environmental issues in
Louisiana relative to risk to the
public.
The health effects assessment will
assess the health risk associated with
each issue. The ecological effects will
include effects on the economy.
Welfare effects include those that
affect quality of life.
Access/Use Info Resources Assess Health Risk Chem Expos '93'
157
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Access and Use of Information Resources by
Massachusetts
Carol Rowan West, Massachusetts Department of Environmental Protection
This paper describes the way in which the Massachusetts Department of Environmental Protection uses risk assessment to
implement the slate 5s environmental laws. It focuses on the Office of Research and Standards, which was created to provide
information on adverse health effects of environmental contaminants, to recommend exposure levels, and to direct and manage
ttsearch programs.
Introduction
The Massachusetts Depart-
ment of Environmental
Protection (DEP) is the
state agency charged with pro-
tecting and enhancing the quality
of me Commonwealth's natural
resources—its air, water, and
land—to provide for the health,
safety, welfare, and enjoyment of
the public and the protection of
private property.
DEP fulfills its mission by imple-
menting a number of environ-
mental laws. The laws passed
and enforced to date
include
• Clean Air Act (state and
federal)
• Clean Water Act (state and
federal)
• Safe Drinking Water Act
(state and federal)
• State Solid Waste Regulatory
Law(21H)
• State Hazardous Waste
Regulatory Law (21C)
• Federal Resource Conserva-
tion and Recovery Act
• Superfund Law (state and
federal)
• State Right to Know Law
• Wetlands Protection Act (state)
• Wetlands Restriction Act
(state)
• Tidelands Law (Chapter 91)
(state)
• Low Level Radioactive Waste
Law (state)
• Toxic Use Reduction Act
(state)
Some of these laws are estab-
lished to protect a particular
resource such as air and drinking
water, whereas others are aimed
at solving environmental prob-
lems, such as solid and hazard-
ous waste disposal. The
common characteristic is the
focus on toxic chemicals—to pre-
vent environmental pollution and
adverse impacts on public health
and the environment.
The Office of Research and
Standards (ORS) was created in
1980 to serve all DEP programs
by providing information on
adverse health effects of environ-
mental contaminants, to recom-
mend exposure levels protective
of public health and the environ-
ment, and to direct and manage
the departmental research pro-
grams that serve as the technical
The DEP fulfills its mission by
implementing a number of
environmental laws.
Some of these taws are established to
protect a particular resource such as
air and drinking water, whereas
others are aimed at solving
environmental problems, such as
solid and hazardous waste disposal.
Access/Use Info Resources Assess Health Risk Chem Expos "93
159
-------
basis for appropriate policy and
program development. ORS cur-
rently has 12 full-time toxicolo-
gists and environmental
scientists on staff.
To achieve its mission within
DEP, ORS has many duties and
performs many functions. The
major areas of responsibility of
ORS are shown in Table 1.
Although the ability of ORS to
conduct all of these activities
effectively depends on many fac-
tors, the timely access of quality
and useful information is among
the most important requirements.
General Description of
Methods Used by ORS
ORS conducts risk assessment
work for the DEP programs by
using the four step process out-
lined by the National Academy
of Science (1983). In addition,
ORS participates in the DEP risk
management decisions by provid-
ing not only the results, but also
the description of uncertainty
inherent in the risk assessment
work. Risk management deci-
sions may consider technical fea-
sibility and economic and social
impacts along with risk assess-
ment results, depending on the
particular statute. After risk man-
agement decisions are made,
DEP next develops and imple-
ments a risk communication
plan, generally under a team
approach, in which staff from the
particular program, the public
affairs office, and ORS all partici-
pate. Here, ORS assists the DEP
to involve the public in under-
standing the risk assessment
process and results.
ORS accesses information for its
risk assessment work in a variety
of ways, as presented in Table 2.
Table 1. Major responsibilities of the Office of Research
and Standards (ORS)
• Develop risk assessment protocols to assess impacts of toxic
chemicals
• Establish standards and health-based guidelines for chemicals in
air, water, and soil
• Conduct hazardous waste site risk characterization work
• Evaluate environmental monitoring data and advise DEP on pub-
lic health protection
• Develop Health Hazard Indices for chemicals
• Recommend listing of chemicals for inclusion in regulatory pro-
grams
• Maintain toxicity databases
• Provide technical support on enforcement cases
• Direct and manage environmental research
Manual searches are very effec-
tive for ORS because the office is
located in the Boston area, which
is well-endowed with medical
and research institutions. Access
to these numerous libraries
allows ORS to obtain virtually
any journal or reference material
locally or through interlibrary
loan systems. ORS has also been
provided an annual budget to
maintain an in-house library.
Although ORS manual searches
are very productive, the time nec-
essary to conduct them can have
drawbacks in situations in which
immediate response is needed.
Another way ORS obtains infor-
mation is through on-line com-
puter access, the U.S. Environ-
mental Protection Agency's
(EPA's) Integrated Risk Informa-
tion System (IRIS), miscellane-
ous technical bulletin boards,
and the ORS-developed on-line
reference database. Use of these
systems is expedient but is lim-
Table 2. ORS access
to information
• Manual searches
• On-line access
• Reliance on others—EPA,
ORNL, other state agencies
160 Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
ited by the number of chemicals
for which information is main-
tained in these systems relative
to the ORS needs. ORS is lim-
ited by lack of on-line informa-
tion resources, and so must rely
on another means of information
access—consultation with oth-
ers, most notably the EPA, Oak
Ridge National Laboratory
(ORNL), and other state agen-
cies. In many instances ORS
received information transfer
assistance from others, including
the EPA, Air Risk Information
Support Center (Air RISC),
Office of Health and Environ-
mental Assessment, the Federal-
State Toxicology and Regulatory
Alliance Committee (FSTRAC),
Office of Pesticides and Toxics
Substances, and ORNL. In these
cases, information access is typi-
cally faster than manual searches
but slower than on-line systems.
ORS utilizes a number of infor-
mation resources in conducting
risk assessments. Key resources
are shown in Table 3.
Practical Problems With
Information Access
ORS has two types of problems
with access and use of informa-
tion resources in assessing health
risks from chemical exposure:
one is accessibility, the other is a
technical problem.
Accessibility problems arise
because of resource constraints.
For example, the agency does
not have a professional librarian
to obtain all information that is
available, and staff time for infor-
mation access is limited. ORS'
direct access to on-line systems
is very limited. ORS relies heav-
ily on other agencies for access
to information, which has
worked fairly well, but the
Table 3. Key data sources used by the Office of Research
and Standards
1. Hazard identification
IRIS
ATSDR Toxicity Profiles
EPA Criteria and Health Assessment Documents
HEAST
GENE-TOX Database
IARC
NTP/NCI bioassays
NIOSH, ACGIH, OSHA occupational literature
NATICH
EPA One-Liners
FDA Tolerance Limits/Advisories
2. Dose response assessment
IRIS
HEAST
Occupational literature
Primary literature
3. Exposure assessment
EPA guidelines for exposure assessment
ORS default values
Risk characterization and
uncertainty analysis
All of the above
office's needs cannot always be
met. In addition, because of the
nature of the public health protec-
tion work that we conduct, there
are instances in which ORS
results are needed immediately.
In such cases, information gather-
ing activities are limited by dead-
lines, hence information that
could be useful may not be
obtained.
Access/Use Info Resources Assess Health Risk Chem Expos '93
161
-------
With regard to technical prob-
lems, it is evident that access to
information resources does not
translate directly into the ability
to provide all of the answers to
environmental health problems.
Typical examples of risk assess-
ment issues that result from tech-
nical data limitations are shown
in Table 4.
Conclusions
To conduct risk assessments for
the protection of public health
from environmental contami-
nants, access to information
should be readily available,
reliable, able to meet time con-
straints, and affordable. Improve-
ments in risk assessment work
will be achieved only when more
complete data on chemicals can
be generated (including informa-
tion on adverse health effects,
routes of administration, and
duration of exposure) and better
methods (including appropriate
animal models and extrapolation
to humans) can be developed.
These ideal conditions are not
now within our reach, but profes-
sionals involved in this field
Table 4. Technical problems
• Evaluating less than lifetime exposure
• Lack of toxicity testing of chemicals
• Standard toxicity testing protocols not followed
• Route of administration
• High to low dose extrapolations
• Chemical form, specification
• Appropriate animal model for humans
• Lack of human toxicity data
• Uncertainty factors
from state, federal, and interna-
tional agencies, as well as private
institutions should work together
to achieve what is possible. The
importance of this work in terms
of lives saved and human suffer-
ing reduced is worthy of such an
effort.
References
National Academy of Science. 1983.
Risk Assessment in the Federal Govern-
ment: Managing the Process. National
Research Council. National Academy
Press, Washington, D.C.
These ideal conditions are not now
within our reach, but professionals
involved in this field from state,
federal, and international agencies, as
well as private institutions should work
together to achieve what is possible.
162 Access/Use Info Resources Assess Health Risk Cbem Expos '93
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Information Resources Used in Health Risk
Assessment by the New Jersey Department of
Environmental Protection
Gloria B. Post, Maria Baratta, Sharon Wolfson, and Leslie McGeorge,
New Jersey Department of Environmental Protection
The New Jersey Department of Environmental Protection's responsibilities related to health-based risk assessment are described,
including its research projects and its development of health based compound specific standards and guidance levels. The
resources used by the agency to support health risk assessment work are outlined.
The New Jersey Depart-
ment of Environmental
Protection (NJDEP) per-
forms a number of functions
relating to health risk assessment
which require information
resources. NJDEP is unique in
including a Division of Science
and Research (DSR), which con-
ducts research projects and pro-
vides other types of technical
support to the department. A
major strength of DSR is in toxi-
cology and assessment of health
risks. Activities in these areas
include developing and manag-
ing research projects; developing
compound-specific standards
and guidance levels; site-specific
evaluations; replies to citizen's
inquiries; and providing techni-
cal assistance to other NJDEP
Divisions.
NJDEP has its own Information
Resource Center (IRC), which is
part of DSR and is available to
the entire department. The IRC is
a technical library that has refer-
ence materials, technical jour-
nals, government documents,
books, and data base searching
capabilities; a staff of five oper-
ates the center. Information
resources used in assessing
human health risks include data
bases such as the National
Library of Medicine (NLM) files
(specifically HSDB and TOX-
LINE), IRIS, and DIALOG, as
well as information retrieval,
interlibrary loans, and access to
federal government documents.
Additionally, DSR is cosponsor-
ing, along with EPA and the Cali-
fornia Department of Health
Services, the development of
Risk Assistant, a microcomputer-
based software system that will
be used by individuals with lim-
ited expertise in risk assessment
to assess health risks at hazard-
ous waste sites. Risk Assistant
includes databases on toxicity,
regulatory standards, chemical
properties, and analytical limits
and is capable of estimating
exposures and risk levels. These
capabilities allow NJDEP to per-
form original compound-specific
and site-specific risk assessments
and to provide the technical basis
for research activities.
NJDEP is a large agency that has
about 4000 employees. As
shown in the departmental
organizational chart (Fig. 1),
NJDEP consists of a number of
DSR's Information Resource Center
provides access to technical
information required for risk
assessments.
These capabilities allow NJDEP to
perform original compound-specific
and site-specific risk assessments.
Access/Use Info Resources Assess Health Risk Chem Expos '93
163
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divisions and is organized gener-
ally along media-specific lines.
Many of the divisions with
responsibilities relating to par-
ticular environmental media per-
form or use human health-based
risk assessment to some extent.
For example, the Bureau of Envi-
ronmental Evaluation and Risk
Assessment within the Division
of Hazardous Site Mitigation
reviews risk assessments of con-
taminated sites that have been
submitted to NJDEP; the Bureau
of Air Quality Planning and
Evaluation within the Division of
Environmental Quality uses risk
assessments in developing per-
mits for certain types of air emis-
sions; and the Bureau of Safe
Drinking Water in the Division
of Water Resources relies on risk
assessment information to pro-
vide guidance in situations of
contaminated potable water.
NJDEP is unique in that it
includes the Division of Science
and Research (DSR), which
reports to the Commissioner's
Office. DSR conducts research
projects and provides other types
of technical support to NJDEP,
particularly in addressing cross-
media issues or nonroutine situ-
ations. DSR is responsible for
overall coordination of the risk
assessment activities of NJDEP
and sponsors the Interagency
Risk Assessment Committee
(IRAC), which consists of staff
from various divisions of NJDEP
and the New Jersey Department
of Health who are involved with
risk assessment. IRAC meets
regularly to hear invited speakers
present topics of general interest
and to discuss risk assessment
issues.
DSR was originally founded in
1976 as the Program in Environ-
1
HAZARDOUS
WASTE
MANAGEMENT
L.
Hazardous Wasl
Management
Hazardous Site
Management
NEW
ENVII
SCIENCE AND
RESEARCH
' JERSEY DEPARTMENT OF
3ONMENTAL PROTECTION
COMMISSIONER j
DEPUTY COMMISSIONER
1
NATURAL AND
HISTORIC
RESOURCES
L _
D Parks and
Forestry
Green Acres and
Recreation
Fish, Game
and Wildlife
Coastal
Resources
Press Office
Office of
policy ana
Planning
L
EXTERNAL
AFFAIRS
1
MANAGEMENT
AND BUDGET
Personnel
Financial
Management
Planning and
General
Services
ENVIRONMENTAL
MANAGEMENT
CONTROL
Water
Resources
Environmental
Quality
Solid Waste
Management
Fig. 1. New Jersey Department of Environmental Protection.
mental Cancer and Toxic Sub-
stances to evaluate the potential
carcinogenicity of environmental
contaminants. Although it has
branched out into many other
areas since that time, its primary
emphasis remains that of assess-
ing the extent of exposure and
the health effects of environ-
mental contaminants. In 1986,
the Office of Environmental
Health Assessment (OEHA) was
implemented within DSR
through a governor's initiative.
OEHA's mandate is to provide
expertise in the areas of risk
assessment, risk communication,
and risk reduction to NJDEP.
DSR consists of approximately
40 professional staff, with exper-
tise in many fields including toxi-
cology, genetic toxicology,
public health, environmental
science, physics, geology, chem-
istry, aquatic biology, geography,
Areas of research include
toxicology, exposure assessment,
epidemiology, biological
monitoring, and risk assessment
modeling.
164 Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
communication, and library sci-
ence. The organizational struc-
ture of DSR is shown in Fig. 2.
Within DSR, the Risk Assess-
ment Unit and the Environ-
mental Exposure Unit are the
major groups that perform risk
assessment-related work.
DSR has sponsored and/or con-
ducted a number of research pro-
jects relating to human health
risk assessment. Areas of
research include toxicology,
exposure assessment, epidemiol-
ogy, biological monitoring, and
risk assessment modeling. The
research projects are designed to
provide specific information
required by NJDEP to address
New Jersey environmental prob-
lems and to contribute to the gen-
eral knowledge in the field.
DSR research projects include
the following: bioavailability
studies of dioxin and chromium
from contaminated soils; determi-
nation of pesticide residues in
crops grown or sold in New Jer-
sey and risk assessment based on
these levels; total human expo-
sure study of benzo[a]pyrene,
including measurement of
benzo[a]pyrene-DNA adducts in
blood samples from subjects;
total exposure and biological
monitoring of subjects living on
chromium-contaminated sites;
exposure assessment and
neurobehavioral effects of
Orchard farmers with chronic pes-
ticide exposure; pulmonary car-
cinogenicity of chromium-
contaminated soil; toxic interac-
tions of two chlorinated drinking
water contaminants; and use of
quantitative structure activity
relationships to predict carcino-
genicity of trihalomethanes and
related compounds.
NEW JERSEY DEPARTMENT OF
ENVIRONMENTAL PROTECTION
DIVISION OF SCIENCE AND RESEARCH
tsite
vestigation
En
L_
Environmental
Exposure
DIRECTOR'S OFFICE 1
Director
Deputy Director
^^^^^^
Policy and 1 Information Is
Planning Resource Adr
1 Center
Policy and
Information
Management
-""/ \
etwork Administrative
ninlstration Services
1
vironmenlal GIS Enviro
Research He
1
Environmental
Assessment
1
Risk 1
Communication ASSE
nmental
alth
1
Risk I Risk I
ssment Reduction
Fig. 2. New Jersery Department of Environmental Protection
Division of Science and Research.
DSR has also provided partial
funding, along with EPA and the
California Department of Health
Services, for the development
of Risk Assistant, a software
package that has databases on
toxicity, chemical properties,
exposure assumptions, ARARs,
and analytical limits. When com-
pleted, Risk Assistant will be util-
ized by individuals with limited
risk assessment training to assist
with exposure and risk assess-
ment of contaminated sites.
In addition to research projects,
DSR is responsible for develop-
ing health based compound spe-
cific standards and guidance
levels. A major project involved
the development of health-based
Maximum Contaminant Levels
(MCLs) for 28 compounds, as
required by the A-280 amend-
ments to the New Jersey Safe
Drinking Water Act, which
require New Jersey to develop its
own drinking water standards.
New Jersey began this process
Research projects Include
bioavailability studies of dioxin
and chromium from contaminated
soils; determination of pesticide
residues in crops grown or sold in
New Jersey; and risk assessment
based on these levels and others.
DSR participates in site-specific risk
assessments on a case-by-case basis.
165
-------
before EPA promulgated its first
MCLs in 1987. The development
of these drinking water standards
by DSR involves evaluating the
primary toxicology and epidemi-
ology literature on the com-
pound; developing a Support
Document, which reviews back-
ground information and health
effects; and performing the risk
assessment for the compound.
The documents were peer
reviewed and became part of the
basis and background for the
regulations. As one of the lead-
ing states in the development of
health-based drinking water
standards, New Jersey actively
participates in FSTRAC (Federal-
Slate Toxicology and Regulatory
Alliance), an organization of fed-
eral and state scientists that
meets regularly to discuss issues
relating to drinking water risk
assessment.
DSR is also involved with the
development of the human health
basis for soil standards, ground-
water guidance, and surface
water quality standards.
Additionally, DSR participates in
site-specific risk assessments on
a case-by-case basis, particularly
when the situation requires a non-
standard technical approach. For
example, DSR is currently devel-
oping a risk assessment approach
for chromium-contaminated sites
in Hudson County, New Jersey.
DSR has also participated in a
contract funded by the Agency
for Toxic Substances and Dis-
ease Registry through the New
Jersey Department of Health to
develop health assessments for
Superfund sites in New Jersey.
Finally, DSR provides technical
consultation to NJDEP and to the
public on questions relating to
toxicology and risk assessment.
These varied activities require
many types of information
resources. Information is
required from the basic scientific
literature in a number of disci-
plines, from technical documents
prepared by EPA and other fed-
eral and state agencies, and from
regulatory sources such as the
Federal Register and New Jersey
Register,
NJDEP is fortunate to have its
own library, the Information
Resource Center (IRC), which
was started with a TSCA (Toxic
Substances Control Act) grant to
states in the early 1980s. The
IRC is part of DSR and serves
the entire NJDEP. It has a staff of
five, including three professional
librarians. Its collection has a
large emphasis on toxicology
and environmental health and is
also strong in die areas of water
resources, waste management,
hazardous substances, and
chemical-specific information.
The collection includes approxi-
mately 2500 books, 5000 govern-
ment documents, regulatory
materials, and 125 journals. The
chemical reference file, a collec-
tion developed by the IRC,
includes information on approxi-
mately 2000 chemicals. The IRC
also holds Toxic Release Inven-
tory reports from New Jersey
industries in 1987 and 1988.
The database searching capabili-
ties of the IRC include both bibli-
ographic and factual databases
such as MEDLARS, Integrated
Risk Information System (IRIS),
and DIALOG. The use of these
data bases allows for rapid
access to the primary scientific
literature on compounds of inter-
est, as well as to summaries of
their chemical and toxicological
properties. The IRC uses
The chemical reference fib? includes
information on approximately 2000
chemicals.
Ttu IRC uses interlibrary loan
capabilities and can access fe denil
technical documents.
166 AccessAJse Info Resources Assess Health Risk ("hem Expos '93
-------
interlibrary loan capabilities, and
can access federal technical docu-
ments. Although the library and
its collections are open to the
public, services for which fees
are charged are available only to
NJDEP staff.
All of these information
resources are utilized extensively
by the NJDEP technical staff and
are invaluable in efficiently
accessing the information needed
to carry out the department's
risk-assessment related work.
These resources are indispensa-
ble in allowing NJDEP to per-
form risk assessment-related
research and to develop original
approaches toward health-based
risk assessment.
167
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Use of Information Resources by the State
of Tennessee in Risk Assessment Applications
Bonnie S. Bashor, Tennessee Department of Health and Environment
The major resources used by the Bureau of Environment, and Environmental Epidemiology (EEP)for risk assessment are: the
Integrated Risk Information System (IRIS), Health and Environmental Effects Summary Table (HEAST), Agency for Toxic
Substances and Disease Registry (ATSDR) Toxicological Profiles, databases at the National Library of Medicine (NLM), World
Health Organization (WHO) Environmental Criteria, and documents t)iat tlie Environmental Protection Agency (EPA) has
published on Compretensive Environmental Response, Compensation, and Liability Act (CERCLA) risk assessment activities. Tlie
Risk Assessment Review has been helpfid in providing information about availability of new documents or information. No
systematic metliod )tas been made a\'ailable to us to locate information resources. IRIS User's Support )ias been helpful in making
appropriate and timely referrals. Most other EPA resources were located by serendipity and persistence. The CERCLA metliodology
far risk assessments is being used in all environmental programs, and at present, one person is responsible for all risk assessment
activities in die department, but plans are underway to train one or two people from each program area.
The Tennessee Department
of Health and Environ-
ment (TDHE) is made up
of four bureaus: Environment,
Health Services, Medicaid, and
Manpower and Facilities. All the
environmental regulatory pro-
grams are within the Bureau of
Environment, while risk assess-
ment activities, health screening
of environmental field workers,
and health studies centered
around pollution are within the
Bureau of Health Services, Divi-
sion of Environmental Epide-
miology (EEP). See Figs. 1 and 2
for a description of the organiza-
tion of TDHE. EEP is the link
between the environmental pro-
grams and public health, dealing
with health aspects of environ-
mental pollution.
EEP began in 1982 as a very
small program with no clear-cut
goals or objectives. The division
began slowly, but has built into a
creditable program as its person-
nel learned about Environmental
Epidemiology and acquired
information on the toxicity of
chemicals.
EEP began conducting risk
assessments in 1983 when infor-
mation was disclosed about
mercury releases by the Depart-
ment of Energy in Oak Ridge
into East Fork Poplar Creek.
Because estimates of a "safe"
level of mercury in soil were not
available at the time, EEP devel-
oped an equation for calculating
such estimates.
Access to the Integrated Risk
Information System (IRIS) has
been especially helpful to EEP
by providing timely, accurate tox-
icity information. Even with this
resource, however, and with
information available on
TOXNET and MEDLINE and at
national workshops, it was not
until EPA began publishing its
toxicity guidelines that EEP had
sufficiently reliable data to confi-
dently perform risk assessments.
When the Division of Superfund
(DSF) in 1988 asked EEP for
assistance in learning to do risk
Because estimates of a "safe" level of
mercury in soil were not available at
the time, EEP developed an equation
for calcidating such estimates.
It was not until EPA began pubUs)iing
its toxicity guidelines tltat EEP had
sufficiently reliable data to
confidently perform risk assessments.
Access/Use Info Resources Assess Health Risk Chem Expos '93
169
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TENNESSEE DEPARTMENT OF
HEALTH AND ENVIRONMENT
BUREAU OF
ENVIRONMENT
BUREAU OF
MEDICAID
BUREAU OF
MANPOWER & FACILITIES
BUREAU OF
HEALTH SERVICES
WATER PROGRAM
ADMINISTRATION
CONSTRUCTION
- GRANTS &
LOANS
GROUNDHATER
" PROTECTION
WATER
- POLLUTION
CONTROL
WATER
SUPPLY
HEALTH PROGRAM
ADMINISTRATION
—
FOOD a
GENERAL
SANITATION
ADMINISTRA-
TIVE
SERVICES
TRAINING
CENTER
STAFF
SUPPORT
SERVICES
LAND/AIR PROGRAM
ADMINISTRATION
H
AIR
POLLUTION
CONTROL
SUPERFUND
RADIOLOGICAL
HEALTH
SOLID/
HAZARDOUS
WASTE
MANAGEMENT
-(HEALTH ACCESS!
PRIMARY CARE
INDIGENT CARE
PHYSICIAN
' PLACEMENT
HEALTH PROMOTION/
' DISEASE CONTROL
COMMUNICABLE
' DISEASE CONTROL
-I AIDS!
-
MATERNAL &
CHILD HEALTH
ENVIRONMENTAL
EPIDEMIOLOGY
PROGRAM
SERVICES
COMMUNITY
HEALTH
REGIONAL
OFFICES
( LOCAL
HEALTH
DEPARTMENTS
UNDERGROUND
STORAGE
TANKS
Fig. 1. Organizational chart fdr the Tennessee Department of Health and Environment.
TENNESSEE DEPARTMENT OF
HEALTH AND ENVIRONMENT
BUREAU OF
HEALTH SERVICES
WATER PROGRAM
ADMINISTRATION
LAND/AIR PROGRAM
ADMINISTRATION
GROUNDWATER
PROTECTION
WATER
POLLUTION
CONTROL
_L
WATER
SUPPLY
SOLID/
HAZARDOUS
WASTE
MANAGEMENT
UNDERGROUND
STORAGE
TANKS
170
Fig. 2. Organization chart for Environmental Regulatory Programs and Environmental Epidemiology.
Access/Use Info Resources Assess Health Risk Chem Expos '93
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assessments, access to existing
information proved to be diffi-
cult. Some of the most helpful
resources that were ultimately
obtained were EPA's guidelines
published in: The Superfund
Exposure Assessment Manual,
The Development of Statistical
Distributions or Ranges of Stand-
ard Factors Used in Exposure
Assessments, The Risk Assess-
ment Guidance for Superfund,
Volume 1, Human Health Evalu-
ation Manual (Part A). EEP uses
these regularly, along with the
periodical, Risk Assessment
Review, which reports new infor-
mation.
Although the publications depart-
ment at EPA-Cincinnati is par-
ticularly helpful in sending hard
copies of publications, when
only a partial reference is avail-
able (as often happens in draft
documents), it is difficult to find
the person at EPA with informa-
tion about the reference. The
Catalog of Superfund Program
Publications and the EPA Infor-
mation Resources Directory are
somewhat helpful in tracking
down this kind of information.
The division has been unable to
acquire an EPA telephone direc-
tory but IRIS User Support has
often directed EEP staff to the
appropriate resource person. If
there is a more timely way to get
information on chemical toxicity,
exposure assessments, or locat-
ing EPA publications than this
personal contact network, the
division would find it helpful. If
resources are available that EEP
has not found, information about
them would be appreciated. EEP
presently receives several jour-
nals and other publications. As
funding increases, the division
would like to subscribe to addi-
tional publications.
EEP is preparing a basic course
in risk assessment for the DSF
and for the Division of Solid
Waste Management (SWM). Its
purpose is to acquaint their engi-
neers with the basics of toxicol-
ogy, the definitions of slope
factors and reference doses, and
describe how these fit in the haz-
ard identification and dose-
response portions of risk
assessments. The course will
also cover exposure assessments
and risk characterizations. EEP
staff has worked in the field with
environmental professionals to
learn more about problems they
face and to assist them in deter-
mining the sampling locations
that are likely to provide the
most useful information for deter-
mining risks to people living
near Superfund sites.
EEP staff performs simple risk
assessments for DSF to help
their staff determine the urgency
of actions to be taken to protect
the public exposed to contami-
nants .at Superfund sites. EEP
also reviews risk assessments
performed by contractors as part
of the Remedial Investigation/
Feasibility Study (RI/FS)
process.
Risk assessment in Tennessee is
no longer limited to DSF. All
environmental programs need
risk assessment information in
managing programs. EEP uses
the process in assisting SWM to
write and negotiate Resource
Conservation and Recovery Act
permits for which industries have
requested Alternate Concentra-
tion Limits and to review the risk
assessment portions of RI/FS
documents. EEP used the risk
assessment process to derive a
water quality standard for 2,3,7,8-
tetrachlorodibenzo-p-dioxin
EEP staff performs simple risk
assessments for DSF to help their
staff determine the urgency of actions
to be taken to protect the public
exposed to contaminants at
Superfund sites.
Risk assessment in Tennessee is no
longer limited to DSF. All
environmental programs need risk
assessment information in managing
programs.
Access/Use Info Resources Assess Health Risk Chem Expos '93
171
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(TCDD) for the Division of
Water Pollution Control.
At the state level, hazard identifi-
cation is limited to sampling to
determine if toxic chemicals
exist at a certain location. EEP
seldom determines slope factors,
reference doses, or No Observed
Adverse Effect Levels
(NOAEL). Therefore, EEP does
not usually use laboratory data or
academic publications to per-
form dose-response assessments.
It is necessary, however, to under-
stand the basis for dose-response
calculations and the mechanisms
of toxicity on which the calcula-
tions are based. On occasion,
EEP has needed to use basic sci-
entific information, as when a
water quality standard was being
derived for TCDD.
Environmental programs are
using risk assessment processes
more frequently. There is con-
cern that resources have been
and will continue to be missed
because there is no systematic
method to find them. No coopera-
tive agreement exists with the
ATSDR, which means that
resource is of limited usefulness.
There is also concern that EEP
may lack adequate perspective
and a system of checks and
balances in its risk assessment
process because there is no sys-
tematic way for EEP staff to dis-
cuss problems with other
professionals.
EEP is doing a creditable job in
performing risk assessments and
health screening of TDHE's high-
risk employees and in investigat-
ing potential disease clusters.
The division would be most
aided by continued expansion of
IRIS, assistance in predicting
concentrations of chemicals
migrating from one medium to
another, easy-to-use methods to
calculate the number of needed
samples, and current information
about values for variables to use
in exposure equations. Informa-
tion on the use of biomarkers
in exposed populations and
methods of disease cluster analy-
sis are also needed, as is informa-
tion on the use of user-friendly
geographical information sys-
tems.
There is concern that resources have
been and will continue to be missed
because there is no systematic method
to find them. No cooperative
agreement exists with the Agency for
Toxic Substances and Disease
Registry, which means that resource
is of limited usefulness.
172 Access/Use Info Resources Assess Health Risk Chem Expos '93
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Integrated Risk Information System (IRIS)
Linda Tuxen, U.S. Environmental Protection Agency
The Integrated Risk Information System (IRIS) is an electronic information system developed by the U.S. Environmental Protection
Agency (EPA) containing information related to health risk assessment. IRIS is the Agency's primary vehicle for communication of
chronic health hazard information that represents Agency consensus following comprehensive review by intra-Agency workgroups.
The original purpose for developing IRIS was to provide guidance to EPA personnel in making risk management decisions. This
role has expanded and evolved with wider access and use of the system, IRIS contains chemical-specific information in summary
format for approximately 500 chemicals. IRIS is available to the general public on the National Library of Medicines's Toxicology
Data Network (TOXNET) and on diskettes through the National Technical Information Service (NTIS). For further general
information on IRIS and how to access the system contact: IRIS User Support (Staffed by Computer Sciences Corporation, USEPA,
ECAO (MS-190), Cincinnati, Ohio, 45268. Telephone: (513) 569-7254, Facsimile: (513) 569-7916.
Background
Many U.S. Environ-
mental Protection
Agency (EPA) pro-
gram offices and program sup-
port offices, including the Office
of Research and Development,
both at Headquarters and in
EPA's ten Regional offices, are
involved in assessment activities
in support of various legislative
mandates. In the 1980s, as health
risk assessment became a more
widespread practice across
Agency programs, the need for
greater consensus and consis-
tency in the areas of hazard iden-
tification and dose-response
assessment became clear. It was
determined that an internal proc-
ess should be established for
reaching an Agency-wide judg-
ment on the potential health
effects of substances of common
interest to these offices, and a
system developed for communi-
cating that Agency judgment to
EPA risk assessors-and risk man-
agers. These would provide the
needed consistency and coordina-
tion. In 1986, two EPA work
groups with representation from
program offices involved in risk
assessment were convened to
carry out such an internal proc-
ess to reach consensus Agency
positions on a chemical-by-
chemical basis. In 1986, the Inte-
grated Risk Information System
(IRIS) data base was created for
EPA staff as the official reposi-
tory of that consensus informa-
tion.
On June 2,1988, a Federal Reg-
ister (53 FR 20162) notice of
public availability of IRIS was
published. That notice described
IRIS, the types of risk informa-
tion it contains, and how to get
access to the system. It informed
the public about the establish-
ment of the IRIS Information
Submission Desk and the pres-
ence of a separate file on IRIS
listing the substances scheduled
for work group review. The sub-
mission desk was intended to
provide opportunity for public
input. The notice explained the
procedures for submission of
data or comments by interested
parties on substances either on
IRIS or scheduled for review by
the work groups.
In the 1980's, as health risk
assessment became a more
widespread practice across Agency
programs, the need for greater
consensus and consistency in the
areas of hazard identification and
dose-response assessment became
clear.
IRIS contains summaries of EPA
qualitative and quantitative human
health information that support two
of the four major steps of the risk
assessment process.
Access/Use Info Resources Assess Health Risk Chem Expos '93 173
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IRIS contains summaries of EPA
qualitative and quantitative
human health information that
support two of the four major
steps of the risk assessment proc1
ess as outlined by the National
Research Council (NRC 1983).
That process consists of four
major steps: hazard identifica-
tion, dose-response evaluation,
exposure assessment, and risk
characterization. IRIS includes
information in support of the
first two of those steps, hazard
identification and dose-response
evaluation. Hazard identification
is the qualitative determination
of how likely it is that a sub-
stance will increase the incidence
and/or severity of an adverse
health effect. Dose-response
evaluation is the quantitative rela-
tionship between the magnitude
of the effect and the dose induc-
ing such an effect. In general,
quantitative human health hazard
information, such as that in IRIS,
is developed in light of numer-
ous uncertainties involved in risk
assessment, including those asso-
ciated with extrapolations from
animal data to humans and from
high experimental doses to lower
experimental doses to lower envi-
ronmental exposures.
Exposure assessment is the evalu-
ation of the nature and extent of
exposure and the number and
types of people exposed. IRIS
does not include exposure assess-
ment information. Combined
with specific situational expo-
sure assessment information, the
summary health hazard informa-
tion in IRIS may be used as one
source in evaluating potential
public health risks of, or from,
environmental contaminants.
Risk characterization is the com-
bining of the hazard identifica-
tion assessment, dose-response
evaluation, and exposure assess-
ment to produce a synopsis and
synthesis of all the data that
should contribute to a conclusion
with regard to the nature and
extent of the risk. This includes
discussion of the overall uncer-
tainty in the analysis, including
the major assumptions made, the
scientific judgments employed,
and an estimate of the degree of
conservatism involved. IRIS con-
tains limited information support-
ing the risk characterization step
of the risk assessment process.
That limited information in IRIS
consists of brief statements on
the quality of data and very gen-
eral statements on confidence in
the dose-response evaluation.
Data Base Contents
The core of IRIS is the three con-
sensus health hazard information
summary sections: the reference
dose (RfD) for non-cancer health
effects resulting from oral expo-
sure; the reference concentration
(RfC) for non-cancer health
effects resulting from inhalation
exposure; and the carcinogen
assessment for both oral and
inhalation exposure. All of these
terms are commonly used for
judging the effects of lifetime
exposure to a given substance or
mixture.
In addition, an IRIS substance
file may include supplemental
information such as summaries
of health advisories, regulatory
actions, and physical/chemical
properties.
Non-Cancer Health
Effects Information
An RfD is an estimate (with
uncertainty spanning perhaps an
Quantitative human health hazard
information, such as that in IRIS, is
developed in light of numerous
uncertainties involved in risk
assessment.
The three consensus health hazard
information summary sections are: the
reference dose (RfD) for non-cancer
health effects resulting from oral
exposure; the reference concentration
(RfC) for non-cancer health effects
resulting from inhalation exposure;
and the carcinogen assessment for
both oral and inhalation exposure.
174 Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
order of magnitude) of a daily
oral exposure to the human popu-
lation (including sensitive sub-
groups) that is believed likely to
be without an appreciable risk of
certain deleterious effects during
a lifetime (EPA 1988), RfDs are
developed by an assessment
method that assumes that there is
a dose threshold below which
adverse effects will not occur.
An RfD, which is expressed in
milligrams per kilogram per day
(mg/kg-day), is based on the
determination of a critical effect
from a review of all toxicity data
and a judgment of the necessary
uncertainty and modifying fac-
tors based on a review of avail-
able data. IRIS substance files
contain the following informa-
tion pertaining to the oral RfD:
reference dose summary tables,
principal and supporting studies,
uncertainty and modifying fac-
tors used in calculating the RfD,
a statement of confidence in the
RfD, EPA documentation and
review, EPA scientific contacts,
and complete bibliographies for
references cited.
The inhalation reference concen-
tration (RfC) is analogous to the
oral RfD (EPA 1990) and is also
based on the assumption that
thresholds exist for non-cancer
toxic effects. The RfC considers
toxic effects for both the respira-
tory system (portal-of-entry) and
for effects peripheral to the respi-
ratory system (extra-respiratory).
The inhalation RfC is expressed
in milligrams per cubic meter
(mg/cu.m). The RfC method
departs from that used to deter-
mine the oral RfD primarily by
the integration of the anatomical
and physiological dynamics of
the respiratory system (i.e.,
portal-of-entry) with the physico-
chemical properties of the sub-
stance or substances entering the
system. Different dosimetric
adjustments are made according
to whether the substance is a par-
ticle or gas and whether the
observed toxicity is respiratory
or extra-respiratory. These adjust-
ments scale the concentration of
the substance that causes an
observed effect in laboratory ani-
mals (or in humans, when avail-
able from occupational epide-
miology studies) to a human
equivalent concentration for
ambient exposures. IRIS sub-
stance files contain the following
inhalation RfC information: ref-
erence concentration summary
tables; description of dosimetric
adjustment; principal and sup-
porting studies; uncertainty and
modifying factors used to calcu-
late the RfC; a statement of confi-
dence in the RfC; EPA
documentation and review; EPA
scientific contacts; and complete
bibliographies for references
cited.
Cancer Health Effects
Information
The carcinogen assessment of an
IRIS substance file contains
health hazard identification and
dose-response assessments devel-
oped from procedures outlined in
the EPA Guidelines for Carcino-
gen Risk Assessment (51 FR
33992-43003, September 24,
1986). Each cancer assessment,
as a rule, is based on an Agency
document that has received exter-
nal peer review. The hazard iden-
tification involves a judgment in
the form of a weight-of-evidence
classification of the likelihood
that the substance is a human car-
cinogen. It includes the type of
data used as the basis of the clas-
sification. This judgment is made
independently of considerations
RfDs are developed by an assessment
method that assumes that there is a
dose threshold below which adverse
effects will not occur.
Each cancer assessment, as a rule, is
based on an Agency document that
has received external peer review.
Access/Use Info Resources Assess Health Risk Cheni Expos '93 175
-------
of the strength of the possible
response. The dose-response
assessment is a quantitative esti-
mate of the potential activity or
magnitude of a substance's car-
cinogenic effect, usually
expressed as a cancer unit risk. A
cancer unit risk is an upper-
bound on the increased likeli-
hood that an individual will
develop cancer when exposed to
a substance over a lifetime at a
concentration of either 1 micro-
gram per liter (1 (ig/L) in drink-
ing water for oral exposure or 1
microgram per cubic meter
(1 ug/cu.m) in air for continuous
inhalation exposure. Generally, a
slope factor for dietary use is
also given. It is an upper-bound
estimate of cancer risk for
humans per milligram of agent
per kilogram of body weight per
day.
IRIS contains the following infor-
mation in the cancer assessment
section: EPA weight-of-evidence
classification and its basis; a sum-
mary of human carcinogenicity
studies when available; a sum-
mary of animal carcinogenicity
studies; a summary of other data
supporting the classification; oral
and/or inhalation quantitative
estimates; dose-response data
used to derive these estimates
and the method of calculation;
statements of confidence in mag-
nitude of unit risk; documenta-
tion and review; EPA scientific
contacts; and complete bibliog-
raphies for references cited.
Scientific Contacts
It is important to note that in
each of the three sections
described above, EPA staff
names and telephone numbers
are included as scientific con-
tacts for further information. The
Agency believes that the inclu-
sion of Agency scientific con-
tacts able to discuss the basis for
the Agency's position, has been
very valuable. These individuals
play a major role in providing
public access to IRIS and a con-
duit for valued public comment.
Bibliographies
IRIS contains full bibliographic
citations for each substance file,
directing the user to the primary
cited studies and pertinent scien-
tific literature. One of the major
intents of IRIS was to encourage
users to evaluate the primary lit-
erature used to develop the IRIS
information in light of the
assumptions and uncertainties
underlying the risk assessment
process.
Supplementary Information
In addition to the RfD, RfC, and
carcinogenicity sections, IRIS
substance files may contain one
or more of three supplementary
information sections: a summary
of an Office of Water's Drinking
Water Health Advisory, a sum-
mary of EPA regulatory actions,
and a summary of physical/
chemical properties. The only
purpose of these supplemental
sections is as accessory informa-
tion to the consensus health haz-
ard information. Since the
primary intent of the IRIS date
base is to communicate EPA con-
sensus health hazard informa-
tion, these other sections are only
included as auxiliary material to
provide a broader profile of a
substance and are never added
until at least one of the consen-
sus health hazard sections
described above (namely, the
RfD section, RfC section, or car-
cinogenicity section) is prepared
and approved for final inclusion
The Agency believes that the inclusion
of Agency scientific contacts able to
discuss the basis for the Agency's
position, has been very valuable.
One of the major intents of IRIS was to
encourage users to evaluate the
primary literature used to develop the
IRIS information in light of the
assumptions and uncertainties
underlying the risk assessment process.
176
Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
on the data base. These supple-
mental sections should not be
used as tihe sole or primary
source of information on the cur-
rent status of EPA substance-
specific regulations.
Information Development
Process
There are two EPA work groups,
the Carcinogen Risk Assessment
Verification Endeavor (CRAVE)
and the Oral Reference Dose/
Inhalation Reference Concentra-
tion (RfD/RfC) Work Group,
that develop the consensus health
hazard information for IRIS.
Each group consists of EPA sci-
entists from a mix of pertinent
disciplines and represents intra-
Agency membership, and serves
as the Agency's final review for
EPA risk assessment informa-
tion. When the work groups
reach consensus on the health
effects information and the dose-
response assessment for a par-
ticular substance, the descriptive
summary is added to IRIS.
Consensus generally means that
no member office is aware of
information that would conflict
with the RfD, RfC, or cancer
assessment, nor of analyses that
would suggest a different value
that is more credible. Such assur-
ance rests on the capabilities of
the individuals who represent
their offices; thus, a large effort
is conducted biannually to seek
scientists who are both expert in
this area of assessment and can
represent their office.
The goals of the CRAVE are to
reach Agency consensus on
Agency carcinogen risk assess-
ments; to arrive at a unified view
on potential cancer risk from
exposure to specific substances
across Agency programs; and to
identify, discuss, and resolve gen-
eral issues associated with meth-
ods used to estimate carcino-
genic risks for specific agents.
The major outputs of the Work
Group are summaries of risk
information that have been pre-
viously developed and docu-
mented by scientific experts in
Agency program and program
support offices, and results of dis-
cussions of general issues in car-
cinogen risk assessment.
The purpose of the RfD/RfC
Work Group is to reach consen-
sus on oral RfDs and inhalation
RfCs for non-cancer chronic
human health effects developed
by or in support of program
offices and the Regions. The
Work Group also works to
resolve inconsistent RfDs or
RfCs among program offices and
to identify, discuss, and resolve
generic issues associated with
methods used to estimate RfDs
and RfCs.
Conclusion
IRIS is not meant to be a compre-
hensive toxicological data base,
a compendium of risk assess-
ment knowledge, nor a sophisti-
cated research tool. IRIS is
primarily a communication sys-
tem for the publication of EPA
consensus human health hazard
information. It directs users to
the underlying animal and
human data on which this risk
information is based. Further,
IRIS consensus health hazard in-
formation is not a completed risk
assessment because, among other
things, it contains no specific
exposure assessment information
and, thus, no complete risk char-
acterization. A risk assessment,
along with political, social, and
economic considerations, may be
These supplemental sections should
not be used as the sole or primary
source of information on the current
status of EPA substance-specific
regulations.
Consensus generally means that no
member office is aware of information
that would conflict with the RfD, RfC,
or cancer assessment, nor of analyses
that would suggest a different value
that is more credible.
Access/Use Info Resources Assess Health Risk Chem Expos '93 177
-------
one of the bases of a risk manage-
ment decision. Therefore, IRIS
information is also not risk man-
agement information. Finally,
because of the assumptions and
uncertainties used in risk assess-
ment, IRIS consensus informa-
tion is provided with specific
caveats and should be used care-
fully. It requires scientific judg-
ment to properly use it as a tool
for making risk-based decisions.
Reference
National Research Council. 1983.
"Risk Assessment in the Federal Govern-
ment: Managing the Process." Commit-
tee on the Institutional Means for
Assessment of Risks to Public Health,
Comission on Life Sciences, NRC.
National Academy Press, Washington,
D.C.
U.S. EPA. 1988. 'Reference Dose
[RiD]; Description and Use in Health
Risk Assessment". Regulatory Toxicol-
ogy and Pharmacology 8:471-86.
U.S. EPA. 1990. Interim Methods for
Development of Inhalation Concentra-
tions. EPA/600/8-90/066A.
Because of the assumptions and
uncertainties used in risk assessment,
IRIS consensus information is
provided with specific caveats and
should be used carefully.
178 Access/Use Info Resources Assess Health Risk Chem Expos '93
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Risk Assessment and Toxicology Databases for
Health Effects Assessment
Po-Yung Lu and John Sf Wassom, Oak Ridge National Laboratory
Scientific and technological developments bring unprecedented stress to our living environment. Society is in the position of having
to predict the results of potential health risks from technologically based actions that may have serious, far-reaching consequences.
The potential for error in making such predictions or assessments is great and multiplies with the increasing size and complexity of
the problem being studied. Because of this, the availability and use of reliable data is the key to any successful forecasting effort.
Scientific research and development generate new data and information. Much of the scientific data being produced daily is stored
in computers for subsequent analysis, This situation provides both an invaluable resource and an enormous challenge. With large
amounts of government funds being devoted to health and environmental research programs and with maintenance of our living
environment at stake, we must make maximum use of the resulting data to forecast and avert catastrophic effects. Along with the
development of large databases have come various levels of accuracy. The data used in predictive studies must be accurate and
readily available. The most efficient means of obtaining the data necessary for assessing the health effects of chemicals is to utilize
databases and other resources specifically designed and developed for this purpose. Resources available for risk assessment
applications include the toxicology databases and information files developed at ORNL. To make the most efficient use of the
data/information that has already been prepared, attention and resources should be directed toward projects that meticulously
evaluate the available data/information and create specialized peer-reviewed value-added databases. Examples of such projects
and databases include the U.S. Environmental Protection Agency's (EPA) Gene-Tox Prog ram that produces the Gene-Toy. Database,
the National Library of Medicine's Hazardous Substances Data Bank, and the U.S. Air Force Installation Restoration Toxicology
Guide. These and similar value-added toxicology databases were developed at ORNL and are being maintained and updated. These
databases and supporting information files, as well as some data evaluation techniques are discussed in this paper with special
focus on how they are used to assess potential health effects of environmental agents.
Introduction
The scientific community
is one of the largest pro-
ducers and consumers of
information. Advances in science
are fueled by the use of informa-
tion, and for this reason its
access and use should be facili-
tated. However, significant
impediments exist. For instance,
an intrinsic problem touching all
areas of scientific endeavor is
that information is accumulating
at a rate that overwhelms individ-
ual or collective efforts to keep
up with and take advantage of it.
Because advances within a par-
ticular scientific discipline are
greatly influenced by the avail-
ability and utilization of existing
information, it stands to reason
that everything possible should
be done to ensure that no impedi-
ments exist to the ready access of
that information.
The level of effort being exerted
within some disciplines (such as
toxicology) to effect unimpaired
and easy access to information is
significant; however, funding for
this effort is not equal to that
appropriated for research. This
imbalance in funding creates a
paradox because increased fund-
ing levels for research mean that
greater amounts of information
will be generated and published,
thus overwhelming the access
capabilities of users. Hence, the
entities within government,
industry, and the private sector
that fund research should also be
motivated to provide adequate
financial support for the manage-
Information is accumulating at a rate
that overwhelms individual or
collective efforts to keep up with and
take advantage of it.
Access/Use Info Resources Assess Health Risk Chem Expos '93
179
-------
ment, access, and use of the infor-
mation derived from or gener-
ated by their research dollars.
Information facilities shown to
be of proven value should be
viewed as permanent national
resources for the advancement of
science and the understanding of
scientific discovery.
Because information availability
is vital to the success and
advancement of scientific
endeavors such as assessing pos-
sible health hazards from envi-
ronmental agents, it is imperative
that those making decisions
regarding the safety of environ-
mental agents know how to maxi-
mize the available information
resources. Access to relevant and
reliable information is essential
to the proper planning and con-
duct of any research project and
is absolutely necessary for con-
ducting health risk assessments.
The foundation of all research
studies and health risk assess-
ments is the scientific literature.
To obtain the experimental data
needed to make a health risk
assessment, one must either go to
the primary toxicology literature
or make use of a reliable special-
ized information resource.
This paper discusses the dilem-
ma faced by individuals who
must assess human health risks
from environmental agents in
their quest to find quality toxicol-
ogy information and evaluated
data for use in assessing health
hazards. Federal and state laws
require that such assessments be
made (Table 1). The paper also
describes how certain resources
that have either been developed
or are available from ORNL can
be used to derive maximum bene-
fit of available evaluated or peer-
reviewed databases for specific
Table 1. Federal laws governing exposures to toxic substances
(grouped by year law became effective)3
Legislation
Food, Drug and Cosmetics Act (1906,
1938, amended 1958)
Federal Insecticide, Fungicide and
Rodenticide Act (1947, amended
1960, 1962, 1968, 1972, 1975, 1976,
1978, 1984, 1988)
Dangerous Cargo Act (1952)
Atomic Energy Act (1946, amended
1954, 1959, 1964, 1983, 1986,1988)
Federal Hazardous Substances Act
(1960, amended 1988)
Federal Meat Inspection Act
Occupational Safety and Health Act
(1970)
Poison Prevention Packaging Act
(1970, amended 1983, 1984)
Clean Air Act, 1955 [amended 1963,
1966, 1967 (called Air Quality Act),
1970, 1977, 1983, 1990]
Hazardous Materials Transportation
Act (1974, amended 1990)
Water Quality (1987) (formerly Clean
Water Act 1948), and Federal Water
Pollution Control Act (1972, amended
1977, 1978)
Marine Protection, Research and
Sanctuaries Act (1972, amended 1984,
1986, 1987)
Consumer Product Safety Act (1972,
amended 1981)
Lead-Based Paint Poison Prevention
Act (1973, amended 1976)
Safe Drinking Water Act (1974,
amended 1976, 1977, 1979, 1980,
1984, 1986)
Resource Conservation and Recovery
Act (1976, amended 1984, 1986)
Toxic Substances Control Act (1976,
amended 1986, 1988)
Uranium Mill Tailings Radiation
Control Act (1978, amended 1988)
Federal Mine Safety and Health Act
(1977)
Nuclear Waste Policy Act (1982,
amended 1988)
Radon Gas and Indoor Air Quality Act
(1986)
Agency
FDA
EPA
DOT, USCG
NRC, DOE, EPA
CPSC
USDA
OSHA, NIOSH
CPSC
EPA
DOT
EPA
EPA
CPSC
CPSC, HHS, HUD
EPA
EPA
EPA
EPA
DOL, NIOSH
NRC, EPA
EPA
Area of concern
Foods, drugs, cosmetics, food
additives, new drugs, animal and
feed additives, medical supplies
Pesticides
Water shipment of toxic materials
Radioactive substances
Toxic household products
Food, feed, color additives and
pesticide residues
Workplace toxic chemicals
Packaging of hazardous
household products
Air pollutants
Transport of hazardous materials
Water pollutants
Ocean dumping of hazardous
substances
Hazardous consumer products
Use of lead paint in federally
assisted housing
Drinking water contaminants
Solid waste, including hazardous
waste
Hazardous chemicals not covered
by other laws, includes premarket
review
Uranium and thorium tailings
Toxic substances in coal and other
mines
Radioactive wastes
Radon gases, air pollutants
continued
180
Access/Use Info Resources Assess Health Risk Chem Expos '93
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areas of toxicology. To properly
focus on these issues, it is neces-
sary to look at the evolutionary
history of toxicology information
files during the last 20 years.
Such a review provides an under-
standing of the usefulness of spe-
cific information files as well as
the quality assurance measures
used in their creation. The histori-
cal development of toxicology
information resources has
recently been adroitly addressed
elsewhere (Kissman and Wexler
1983; Wassom and Lu 1992).
State of the Toxicology
Literature and Problems
of Access
The literature of toxicology and
the information contained in it
are increasing at an exponential
rate (Lu and Wassom 1985). A
number of bibliographic and/or
numeric on-line databases are
available to assist investigators
engaged in scientific research
and risk assessment to access the
toxicology literature (Table 2).
To obtain maximum use of these
databases, users should consider
the strengths and weaknesses of
each. These factors must be rec-
ognized to ensure the most appro-
priate application of the database
to find information for a particu-
lar need. For example, the
emphasis placed on quality con-
trol among these databases var-
ies. Rigid quality assurance
guidelines are not part of the
operational procedures of most
databases, handicapping their
effective use.
Evolution of Toxicology
Databases
During the 1960s, toxicology
became recognized as a science
in its own right. Along with this
Table 1. Federal laws governing exposures to toxic substances
(grouped by year law became effective)3
Legislation
Comprehensive Environmental
Response, Compensation, and
Liability Act (Superfund) (1980,
amended 1986)
Asbestos Hazard Emergency Response
Act (1986)
Emergency Planning and Community
Right-to-Know Act (1986)
Medical Waste Tracking Act (1988)
Oil Pollution Act (1990)
Agency
EPA
EPA
EPA
EPA
EPA
Area of concern
Hazardous substances, pollutants
and contaminants
Asbestos
Hazardous substances, toxic
chemicals, pollutants, and
contaminants
Medical wastes
Oil pollutants in water
Adapted from Fed. Regis. 50 (50), 10373-10374, March 14, 1985, and Environmental Laws,
Bureau of National Affairs, 1985.
CPSC, Consumer Product Safety Commission; DOL, Department of Labor; DOT,
Department of Transportation; EPA, Environmental Protection Agency; FDA, Food and Drug
Administration; HHS, Department of Health and Human Services; HUD, Department of
Housing and Urban Development; NRC, Nuclear Regulatory Commission; NIOSH, National
Institute of Occupational Safety and Health; OSHA, Occupational Safety and Health
Administration; USCG, United States Coast Guard; and USDA, United States Department of
Agriculture; DOE, Department of Energy.
recognition came the formation
of two separate Presidential Sci-
ence Advisory Committees
(PSAC) that issued in-depth
reviews and commentary regard-
ing the current and future needs
with respect to the collection,
storage, retrieval, and use of sci-
entific and technical information.
These reports had a profound
effect on the future of toxicology
information that, up until the
1960s, was primarily library-
based and scattered among sev-
eral large-scale multidisciplinary
indexing and abstracting services.
These include Chemical
Abstracts, Biological Abstracts,
Index Medicus, and Excerpta
Medica. A PSAC report publish-
ed in 1963 entitled "Science,
Government, and Information"
stated, "The technical community
must recognize that handling
technical information is a worthy
and integral part of science"
These reports had a profound effect
on the future of toxicology
information.
Access/Use Info Resources Assess Health Risk Chem Expos '93
181
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Table 2. Sampling of secondary on-line bibliographic and/or numeric information sources containing
lexicological information
Name
File, number of
records, and
period covered
File description
BRS
Bibliographic Retrieval
Services, Lalham, N.Y.
CAS ONLINE
Chemical Abstracts
Service
American Chemical
Society
Columbus, Ohio
DIALOG
Dialog Information
Services, Inc.
Palo Alto, Calif.
BIOSIS Previews
7,196,209
1969-present
CA SEARCH
8,900,000
1967-present
HAZARDLINE
4,000 substances
MEDLINE
MEDLARS On-
Line
7,000,000
1966-present
CAS ONLINE
Chemical Search
System from
Chemical Abstracts
Service
8,900,000
1967-present
CAS CHEMICAL
REGISTER
10,000,000
compounds
EMBASE
4,311,401
June 1974-present
BIOSOENCES INFORMATION SERVICE
Worldwide coverage of research in the life sciences from more than 9000 journals, as well as
monographs, reports, and symposia proceedings. Subjects include microbiology, plant and animal
science, biochemistry, botany, environmental biology, experimental medicine, genetics, public
health, toxicology, virology, and other interdisciplinary areas. Citations from both Biological
Abstracts and Biological AbstractsfRRM
CHEMICAL ABSTRACTS SERVICE (CAS)
Bibliographic data, keyword phrases, index entries, general subject headings, and CAS Registry
Number(s) for documents covered by Chemical Abstracts Service
OCCUPATIONAL HEALTH SERVICES, INC.
Provides chemical names, formula, CAS Registry Number(s), Registry of Toxic Effects of
Chemical Substances (RTECS) number, physical description, chemical and physical properties,
toxicology, permissible exposure levels, symptoms of exposure, disposal methods, protective
procedures, test references, government regulations, and many other areas of information on
specific chemical substances
NATIONAL LIBRARY OF MEDICINE
Contains references from more than 3000 biomedical journals published throughout the world.
Monographs and conference proceedings added in 1976. Corresponds to Index Medicus. Contains
full bibliographic citations and index terms for all records. Some abstracts included. SDIUNE, the
monthly update to the main file, used for current awareness service
Equivalent of the printed Cliemical Abstracts (CA). Bibliographic data, keyword phrases, index
entries, general subject headings, and CAS Registry Number(s) for chemistry-related publications
in 50 languages from 150 countries. Includes worldwide patent documents. Easy crossover to the
CAS CHEMICAL REGISTRY
The world's largest file of substance information, including coordination compounds, polymers,
incompletely defined substances, alloys, mixtures, and minerals. In each record the registry number
is linked to molecular structure diagram, molecular formula, CA index name, synonyms, and the ten
most recent references in Chemical Abstracts. Easy crossover to the bibliographic file
EXCERPTA MEDICA
Abstracts and citations of articles from over 4000 biomedical journals published throughout the
world. Covers entire field of human medicine and related disciplines
ENERGYLINE
Comprehensive coverage of 20 different energy-related areas, including environmental impact
ENVIROLINE
Covers the world's environmental information by indexing and abstracting more than 5000
international primary and secondary source publications reporting on all aspects of the
environment. Also includes rulings from the Federal Register and patents from the Official Gtaflta
INTERNATIONAL AMERICAN SOCIETY OF HOSPITAL PHARMACISTS
PHARMACEUT- More than 650 pharmaceutical, medical, and related journals are indexed and abstracted
ICAL
ABSTRACTS
175,587
1970-presenl
182 Access/Use Info Resources Assess Health Risk Cbem Expos '93
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Table 2. Sampling of secondary on-line bibliographic and/or numeric information sources containing
toxicological information
Name
File, number of
records, and
period covered
File description
MEDLARS
National Library of
Medicine
Bethesda, Md.
LIFE SCIENCES
COLLECTION
1,254,581
1978-present
MEDLINE
NTIS
OCCUPATIONAL
SAFETY AND
HEALTH (NIOSH)
162,316
1973-present
POLLUTION
ABSTRACTS
SCISEARCH
10,029,029
1974-present
CANCERLIT
Cancer Literature
806,157
1963-present
MEDLINE
RTECS
100,000 chemicals
CAMBRIDGE SCIENTIFIC ABSTRACTS
Abstracts of worldwide literature in the fields of animal behavior, biochemistry, ecology,
entomology, genetics, immunology, microbiology, toxicology, and virology
See entry under BRS system
The National Technical Information Service (NTIS) is the central source for the public sale and
dissemination of U.S. government-sponsored research. The database consists of unclassified
government-sponsored research, development, and engineering reports, as well as other analyses
prepared by government agencies, their contractors, or grantees. The database corresponds to
Government Reports Announcements & Index.
U.S. NATIONAL INSTITUTE FOR OCCUPATIONAL SAFETY AND HEALTH TECHNICAL
INFORMATION CENTER
Includes citations to more than 400 journal titles as well as over 70,000 monographs and technical
reports
Pollution abstracts is a leading resource for references to environmentally related technical literature
on pollution, its sources and its control. Produced by Cambridge Scientific Abstracts, the database
corresponds to the printed Pollution Abstracts.
INSTITUTE FOR SCIENTIFIC INFORMATION
Multidisciplinary index to the literature of science and technology, including animal and plant
science, biochemistry, drug research, experimental medicine, and microbiology. Unique feature is
indexing cited papers. Corresponds to the printed Science Citations Index
NATIONAL CANCER INSTITUTE
Cancer therapy and chemical, physical, and viral carcinogenesis from Carcinogenesis Abstracts and
Cancer Therapy Abstracts
See entry under BRS system
NATIONAL INSTITUTE OF OCCUPATIONAL HEALTH AND SAFETY
Provides chemical names, formula, CAS Registry Number(s), RTECS number, physical description,
chemical and physical properties, toxicology, permissible exposure levels, symptoms of exposure,
disposal methods, protective procedures, test references, government regulations, and many other
areas of information on specific chemical substances
TOXNET A computerized system consisting of a collection of selected toxicology-oriented databases and
Toxicology Data information files.
Network Environmental Mutagen Information Center (EMIC) File
Environmental Teratology Information Center (ETIC) File
Development and Reproductive Toxicology (DART) File
Hazardous Substances Data Bank (HSDB)
Chemical Carcinogenesis Research Information System (CCRIS)
U.S. Environmental Protection Agency Genetic Toxicology Database (Gene-Tox)
Registry of Toxic Effects of Chemical Substances (RTECS)
Directory of Biotechnology Information Resources (DBIR)
Toxic Chemical Release Inventory (TRI)
U.S. Environmental Protection Agency Integrated Risk Information System (IRIS)
Access/Use Info Resources Assess Health Risk Chem Expos '93
183
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Table 2. Sampling of secondary on-line bibliographic and/or numeric information sources containing
lexicological information
Name
File, number of
records, and
period covered
File description
ORBIT
System Development
Corporation
Santa Monica, Calif.
TOXLINE
Toxicology
Information On-
Line
Current File: 1981-
present
> 100,000
Backfiles
(TOXBACK): 1980
and
older material >
1,160,000
TOXLIT and
TOXLIT 65
PESTDOC
approximately
300,000
1968-present
RINGDOC
Pharmaceutical
Literature
Documentation
approximately 1.2
million
1976-present
VETDOC
Veterinary
Literature
Documentation
approximately
96,000
1968-present
An extensive collection of toxicology information with references to human and animal toxicity
studies, effects of environmental chemicals, pesticides, and pollutants, adverse drug reactions, and
analytical methodology. Abstracts and/or indexing terms included in addition to full bibliographic
citations. Information derived from secondary sources and special collections of material:
Environmental Mutagen Information Center (EMIC) File
Environmental Teratology Information Center (ETIC) File
Epidemiology Information System (EPIDEM)
Federal Research in Progress (FEDRIP)
International Labour Office (CIS)
International Pharmaceutical Abstracts (IPA)
NIOSHTIC (NIOSH)
Pesticides Abstracts (PESTAB)
Poisonous Plants Bibliography (PPBIB)
Toxicity Bibliography (from MEDLINE) (TOXBIB)
Toxicology Document and Data Depository (NTIS)
Toxicological Aspects of Environmental Health (BIOSIS)
Toxicology Research Projects (CRISP)
Toxic Substances Control Act Test Submissions (TSCATS)
A collection of bibliographic citations and abstracts assembled by the Chemical Abstracts Service
under the title of Chemical-Biological Activities (CBC). The specific focus of this collection is the
pharmacological, biochemical, physiological, and toxicological effects of drugs and other
chemicals
DERWENT PUBLICATIONS LIMITED
Covers worldwide journal literature on pesticides, herbicides, and plant protection. Includes
analysis, biology, chemistry, and toxicology
DERWENT PUBLICATIONS LIMITED
Covers scientific journal literature on Pharmaceuticals. Specifically designed to meet the
information requirements of manufacturers. Includes papers from over 750 world wide journals
DERWENT PUBLICATIONS LIMITED
Covers journal literature concerning developments and usage of drugs, hormones, vaccines,
growth promoters, etc., in farm and domestic animals. Includes analysis, chemistry, therapeutics,
pharmacology, toxicology, and management
184 Access/Use Info Resources Assess Health Risk Chem Expos '93
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(President's Science Advisory
Committee 1963). In 1966, the
PSAC published another report
on the "Handling of Toxicologi-
cal Information" (President's Sci-
ence Advisory Committee 1966).
This report defined toxicology
information as "All information
descriptive of the effects of
chemicals on living organisms or
their component subsystems"
and further indicated the neces-
sity of a "... computer-based
comprehensive exhaustive sys-
tem for storage and retrieval of
valid information on the interac-
tion between chemicals and bio-
logical systems."
These two reports set the direc-
tion and development of toxico-
logical databases during the two
decades since their publication.
Correlated with the increased
need for and use of computerized
toxicology databases has come
the appearance and proliferation
of computer software and hard-
ware to facilitate manipulation of
information in these databases.
The notable developments in this
area have been supported by
unprecedented quantum leaps in
electronic technology. Further
details regarding the evolving
nature of toxicology databases
and information files are pro-
vided in another paper in these
symposium proceedings (Was-
som and Lu 1992).
Types of Toxicology Databases
and Information Resources
As shown in Table 2, an array of
toxicological and chemical infor-
mation resources are available
for the researcher. These
resources have been catalogued
in other publications, and the
reader should consult these publi-
cations for a more complete list-
ing (Kissman 1980; Wassom
1980; Akland and Waters 1983;
Lu and Wassom 1985). The
majority of the current toxico-
logical information files are
literature-based or oriented
toward specific subject matter
such that a single record equals a
published paper.
Other types of toxicological data-
bases are available that are con-
structed around a specific
subject, such as a chemical. In
such a file, a single record equals
one specific chemical. Such
chemical-oriented files can be
classified as (1) numerical/
factual—records contain data
that has been peer reviewed or
(2) numerical/factual—records
contain data that has not been
peer reviewed. Examples of
these two classifications are the
Hazardous Substances Data
Bank (HSDB) and the Registry
of Toxic Effects of Chemical
Substances (RTECS) [TOXNET
1991], respectively. These files
are discussed more fully in a
later section.
The variety of toxicology infor-
mation files and the increasing
number of computerized
retrieval systems presents users
with two major problems: (1) the
rapidly growing volume of acces-
sible literature and (2) the incom-
patibility of the various com-
puter files. To these two prob-
lems we add a third, quality
assurance that will always be the
most critical and controversial of
all.
How can these problems be over-
come to maximize available
resources? For toxicology, this
can only be achieved by using
those resources that have proven
utility and merit. In the follow-
ing sections we suggest ways to
maximize the toxicology infor-
The notable developments In this area
have been supported by
unprecedented quantum leaps in
electronic technology.
The majority of the current
toxicological information files are
literature-based or oriented toward
specific subject matter.
Access/Use Info Resources Assess Health Risk Chem Expos '93
185
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mation resources now available.
Currently, only a small number
of peer-reviewed or value-added
databases exist that are useful to
individuals interested in the areas
of genetic toxicology, carcino-
genicity, developmental toxicol-
ogy, or teratogenicity. These
sources are shown in Table 3 and
are described in the following
section.
Table 3. Short-term bioassays reviewed by the Gene-Tox Program
Assays Detecting Gene Mutation
Salmonella typhimurium (histidine reversion test) — use of one or
more of ihe five standard strains (TA98, TA100, TA1535, TA1537
andTA1538)
Escherichia coli WP2 — reverse mutation studies
Escherichia coli WP2uvrA — reverse mutation studies
Host-mediated assay studies
Body fluid assay — urine
Saccharomyces cerevisiae — forward mutation studies
Saccharomyces cerevisiae — reverse mutation studies
Scliizosaccharomyces pombe — forward mutation studies
Schizosaccharomyces pombe — reverse mutation studies
Aspergillus — forward mutation studies
Aspergillus — reverse mutation studies
Neurospora crassa — forward mutation studies
Neurospora crassa — reverse mutation studies
Chinese hamster ovary cells in culture — gene mutation at HGPRT
locus
Mouse lymphoma (L5178Y) cells in culture — gene mutation at TK
locus
Chinese hamster lung cells in culture — gene mutation studies, all loc
Drosophila melanogaster— sex-linked recessive lethal test
Mouse spot test
Mouse specific locus test — all tests
Plant gene mutation studies — grouping of tests with Arabadopsis,
Glycine, Hordeum, Tradescantia, and Zea mays
Assays Detecting Chromosomal Effects
Saccliaromyces cervisiae — aneuploidy studies
Aspergillus—aneuploidy studies
Neurospora crassa — aneuploidy studies
Plant chromosome studies — grouping of tests with Allium, Hordeum,
Tradescantia, and Vicia
Drosophila melanogaster aneuploidy studies — whole sex chromo-
some loss
Drosophila melanogaster aneuploidy studies — sex chromosome gain
Drosophila melanogaster aneuploidy studies — sex chromosome loss
Drosophila melanogaster heritable (reciprocal) translocation test
Mammalian cytogenelics — all in vitro cell culture studies, nonhuman
studies
Mammalian cytogenetics — all in vivo bone marrow studies, nonhu-
man studies
Mammalian cytogenetics — all in vivo lymphocyte or leukocyte
studies, nonhuman
Mammalian cytogenetics — all male germ cell studies
Mammalian cytogenetics — in vivo oocyte or early embryo studies
Micronucleus test — mammalian polychromatic erythrocyte assay, all
species
Micronucleus test — plant
Micronucleus test— in vitro mammalian cell culture studies, nonhu-
man
Micronucleus test — in vitro human lymphocyte studies
Dominant lethal test — rodents
Heritable translocation test — rodents
Mammalian cytogenetics — in vitro cell culture studies, human
Mammalian cytogenetics — in vitro lymphocyte or leukocyte studies,
human
Mammalian cytogenetics — in vivo bone marrow studies, human
Mammalian cytogenetics — in vivo lymphocyte or leukocyte studies,
human
Assays Detecting Other Types of Genotoxic Effects
Escherichia colipolA. (W3110-P3478) — all tests without S9
Escherichia coli polh. (W3110-P3478) — all tests with S9
Bacillus subtilis rec (H17-M45) — spot test
Bacillus subtilis rec (H17A-45T) - spot test
Saccliaromyces cerei-isiae — gene conversion studies
Saccliaromyces cerevisiae — homozygosis studies through
recombination
Aspergillus — crossing-over studies
Unscheduled DNA synthesis in mammals — studies with rat primary
hepatocytes
Unscheduled DNA synthesis in mammals — studies with mouse germ
cells
Sister chromatid exchange — in vitro studies, nonhuman
Sister chromatid exchange — in vivo studies, nonhuman
Effects on mammalian sperm — rat studies
Effects on mammalian sperm — mouse sperm morphology studies
Effects on mammalian sperm — rabbit studies
Effects on mammalian sperm — mouse, FI assay studies
Unscheduled DNA synthesis in mammals — in vitro studies, human
diploid flbroblast
Sister chromatid exchange — in vitro studies, human cells
Sister chromatid exchange — in vitro studies, human embryonic lung
fibroblasts (Wl-38 cells)
Sister chromatid exchange — in vitro studies, human lymphocytes
Sister chromalid exchange — in vivo studies, human lymphocytes
Effects on mammalian sperm — human studies
186 Access/Use Info Resources Assess Health Risk Chem Expos '93
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Table 3 (Continued)
Assays Detecting Cell Transformation and Carcinogenicity
Cell transformation studies — BALB/C-3T3 cells
Cell transformation studies — C3H/10T1/2 cells
Cell transformation studies — mouse prostate cells
Syrian hamster embryo — clonal assay
Syrian hamster embryo — focus assay
Cell transformation studies — RLV/1706 cells (Fischer rat embryo
cells)
Cell transformation studies — AKR/ME cells (mouse embryo cells)
Cell transformation studies — SA7/SHE cells (Syrian hamster embryo
cells)
Cell transformation Studies — SA7/RAT cells (Fischer)
Mammalian carcinogenicity — animal in vivo studies, nonhuman
Value-Added or Peer-
Reviewed Toxicology
Databases
U.S. EPA Gene-Tox Database
Perhaps the best illustration or
perspective on the issue of qual-
ity within the realm of the cur-
rent toxicology literature comes
from the EPA's Genetic Toxicol-
ogy (Gene-Tox) Program
(Waters and Auletta 1981). The
Gene-Tox Program is a system-
atic evaluation of selected short-
term bioassays for detecting
mutagenicity and presumptive
carcinogenicity. Sponsored and
directed by the Office of Testing
and Evaluation within the EPA
Office of Pesticides and Toxic
Substances, the EPA uses Gene-
Tox as a resource in establishing
standard genetic testing and
evaluation procedures for the
regulation of toxic substances.
Gene-Tox also helps to deter-
mine the direction of research
and development in the field of
genetic toxicology (Russell et al.
1984, Brusick and Auletta, 1985,
Dearfield et al. 1991).
The Gene-Tox database, a prod-
uct of the Gene-Tox Program, is
now available on-line through
the National Library of Medi-
cine's TOXNET system (Vasta
and Wexler 1985). Information
from Gene-Tox is also included
in chemical records of HSDB,
and locator tags are also placed
on chemical records in the
RTECS file.
In the initial phase (Phase I) of
the Gene-Tox Program, 23 pan-
els (each consisting of 5 to 10 sci-
entists) reviewed the existing
literature from ORNL's Environ-
mental Mutagen Information
Center (EMIC) information file
through mid-1979 and prepared
reports on the applicability and
performance of each selected bio-
assay (Table 3). The data were
edited and placed in a computer
file. During subsequent phases of
Gene-Tox (Phases II and III) the
literature through 1990 was
reviewed for selected assays. To
date, information on over 4600
different chemicals has been
entered into the database. The
distribution of these compounds
among the various short-term
bioassays (64 genetic toxicology
and 9 cell transformation)
reviewed by Gene-Tox is spo-
radic. Some bioassays have
results on less than ten com-
pounds (e.g., the in vivo sister
chromatid exchange test with
human lymphocytes has only
one), whereas other bioassays,
such as the Ames/Salmonella
test, have more than 2000. Evalu-
ated in vivo carcinogenicity
results on 392 compounds are
also available in the Gene-Tox
file.
The structural classification of
all Gene-Tox evaluated com-
pounds, as they occur within a
The Gene-Tox Program Is a systematic
evaluation of selected short-term
bioassays for detecting mutagenicity
and presumptive carcinogenicity.
Information on over 4600 different
chemicals has been entered into the
Gene-Tox database.
Access/Use Info Resources Assess Health Risk Chem Expos '93
187
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given bioassay, show an erratic
clustering pattern with respect to
their common structural charac-
teristics. This clustering or distri-
bution, of course, varies with
respect to the number of com-
pounds tested in each bioassay.
During the Gene-Tox process,
some provocative insights into
the quality of the literature were
revealed. It was shown that most
journals failed to maintain a
strict editorial policy with
respect to format, data presenta-
tion, and the inclusion or refer-
encing of key or essential
information elements regarding
such obviously vital items as spe-
cific details of agent(s) tested,
control data, experimental
design, and/or protocol used.
Because of these deficiencies,
only 52% of the papers reviewed
were used in Gene-Tox; it is
indeed interesting that almost
half (48%) of the literature was,
for one reason or another, not
used. Some of the papers in this
latter category were not used
because they were either written
in a foreign language, not pub-
lished in a refereed source, or did
not contain original data. The
majority, however, did not meet
the rigid criteria established by
the various Gene-Tox review pan-
els. The criteria used for each
specific bioassay reviewed by
Gene-Tox may be found in the
various published panel reports
for each bioassay. The number of
papers used varied with each
panel and bioassay. For example,
the Chinese hamster ovary
(CHO) cell gene mutation panel
used only 8% of the papers
screened (Hsie et al. 1981).
DeMarini and Shelby (1984)
recently commented on the state-
of-the-scientific literature and the
lack of published data to prop-
erly evaluate test results. These
authors, in a survey of the litera-
ture, found that papers often
omitted certain key information
necessary for readers to make an
independent evaluation of the
reported results and conclusions.
An appeal was issued to authors,
reviewers, and journal editors to
recognize this problem and insti-
tute measures to correct it. Pri-
marily because of the Gene-Tox
Program's review of the 1960-
1979 literature and subsequent
recommendations on assay proto-
cols and data reporting, the per-
centage of literature published
during the 1980-1988 era and
used by Gene-Tox to update
results from the 1980-1988 lit-
erature for several selected
assays increased noticeably. 75
to 90% of the literature was used
compared to the dismal showing
of 8 to 25% from the 1969-1979
literature.
During the current update (Phase
III) of the Gene-Tox Program,
panels of scientists are critically
evaluating the reports published
by the program for each bioassay
and comparing the test results
between specific assays or assay
groups on a chemical-by-
chemical and chemical class
basis (Ray et al. 1987). For this
evaluation, attempts will be
made to determine the sensitivity
of the tests to specific classes of
chemicals and to identify major
strengths and weaknesses of each
bioassay. The database resulting
from the Gene-Tox Program is
the most comprehensive collec-
tion of evaluated genetic toxicol-
ogy data available. Work is
under way to keep this database
updated at regular intervals with
material screened from papers in
the EMIC file selected from the
The criteria used for each specific
bioassay reviewed by Gene-Tox may
be found in the various published
panel reports.
Panels of scientists are critically
evaluating the reports published by the
program for each bioassay and
comparing the test results between
specific assays or assay groups on a
chemical-by-chemical and chemical
class basis.
188 Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
current literature. Thus far, the
Gene-Tox Program has evaluated
over 4600 chemicals as tested in
1 or more than 23 genetic toxicol-
ogy bioassays.
International Agency for
Research on Cancer Monographs
In 1971, the International
Agency for Research on Cancer
(IARC) initiated a program to
evaluate the carcinogenic risk of
chemicals to humans (Tomatis
1988). The object of the program
was to provide government
authorities with expert indepen-
dent scientific opinions regard-
ing environmental carcino-
genesis through the publication
of critical reviews of carcino-
genicity and related data. The
aim of IARC is to evaluate possi-
ble human carcinogenic risk
from detailed review and analy-
sis of pertinent literature. lARC's
work is partially funded by the
National Cancer Institute.
The IARC Monographs summa-
rize evidence for the carcino-
genicity of individual chemicals
and other relevant information
on the basis of data compiled,
reviewed, and evaluated by a
working panel of experts. Prior-
ity is given to chemicals, groups
of chemicals, or industrial proc-
esses for which there is at least
some suggestion of carcinogen!c-
ity, either from evidence of
human exposure and/or observa-
tions in animals. It should be
emphasized that the inclusion of
a particular compound in an
IARC volume does not necessar-
ily mean that it should be consid-
ered carcinogenic nor does the
fact that a chemical is absent
from an IARC review imply that
it is not a carcinogenic hazard.
As new data become available
on chemicals for which Mono-
graphs have already been pre-
pared and/or new principles for
evaluation become available,
reevaluations may be made at
subsequent IARC meetings. If
the new evidence warrants,
revised Monographs will be
published.
The IARC Monographs are dis-
tributed internationally to govern-
mental agencies, industries, and
scientists. They are also offered
to any interested person through
World Health Organization publi-
cation outlets.
Through August 1991,52 vol-
umes of the Monographs and sev-
eral supplements had been
published. These volumes con-
tain indexes both for chemical
name and molecular formula as
well as Chemical Abstracts Serv-
ice Registry Number(s). More
than 960 chemicals or chemical
groups were reviewed by IARC
through monograph vol. 52. Car-
cinogenicity evaluations have
not been made on all the chemi-
cals reviewed because either no
data were available or the data
available to IARC were judged
inadequate for evaluation. Spe-
cialized information files and
databases developed at ORNL,
such as EMIC, the Environ-
mental Teratology Information
Center (ETIC) file, and the Gene-
Tox database, are used routinely
by IARC in the production of
their monographs.
In a survey of 751 users con-
ducted in January 1991, some
interesting facts regarding use of
the monographs were obtained.
The most important uses of the
monographs are (1) a source of
epidemiological studies (68%);
(2) a general overview of carciho-
genicity (63%), (3) detailed infor-
The IARC Monographs summarize
evidence for the carcinogenicity of
individual chemicals.
More than 960 chemicals or chemical
groups were reviewed by IARC.
Access/Use Info Resources Assess Health Risk Chem Expos '93
189
-------
mation on animal carcinogenic-
ity studies (57%), (4) detailed
information on other toxic
effects (48%), (5) an overview of
data on other toxic effects (34%),
(6) background information for
regulatory action (32%), and (7)
application of evaluation in regu-
latory action (18%). Overall,
71% of the individuals surveyed
found the monograph a useful
source of information (Vainio,
H., personal communication to
John S. Wassom, September 5,
1991).
Hazardous Substances Data Bank
The Hazardous Substances Data
Bank (HSDB), formerly called
the Toxicology Data Bank, was
originated by the National
Library of Medicine (NLM) in
the early 1970s. HSDB is a
numerical/factual database com-
posed of over 4300 comprehen-
sive chemical records (Oxyman
et al. 1970, Vasta and Wexler
1985, TOXNET 1991). These
records contain approximately
140 different data elements,
which are grouped into ten cate-
gories and administrative infor-
mation. These categories include
pharmacological and toxicologi-
cal data (e.g., LDso values), envi-
ronmental and occupational
information, manufacturing and
use data, regulatory information,
and analytical methods, as well
as information on the chemical
and physical properties of each
chemical. Components included
in the toxicology category are
shown in Table 4. Substances
selected for HSDB include high-
volume production or exposure
chemicals, drugs and pesticides
exhibiting potential toxicity or
adverse effects, and other sub-
stances subject to regulation
under the provisions of the Com-
prehensive Environmental
Response, Compensation, and
Liability Act (CERCLA) of 1980
(Superfund) and the Superftmd
Amendment Reauthorization Act
(SARA) of 1986.
Table 4. Data elements of toxicity/
biomedical effects of the Hazardous
Substances Data Bank, National
Library of Medicine
Toxicity summary
Toxic hazard rating
Antidote & emergency treatment
Medical surveillance
Toxicity excerpts
Human toxicity excerpts
Nonhuman toxicity excerpts
Toxicity values
Human toxicity values
Nonhuman toxicity values
Ecotoxicity values
Minimum fatal dose level
Populations at special risk
Pharmacokinetics
Absorption, distribution and excretion
Metabolism/metabolites
Biological half-life
Mechanism of action
Interactions
The information used in an
HSDB record is selected from
secondary sources such as stand-
ard reference books, handbooks,
criteria documents, and mono-
graphs and is supplemented with
information from other on-line
databases, such as TOXLINE,
etc. The data extracted from sec-
ondary sources are reviewed
quarterly by a scientific review
panel (SRP) of experts convened
by the NLM. Members of the
SRP are professional toxicolo-
gists, industrial hygienists, and
environmental engineers from
academia or industry. Additional
information from pertinent litera-
ture (secondary or primary and
consensus statement) may be
selected/developed by the SRP
These records contain 140 different
data elements, grouped into ten
categories.
Data extracted from secondary sources
are reviewed quarterly by a scientific
review panel.
190 Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
and incorporated into an HSDB
record to ensure that the record
contains the most relevant and
accurate information known
today. Readers can obtain further
information on HSDB or
TOXNET by contacting Special-
ized Information Service, Toxi-
cology Information Program,
National Library of Medicine,
8600 Rockville Pike, Bethesda,
MD 20894.
The U.S. Air Force Installation
Restoration Toxicology Guide
The Toxicology Guide was spon-
sored by the U.S. Air Force. A
collaborative effort with the
Harry G. Armstrong Aerospace
Medical Research Laboratory at
Wright-Patterson Air Force Base
resulted in five, peer-reviewed
volumes, written and compiled
by technical staff of the Biomedi-
cal and Environmental Informa-
tion Analysis Section of the
Health and Safety Research Divi-
sion of Oak Ridge National Labo-
ratory.
One of the objectives of the U.S.
Air Force Installation Restora-
tion Program (IRP) is to provide
individuals responsible for the
management and implementation
of the IRP with information to
evaluate the health hazards asso-
ciated with actual or potential
contamination of drinking water
supplies. Volumes 1 through 4 of
the U.S. Air Force IRP Toxicol-
ogy Guide contain information
on 70 chemicals and complex
mixtures of environmental con-
cern to the U.S. Air Force. Vol-
ume 5 of the IRP Toxicology
Guide contains similar informa-
tion on seven metals and over
80 environmentally significant
compounds containing these met-
als. Data summary sections pro-
viding concise, easily accessible
data useful to environmental
engineers precede detailed envi-
ronmental and lexicological
review sections. These summa-
ries include chemical names and
synonyms, registry numbers;
physicochemical data; informa-
tion on reactivity and handling
precautions; soil-water persist-
ence; pathways of exposure;
health hazard data; environ-
mental standards and criteria;
and state, federal, and European
Economic Community regula-
tory status.
The toxicology review sections
for each chemical in the IRP
Toxicology Guide include
detailed information on acute,
subchronic, and chronic toxicity
data, as well as information on
developmental toxicity, geno-
toxicity, and carcinogenicity.
Environmental information for
each chemical encompasses envi-
ronmental fate and exposure
pathways and fate and transport
in soil/groundwater. A section on
biological monitoring for each
metal-containing compound is
included. Compounds were
included in this volume based on
production volume and usage,
existing regulatory concern for
the specific compound, and the
available toxicologic data.
Information on the U.S. Air
Force IRP Toxicology Guide
may be obtained from: Harry G.
Armstrong Aerospace Medical
Research Laboratory, Human
Systems Division, Wright-
Patterson AFB, OH 45433-6573,
or Biomedical and Environ-
mental Information Analysis,
Health and Safety Research Divi-
sion, Oak Ridge National Labora-
tory, Oak Ridge, TN 37831-6050.
One of the objectives is to evaluate
the health hazards associated with
actural or potential contamination of
drinking water supplies.
The toxicology review sections include
detailed information on acute,
subchronicf and chronic toxicity data,
as well as information on
developmental toxicity, genotoxicity,
and carcinogenicity.
Access/Use Info Resources Assess Health Risk Chem Expos '93
191
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Teratology/Developmental
Toxicology
No specific evaluated or peer-
reviewed database for teratology
or developmental toxicology
comparable with those for
genetic toxicology or carcino-
genicity is available by which
individuals can access test results
on specific agents. There is a
clear and urgent need for a value-
added database for teratology or
reproductive and developmental
toxicology that is structurally
similar to the Gene-Tox data-
base. Until this happens, indi-
viduals who need to access
evaluated data from these areas
of research will have to rely on
review articles, books, IARC
Monographs, or the primary
literature.
Summary and
Conclusion
With today's high-tech communi-
cations systems saturating us
daily with enormous amounts of
information from around the
world, it is very easy to suffer
from information overload. We
find ourselves struggling with
the questions of how to interpret
information. What does it mean
for us? What should we do about
it? How do we discern high-
quality from lesser-quality infor-
mation? Particularly in the scien-
tific arena, the daily production
of data is enormous and the need
for high-quality data is greater
than ever to answer such ques-
tions as, How do we extrapolate
animal data for human applica-
tion? and How do we conduct a
valid predictive study?
Evaluated data should be the
basis of predictive scientific
efforts and must be a part of any
database building/maintenance
effort. We have addressed the
issue of evaluated data and infor-
mation resources for the field of
toxicology, specifically for three
of its major components — gene-
tic toxicology, carcinogenicity,
and teratology. ORNL, through
development of specialized
value-added information sys-
tems, is contributing signifi-
cantly to the process of
providing knowledge bases for
specific lexicological disciplines
by addressing the problem of
duplication of effort and the sav-
ing of resources (such as time
and money). Unfortunately,
because funds for the mainte-
nance of these databases have
been reduced, the ability to make
factual health risk assessments is
in jeopardy. Those who need
access to reliable data/informa-
tion must ensure that funding for
the development of specialized
(value-added and peer-reviewed)
databases and/or information
files is proportional to that allo-
cated for research. Table 5 lists
key resources that we recom-
mend for use in accessing toxi-
cology information.
We find ourselves struggling with the
questions of how to interpret
information.
Because funds for the maintenance of
these databases have been reduced,
the ability to make factual health risk
assessments is in jeopardy.
192 Access/Use Info Resources Assess Health Risk Cuem Expos '93
-------
Table 5. Recommended sources3 for accessing the toxicology literature
Genetic toxicology
Recommended source for access to primary literature
Environmental Mutagen Information Center files available through the National Library of Medicine's
(NLM) TOXNET system (74,000 records). This file covers literature published from 1968-1991
Recommended source for evaluated (peer-review) data
a. Gene-Tox through NLM's TOXNET system (4600 chemicals)
b. International Agency for Research on Cancer Monograph, Supplement 7,1987 (950 chemicals)
c. Hazardous Substances Data Bank (4200 chemicals)
Teratology/reproductive/developmental toxicology
Recommended source for access to primary literature
Environmental Teratology Information Center files available through the NLM TOXNET system for litera-
ture published from 1950-1987 (46,000 records); literature published since 1988 may be obtained from
NLM's Developmental and Reproductive Toxicology file, also available on TOXNET
Recommended source for evaluated (peer-review) data
Although several books and monographs are available summarizing experiments, no comprehensive peer-
reviewed computerized database is publicly available currently (through 1990). However, selected studies
that derive health risk assessment parameters are compiled by the U.S. Environmental Protection Agency's
(EPA) Office of Health and Environmental Assessment's Chemical Unit Record Estimates Database. Cur-
rently, this is an internal EPA file
Carcinogenicity
Recommended source for access to primary literature
No specific information file devoted solely to this area of research is available. Bibliographic information
is found scattered throughout numerous biological-oriented information files
Recommended source for evaluated (peer-review) data
a. International Agency for Research on Cancer monograph (52 volumes covering over 960 chemicals)
b. Gene-Tox database available through the NLM TOXNET system (392 chemicals)
General toxicology
Recommended source for access to primary literature
NLM's TOXLINE and TOXLIT systems
Recommended source for evaluated (peer-review) data
a. Hazardous Substances Data Bank available through the NLM TOXNET system
b. U.S. Air Force Installation Restoration Toxicology Guide, available through DTIC No. Vol. 1:
ADA219797, Vol. 2: ADA214999, Vol. 3: ADA215001, Vol. 4: ADA 215002, and Vol. 5: ADA 238093
(Volumes 1-4 covers 70 organic chemicals and Volume 5 covers 6 metals with 87 environmentally signifi-
cant metal-containing compounds)
aFor an explanation of the information files, databases, or computer systems referred to in this table, see
Table 1.
Access/Use Info Resources Assess Health Risk Chem Expos '93 193
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References
Akland, A. H., and M. D. Waters.
1983. Chemical and lexicological data
bases for assessment of structure-activ-
ity relationships, pp. 23-48. In: L. Gold-
berg (ed.), Structure Activity Correlation
as a Predictive Tool in Toxicology.
Hemisphere Publishing Corporation,
Washington, D.C.
Brusick, D., and A. E. Auletta. 1985.
Developmental status of bioassays in
genetic toxicology. A report of Phase n
of the U.S. Environmental Protection
Agency Gene-Tox Program. Mutat. Res.
153:1-10.
Dearfield, K. L., A. E. Auletta, M. C.
Cimino, and M. M. Moore. 1991. Con-
siderations in the U.S. Environmental
Protection Agency's testing approach for
mutagenicity. Mutat. Res. 258:259-83.
DeMarini, D. M., and M. D. Shelby.
1984. Test data — how much is not
enough? Environ. MutaL 6:119.
Hsie, A. W., D. A. Casciano, D. B.
Couch, D. F. Krahn, J. P. O'Neil, and B.
L. Whitfield. 1981. The use of Chinese
hamster ovary cells to quantify specific
locus mutation and to determine muta-
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Kissman, H. M. 1980. Information
retrieval in toxicology. Annu. Rev. in
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Kissman, H. M., and P. Wexler. 1983.
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of Inf. Sci. Technol. 18M:185-230.
Lu, P. Y., and J. S. Wassom. 1985.
Information science in toxicology, pp.
27-47. In: James L. Way (ed.). Seminar
on Environmental Toxicology, Spon-
sored by Coordination Council for North
American Affairs and American Insti-
tute in Taiwan, Tapei, Taiwan, Republic
of China, March 26 — April 2.
Oxyman, M. A., H. M. Kissman, J. M.
Bumsides, J. R. Edge, C. B. Haberman,
and A. A. Wyes. 1976. The Toxicology
Data Bank. J. Chem. Inf. Comput. Sci.
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Ray, V. A., L. D. Kier, K. L. Kannan,
R. T. Haas, A. E. Auletta, J. S. Wassom,
S. Nesnow, and M. D. Waters. 1987. An
approach to identifying specialized bat-
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chemicals; class analysis using muta-
genicity and carcinogenicity relation-
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discordance patters. I. Composition and
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Russell, L. B., C. S. Aaron, F. de Ser-
res, W. M. Generoso, K. L. Kannan, M.
Shelby, J. Springer, and P. Voytek. 1984.
Evaluation of mutagenicity assays for
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Tomatis, L. 1988. The contribution of
the IARC Monographs Program to the
identification of cancer risk factors.
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National Library of Medicine, Bethesda,
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Vasta, B. M., and P. Wexler. 1985.
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194 Access/Use Info Resources Assess Health Risk Chem Expos '93
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EPA and the Federal Technology Transfer Act:
Opportunity Knocks
Annette M. Gatchett, Larry Fradkin, Michael Moore, Thomas Gorman, and Alan Ehrlich,
U.S. Environmental Protection Agency
In 1986, the Federal Technology Transfer Act (FTTA) was established to promote a closer, collaborative relationship between
federal government agencies and the private sector. With the increasing need for new cost-effective technologies to prevent and
control pollution, both the U.S. Environmental Protection Agency (EPA) and private industry are encouraged to facilitate the
transfer of knowledge and technology under this Act. The FTTA removed several of the legal and institutional barriers to
cooperative research that existed before the Act's passage. Through the FTTA, the government strives to promote the movement of
its products, processes, skills, and knowledge into the private sector for further development and commercialization by encouraging
the exchange of technical personnel and the sharing of facilities and other resources. Collaborative efforts between industry,
federal agencies, and academia are made possible through cooperative research and development agreements (CRADAs).
Forty-two CRADAs and five licensing agreements have been initiated with EPA under this program. This paper provides an
overview of this new and innovative program within the EPA.
Introduction
Both federal agencies and
the private sector find an
increasing need for new
cost-effective technologies to pre-
vent and control pollution. In the
past, however, legal and institu-
tional .barriers have prevented
government and industry from
collaborating in the development
and marketing of these technolo-
gies. The FTTA 1986 (P.L. 99-
502) established a program
designed to promote a closer, col-
laborative relationship between
federal government agencies and
the private sector. Under the
FTTA, each governmental
agency that conducts research is
encouraged to facilitate the trans-
fer of knowledge and technology
to the private sector. In the EPA,
the Office of Research and
Development's (ORD) Office of
Technology Transfer and Regula-
tory Support (OTTRS) is respon-
sible for implementing the FTTA.
Innovative technologies may
flow in either direction between
the government and the private
sector. EPA's FTTA program rec-
ognizes that exciting and innova-
tive research is being performed
in private, as well as agency labo-
ratories. Through the FTTA, the
government strives to promote
the movement of its products,
processes, skills, and knowledge
into the private sector for further
development and commercializa-
tion by encouraging the
exchange of technical personnel
and the sharing of facilities and
other resources. By permitting
the pooling of resources with
industry, universities, founda-
tions (profit and nonprofit), and
other federal, state, and local gov-
ernmental agencies, the federal
government is seeking to over-
come many of the barriers that
have impeded the development
and commercialization of
federally-developed, innovative
technologies in the past.
Through the FTTA, the government
strives to promote the movement of its
products, processes, skills, and
knowledge into the private sector for
further development and
commercialization by encouraging
the exchange of technical personnel
and the sharing of facilities and other
resources.
Access/Use Info Resources Assess Health Risk Chem Expos '93
195
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Participation in the FTTA pro-
gram can benefit many parties
and allow the private sector to
become more competitive in
both domestic and international
markets. The FTTA has encour-
aged federal laboratories to
assess the scientific and commer-
cial potential of their ongoing
and planned projects to deter-
mine whether a private sector
organization might be interested
in entering into a collaborative
effort. The collaboration, which
may involve the conception
and/or development of an idea or
invention, is usually formalized
by the signing of a CRADA.
CRADAs are one of the primary
mechanisms through which the
exchange of information and
technology takes place under the
FTTA. CRADAs often contain
provisions regarding licensing of
the final product. Licensing of an
innovative technology may take
place independently of a
CRADA in accordance with the
Bayh-Dole Act of 1980 and the
FTTA.
Federal Technology
Transfer Act
Since its inception, EPA's mis-
sion has been to protect human
health and the environment. No
other department or agency of
the federal government has this
function as a primary mandate.
As an institution, EPA is largely
concerned with fulfilling regula-
tory functions that have been
mandated by federal legislation.
The EPA FTTA program is based
primarily on three pieces of legis-
lation and two executive orders:
• The Stevenson-Wydler Tech-
nology Innovation Act of
1980.
• The Bayh-Dole Act of 1980.
• The Federal Technology
Transfer Act of 1986.
• Executive Order 12591,
April 10, 1987, as amended by
Executive Order 12618,
December 22,1987.
The Stevenson-Wydler Act
required all federal agencies con-
ducting research and develop-
ment to include technology
transfer in their mission. It also
required federal agencies to
establish an Office of Research
and Technology Applications to
identify technologies and ideas
with potential applications in
other settings. The Bayh-Dole
Act permitted government-
owned laboratories to grant
exclusive licenses to patents and
permitted universities, non-
profit, and small businesses to
obtain titles to inventions devel-
oped with government support.
The third statute, the Federal
Technology Transfer Act of 1986
amended the Stevenson-Wydler
Act and empowered federal agen-
cies to give their laboratory direc-
tors authority to enter into
CRADAs. The CRADA could
include advance agreements on
title and license to inventions
resulting from the CRADA.
FTTA also required that a signifi-
cant portion of license royalties
be paid to federal laboratories
and their employee inventors
whether the invention came out
of a CRADA or was licensed
using the procedure of the Bayh-
Dole Act. The FTTA also pro-
motes collaboration between
federal agencies and government-
operated laboratories and other
government and nongovernment
entities. The primary mechanism
through which such collabora-
tion takes place, the CRADA,
The FTTA has encouraged federal
laboratories to assess the scientific
and commercial potential of their
ongoing and planned projects to
determine whether a private sector
organization might be interested in
entering into a collaborative effort.
The FTTA also promotes
collaboration between federal
agencies and government- operated
laboratories and other government
and nongovernment entities.
196 Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
was established by the FTTA.
Executive Order 12591, as
amended by 12618, reiterates the
purpose and goals of the FTTA.
Scenarios of Technol-
ogy Transfer
Under EPA's FTTA program,
co-development of technologies
by government and the private
sector can take place in a variety
of ways. For example, technolo-
gies developed entirely in EPA
laboratories can be transferred to
the private sector for further
development and/or commerciali-
zation. Also, technologies con-
ceived or developed in the
private sector may be further
developed or improved upon
jointly by EPA and the coopera-
tor using EPA and cooperator
personnel, equipment, and facili-
ties if the development work is
within the mission of the labora-
tory. Likewise, technology co-
developed by both the govern-
ment and the private sector can
be further developed and com-
mercialized by private industry.
In each of these scenarios, the
EPA and the cooperator could
enter into a CRADA, which
would set forth the terms of the
collaboration. The CRADA is an
adaptable document; the specific
terms will vary with each col-
laborative effort. For example,
EPA may share technical exper-
tise, facilities, equipment, sup-
plies, or any combination
thereof, with the cooperator. The
cooperator may provide the same
resources to the government, and
also has the option of providing
direct funding to a particular pro-
ject. The government, however,
is not permitted to provide direct
funding to the cooperator.
FTTA Agreements
EPA has been entering into coop-
erative agreements with other
agencies and organizations for
years. These cooperative agree-
ments have been a prime funding
vehicle between EPA's ORD
laboratories and nonprofit organi-
zations. However, CRADAs
authorized by FTTA are an
entirely new kind of cooperative
agreement.
A CRADA is an agreement that
provides a written and legal
framework for collaborative
efforts between federal laborato-
ries and private sector coopera-
tors. CRADAs are one of the
primary mechanisms through
which collaboration between the
government and the private sec-
tor takes place under the FTTA.
As previously mentioned,
CRADAs permit EPA Labora-
tory/Office Directors to pool
resources with state and local
governments, universities, and
private industry to develop or to
extend federally funded technolo-
gies to the commercial market-
place. In addition, a concept or
technology that a cooperator
originates may be developed or
extended through the use of a
CRADA.
Under the Bayh-Dole Act, EPA
may also enter into licensing
agreements for the commercial
marketing of independently
developed, federally-owned tech-
nologies. The licensing activity
is primarily a business activity
and the final, written record is a
legal document called a licensing
agreement. A license represents a
contractual business relationship
between a seller (EPA), who
authorizes a buyer to use the
seller's invention or intellectual
Under EPA's FTTA program,
co-development of technologies by
government and the private sector can
take place in a variety of ways.
The licensing activity is primarily a
business activity and the final, written
record is a legal document called a
licensing agreement.
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197
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property rights. Most often in the
commercial arena, this transfer
of intellectual property rights is
for financial gain. Whether a
licensing agreement evolves
from a CRADA or from inde-
pendently developed federally-
owned technologies, FTTA
requires the return of royalties to
the laboratories for technology
transfer activities, and to the
inventors.
Advantages to
CRADAs
There are many advantages to
industry in signing a CRADA or
licensing agreement. These agree-
ments make possible the sharing
of technical expertise, equip-
ment, facilities and supplies.
Under EPA's FTTA program,
however, the overriding goal is
the development and application
of environmentally-beneficial
products and technologies.
CRADAs provide the following
advantages:
• Access to high-quality science
through EPA's 12 research
laboratories. Many of these
laboratories offer an attractive
combination of world-class
personnel with state-of-the-art
equipment and fully permitted
facilities.
• Expanded working relation-
ships between EPA and the pri-
vate sector. Interaction
between the two parties pro-
vides a stronger knowledge
base for problem solving capa-
bilities during technology
development.
• Exclusive agreements for
developing new technologies.
Companies, under some
CRADAs, are given exclusive
rights to market and commer-
cialize new technologies
developed through joint
research.
• Agreement flexibility.
CRADAs are flexible enough
to fit the goals of many differ-
ent sizes and types of compa-
nies.
• Decentralized structure. The
FTTA gives authority to Labo-
ratory/Office Directors for
administering the program.
This accelerates the agreement
process.
Current Program
Information
Since 1989, EPA's FTTA pro-
gram has been expanding rap-
idly. To date, 42 CRADAs and 5
licensing agreements have been
signed. Tables 1 and 2 are lists of
the present participants. The list
of agreements includes the lead
laboratory within EPA, the coop-
erator and a brief description of
the technology being transferred.
Currently, approximately 25
CRADAs and 5 licensing agree-
ments are in negotiations.
A variety of organizations partici-
pate in this program. Participants
encompass a broad range of
organizations from private indus-
try, academia, and trade associa-
tions. Figure 1 represents the
types of organizations working
with us. The majority of partici-
pants are small and large size
businesses.
FTTA and the Future
As we look ahead at the eco-
nomic growth within our nation,
there is a need for stability and
competitiveness. Many compa-
nies are faced with the lack of
Under EPA's FTTA program,
however, the overriding goal is the
development and application of
environmentally-beneficial products
and technologies.
As we look ahead at the economic
growth within our nation, there is a
need for stability and competitiveness.
Many companies are faced with the
lack of resources, such as scientific
expertise in a particular field, or highly
specialized equipment.
198
Access/Use Info Resources Assess Health Risk Chem Expos '93
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Table 1. Signed FTTA Agreements—U.S. EPA Cooperative Research and
Development Agreements (CRADAs)
Office/Lab
Cooperator
Technology/Purpose of CRADA
ORD/HQ
ORD/OEETD/AEERL
ORD/OEETD/AEERL
ORD/OEETD/AEERL
ORD/OEETD/AEERL
ORD/OEETD/RREL
ORD/OEETD/RREL
ORD/OEETD/RREL
ORD/OEETD/RREL
ORD/OEETD/RREL
ORD/OEETD/RREL
ORD/OEETD/RREL
ORD/OEPER/CORVALLIS-ERL
ORD/OEPER/RSKERL
ORD/OEPER/GULF BREEZE, FL-
ERL
ORD/OEPER/GULF BREEZE, FL-
ERL
ORD/OEPER/GULF BREEZE, FL-
ERL
ORD/OHR/HERL
ORD/OHR/HERL
ORD/OHR/HERL
ORD/OMMSQA/AREAL
ORD/OMMSQA/AREAL
ORD/OMMSQA/AREAL
ORD/OMMSQA/AREAL
ORD/OMMSQA/AREAL'
ORD/OMMSQA/AREAL
Exxon Corporation, USA
ABB FLAKT, Inc.
Aladdin Steel Products, Inc.
Nalco Fuel Tech, L.P.
Nalco Fuel Tech, L.P.
Chapman, Inc.
Cold Jet, Inc.
Drysdale and Associates, Inc.
Levine-Fricke, Inc.
Lewis Publishers, Inc./CRC Press, Inc.
Vulcan Iron Works, Inc.
Water Quality Association
Niagara Mohawk Power Company
Coastal Remediation Company
Electric Power Research Institute
Southern Bioproducts, Inc.
Southern Bioproducts, Inc.
E.I. DuPont de Nemours and Company
Pathology Associates, Inc.
Spiral Systems Instruments, Inc.
Autoclave Engineers, Inc.
Dow Corning Corporation
Ford Motor Company
Frandon Enterprises, Inc.
Georgia Institute of Technology
NuTech Corporation
Development and demonstration of the feasibility of accelerating
the rate of biodegradation of oil spill residues on Alaskan Shores
Development of absorbents for air pollution control technology
Further the development and commercialization of an EPA-patent
for gas-enhanced woodstove technology for reducing emissions
into the atmosphere
Determining the sulfur dioxide and nitrogen removal efficiency by
the EPA-patented calcium-based and urea-based sorbents
Development of a combination Selective Catalytic
Reduction/Selective Non-Catalytic Reduction process for nitrogen
oxides emissions in combustion effluent
Use of EPA's mobile in-situ soil containment technology for
treating hazardous wastes
Evaluate dry ice particle blasting and other abatement processes
for the removal of lead paint
Development and evaluation of automatic sensors and data
acquisition equipment for drinking water treatment plants
Lab and pilot scale study of biodetoxification waste treatment
technology for degrading solid
Development of a cost and performance model for safe drinking
water clean-up technologies
Use of EPA's mobile incinerator for destruction of hazardous
wastes
Evaluation of a home water softener on the corrosiveness of water
Use of a Biological Earthworm Assay to evaluate the efficiency of
a thermal desorption technique
Development of bioremediation process to remove alkylbenzene.
contamination through injection into subsurface of a nutrient mix
Identification of a bioremediation technique to remediate mercury
contaminated freshwater environments
Development of microbial isolates to degrade toxic chemicals
Performance of research on bioremediation of wood treatment
waste sites
Visual function research testing of a mixture of aliphatic dibasic
esters
Use of the SENCAR Mouse Assay for identifying complex
mixtures in drinking water treatment plants
Development and utilization of automated and semi-automated
microbial mutagenicity assays
Development and/or improvement of methods that use
programmable pyrolysis for the analysis of trace organic species
(hat occur in a condensed or other phase in the atmospheric
environment
Investigation of environmental effects on damage to coatings and
sealants used on automotive products
Use of EPA's Ehvironmental Chamber Facility for evaluating
effects of Environmental fallout on automotive products
Development of a test kit method for lead
Hydraulic model study for improved ocean outfall design at
Boston Harbor
Design, development, production, and testing of automated gas
chromatographic injection equipment to determine organic
compounds in ambient air
(continued)
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Table 1. Signed FTTA Agreements—U.S. EPA Cooperative Research and
Development Agreements (CRADAs)
Office/Lab
Cooperator
Technology/Purpose of CRADA
ORD/OMMSQA/AREAL
ORD/OMMSQA/AREAL
ORD/OMMSQA/EMSL-CI
ORD/OMMSQA/EMSL-CI
ORD/OMMSQA/EMSL-CI
ORD/OMMSQA/EMSL-a
ORD/OMMSQA/EMSL-CI
ORD/OMMSQA/EMSL-CI
ORD/OMMSQA/EMSL-CI
ORD/OMMSQA/EMSL-LV
ORD/OMMSQA/EMSL-LV
ORD/OMMSQA/EMSL-LV
OAR/NVFEL&
ORD/OMMSQA/AREAL
OSWER/OUST
OSWER/OUST OEETD/RREL
OW/OGWDW/TSD
Perkin-Elmer Corporation
Rohm & Haas Company
American Water Works Association
Research Foundation
Fisher-Scientific Company and R.T.
Corporation
NSI Technologies, Inc.
Perkin-Elmer Corporation
Spex, Inc.
Supelco, Inc.
Ultra Scientific, Inc.
Dow Corning Corporation
Fiber Chem, Inc.
Hewlett-Packard Company
US CAR Env. Res. Consortium (Ford,
GM, Chrysler, Navistar) and State of CA
In-Situ, Inc.
Shell Oil Company
CH2M Hill Southeast, Inc.
Development and improvement of physical and chemical methods
for trace contaminant analysis, automated canisters sampling for
gaseous contaminants, and diffusion monitoring technologies
Paint substrate exposure study using covering-spray devices
Biotechnology and tissue culture methods for monitoring viruses
in ground water
R&D of solid matrix quality control samples
R&D of liquid organic standards and preparation, verification,
distribution, and stability of these samples
Development of sampling methods for the PCR technology
R&D of inorganic reference materials and preparation,
verification, distribution, and stability of these materials
R&D of liquid organic standards and preparation, verification,
distribution, and stability of these samples
R&D of organic reference materials and preparation, verification,
distribution, and stability of these samples
Use of EPA's Indoor Air Chamber to test a Dow-developed
instrument
Development of fiber optic chemical sensors
Development of advanced laboratory instrumentation for exposure
analysis
Develop new technology to identify evaporative emissions and
hard-to-detect low-level exhaust emissions from cars and trucks
Development of a field method for testing soil and water for VOCs
Evaluation of vacuum extraction technology for USTs
Use of EPA mobile packed column air stripping technology for
treating drinking water contaminants
Table 2. Signed FTTA Agreements—U.S. EPA LICENSING AGREEMENTS
Office/Lab
Cooperator
Technology
ORD/OEETD/AEERL
ORD/OEETD/AEERL
ORD/OEETD/RREL
ORD/OEPER/Athens
ORD/OEPER/GBERL
ABB FLAKT, IncAlniversity of Texas
GenLime Group, L.P.
Boyle Engineering, Inc.
Bio-Rad Laboratories, Inc.
SBP Technologies, Inc.
Licensing of absorbents for air pollution control technology
Licensing of Limestone Injection Multistage Burner process for
reducing sulfur emission from coal plants
Licensing of EPA patent on butylamine group-containing ion
exchange resins for water purification
Licensing of method for interfacing between a liquid chromalograph
and a mass spectrometer for conditioning liquid stream from the
chromatograph to the spectrometer
Licensing of two EPA-patents on biological remediation of creosote-
and similarly-contaminated soil and ground water
200 Access/Use Info Resources Assess Health Risk Chem Expos '93
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resources, such as scientific
expertise in a particular field or
highly specialized equipment.
Partnerships among industry, aca-
demia, and the federal govern-
ment bridge the gap between the
market oriented private sector
and the environmental protection
prospective of EPA. Industry
often lacks resources, such as
time and money, for the develop-
ment of new technologies. This,
in turn, may impede or inhibit
the development of a viable tech-
nology. If the U.S. is to become
more competitive internationally,
our industries, universities, and
the federal government must join
forces and work together toward
a common goal. The FTTA per-
mits speed in development and
commercialization of innovative
technologies. In our changing
world and economy, this is cru-
cial to our economic growth and
stability.
small business
large business
academia
trade associations
medium business
Fig. 1. Types of FTTA agreement cooperators.
Access /Use Info Resources Assess Health Risk Chem Expos '93
201
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Information Resources for Assessing Health
Effects From Chemical Exposure: Office of
Pesticides Programs
Penelope Fenner-Crisp, U.S. Environmental Protection Agency
The U.S. Environmental Protection Agency (EPA) Office of Pesticide Programs is trying to develop a complete picture of a
chemical's toxicity and exposure profile. It is also important to share information in the office's files because pesticides,
particularly as a consequence of agricultural use, find their way into places not necessarily intended.
FIFRA 88 refers to the last
time major amendments
were made to the Federal
Insecticide, Fungicide, and
Rodenticide Act. FIFRA 88 con-
tains some significant directives
for the Environmental Protection
Agency (EPA). Over the last 20
years, Congress has asked EPA
to re-register all pesticides that
had been registered prior to
November 1984. Re-registration
was attempted in 1972 and 1976,
both times with meager results.
In 1988 Congress "asked" again,
but this time mechanisms were
included to acquire financial sup-
port for resources. They also
gave a time frame in which to
accomplish this task; it must be
complete by 1997. This means
we must identify the data gaps
that are inadequately filled. It
also means that registrants of pes-
ticide products will have to gen-
erate new data as appropriate.
The agency then must review
these new data and provide an
opinion regarding the validity of
the data with respect to continu-
ing registration of the product.
We started out with about 800
active ingredients but now are
down to close to half of that,
fewer than expected based upon
preliminary evaluations.
The room next to my EPA office
contains the world's mother lode
of toxicology data: the largest
database in the world on human
health effects of pesticides. My
colleague, Anne Barton, has the
same sort of information avail-
able to her on environmental fate
and ecological effects. I think the
only other database that might
closely compare in size is that of
the World Health Organization's
Expert Panel, which derives
Acceptable Daily Intakes for pes-
ticides. This is part of the work
of the Joint Meeting on Pesticide
Residues in cooperation with the
Food and Agricultural Organiza-
tion in recommending Maximum
Residue Limits (international
food tolerances) to Codex Ali-
mentarius Commission.
You would think that all of this
information ought to be more
than enough for the Program to
make decisions with respect to
the registration, re-registration or
cancellation of the uses of a pesti-
cide. Generally, the Office has
had a relatively parochial attitude
on that point. Little information
We must identify the data gaps that
are inadequately filled.
The largest database in the world
on human health effects of
pesticides is located at EPA.
Access/Use Info Resources Assess Health Risk Chem Expos '93
203
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in addition to the industry-
sponsored data has been consid-
ered and integrated into our risk
assessments and regulatory deci-
sions. This practice may be satis-
factory for registration purposes
because usually, there are few
data available from outside
sources on the new(er) chemi-
cals. However, the re-registration
process covers only those pesti-
cides registered before 1984. The
Special Review process, which
may lead to the banning or can-
cellation of a chemical, also
tends to focus on older chemi-
cals; thus, additional information
on these is likely to exist. We
receive many new studies during
the course of re-registration and
we often must ask for new data
in the Special Review process.
Even so, to conduct a high-
quality risk assessment we must
consider not just the sponsor's
data, but also information on the
chemical from other sources as
well as data on agents in the
same chemical class to use for
structure activity analysis.
It is important that we develop a
complete picture of a chemical's
toxicity and exposure profile. I
see it as a challenge to us in the
Office of Pesticide Programs to
make use of the many data bases
described during the last few
days. I have been aware of them,
and during the year I have been
in the Office of Pesticide Pro-
grams, I have prompted interest
in them among my co-workers.
We are gathering this informa-
tion for incorporation into the
database comprised of data sub-
mitted to us by the registrants. It
is also important, as the law per-
mits, for us to share information
in our files with the rest of you
because pesticides, particularly
as a consequence of their agricul-
tural use, find their way into
places not necessarily intended.
We also find them at waste sites
such as Superfund sites. We find
them as a result of agricultural
run-off in our surface waters, and
in groundwater, whether or not it
is being used for drinking water.
So, certainly other program
offices in EPA and our sister Fed-
eral agencies, as well as the state
and local governments, have sig-
nificant interest in both the toxic-
ity and environmental fate of
pesticides. We hope to soon pro-
vide that information to you in a
more expanded manner than we
have in the past, and we can
gather from you the information
you may have collected, particu-
larly on exposure, to assist us in
developing sound regulatory
decisions.
The Special Review process, which
may lead to the banning or
cancellation of a chemical, tends to
focus on older chemicals.
It is important for us to share
infomiation in our files because
pesticides find their way into
places not necessarily intended.
204 Access/Use Info Resources Assess Health Risk Chem Expos '93
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Air Risk Information Support Center
Chon R. Shoafand Daniel J. Guth, U.S. Environmental Protection Agency
The Air Risk Information Support Center (Air RISC) was initiated in earfy 1988 by the U.S. Environmental Protection Agency's
(EPA) Office of Health and Environmental Assessment (OHEA) and the Office of Air Quality Planning and Standards (OAQPS) as a
technology transfer effort that would focus on providing information to state and local environmental agencies and to EPA Regional
Offices in die areas of health, risk, and exposure assessment for toxic air pollutants. Technical information is fostered and dissemi-
nated by Air RISCs three primary activities: (1) a "hotline," (2) quick turn-around technical assistance projects, and (3) general
technical guidance projects.
Introduction
In 1985, EPA announced its
National Air Toxics Strat-
egy, which included provi-
sion of technical assistance to
state and local agencies; Air
RISC is a formal mechanism for
provision of this assistance (Guth
and Victery 1989). Air RISC is
managed by a steering committee
composed of 6 voting members
from OAQPS, 5 voting members
from OHEA, 1 voting member
from the Center for
Environmental Research Informa-
tion, and 1 advisory member
each from the Health Effects
Research Laboratories, state and
local agencies, regional offices,
and the EPA library. The steer-
ing committee chairperson is
rotated yearly between the Envi-
ronmental Criteria and Assess-
ment Office at the Research
Triangle Park (ECAO-RTP) and
OAQPS.
Technical information is fostered
and disseminated by Air RISCs
three primary activities: (1) a
"hotline," (2) quick turn-around
technical assistance projects, and
(3) general technical guidance
projects. The "hotline" provides
inquirers with quick responses on
health effects and risk assess-
ment questions as well as needs
for quick turn-around technical
assistance projects. The Air
RISC "hotline" is also a data-
base for general technical guid-
ance projects. Quick turn-around
technical assistance projects are
usually more limited in their
scope of health effects and expo-
sure population. General techni-
cal guidance projects include a
wide variety of activities in risk
assessment, risk communication,
and training.
"Hotline"
The Air RISC "hotline" provides
an initial quick response to
inquiries from state and local
agencies and EPA Regional
Offices. Responses are based on
health and exposure information
available through the expertise of
Air RISC staff, resources (docu-
ments, databases, and library),
and contractors. Experts in a
variety of areas can answer ques-
tions from the caller directly or
provide the appropriate informa-
tion resources. Calls may also be
referred to other EPA staff mem-
bers with the appropriate
expertise. The "hotline" oper-
ates Monday through Thursday
from 8:00 a.m. to 5:00 p.m. and
Technical information is fostered
and disseminated by Air RISC's
three primary activities.
Responses are based on health and
exposure information available
through the expertise of Air RISC
staff, resources (documents,
databases, and library), and
contractors.
Access/Use Info Resources Assess Health Risk Chem Expos '93
205
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Friday from 8:00 a.m. to 4:00
p.m. Anyone on the staff of a
local or state air pollution control
agency or in the EPA Regional
Office may make "hotline"
inquiries.
"Hotline" calls are logged into a
database by the receiving EPA
staff member. Information stored
includes the date of request; the
staff member receiving the call;
the requestor's name, address, af-
filiation, and phone number; the
type (state, local, or federal) of
call; the subject and pollutant of
concern; the completion date;
hours to complete; and an ab-
stract of the call. The abstract in-
cludes a narrative description of
the call along with pertinent
names, telephone numbers, and
copies of correspondence gener-
ated by the call. The database is
used to store information and as
an information resource. It can
be used to save time and provide
consistency when responding to
similar requests. It is also used
as a management tool for review-
ing and reporting the status of Air
RISC calls, description of clients
which use Air RISC, the subject
of calls, and time spent by EPA
staff supporting Air RISC. Fig-
ure 1 shows the number of Air
RISC cases by type from its
inception to May 1990. During
this period, scientists at OHEA
and OAQPS responded to 1131
Air RISC calls from all sources.
State agencies made the greatest
use of the service. Local agency
and EPA Regional Office use is
about equal, but less than state
agency use. Air RISC utilization
by state over the same period is
shown in Fig. 2. States with very
active air pollution control efforts
made more requests to Air RISC
as indicated by higher numbers
on the map. Seventy-three local
Fig. 1 Utilization of Air RISC by
May
agencies from 25 states made
inquiries of Air RISC. There
were 1002 calls from state, local,
and Regional Offices, repre-
senting 89% of the total calls.
Thus, the clientele for Air RISC
is largely, as intended, state and
local agencies and EPA Regional
Offices.
The greatest number of questions
about single chemicals concerned
dioxins, asbestos, benzene, sty-
rene, formaldehyde, methylene
chloride, chromium, hydrogen
sulfide, arsenic, and mineral fi-
bers. Questions regarding com-
plex mixtures were asked most
frequently, however. General
questions on health effects, car-
cinogenic unit risk estimates,
documents, or regulatory status
were also asked frequently.
The "hotline" has identified vari-
ous quick turn-around technical
assistance projects needing com-
pletion, and the "hotline" data-
state agencies February 1988 through
1990.
The greatest number of questions
about single chemicals concerned
dioxins, asbestos, benzene, styrene,
formaldehyde, methylene chloride,
chromium, hydrogen sulfide, arsenic,
and mineral fibers.
206 Access/Use Info Resources Assess Health Risk Chern Expos '93
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base has been used to identify
general technical guidance pro-
jects in health, exposure, and risk
assessment that need to be
addressed to meet the needs of
the state, local, and Regional
Office requestors (inter alia, tire
burning and asphalt fumes).
Quick Turn-Around
Technical Assistance
In some cases, an in-depth evalu-
ation or retrieval of information
may be more helpful than a rapid
response. In such cases, detailed
technical assistance projects may
be required. If resources and
time are adequate, such projects
will be initiated. Technical assis-
tance projects can be carried out
in the following subject areas:
assistance in understanding expo-
sure and risk assessment method-
ologies; review and interpre-
tation of toxicological literature;
and review of site-specific expo-
sure assessments, risk assess-
ments, or both for adequacy of
methods used and related inter-
pretation features.
The Air RISC quick response pro-
ject mechanism typically utilizes
contractors when EPA staff are
not available to do the necessary
research or review. EPA staff
then review the contractor's prod-
ucts. These projects are most
often generated by "hotline" re-
quests. The following is a list of
some of the projects using quick
response:
• Review of draft health impact
protocol from incineration in
Quincy, Massachusetts
• Comparison of upper bound
confidence limit and maxi-
mum likelihood estimate
• Review of carbon disulfide
document for Virginia
Air RISC Cases by Type:
February 1988-May 1990
Federal
Regional
State
Local
Other
200 300 400
Number of Cases
500
600
700
Fig. 2. Air RISC cases by type.
• Hexachlorobutadiene—health
effects
• Triethylamine—health effects
• Coal dust—health effects
• Butyl cellusolve—health
effects
• Review of aluminum facility
health/risk assessment plan
• Review of toxicity of alkanes
and alkenes
• Chemical carcinogenicity data
from Kentucky Air Toxics Pro-
gram
• Review of risk assessment
work plan for point sources -
Chattanooga, Hamilton County
• Review of exposure assess-
ment portion of gasoline docu-
ment
A list of some of the projects
using quick response by Air RISC.
Access/Use Info Resources Assess Health Risk Chem Expos '93
207
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• Review of exposure assess-
ment portion of gasoline docu-
ment
• Review of New Hampshire
method for deriving ambient
air guidelines
• Summaries of toxicity data for
7 chemicals for Oregon State
agency
General Technical
Guidance Projects
The third major purpose of Air
RISC is the completion of gen-
eral technical guidance projects.
These projects are of broad reach-
ing lexicological, exposure, or
risk assessment concern, and
sometimes are performed with
the joint collaboration and sup-
port of the Control Technology
Center (CTC).
Air RISC and the CTC supported
a project for the State of Flor-
ida's Department of Environ-
mental Regulation on emissions
and health effects of burning agri-
cultural black plastic. Test
burns, emission sampling, and
simulated burnings were funded
by CTC, and Air RISC funded
the mutagenicity testing of the
emissions by the Ames test. No
mutagenic potential was found in
the vapor or particulate emis-
sions, but concentrated extracts
of the particulate sample were
moderately mutagenic. Muta-
genic potential was similar to
emissions from residential wood
burning as determined from the
literature.
Air RISC supported a project
which reviewed the health effects
of asphalt fumes. CTC provided
information on asphalt produc-
tion and emissions according to
its use. The health effects of
emitted chemicals were
reviewed, but additional emis-
sions data and dose-response
relationships are needed.
Based on a request by Region 8,
Air RISC performed a risk
assessment pertaining to a steel
mill in Utah. Joint participation
by CTC involved characteriza-
tion of emissions from integrated
steel mills. A document describ-
ing the steel-making process,
process stream emissions, and
cancer and noncancer health
effects of the emissions was
prepared.
Air RISC is also involved in tech-
nical guidance projects such as
producing a Glossary of Terms
Related to Health, Exposure, and
Risk Assessment. This document
is a resource for state, local, and
Regional Office personnel who
deal with toxic air pollutants. A
Directory of Information
Resources Related to Health,
Exposure, and Risk Assessment
of Air Toxics was prepared by
Air RISC to assist state, local,
and Regional Office personnel.
Air RISC also offered three-day
workshops on risk assessment
and risk communication for state
and local air pollution control
agency personnel. The work-
shops provided sessions on
health and exposure assessment,
toxicology, and risk assessment.
More in-depth sessions cover pul-
monary toxicology, inhalation
reference concentration (RfC)
methodology, noncancer risk
assessment, pharmacokinetics,
and the most recent agency con-
cepts in cancer risk assessment.
Important concepts in risk com-
munication, such as public
involvement, explanation of tech-
nical issues, risk perception, con-
ducting public meetings, and
dealing with the media were also
General technical guidance projects are
of broad reaching toxicological,
exposure, or risk assessment concern.
Workshops provided sessions on
health and exposure assessment,
toxicology, and risk assessment.
208 Access/Use Info Resources Assess Health Risk Chem Expos '93
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covered. Based on the premise
that odor or sensory irritation
may be related to pulmonary
damage or damage to other
organs, a project characterizing
the odor threshold, sensory irrita-
tion, and critical target organ of
several hundred air toxics was
started by Air RISC.
A project to provide guidance to
state and local air pollution offi-
cials who perform site-specific
risk assessments for point
sources is under way. Carcino-
genic and noncarcinogenic risk
assessment methodologies will
be outlined with areas of conflict
and unresolved differences in
methodologies resolved by pres-
entation of various options and
resource requirements. Air RISC
is also supporting a project that
will provide guidance to agen-
cies for including risk communi-
cation and public involvement as
part of air toxics programs.
References
Guth, D. J., and W. Victory. 1989.
Air Risk Information Support Center
Status Report, February 1988-June
1989, U.S. Environmental Protection
Agency, Air Risk Information Support
Center, Research Triangle Park, North
Carolina, EPA 450/3-89-32.
A project to provide guidance to
state and local air pollution
officials who perform site- specific
risk assessments for point sources
is under way.
Access/Use Info Resources Assess Health Risk Chem Expos '93
209
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Chemical Substructure Analysis in Toxicology
Robert O. Beauchamp, Jr., Center for Information on Toxicology and Environment
A preliminary examination of chemical-substructure analysis (CSA) demonstrates the effective use of the Chemical Abstracts
compound connectivity file in conjunction with the bibliographic file for relating chemical structures to biological activity. The
importance of considering the rote of metabolic intermediates under a variety of conditions is illustrated, suggesting structures that
should be examined that may exhibit potential activity. This CSA technique, which utilizes existing large files accessible with online
personal computers, is recommended for use as another tool in examining chemicals and drugs.
Chemical Substructure
Analysis (CSA) has
become a highly
sophisticated procedure as illus-
trated by its use in the field of
toxicology and other biomedical
disciplines. If a chemical, drug,
or pesticide is modified during
use or exposure, the intermedi-
ates become part of the analysis.
For example, in pharmaceutical
or lexicological research, chemi-
cals are exposed to different
kinds of biological media and
may be subject to metabolic con-
version. CSA techniques in toxi-
cology are similar in many
aspects to development of a novel
drug in which a basic chemical
structure of a known drug may be
changed to yield a more active
and efficacious product. Chemi-
cal structural features of test com-
pounds may vary with functional
groups, physical dimensions,
hydropathicity, electrophilicity,
nucleophiliciry, or susceptibility
to enzymatic modification, to
mention a few. These are impor-
tant features to consider where
chemical bonds are disrupted and
new structures formed that may
bind to biological substrates such
as proteins, by enzymatic cou-
pling, oxidation-reduction reac-
tions, or acid base equilibrium.
Such alterations of the basic
chemical structure can affect the
biological activity. CSA may
employ many technical disci-
plines including organic chemis-
try, medicinal chemistry,
molecular modeling, pharmacol-
ogy, biochemistry, pharmacoki-
netics* pathology, and veterinary
and human medicine. Some of
the principal benefits from CSA
of test compounds under various
experimental or environmental
conditions are to (1) predict
chemical conversion, (2) deter-
mine chemical reactions, (3) elu-
cidate metabolism, and (4) relate
chemical structure to biological
activity.
Important chemical structural
features should be considered where
chemical bonds are disrupted and
new structures formed that may bind
to biological substrates such as
proteins, by enzymatic coupling,
oxidation- reduction reactions, or
acid base equilibrium.
CHEMICAL SUBSTRUCTURE ANALYSES
IN TOXICOLOGY
BENEFITS —
• PREDICT CHEMICAL CONVERSION
• DETERMINE CHEMICAL REACTIONS
• ELUCIDATE METABOLISM
• RELATE CHEMICAL STRUCTURE TO BIOLOGICAL
ACTIVITY
Fig. 1. Benefits of chemical substructure analysis.
Access/Use Info Resources Assess HealtkRisk Chem Expos '93
2.11
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In the early analytical stages of
CSA, after establishing the exact
structure of the model test com-
pound and any contaminants, the
potential metabolic sequence
should be delineated in order to
focus on a set of chemical struc-
tures. If the metabolic sequence
of the test compound has been
established previously, the CSA
can be directed to structures asso-
ciated with the reported metabo-
lites. Certain functional groups
may be susceptible to "biomedi-
cal" modification and should be
considered at this initial stage of
CSA along with closely related
chemical derivatives.
Computerized techniques have
contributed greatly to the CSA
process during the past decade.
The chemical connectivity file
compiled by the Chemical
Abstracts Service (CAS) cur-
rently contains over 11 million
records on reported substances.
Incorporated into each record is
the connectivity code for each
compound in which every atom
and its adjacent attachments can
be searched singly or in multiple
combinations (i.e., chemical sub-
structures). This large chemical
file is available online through
the Scientific and Technical
Information Network (STN)
under the title—REGISTRY
FILE (Reg file). The records in
this file include not only single
compounds but mixtures, salts,
polymers, addition compounds,
and coordination compounds.
Each record contains Registry
Numbers (RN), names, syno-
nyms, molecular formulae, struc-
tural diagrams, and the total
number of references that may be
queried in the CAS bibliographic
files. In addition, the Reg file can
be searched for word fragments
simultaneously in several index
fields of the separate records
along with the substructure
searches giving the user a very
powerful tool. The foregoing
record fields that contain differ-
ent terms can be utilized in prepa-
ration of a search statement.
Terms may be utilized to broaden
or narrow the search. Boolean
logic can be applied to multiple
terms to focus on a particular set
of compounds.
After a set of chemical structure
records is retrieved from these
search queries in the Reg file, the
records may be examined for
cited structures to determine
whether the compound search
should be expanded or limited to
specific structural configura-
tions. The final chosen set of
compounds from the Reg file can
then be searched in a second bib-
liographic file also available on
STN—CHEMICAL
ABSTRACTS FILE (CA file) in
which a particular activity such
as metabolism or toxicology is
searched for in abstracted
publications.
The CA file contains the com-
plete bibliographic record for
publications abstracted by CA
since about 1965 and contains
approximately 5 million refer-
ence citations. The reference cita-
tions include author names,
titles, document sources plus
other searchable fields—docu-
ment type, major subject sections
(such as toxicology, pharmacol-
ogy, etc.), publication year, lan-
guage, abstract, keywords and
index terms. Proximity term
searching can be employed also
in which search terms must be
positioned either in the same
index field or different fields and
in a prescribed order. Boolean
logic can be applied to the search
Computerized techniques have
contributed greatly to the CSA process
during the past decade. The chemical
connectivity file compiled by the
Chemical Abstracts Service (CAS)
currently contains over eleven million
records on reported substances.
The CA file contains the complete
bibliographic record for publications
abstracted by CA since about 1965
and contains approximately 5 million
reference citations.
112 Access/Use Info Resources Assess Health Risk Chem Expos '93
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terms in searching the CA file as
with the Reg file. For example, a
set of compounds (substructure
set from Reg file) can be
searched in the CA file and the
separate bibliographic references
queried for specific biological
activity such as inhalation toxic-
ity in the rat
Before performing a CSA search
of the computer files, selection
of the chemical substructures
based on the "parent" compound
should be carried out according
to the following general proce-
dure.
Stepl —
Test compound: Examine the
compound for chemical class
(e.g., amine, acid, alcohol, or
epoxide), potential for bio-
transformation or metabolism
(e.g., enzymatic reduction/
oxidation, or coupling), reac-
tivity with substrates (e.g,
water, DNA, or peptides), and
bonding characteristics (e.g.,
covalent, H-bonding, pi bond-
ing, or van der Waals).
Test compound intermediates:
Modify the chemical structure
of the test compound accord-
ing to reported metabolic data
or probable conversion prod-
ucts based on analyses in the
first step. The complete struc-
ture of test compound can be
entered in the Reg file and
modified by either addition or
deletion of chemical frag-
ments. Starting with the origi-
nal compound has the
advantage of visually follow-
ing the conversion steps. Also,
this approach focuses on the
points of attachment or chemi-
cal change and usually
includes a larger portion of the
test compound, which poten-
tially yields a smaller number
of compounds in the substruc-
ture set.
Ultimate activity structure: Deter-
mine the probable chemical
structure causing adverse
effect or pharmacological
action (may be final conju-
gated product excreted/
released or an intermediate
resulting from biotransforma-
tion, etc.).
Preliminary CSA Study
Phenylbutazone (PBZ), orbuta-
zolidine (Fig. 2), was selected as
a prototype to illustrate the CSA
procedure as outlined in the
foregoing section. This drug
has been used as an anti-
inflammatory agent since the late
1940s. Many references are avail-
able in the open literature report-
ing its activity in various animal
species and under a variety of
conditions. Numerous variations
in the basic chemical configura-
tion of PBZ have been synthe-
sized and tested for alteration in
activity. Also, this drug was
reviewed recently by the Peer
Review Panel of the National
Toxicology Program (NTP)
Board of Scientific Counselors
and Technical Reports Review
Phenylbutatone (PBZ), or
butazolidine, was selected as a
prototype to illustrate the CSA
procedure as outlined in the foregoing
section. This drug has been used as an
anti-inflammatory agent since the late
1940s.
Ph
N-
N
Ph
0
n-Bu
H
Fig. 2. Strucutre of phenylbutazone.
Access/Use Info Resources Assess Health Risk Chem Expos '93 213
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Subcommittee for its potential
toxicity and carcinogenicity.
Evaluation by the Peer Review
Panel indicated the following
conclusions from a 2-year bioas-
say gavage study with rats and
mice (NTP 1990) :
1. Equivocal evidence of carcino-
genic activity in male rats
(F344/N)—renal cell ade-
nomas and carcinomas.
2. Some evidence of carcino-
genic activity in female rats
(F344/N) —transitional cell
carcinomas in kidney. Nephro-
toxic to rats.
3. Some evidence of carcino-
genic activity in male mice
(B6C3F1)—increased
incidence of hepatocellular
adenomas and carcinomas.
4. No evidence of carcinogenic-
ity in female mice (B6C3F1)
at elevated exposures (150 or
300 mg/kg in corn oil).
These conclusions have been
accepted relative to animal toxic-
ity by the National Institute of
Environmental Health Sciences
(NIEHS) and were subsequently
released in a NTP report (March
1990).
The chemical structure of PBZ is
composed of a pyrazolidine het-
erocyclic ring that has been sub-
stituted in five positions. The
heterocyclic ring contains two
nitrogen atoms adjacent to each
other in the 1- and 2- positions.
Two unsubstituted phenyl groups
are positioned at the 1- and 2-
positions on the nitrogen atoms,
two keto groups at 3- and 5-
positions, and an alkyl straight C-
chain (butyl) at the 4- position of
the heterocyclic ring. PBZ may
be synthesized by the reaction of
1,2-diphenylhydrazine and the
n-buryl alpha-substituted malo-
nic acid ester. In the CSA the
chemical structures of the start-
ing materials also should be con-
sidered for clues to metabolite
structures and possible tech-
niques for modifying the test
compound.
Metabolism of PBZ has been
studied in numerous biological
systems and the chemical sites
associated with metabolic trans-
formation have been noted. As
yet, no particular metabolite has
been designated as the putative
structure associated with dis-
closed carcinogenicity. Toxic
components of the test com-
pound may be elucidated by
blocking the reactive sites
observed in the metabolism
sequence or by administering
large doses of a certain metabo-
lite and observing any changes in
toxicity. From the metabolic
sequence data reported for PBZ,
there are six principal reaction
sites: (1) hydroxylation of the
phenyl groups in the para-
positions, (2) omega-1 oxidation
of the butyl chain yielding a
butanone or butanol, (3) omega-
2 oxidation of the butyl chain
forming a beta-hydroxybutane,
(4) ring cleavage of the pyra-
zolidine ring between the 4- and
5- positions and subsequent for-
mation of a lactone ring with the
hydroxyl group of the butyl
chain, (5) hydroxylation of the 4-
position of the pyrazolidine ring,
and (6) formation of glucuro-
nides/sulfates at possible reactive
sites. Depending on the biologi-
cal conditions, it is possible for
more than one of these metabo-
lites to be present or even more
than one reactive site to be modi-
fied simultaneously in the origi-
nal parent compound.
The chemical structure of PBZ is
composed of a pyrazolidine
heterocyclic ring that has been
substituted in five positions.
From the metabolic sequence data
reported for PBZ, there are six
principal reaction sites.
214 Access/Use Into Resources Assess Health Risk Chem Expos '93
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From this metabolic information,
the CSA is focused on certain
chemical substructures for analy-
sis of PBZ. Several of these sub-
structures have been searched in
the Reg file and then submitted
to the CA file for possible bio-
logical activity. The following
procedure is suggested as a
model in conducting a CSA and
relating structure to activity.
Two principal substructures of
PBZ were selected for initial
investigation. The first structure
is symmetrical diphenylhy-
drazine in which definite atoms
or substituents have been desig-
nated. This substructure repre-
sents ring cleavage of the
pyrazolidinedione ring and
retains the two phenyl groups on
adjacent ring N-atoms. The
phenyl groups may be substi-
tuted only in the para-position, as
suggested by hydroxylation lim-
ited to these positions.
The second selected principal
substructure consists of five- or
six-membered 1,2-dinitrogen het-
erocyclic rings and phenyl
groups on each of the ring N-
atoms and keto groups on the het-
erocyclic rings adjacent to each
of the ring N-atoms. The five-
membered heterocyclic ring is a
pyrazolidine-3,5-dione, and the
six-membered heterocyclic ring
is apyridazine-3,6-dione. These
two heterocyclic ring structures
were queried separately in the
computer Reg file to obtain sets
of compounds possessing the
desired chemical substructure
characteristics. The sets were
then queried in the activity file
(CA file) to determine any
reported toxic activities.
The STN system was entered
through a computer terminal
(IBM PC/XT) with a modem and
the Reg file queried for the
diphenylhyrazine (DPH) sub-
structure. Registry numbers may
be used to enter structures in the
Reg file and then modified
according to the desired struc-
ture. A sample search was per-
formed with only 5% of the file,
and this search projected 53 to
477 compounds in the full 10
million-compound file. A com-
plete search gave 136 com-
pounds. When this structure set
was searched in the CA file, 492
references were found. This refer-
ence set was then restricted to
the following word fragments:
[mutat?, mutag?, carcino?, neo-
plas?, terato?, metaboli?, or
DNA]. The total number 492
was reduced to 34 references.
Figure 3 lists the three deriva-
tives with indicated toxicity as
derived from this search
procedure.
Two principal substructures of PBZ
were selected for initial Investiga-
tion. The first structure is symmetr-
ical dlphenylhydrazine. The second
selected principal substructure
consists of five- or six-membered
1,2-dinitrogen heterocyclic rings and
phenyl groups on each of the ring
N-atoms and keto groups on the
heterocyclic rings adjacent to each of
the ring N-atoms.
Diphenylhydrazine
RN=122-66-7
Mutagenicity; CA 104:143623
4,4' -Hydrazobenzenedisulfonamide RN = 4392-55-6
0 H H
NH, 5
Immune cross-reactivity
CA 91:117287
l,r-Bipbenyl-4,4'-diamine sulfate mixture with diphenylhydrazine
H H RN = 60108-63-6
HN
Carcinogenicity; CA 85:105041
Fig. 3. DPH substructure derivatives and toxicity.
Access/Use Info Resources Assess Health Risk Chem Expos '93
215
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The second set of proposed
chemical substructures was que-
ried in the Reg file (i.e., pyra-
zolidinedione and pyridazine-
dione) and a set of 1355 com-
pounds was obtained. PBZ was
eliminated because it is not con-
sidered one of the substructures
leaving 1354 derivatives. (Refer-
ences to toxicity of PBZ can be
performed in a single search and
should not be considered with
the chemically modified compo-
nents.) Searching this substruc-
ture set of 1354 compounds in
the CA file gave 1769 refer-
ences. This reference set was
then limited to the following
terms: carcino? neoplas?
mutat? mutag? terato? DNA,
metaboli? or genet?. Only 358
references were cited. Examina-
tion of this set of references indi-
cated that only six derivatives
(for pyrazolidinedione) were
reported to be mutagenic. The
structures for these derivatives
are shown (Fig. 4).
In the course of this analysis, a
novel software program entitled
METABOLEXPERT (available
from CompuDrug USA, Inc.,
P.O. Box 202078, Austin, TX
78720) was examined to deter-
mine whether metabolic
sequences could be predicted
based on similar reactions
observed with structurally
related compounds. Preliminary
results are being examined with
this novel approach, and it repre-
sents a general technique that
may be useful in investigating
metabolic sequences. Ouchi and
Wipke (1978) used the program
to predict metabolites of xenobi-
otic compounds. As more infor-
mation is introduced into each of
these computer systems, the prob-
ability increases of predicting
metabolic transformation for a
4-(Piperidinomethyl)phenylbutazone RN = 74152-34-4
N - N
4-Hydroxymethylbutazolidine hemisuccinate RN = 27470-51-5
.Ph
n-Bu CH2OCO(CH2)2COOH
4-[(4-Methyl-l-piperazinyl)methyl]phenylbutazone RN = 27315-91-9
Ketophenylbutazone RN = 853-34-9
Ph Ph
^
H CH2CH2COCH3
Oxyphenylbutazone RN = 129-20-4
Ph
~N N
H n-Bu
1,2 DiphenyM-[2-(phenylsulfinyl)ethyl]-3,5-pyrazolidinedione RN = 57-96-5
H
Fig. 4. Mutagenic pyrazolidinedione substructures.
216 Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
candidate chemical. Such a sys-
tem would be highly useful to
the biochemist studying the phar-
maceutical or environmental
activity of compounds.
Summary
This preliminary examination of
CSA has demonstrated the
effective use of the Chemical
Abstracts compound connectiv-
ity file in conjunction with the
bibliographic file for relating
chemical structures to biological
activity. The importance of con-
sidering the role of metabolic
intermediates under a variety of
conditions was also illustrated,
suggesting structures that should
be examined that may exhibit
potential activity. This CSA tech-
nique, which utilizes existing
large files accessible with online
personal computers, is recom-
mended for use as another tool in
examining chemicals and drugs.
Acknowledgment
The author wishes to express
appreciation to the Chemical
Industry Institute of Toxicology
for support in the early stages of
mis study in evaluating the poten-
tial of CSA.
References
NIP, Technical Report Series Number
367 (March 1990).
Oucfai, GI. 1978, "Computer-Assisted
Prediction of Plausible Metabolites of
Xenobiotic Compounds." Dissertation at
University of California, Santa Cnrz-
Aceess/Use Info Resources Assess Health Risk Chem Expos '93 217
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Information Resources and the Correlation of
Response Patterns Between Biological End Points
Heinrich V. Mailing, National Institute of Environmental Health Sciences
and John S. Wassom, Oak Ridge National Laboratory
This paper focuses on the analysis of information for mutagenesis, a biological end point that is important in the overall process of
assessing possible adverse health effects from chemical exposure.
From 1966 until 1972, John
Wassom and I worked
together in the Biology
Division of the Oak Ridge
National Laboratory (ORNL). In
1968, at the request of the Envi-
ronmental Mutagen Society, we
started the Environmental
Mutagen Information Center
(EMIC) that you have heard
about during this meeting, espe-
cially at the poster session. Since
I left Oak Ridge in 1972, my
work has been such that I have
not been directly involved with
the problems associated with
information management and
use. This symposium has
brought me back to Oak Ridge
once again to talk and think
about these issues and has been a
pleasant homecoming for me.
In this short presentation, we
would like to focus on the analy-
sis of information on one spe-
cific biological end point that is
important in the overall process
of assessing possible adverse
health effects from chemical
exposure. This important end
point is mutagenesis. Many peo-
ple today use the broader term
"genetic toxicology" to describe
the research area that attempts to
identify agents that induce
genetic damage rather than
"mutagenesis," but in this paper
the old-fashioned term of
"mutagenesis" will be used.
During the last 20 years,
mutagenesis came to be known
as the 'little brother" of carcino-
genesis. This particular relation-
ship is especially true for the
field of risk assessment.
Mutagenesis has been mainly
used during the last two decades
as a diagnostic tool to predict the
carcinogenic potential of agents,
especially chemical agents. The
majority of these short-term
mutagenicity test systems have
come and gone as they have
fallen into disgrace and nonuse
as a result of data that indicate
the inability of these systems to
function as predictive tools for
identifying potential human car-
cinogenic agents. Scientists and
health administrators sometimes
get disillusioned when this hap-
pens because there is no quick
and easy means to identify such
hazards. We think, however, that
when the issue of employment of
mutagenicity assays to identify
potential carcinogenic agents is
put into historical perspective, it
takes some of the edge off the
disappointment.
This paper gives a brief histori-
cal overview of short-term
During the last 20 years, muta-
genesis came to be known as the
"little brother" of carcinogenesis.
Scientists and health administrators
sometimes get disillusioned because
there is no quick and easy means to
identify potential human
carcinogenic agents.
Access/Use Info Resources Assess Health Risk Chem Expos '93
219
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mutagenesis test systems and the
problems of (1) interpreting
information obtained from them
to correlate response patterns
among them and (2) comparing
these end points to other biologi-
cal end points such as carcino-
genesis. This historical perspec-
tive will be used to see where all
this may lead in the future.
Short-term mutagenesis test
systems come and go, as informa-
tion available from the EMIC
documents show. In John Was-
som's talk, the creation of EMIC
was correlated with high interest
in the field of mutation research
and the proliferation of assay sys-
tems developed for the purpose
of identifying agents that induce
genetic damage (Mailing and
Wassom 1977).
In 1968, John and I were asked
to serve on the Mrak Commis-
sion that was formed to evaluate
hazardous effects of pesticides.
The formation of this commis-
sion marked one of the first seri-
ous attempts to assess the
potential adverse health effects
of a specific group of chemical
agents. At that time, the need or
importance of including metabo-
lic activation as part of the
experimental protocol for in vitro
mutagenicity assays was not yet
appreciated (although it was
thought about) and the Ames/
Salmonella microsome test sys-
tem did not exist. Nevertheless,
hundreds of compounds were
being tested for genetic activity
in a variety of easy-to-use sys-
tems. Prevalent among these
early systems were two plant
assays, Allium cepa and Vicia
faba, that measure the ability of
test agents to induce chromo-
some aberrations in root dps.
These test systems were reason-
ably simple to do and were quick
and inexpensive.
Today, with the literature and
data compilation capabilities of
EMIC, it would be easy to sur-
vey the literature for data on the
mutagenicity of the pesticides
being reviewed by the Mrak
Commission. However, in the
summer of 1968, EMIC was not
in existence, so we found our-
selves working long hours in a
hotel room in New Jersey, read-
ing the papers that had taken us
so long to locate and copy for the
purpose of summarizing the
mutagenicity data on pesticides.
Most of the data we reviewed
were for pesticides evaluated in
either the Allium or Vicia test.
This large compendium was
assembled without the aid of a
computer. The tables that
resulted from this review and
evaluation effort served as the
principal component of the Mrak
Commission Report (1969). This
laborious data analysis project
led us to several conclusions.
First and most important of all, it
helped to solidify our thinking
about the importance of our
involvement in establishing an
information and data gathering
facility for the field of mutagene-
sis. EMIC was formally organ-
ized in 1969 at ORNL's Biology
Division to serve the area of
mutagenesis. Fortunately for the
field of mutation research, this
activity is still in operation today,
21 years later. Elizabeth Von
Halle presented a poster about
EMIC at this meeting. The Mrak
Commission report also made it
clear that the Allium and Vicia
tests did not distinguish between
the active or the inert ingredients
of pesticide mixtures. This reve-
lation contributed to the eventual
fall from grace of these two test
Short-term mutagenesis test
systems come and go.
This large compendium was
assembled without the aid of a
computer.
220 " Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
systems — which is somewhat
similar to what has happened in
more recent times with the
Ames/Salmonella microsome
system.
After the Allium and Vicia test
systems failed to meet expecta-
tions, many other assay systems
arrived on the scene; the most
notable of these new test systems
was the Ames/Salmonella
microsome assay (Kier et al.
1986).
With this system, researchers and
health administrators started to
correlate the mutagenicity and
carcinogenic activity of com-
pounds by simple qualitative
means by assigning each com-
pound either a "+," "-," or a
"+/-" to indicate its mutagenic
and carcinogenic activity.
A little more sophistication was
added to this type of comparative
compilation when the degree of
mutagenic activity for com-
pounds was indicated by assign-
ing them various numbers of
"+"s according to their muta-
genic potential. Needless to say,
such compilations produced a
highly subjective information
base. It was soon learned that
chemicals have different degrees
of mutagenic specificity, some
low and some very high. Even
with the Ames/Salmonella
microsome assay, investigators
were finding chemicals that
would induce quite a high level
of mutations in one of the five
standard test strains but not in
the others. This observation led
Dr. Bruce Ames, who developed
this popular and widely used test
system, to make the statement
that carcinogens are frameshift
mutations. This same specificity
was noted in other mutagenesis
assays and prompted other work-
ers to make similar observations,
including my own statement that
carcinogens mainly induce base-
pair substitution mutations that
result in the production of
changed but functional proteins
(Mailing and de Serres 1969).
Today, we know that both of
these statements are still valid as
examples of possible types of
genetic events or mechanisms
that may lead to the initiation of
the carcinogenic process but they
are not exclusive. There are
many other mutagenic events
that could be causative factors in
the initiation and development of
neoplastic growth. As a result of
further research on the question
of whether all mutagens are car-
cinogens, it was discovered that
some carcinogens were not
mutagenic at all. Even though
this came as a surprise and disap-
pointment to some, it is some-
thing that should have been
expected (Mailing and Chu
1974).
Why did we choose to use the
simple method of using "+"s and
"-"s to analyze data when we
knew this method was limiting
and when it was clear that we
were not using all the available
data? This was done because it
was the only approach we knew
that could be easily used with the
information systems available at
that time.
In 1979,10 years after the forma-
tion of EMIC, a program sup-
ported by the U.S. Environ-
mental Protection Agency was
initiated that helped revolution-
ize our thinking about the useful-
ness of short-term mutagenicity
test systems to predict carcino-
genesis and to identify agents
capable of inducing heritable
genetic damage. This program
Researchers and health administra-
tors started to correlate the
mutagenicity and carcinogenic
activity of compounds by simple
qualitative means.
There are many other mutagenic
events that could be causative
factors in the initiation and
development of neoplastic growth.
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221
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came to be known as the Gene-
Tox Program, or Gene-Tox for
short, and this activity is ongoing
(Waters 1979; Green and Auletta
1980; Waters and Auletta 1981;
Ray et al. 1987). The extensive
data collection and review effort
of Gene-Tox provides a unique
resource of peer-reviewed
genetic toxicology test data on
over 4600 chemicals evaluated in
one or more of 73 short-term bio-
assays. These data can be util-
ized as a primary source of
data/information for more
in-depth analysis and review
studies.
Out of the Gene-Tox Program
came the idea of combining the
"+"s and "-"s from different
mutagenicity test systems to see
what combinations correlated
best with the carcinogenicity of a
compound. This type of data
analysis became rather convo-
luted, but something positive
came out of it. It was found that
by combining data from the
Ames/'Salmonella microsome
assay and from the rodent micro-
nucleus test, one could obtain the
best battery for predicting car-
cinogenicity. Without Gene-Tox,
such an observation would not
have been possible.
During the last few years, several
techniques have been proposed
to aid in the review and analysis
of biological test results. One
such method was suggested by
Dr. David Brusick (Brusick
1987), and Committee 1 of the
International Commission for
Protection against Environmental
Mutagens and Carcinogens
(ICPEMC) (Lohman et al. 1990).
The thinking behind this pro-
posed technique was that if each
chemical under study was given
an activity number that takes into
consideration the different tests
that have been performed with
that chemical, then data analysis
would be made easier and more
systematic. It has been proposed
that this activity number may be
related to carcinogenic potency
(Nesnow 1990).
Another of the techniques pro-
posed in the quest to obtain
usable methods to enhance our
ability to review and analyze
data was developed by Waters
and colleagues (Garrett et al.
1984,1986; Waters et al. 1988a).
This technique is called the
graphical activity profile (GAP)
method and provides a visual por-
trait of the genetic activity for a
given chemical as a function of
dose (Waters et al. 1988b). Dr.
Michael Waters presented a
paper on this method and "hands-
on" experience with the GAP
computer program was available
during the poster session of this
symposium. The graphical plot-
ting of the lowest effective dose
for each chemical with a positive
response and the highest ineffec-
tive dose for chemicals with a
negative response provides an
easy means to depict test data
individually for each test system.
In this technique, there is no
attempt to combine data from
various test systems. In other
words, this method does not mix
apples and oranges. This system
has one important feature—the
data points used in plotting a
chemical's activity profile is
selected from a set of references
obtained from the published lit-
erature, and these references are
linked to the GAP data in an
accompanying information file.
This means that if the lowest
effective dose used to generate
the data point on the graph is
questioned or if use of the initial
In 1979, a program was initiated that
helped revolutionize our thinking
about the usefulness of short-term
mutagenicity test systems.
Several techniques have been
proposed to aid in the review and
analysis of biological test results.
Access/Use Info Resources Assess Health Risk Chem Expos '93
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genotoxic rate per concentration
unit is preferred, the original pub-
lication cited in the associated
information file can be consulted
and modifications made as
necessary.
The mutagenicity of a chemical,
as pointed out earlier, is some-
times used as an indicator for car-
cinogenicity, and one of the best
ways to describe the mutagenic-
ity of a chemical is through use
of a pattern or profile that depicts
the response of the chemical in
various test systems. If a parallel
system existed for carcinogene-
sis, we would not have to rely on
"+" or "-" to analyze carcino-
genicity data; we would be able
to consider and think more
intently about the patterns
observed in the data. Some car-
cinogens have shown an increase
in the incidence of tumors above
the spontaneous level in one tis-
sue, while at the same time show-
ing a lower than spontaneous
yield in another tissue or body
site of the same animal. This fea-
ture is clearly evident in the car-
cinogenicity test data amassed by
the National Toxicology Pro-
gram (NTP). The NTP has rules
for handling cases of this type in
order to arrive at a "+" or "-" for
the chemical being tested. If the
technique to generate graphical
activity profiles from carcino-
genesis data were available to
analyze the NTP data, it would
not be necessary to have such
rules when working with patterns
or profiles. If we had the capabil-
ity of generating such patterns of
response for chemicals evaluated
for carcinogenicity, ,we would be
able to explore such questions as
1. What type of tumors were
induced by these chemicals?
2. In what animals/strain/sex?
3. At what doses?
4. At what body site, etc.?
With this information we could
also link carcinogenicity data
with mutagenicity data that
could be used to answer ques-
tions such as, What features and
conditions characterize nongeno-
toxic carcinogens? and Which of
these may trigger carcinogenic
activity? Having answers to
these questions could provide us
the basis to formulate a workable
carcinogenesis model.
With such a combined database,
other questions could also be
more adroitly pursued. Are there
correlations between tumori-
genic specificity with respect to
strain, species, tissue, etc.? Are
there correlations between the
types of induced tumors and the
pattern or mutagenicity for a spe-
cific chemical or class of chemi-
cals?
One of the greatest challenges,
with respect to making maxi-
mum use of the current informa-
tion and data, is to have available
the kind of data analysis tools
that will allow the development
of meaningful risk assessments.
Currently, the GAP technique is
one such tool that merits serious
consideration for application to
most areas of toxicology where
the adverse effects of a chemical
or class of chemicals are being
reviewed and evaluated. It has
been pleasing to learn at this
symposium (in the poster by
Elizabeth T. Owens et al.) about
the application of the GAP meth-
odology to the analysis of
response patterns obtained with
chemicals evaluated for the
induction of developmental
and/or reproductive toxicology
end points. The initial results
One of the best ways to describe the
mutagenicity of a chemical is
through use of a pattern or profile
that depicts the response of the
chemical in various test systems.
One of the greatest challenges is to
have available the land of data
analysis tools that will allow the
development of meaningful risk
assessments.
Access/Use Info Resources Assess Health Risk Chem Expos '93
223
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from these studies are published
in the journal Teratology
(Kavlock et al. 1991).
As we look to the challenges of
the future, more information will
be generated and developed
regarding the adverse health
effects of chemicals. Toxicity
data and other information from
many different types of biologi-
cal systems will become avail-
able including the accumulation
of human health data. If we are
going to make proper use of this
data/information, then proce-
dures that allow us to correlate
biological activity patterns with
human health protection must
become a standard part of the
risk assessment process. With
such a capability, we may be able
to learn much more about the ani-
mal models we are using and
their applicability in human haz-
ard assessment. The capability to
study patterns in biological test
data through, for example, a pro-
file correlation system will give
us the ability to investigate the
exceptions that may be found in
the data. In so doing, we will be
able to focus on the more crucial
experiments needed to determine
the validity of a particular model
before a lot of time and money
are spent. Such capabilities can
also be applied to increasing our
knowledge of the underlying
processes or causative factors
responsible for initiating a spe-
cific type of toxicological event.
References
Brusick, D. J. 1987. Principles of
Genetic Toxicology, Plenum Press, New
York, 284 pp.
Garrett, N. E., H. F. Stack, M. R.
Gross, and M. D. Waters. 1984. An
analysis of the spectra of genetic activity
produced by known or suspected human
carcinogens. Mutat. Res. 134:89-111.
Garrett, N. E., H. F. Stack, and M. D.
Waters. 1986. Evaluation of the genetic
activity profiles of 65 pesticides. Mutat.
Res. 168:301-25.
Green, S., and A. Auletta. 1980. Edito-
rial introduction to the reports of the
Gene-Tox Program. An evaluation of
bioassays in genetic toxicology. Mutat.
Res. 76:165-68.
Kavlock, R. J., J. A. Greene, G. L.
Kimmel, R. E. Morrissey, E. T. Owens,
J. M. Rogers, T. W. Sadler, H. F. Stack,
M. D. Waters, and F. Welsch. 1991.
Activity profiles of developmental toxic-
ity: Design considerations and pilot
implementation. Teratology 43:159-85.
Kier, L. D., D. J. Brusick, A. E.
Auletta, E. S. Von Halle, M. M. Brown,
V. F. Simmons, V. Dunkel, J. McCann,
K. Mortelmans, M. Prival, T. K. Rao,
and V. A. Ray. 1986. The Salmonella
typhimuriumJmammalian microsome
mutagenicity assay. A report of the U.S.
Environmental Protection Agency Gene-
Tox Program. Mutat. Res. 168:69-140.
Lohman, P. H. M., M. L. Mendelsohn,
D. H. Moore E, M. D. Waters, and D. J.
Brusick. 1990. The assembly and analy-
sis of short-term genotoxicity test data—
An ICPEMC Committee 1 working
paper, pp. 283-94. In: Mutation and
Environment, Part D, Carcinogenesis,
Vol. 340 D, Progress in Clinical and Bio-
logical Research, Proceedings of the
Fifth International Conference on Envi-
ronmental Mutagens, Cleveland, Ohio.
July 1989, Wiley-Liss, New York.
Mailing, H. V, and Chu, E. H. Y.
1974. Development of mutational model
systems for study of carcinogenesis. pp.
545-63. In: Proceedings of the First
World Symposium on Model Studies in
Chemical Carcinogenesis, Baltimore,
Maryland, Marcell Dekker, Inc., New
York.
Mailing, H. V, and F. J. de Serres.
1969. Mutagenicity of alkylating car-
cinogens. Ann. N. Y. Acad. Sci. 163:788-
800.
Mailing, H. V, and J. S. Wassom.
1977. Action of mutagenic agents, pp 99-
152. In: Handbook of Teratology, Vol. 1,
Chapter 4, Plenum Press, New York.
Mrak Commission Report, U.S.
Department of Health, Education and
Welfare, December 1969, 677 pp.
Nesnow, S. 1990. A multi-factor rank-
ing scheme for comparing the carcino-
genic activity of chemicals. International
Commission for Protection Against
Environmental Mutagens and Carcino-
gens, ICPEMC Working Paper 1/2. Mu-
tat. Res. 239:83-115.
Ray, V. A., L. D. Kier, K. L. Kannan,
R. T. Haas, A. E. Auletta, J. S. Wassom,
The capability to study patterns in
biological test data through, for
example, a profile correlation
system will give us the ability to
investigate the exceptions that may
be found in the data.
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S. Nesnow, and M, D. Waters. 1987. An
approach to identifying specialized bat-
teries of bioassays for specific classes of
chemicals: Class analysis using
mutagenicity and carcinogenicity rela-
tionships and phylogenetic concordance
and discordance patterns. 1. Composi-
tion and analysis of the overall data
base. A Report of Phase n of the U.S.
Environmental Protection Agency Gene-
Tax Program. Mutat. Res. 185:197-241.
Waters, M. D. 1979. The Gene-Tax
Program, pp. 161-64. In: A. N. Hsie, J.
P. O'Neill, and V. K. McHheny (eds.),
Banbury Report 2, Cold Spring Harbor
Laboratory Press, Cold Spring Harbor,
N.Y.
Waters, M. D., and A. Auletta. 1981.
The Gene-Tox Program: genetic activity
evaluation. J. Chem. Inf. Compu. Sci.
(ACS) 21:35-38.
Waters, M. D. H. F. Stack, J. R. Robi-
nowitz, and N. E parrett 1988a.
Genetic activity profiles and pattern rec-
ognition in test battery selection, Mutat.
Res, 205:119-38.
Waters, M. D,, H. F. Stack, A. L.
Brady, P. H. M. Lohman, L, Haroun, and
H. Wnio. 1988b. Use of computerized
data listing and activity profiles of
genetic and relation effects in the review
of 195 compounds. Mutat Res. 205:295-
312.
Access/Use Info Resources Assess Health Risk Chem Expos *93
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Information Resources for Assessing Health
Effects From Chemical Exposure: Challenges,
Priorities, and Future Issues
Sidney Siegel, National Library of Medicine
Issues related to developing information resources for assessing the health effects from chemical exposure include the question of
how to address the individual political issues relevant to identifying and determining the timeliness, scientific credibility, and
completeness of such kinds of information resources. One of the important ways for agencies to share information is through
connection tables. This type of software is presently being used to build information products for some DHHS agencies. One of the
challenges will be to convince vendors of data of the importance of trying to make data files available to communities that need
them. In the future, information processing will be conducted with neural networks, object-oriented database management systems,
and fuzzy-set technologies, and meta analysis techniques.
Over the 100 years that
Quantitative Structure-
Activity Relationships
(QSARs) has been evolving, it
has taken interesting shapes,
forms, and directions. I would
like to update your knowledge in
this area so that you can consider
when to apply these decision sup-
port methods and identify for
you some information resources
currently or soon to be in devel-
opment. Two such resources are
now being developed. One is a
Directory of Risk Assessment
Projects—sponsored or con-
ducted by Department of Health
and Human Services (DHHS)
Agencies. Once this directory is
up and running, it will be coordi-
nated with an EPA-sponsored
risk assessment compilation
project
The other project is an inventory
of exposure-related data systems
sponsored by federal agencies
that will encompass the entire
federal establishment and go as
possible into state health and
environment agencies. The chal-
lenge in putting such directories
together is not limited by com-
puter technology but the ability
to address the individual political
issues relevant to identifying and
determining the timeliness, scien-
tific credibility, and complete-
ness (and thus, the usefulness for
decision making) of information
carried by such resources. In the
not distant future we hope to pre-
sent to the Committee to Coordi-
nate Environmental Health and
Related Programs (CCEHRP)
Council a concept for the devel-
opment and deployment of a
directory of epidemiology
research projects supported by
DHHS. CCEHRP is under the
DHHS Assistant Secretary.
Over the years, tens of millions
of dollars have gone into
epidemiology studies that have
"slipped through the cracks" and
thus, their usefulness is impossi-
ble to determine. Directories
make it possible to share this
information across the federal
establishment and into the pri-
vate sector. Appropriately struc-
tured, maintained and deployed
Two resources are now in
development: one is a Directory of
Risk Assessment Projects, the other
is a Directory of Exposure
Information Resources.
Over the years tens of millions of
dollars have gone into epidemiology
studies that have ' 'slipped through
the cracks.''
Access/Use Info Resources Assess Health Risk Chem Expos '93
227
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directories will reduce duplica-
tion of such efforts.
We are all burdened with the
necessity to handle the flow of
huge amounts of data and infor-
mation that come through our
organizations because of our
regulatory or scientific functions.
One federal agency that I have
been involved with over the last
2 years has been the Agency for
Toxic Substances and Disease
Registry (ATSDR). I first went
to help them address their docu-
ment and information manage-
ment problems—one govern-
ment person helping another gov-
ernment agency. At that time
there was storage trailer after
storage trailer of paper that had
been generated that was relevant
to the human health assessments
done by ATSDR around National
Priorities List (NPL) waste sites.
I asked a simple question,
"What's your disaster recovery
procedure, if this stuff is
destroyed?" The response was,
"We don't have any." What I
would like to describe briefly is
an imaging system that they have
since put into place, of which I
will emphasize one component.
The imaging system can effi-
ciently and effectively capture all
ATSDR relevant information
onto optical disk through use of
laser scanning technology —no
matter what kind of paper it is
on, no matter what the font. The
available optical disk capture
technology makes this easy. The
special feature of this module of
their HAZDAT system is that it
contains font independent soft-
ware that allows any frame on
the optical disk to be selected
and translated into the machine
format required by most word
processing software packages.
Right now there is a significant
cost for the software modules
that comprise the ATSDR imag-
ing system. But the capabilities
are intriguing, they advance the
state-of-the-art, and should be
studied for their potential useful-
ness to other organizations.
I would like to give you some
history related to what we have
been dancing around over the
last couple of days—the ability
to accomplish structure or sub-
structure searches. Before Bill
Farland was at EPA, Linda and
some of the participants here for
this symposium were at EPA. At
that time we had some interest-
ing negotiations and dialogue
with Chemical Abstracts Service
(CAS) concerning federal use of
CAS information files and the
CAS connection tables. At one
meeting which was getting no
where, one of us at the table, to
break the impasse, turned to Dale
Baker, the head of CAS, and
said, "What we should seriously
consider doing is nationalizing
the CAS Registry system". Well,
you should have seen the look on
his face; it was interesting. Not
long after that Marilyn Bracken,
the Deputy General Council of
EPA, and I ended up in the con-
gressional office of a repre-
sentative of the state of Ohio and
were asked to explain why we
were trying to destroy a particu-
lar organization in Columbus,
Ohio. The remainder of that
exchange was interesting. At that
time we were not able to make
use of CAS connection tables in
any cost-effective way. Now the
world has moved on and some
elegant, standardized software is
available that can build connec-
tion tables which are not CAS
dependent. Technically, many of
us are now going in this direc-
tion. The use of connection
The imaging system can efficiently
and effectively capture information
from documents relevant to ATSDR.
Such systems are intriguing,
advance the state-of-the-art, and
should be studied for their potential
usefulness.
228 Access/Use Info Resources Assess Health Risk Chem Expos '93
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tables descriptive of chemical
structures will be one important
way for us to share information
across federal, state, and private
sector organizations as means to
more precisely identify data use-
ful in decision making . We are
now using this type of software
to build information products for
some of the DHHS agencies. I
think that is going to be an
increasingly important means of
management support for many of
us.
I have also mentioned over the
last few days my interest in
numeric files that can be derived
from toxicologic experimenta-
tion. If anything is going to
increase the efficient and effec-
tive accomplishment of the
assessment or management of
risk it will be the capability to
efficiently identify relevant num-
bers which are derived from
standardized toxicity evaluation
procedures—numbers on which
reasonable bounds can be placed
as to their timeliness and credibil-
ity. Experiments have been done
that show that building such files
is simply a production-line prob-
lem. The challenge will be to
convince vendors of information
of the importance of making this
kind of data file available to com-
munities that heed it. Once num-
bers are available, it is possible
to begin to identify and under-
stand the use of various kinds of
models applicable to analysis of
the data. In the past we haven't
had the capability to identify and
exchange models relevant to
addressing various scientific
problems or to develop forums to
help us better understand the use-
fulness of a model, including
bounding interpretation of results
derived from application of the
model. These approaches are pos-
sible now. Some of the things
that we heard about joint ven-
tures with the private sector
should be seriously considered.
These approaches are important
because the application of mod-
els to actual human and environ-
mental health problems will be a
significant part of the decision-
making efforts in the future.
There is no need to go in and
reinvent the infamous wheel. As
a matter of fact, one of the Greek
philosophers several thousand
years ago said, 'If we do not
make use of the information of
past ages, the world will remain
in infancy." There is no need to
remain in infancy now, because
we have the technical capability
to share information and to study
the data of other investigators. In
the past, decision-making has
made heavy use of what is called
delphitic techniques. In this
approach, a group of experts sit
around a table and hassle each
other to arrive at a consensus
decision that is reasonable. Too
often, the decision may be based
on the strength of personalities
within the group rather than on
relevant data. We would like to
get you interested in helping us
evolve machine-readable files
relevant to the "mechanism of
action" of chemical agents in bio-
logical systems and to biological
markers which indicate effects
that may be induced or super-
seded by exogenous agents. We
need to show how these files of
data, and information relate to
one other and efficiently and
effectively support decision mak-
ing. At the poster sessions you
saw the application of computer-
based technology called expert
systems. Expert systems are just
the very first blush of what will
be coming. Here, you saw vari-
If anything is going to increase the
efficient and effective accomplish-
ment of risk assessment, it will be
the capability to arrive at relevant
numbers, numbers on which
reasonable bounds can be placed as
to their timeliness and credibility.
Joint ventures with the private sector
should be seriously considered.
These approaches are important
because the application of models to
actual human and environmental
health problems will be a significant
pan of the decision making process
in the future.
Access/Use Info Resources Assess Health Risk Chem Expos '93
229
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ous versions of relational data
base management systems,
including Hypertext In the not
distant future, we will be able to
apply information processing
means called "neural network-
ing" and"object-oriented
DBMS," "fuzzy-set" technolo-
gies, and "meta analysis tech-
niques." The ability to sort the
information and to talk about the
probability of what the results
will mean will be dependent on
the scientific expertise that is, in
part, here in this room. The
future is within our grasp. Let's
not get bogged down in a seman-
tic swamp. Instead, let's talk
about which way to go from
here.
Let's not get bogged down in a
semantic swamp.
230 Access/Use Info Resources Assess Health Risk Chem Expos '93
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Concluding Remarks: Where Do We Go From
Here?
William H. Farland, U.S. Environmental Protection Agency
Where do we go from here in terms of access and use of information resources in assessing health risks from chemical exposure? We
will need to look at new applications of relevant information available to programs at the federal, regional, and state levels and try
to develop additional hands-on tools that will allow all of us to do our jobs. The application of available information to program
decision-making and to risk management is one of the most important things that confronts us.
These concluding remarks
will address the question,
'Where do we go from
here in terms of access and use
of information resources in
assessing health risks from
chemical exposure?" We have
dealt with this topic for the past
two and a half days. First, we
learned that, because science and
risk assessment are evolving, we
need to look toward the future.
We will need to look at new
applications of the relevant infor-
mation available to programs at
the federal, regional, and state
levels and try to develop impor-
tant additional hands-on tools
that will allow all of us to do.our
jobs. The application of available
information to program decision-
making and to risk management
is one of the most important
things that confronts us. To a cer-
tain extent, we have a perspec-
tive based on what we have
learned from this meeting, a per-
spective that suggests we must
proceed. Before we proceed,
however, there are a few ques-
tions that must be asked. One of
these is, "Where doy we go from
here?" We have talked about
where 'here' is over the last few
days, but I want to give you my
personal perspective of where
'here' is.
Characterizing the state of the
field in information sciences is
not simple; it's an issue that we
face all the time. We have a tre-
mendous amount of information,
we have the scientific commu-
nity with which to interact, we
have the regulatory decision-
making process, and we have the
public with whom we have to
communicate our decisions and
policies. We have to let them
know what information we have,
what information we don't have,
and the way that we have taken
information availability into
account in Our decision-making
process. We have to deal with the
challenges, the priorities, and the
future issues regarding informa-
tion access and use.
With regard to priorities, one
thing I think is most important,
which we heard discussed in
detail yesterday, is the impor-
tance of the timeliness of the
data. How are we going to be
able to keep up with the informa-
tion that is being generated out
there in the scientific commu-
nity, and how are we going to get
it into a form that we can use?
What kinds of time sensitivities
We have to let them know what
information we have, what
information we don't have, and the
way that we have taken information
availability into account in our
decision-making process.
Importance of the timeliness of the
data.
Access/Use Info Resources Assess Health Risk Chem Expos '93
231
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are we going to build into the
databases so that we make use of
the most current information?
Use of the most current informa-
tion in our decision-making proc-
ess is the only way we are going
to get the scientific community
to stand behind us or support our
decisions. What are some of the
priorities and priority-setting
mechanisms we might use to
determine the type of informa-
tion that ought to be evaluated
and included in databases? This
whole issue of timeliness and
quality of information is an
extremely important priority for
us in terms of the future.
Speed and ease of access to infor-
mation has been characterized
over the course of this sympo-
sium: user friendliness and
advances in hardware and soft-
ware to facilitate dealing with the
quality and quantity of informa-
tion. One of the things that I am
often told by people in the field
is that they would like to see
improvements in the portability
of information systems. In other
words, they would like to be able
to have the information system
accessible to them in the field or
on-site via portable hardware.
These perspectives are going to
be extremely important as we
begin to deal with access and use
of information in the future.
In the most recent sessions, we
have talked about enhanced ana-
lytical capabilities and the impor-
tance of combining these capabi-
lities in new ways to evaluate the
patterns that might emerge once
we have adequately looked at
particular topics of interest. We
must also be looking to use such
an approach to supplement our
evaluations of chemicals or other
agents for which a tremendous
amount of information is not
available at this point
Another important question with
regard to analytic capability is
how should we actually express
and understand uncertainty in the
work we do? How can we evalu-
ate databases to understand the
uncertainty inherent in specific
decisions?
During this symposium, we have
heard about different approaches
to risk assessment that included
looking at new biological end
points. The fields of neurotoxi-
cology, immunotoxicology, and
ecological effects, in general, are
going to be areas we will have to
include in the risk assessment
process. To do this, we are going
to have to develop new databases
or new approaches to databases.
In addition, we are looking
toward various ways to quantify
our risk assessments both in
these new areas as well as in
some of the older areas. New
approaches for quantifying data
will be needed, and the useful-
ness and acceptance of these
approaches will depend on being
able to go back to the original
data and evaluate the impact of
the newer approaches and com-
pare them with current
approaches.
Will the new approaches facili-
tate improved risk assessment?
Will concepts such as reference
doses or plausible upper bounds
on risks still be used? Will the
information make better or best
estimates of risk possible in the
future? What will the output of
these approaches to these assess-
ments look like? These questions
are particularly important to con-
sider in both the short and long
term in regard to the access and
We must develop enhanced analytical
capabilities and combine these
capabilities in new ways to evaluate
the patterns that might emerge once
we have adequately looked at
particular topics of interest.
The fields of neurotoxicology,
immunotoxicology, and ecological
effects, in general, are going to be
areas we will have to include in the
risk assessment process.
232 Access/Use Info Resources Assess Health Risk Chem Expos '93
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use of information in the risk
assessment process.
The advances being made in sci-
ence create a challenge for the
future. We have enough trouble
dealing with information as it
comes out today. The new and
different types of scientific infor-
mation being produced very
often don't fit our current risk
assessment paradigms nor do
they necessarily fit our current
approaches to database manage-
ment or development. Scientific
advances are to some extent
driven by the better and more
efficient use of the available
information and through develop-
ment of better risk assessment
models, but the new information
that results often increases the
uncertainties of these assess-
ments and models.
Clearly, the expanding informa-
tion bases are going to be impor-
tant. John Wassom spoke about
the trends in scientific publica-
tions that should be taken into
account. For example, in the
genetic toxicology literature the
frequency of publications peaks
in the mid-1980s and then drops
off. How should such a trend be
considered in making decisions
about what information to use to
build databases, and how should
such trends be tracked? What
journals should be included in
databases? What information
should be looked at, and how are
limitations in our information
systems to be explained to users
once these kinds of decisions
have been made? Although we
don't often access the European
information base, it may be use-
ful to do so as we evaluate data
and the expanded databases
available.
In looking at such systems as the
Integrated Risk Information
System (IRIS), the Chemical
Unit Record Estimates (CURE)
database, and other systems that
have been available during this
symposium, it is evident that
some critical decisions are
needed regarding what kinds of
information would be most use-
ful. How much is enough? What
amount of information is perti-
nent to users, and what amount
overloads systems to such an
extent that people will not use
them simply because there is too
much material for them to read
or too much analysis left for
them to do? As information
specialists, we must deal with the
expanding information base and
the level of sophistication neces-
sary to make the system an effec-
tive tool. This question pertains
both to the level of the tools and
the transfer of the resultant prod-
ucts. This is technology transfer
as it relates to training in infor-
mation management, in risk
assessment, and in concepts of
risk communication—some of
the things discussed here over
the last few days.
This type of meeting provides a
rare forum for discussion. The
ability to talk with others and
share experiences is useful. How-
ever, symposia end. We need to
find ways to share the experience
among an increasingly sophisti-
cated user group. For example,
we need to avoid reinventing the
wheel on site-specific assess-
ments. Even though these activi-
ties are 'site-specific' and should
be carried out by local agencies,
a tremendous amount of informa-
tion is contained in those site-
specific assessments, and many
of the elements have broader
application. How do we get this
Critical decisions are needed
regarding what kinds of information
would be most useful How much is
enough?
'We need to find ways to share the
experience among an increasingly
sophisticated user group.
Access/Use Info Resources Assess Health Risk Chem Expos '93 233
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type of information out? The
issue here is not only communi-
cation to the scientific commu-
nity, which is experienced to
some extent with our databases,
but also how these databases can
be used in dealing with the
public.
One of the things that came up in
Linda Tuxen's talk was the fact
that EPA had initially made a
conscious decision to develop
IRIS as an internal database so
that the agency could better inter-
act with the external community.
As the agency has been
extended, stretching its limits by
decentralizing risk assessment
and providing more information
to the public, these tools also had
to be extended. However, the
tools were not designed to pro-
vide information that is ready to
be handed directly over to the
public; the current tools would
be confusing to the public and, in
a lot of cases would be, if not dis-
couraging, perhaps misleading to
the public. It is important, then,
to understand how to use these
tools and how to communicate
better, not only with the scien-
tific community, but also with
the public—not giving the half-
answers that they often hear
about what risk assessment can
do. We need to be more skilled in
dealing with the available infor-
mation and somehow move
toward an understanding of the
uncertainties in the information
so that we can deal with the pub-
lic in a really straightforward
manner about the risks or
hazards that might be identified
from the available information.
Again, this is a real challenge.
We have talked about the con-
cept of the feedback between the
risk assessment process and the
research in the information man-
agement community. Such feed-
back helps information managers
to determine what needs to be
done in terms of research, data
collection, or data management
to support the risk assessment
process. This will continue to be
an issue in the future. The ques-
tion on this particular issue is,
"From whom do we take our sig-
nals?" How do we determine the
critical data needs? How do we
factor what we have heard from
our state and federal colleagues
here? How do we identify those
critical data needs and bring
them to bear in terms of informa-
tion management and then, even-
tually, risk assessment?
The end of our panel discussion
led very nicely into this discus-
sion of changing technology
because one of the things that I
wanted to mention was the opti-
cal disk, or CD-ROM, approach
to management of information.
We are looking at this within my
own program in a number of
areas—in some cases just to
make our own documents more
readily available to us. Currently,
many of the exposure assess-
ments that have been done over
the years in the Exposure Assess-
ment Group are being captured
on CD-ROM. This technology
will be extremely useful in terms
of accessing that information and
providing it to people to use as
an exposure-assessment library.
We hope that we will be able to
do that with more of our docu-
ments. In addition to that, we
have talked about putting the
IRIS system on this type of a
database along with other types
of information that could be used
as a companion to IRIS (e.g., risk
assessment guidelines when they
come out and risk communica-
How do we identify those critical data
needs and bring them to bear in terms
of information management and then
risk assessment?
The optical disk, or CD-ROM,
approach to management of
information is being developed.
234 Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
tion information). These things
will be very useful to us in terms
of disseminating information and
making the information more
usable to decision makers. In
addition to this, a real advance
has been demonstrated at this
meeting with regard to changing
technology, in terms of both soft-
ware and hardware for data man-
agement However, just about
the time we get comfortable with
one system, someone comes
along with a new and better one.
The systems we are using now
will be outmoded or obsolete in
the future. Somehow, we have to
plan for this evolution as we pro-
ject future data management and
use.
Leveraged funding is extremely
important. We must spread the
burden of support for the types
of things that we have been talk-
ing about—access and use of
information, experience, etc.—
over as broad a base as we can.
This means that we have to look
at new ways of leveraging. We
have to look at experienced
information/research centers and
determine how we can generate
the necessary revenue to keep
them going. We don't want to
lose the databases that have been
developed over time simply
because the newness has worn
off. We have to be in a position
to use the types of tools that you
heard about this morning. The
Federal Technology Transfer Act
(FTTA) initiative has provided a
good opportunity for us to think
about some new ways to lever-
age funding. In my own pro-
gram, we have had an oppor-
tunity to address this with regard
to information collection; if we
can build a strong enough case in
information management and
use, we will also be able to bring
in some of this funding. In the
next few days, we will be talking
with our senior agency officials
about a Chemical Manufactures
Association initiative to deter-
mine what role industry might
have in both supporting and help-
ing us with the critical review of
some of the information that
goes into the IRIS system. This
represents an extension of and in-
creased participation by the user
community, which is recognizing
the value of these types of tools.
We hope that over time this will
lead to funding.
The final issue, in terms of the
future, is public perception. The
public perception issue is not just
one of public perception of risk
assessment, but public percep-
tion of the scientific community
and its ability to deal with the
current problems that are facing
the public. This is important in
terms of our ability (1) to reach
consensus on issues and dissemi-
nate information that is particu-
larly useful to the communities
that need to make hard decisions
with regard to the public and (2)
to instill some confidence in the
public that the information that
they use is the best that's avail-
able (i.e., information that will
be widely supported by scien-
tists). One of the most discourag-
ing things that can happen in
terms of public perception is
when the public hears divergent
opinion about a risk issue. A sci-
entist from the EPA, for instance,
makes a statement about a par-
ticular, issue, and then the public '
hears another well-respected sci-
entist taking a very different posi-
tion on the issue and the public
just doesn't understand who to
believe. How do we go about try-
ing to get consensus positions
developed? Although I am not
We must spread the burden of
support over a broader base by
looking at some new ways to
leverage funding.
The public perception issue is not one
of just public perception of risk
assessment, but public perception of
the scientific community and its ability
to deal with problems facing the
public.
Access/Use Info Resources Assess Health Risk Chem Expos '93
235
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particularly afraid of getting con-
sensus around a position that
may not be absolutely the best or
absolutely right, I am concerned
that we don't stifle information
by just trying to present a unified
approach to the public. That is
something that we need to look
at in the terms of future issues.
The question of whether or not
we can continue to make pro-
gress in this field will depend on
public perception of our ability
to use the information that they
have paid for and to make the
right kinds of decisions with
regard to risks. If we lose the
public confidence with regard to
either of those two points, we are
going to lose the potential of hav-
ing risk assessment be a driving
force in decisions. Decisions will
be made for other reasons—as,
for instance, some of the congres-
sional initiatives that have been
developed. It is a real fear for us
in terms of the future, but it is
something that we can deal with.
These are some of my personal
thoughts with regard to some of
the priorities and challenges and
future issues I see with respect to
information use and access. I per-
sonally have found this meeting
to be extremely beneficial; I
think that most of the people
who have talked with me over
the last couple of days have also
found it useful.
I would like to take just a
moment to thank the Organizing
Committee again for putting this
meeting together, particularly the
Biomedical and Environmental
Information Analysis Section
staff at the Oak Ridge National
Laboratory who worked so hard
to make this meeting a success.
In addition, I think it is important
for us to recognize the people
who manned the posters and the
demonstration sessions, because
I believe that these were some of
the most important parts of this
meeting. These sessions gave us
the opportunity to try some new
things and do some hands-on
work. I do not want to leave out
the speakers and the other partici-
pants for their efforts in making
the symposium a success. As you
no doubt hear from my remarks,
the answer to the question,
"Where do we go from here,"
will depend on you.
The question of whether or not we
can continue to make progress in
this field will depend on public
perception of our ability to use the
information that they have paid for
and to make the right kinds of
decisions with regard to risks.
236 Access/Use Info Resources Assess Health Risk Chem Expos '
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APPENDIX
Abstracts
of
Poster Presentations
and
Demonstrations
-------
Biomedical and Environmental Information
Analysis Section: Computing Resources
Sherry C. Campbell, Roswitha T. Haas, Donald G. Kilgore, and Kathy C. Miller,
Oak Ridge National Laboratory
The Biomedical and Environmental Information Analysis (BEIA) Section has a wide variety of
resources available for its computing tasks. The section owns several processors which are net-
worked on a Local Area Vax Cluster. These machines include a VAX 3500, a VAX 3100, a
MicroVAX II, and a VAX 11/785. The in-house software includes ORACLE and BASISplus database man-
agement systems (DBMS) and FOCUS, a fourth-generation programming language. Additionally, BEIA
relies heavily on PCs and has developed applications that use spreadsheets, database managers, expert sys-
tem shells, desktop publishing software, CAD/CAM software, and computer graphics software. The BEIA
resources are also linked to the central Martin Marietta Energy Systems, Inc., computing resources, which
include a whole gamut of processors currently available from high-end VAXs to IBM mainframes to the
Cray supercomputer. Plans are also being developed for obtaining a massively parallel processor for use in
developing applications in the area of large full-text database processing. The software available on these
resources, which can be used primarily for information technology problems, includes DBMSs such as DB2,
INQUIRE, ENTERPRISE, and SYSTEM 1032.
Application of Expert System Shells to the Areas
of Health, Safety, and Environmental
Accountability
Kathy C. Miller, Roswitha T. Haas, Donald G. Kilgore, and Helen A. Pfuderer,
Oak Ridge National Laboratory
An expert, or knowledge-based, system consists of two basic parts: the expertise or knowledge, which
is contained in some form of rule set, and the inference engine, which contains the computer instruc-
tions that guide the reasoning or chaining process through the rule base. Additional peripherals may
be incorporated into the application, including databases, spreadsheets, report generators, electronic forms,
text processors, etc.
The Martin Marietta Energy Systems, Inc., (Energy Systems) Expert Systems Education and Application
Development Team has developed several expert systems relating to human health, safety, and environ-
mental accountability. These include the NEPA Environmental Review and Compliance Reporting System,
the RCRA/TSCA Advisor, and the Air Permits Expert System.
The NEPA Environmental Review and Compliance Reporting System is an expert advisor that assists in the
preparation of documentation for compliance with National Environmental Protection Act (NEPA) require-
Access/Use Info Resources Assess Health Risk Chem Expos '93 239
-------
2 continued
ments, as well as other Department of Energy (DOE) and Oak Ridge National Laboratory (ORNL) stand-
ards, e.g., Best Management Practices Standards, as they apply to activity efforts at ORNL.
The RCRA/TSCA Advisor is designed to be used both as a computer-based instruction tool for training in
compliance issues based on the Resource Conservation Recovery Act (RCRA) and the Toxic Substances
Control Act (TSCA) and as a field-deployed advisor on these issues in actual work environments at Energy
Systems.
The Air Permits Expert Systems is designed to generate accurate, reproducible, uniform air permit applica-
tions, which are then electronically delivered to the Division of Air Pollution Control, Department of Health
and Environment, State of Tennessee.
Another system, the Project Quality Assurance Plan Advisor, which is in development, will address the envi-
ronmental issues of concern to DOE, the Environmental Protection Agency, and others as projects are
planned and completed at Energy Systems.
ROADMAPS to Information Sources on EPCRA
Section 313 (TRI) Chemicals
John S. Leitzke and James F. Darr, U.S. Environmental Protection Agency
ROADMAPS is a database that directs people interested in Emergency Planning and Community
Right-to-Know Act (also known as SARA Title III) Sect. 313 (Toxic Release Inventory) data to
additional information. The first part of the database allows searching by specific chemicals for
information on cancer, health and environmental effects, federal regulations, general information docu-
ments, and state air and water regulations and monitoring information. Other parts of the database allow
searching for chemicals by type of information. Bring a high-density formatted diskette to obtain a copy of
the program.
HARDWARE: IBM-AT or 286-based or compatible PC.
SOFTWARE: MS-DOS 2.1 or greater, 12 KB RAM or greater.
EPA/OTS Information Resources
Linda A. Trovers, U.S. Environmental Protection Agency
The U.S. Environmental Protection Agency (EPA) Office of Toxic Substances has many information
products and databases that are utilized in assessing health risks from chemical exposure. The poster
presentation will highlight two of these databases: GEMS (Geographical Exposure Modeling Sys-
tem) and TRI (Toxic Release Inventory).
240 Access/Use Info Resources Assess Health Risk Chern Expos '93
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4 continued
GEMS is an interactive computer system developed to support integrated exposure assessments. It provides
a set of tools without requiring the user to be familiar with most aspects of computer science and program-
ming. GEMS integrates graphics, mapping, statistics, file management, modeling, and chemical property
estimation with a user-oriented and easy-to-leam interface.
TRI is a publicly accessible database mandated by Congress in SARA, Title III or the Emergency Planning
and Community Right to Know Act of 1986. It contains an annual inventory of releases of specified toxic
chemicals to all environmental media (air, water, land). TRI is available on the National Library of Medi-
cine's TOXNET system and is searchable using both user friendly menu screens and direct command line
language. EPA was directed to make the inventory available either through computer telecommunications or
via other means. The other means products include CD-ROM, COMfiche, magnetic tape, and floppy disks.
All of these products are available through NTIS or GPO.
Dose-Duration Plot
Christopher H. Cubbison, U.S. Environmental Protection Agency
D2PLOT is. designed to plot the results of dissimilar experiments in a common format of dose and
exposure duration. This permits comparison of studies using a variety of species, exposure dura-
tions, dosing scenarios, and other variables. Details of dose and duration are entered on the data base
along with extensive data on the lexicological endpoints, target organs, number of animals tested, number of
animals responding, quality of data, bibliographic information, and comments. Data are searchable on all
fields except comments. Results are plotted by Human Equivalent Duration (fraction of a human lifespan)
vs. Human Equivalent Dose (mg/kg) for oral exposure or Expanded Concentration Scale (mg/m ) for inhala-
tion exposure. The type and severity of effects are indicated by the data points. Optionally, the software will
plot boundary lines which encompass all adverse effects (Adverse Effects Region) and all no-effect-levels
(No-Adverse-Effects Region). Areas outside these regions indicate where no data exist Overlap between
regions constitutes a Region of Ambiguity. Guidelines for use of the identified "regions" are under
development.
Toxicology Information Response Center:
Customized Information Acquisition
Kimberly G. Slusher, Mary W. Francis, and Ida C. Miller, Oak Ridge National Laboratory
The Toxicology Information Response Center (TIRC) serves as a national and international center for
the collection, analysis, and dissemination of toxicology-related information on a variety of chemi-
cals, including food additives, Pharmaceuticals, industrial chemicals, environmental pollutants,
heavy metals, and pesticides. We also have the capability of designing, building, and maintaining custom-
ized databases and writing and publishing reports. TIRC is sponsored by the National Library of Medicine.
Access/Use Info Resources Assess Health Risk Chem Expos '93 241
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The U.S. Environmental Protection Agency's
Integrated Risk Information System (IRIS)
Linda Tuxen and Jacqueline Patterson, U.S. Environmental Protection Agency
The Integrated Risk Information System (IRIS), developed by the U.S. Environmental Protection
Agency (EPA), contains summary information related to human health risk assessment IRIS, which
is updated monthly, is the agency's primary vehicle for communication of chronic health hazard
information that represents EPA consensus positions following comprehensive review by intra-agency work
groups. It is a useful information resource tool that points the user to the underlying human and/or animal
data used to support the agency's consensus opinion. IRIS contains chemical-specific information in sum-
mary format for over 400 chemicals and provides a description of the basis for the hazard assessment and a
discussion of the uncertainties in that assessment. An IRIS chemical file is initiated when consensus is
reached on an assessment for carcinogenic or noncarcinogenic end points and contains the summary for that
assessment. Other information, such as drinking water health advisories and EPA regulatory actions, is
included. IRIS is primarily intended to provide guidance to EPA personnel in making risk management deci-
sions. However, in 1988 it was made available to the public and can currently be accessed via several
different methods: telecommunications link with a commercial carrier (BT Tymnet), through the Public
Health Network to Public Health Foundation members, on the National Library of Medicine's TOXNET sys-
tem, and on diskettes from the National Technical Information Service (NTIS). For more information on
IRIS, contact IRIS User Support at 513-569-7254 or write IRIS User Support, ECAO/EPA (MS-114), 26
West Martin Luther King Drive, Cincinnati, Ohio 45268.
8
Graphical Activity Profiles in Genetic Toxicology
and Developmental Teratology
Elizabeth T. Owens, Oak Ridge National Laboratory, and
T. Owens Vaughan, H. Frank Stack, Marcus A. Jackson, Robert J. Kavlock, and
Michael D. Waters, U.S. Environmental Protection Agency
For many years two specialized information centers, the Environmental Mutagen Information Center
(EMIC) and the Environmental Teratology Information Center (ETIC), have provided easy access to
information available in the fields of genetic and developmental toxicology. Because of information
growth and time and money constraints, it has become increasingly difficult to adequately review and
assimilate relevant literature on any one subject. To address this problem,.the Environmental Protection
Agency's Health Effects Research Laboratory (HERL), using resources from EMIC and ETIC, has provided
for the extraction of specific data to generate Graphical Activity Profiles (GAPs).
GAPs provide a way to demonstrate the genetic or developmental activity of a compound, both qualitatively
and quantitatively. Each profile is plotted from data available in the open literature and keyed to a three-
letter code indicating the test system, e.g., animal, activation, time frame, and the end point examined. The
lowest effective dose (LED) or highest ineffective dose (HID) is obtained from references reviewed for each
242 -Access/Use Info Resources Assess Health Risk Chem Expos '93
-------
8 continued
code and is translated into the logarithmic dose unit [LDU(jj)] for a given test system (i) and chemical (j) as
represented by the expressions:
LDU(ij) = -logic (dose) for HID ,
LDU(ij) = 5-logio (dose) for LED .
Using these data, a pictogram of the agent's activity, including its quantitative and qualitative parameters, is
generated. The activity can be displayed phylogenetically or according to biological end point.
These extractions and profiles can reduce the effort necessary to determine the potential risk of an agent. Pro-
file information can also be used to compare results across multiple assay systems; to compare the activity
of different agents, including calculation of relative potencies; to aid in structure-activity studies; and to iden-
tify research needs. GAPs are novel and useful tools for characterizing an agent's biological activity at a
glance.
Human Genome Management Information System
Betty K. Mansfield, Anne E. Adamson, Roswitha T. Haas, Donald G. Kilgore,
Michael D. Mayes, Elizabeth T. Owens, Judy M. Wyrick, and Laura N. Yust,
Oak Ridge National Laboratory
T
he Human Genome Management Information System (HGMIS), cosponsored by the U.S. Depart-
ment of Energy (DOE) and the National Institutes of Health (NIH), has roles in the International
Human Genome Project to:
(1) assist agencies that administer genome research in communicating issues relevant to the human
genome project to contractors and grantees and to the public and
(2) provide a forum for exchange of information among individuals involved in genome research.
To fulfill these communications goals, HGMIS is producing a bimonthly newsletter, DOE Human Genome
Program reports, an information database, and technical reports. HGMIS updates and maintains the mailing
list database compiled for the human genome programs of both DOE and NIH. Additionally, HGMIS acts to
orient and refer those persons seeking assistance, to sources that can provide appropriate information. These
documents/services are available to all persons upon request and provide both the interested scientist and lay
person with information in this rapidly moving, multidisciplinary project.
• The newsletter, Human Genome News (ISSN # 1050-6101), provides readers with technical and general
interest articles, meeting reports, news items, funding announcements, and meeting and training calen-
dars. Working in collaboration with the international Human Genome Organization, HGMIS also reports
international genome project news.
• The status of the DOE Human Genome Program is described in the Human Genome 1991-92 Program
Report, which includes research highlights, narratives on major DOE research efforts, abstracts of
research in progress, and figures and captions provided by investigators.
• The information database is being developed as a text management and user conferencing mechanism
and contains text from program reports and newsletters as well as bibliographic data from both the scien-
tific and popular literature.
Access/Use Info Resources Assess Health Risk Chem Expos '93 243
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10
Chemical Unit Record Estimates Database
David J. Reisman and Christopher T. DeRosa*, U.S. Environmental Protection Agency and
Mary W. Francis, Ida C. Miller, Robert S. Stafford, Andrew A. Francis, Cheryl B. Bast, and
Po-Yung Lu, Oak Ridge National Laboratory
The Chemical Unit Record Estimates (CURE) database, developed by the U.S. Environmental Protec-
tion Agency (EPA) in cooperation with the General Toxicology Program of Oak Ridge National
Laboratory (ORNL), organizes information related to health risk assessment. In 1987, the Office of
Health and Environmental Assessment (OHEA) of EPA began an extensive project to provide data to
researchers in a variety of output formats and to computerize the quantitative health risk assessment docu-
mentation in a format that would support information transfer. The Chemical Unit Record Estimate (CURE)
database is an on-line interactive database that provides (1) a compilation of numeric health risk estimates
and accompanying experimental data, including data on target organs and on critical and secondary effects
at varying doses; (2) side-by-side comparison of various related risk data; (3) an historical collection of
health risk estimates generated by OHEA over the past 10 years on approximately 1400 chemicals; and (4)
the ability to provide numeric output data sets of previously compiled research for testing current and future
health risk assessment predictive models. The software and database design allow for rapid updating and for
the addition of new data fields to both old and new records. The CURE database presently resides on an
IBM mainframe computer at ORNL. PC versions of CURE have been developed and offer alternatives to
on-line interaction with the mainframe computer. Both versions of the CURE database will be available for
demonstration.
*Now affiliated with Agency for Toxic Substances and Disease Registry.
11
Environmental Mutagen Information Center File
Elizabeth S. Von Halle, Kathleen H. Mavoumin, Bradford L. Whitfield, Mary Ann C. Davidson,
Karen A. Weaver, and John S. Wassom, Oak Ridge National Laboratory
The Environmental Mutagen Information Center (EMIC) was created in 1969, a time when geneticists
were becoming more concerned about the possible genetic effects of environmental agents. These
concerned geneticists founded the Environmental Mutagen Society (EMS), and its first charge was
the formation of a register of chemicals tested for mutagenicity in different systems [Mutation Research 8
(1969), 671]. This registry was the beginning of EMIC.
Today the EMIC file contains over 72,000 indexed publications reporting on more than 22,000 chemical,
physical, and biological agents. The file has developed during the last 21 years to respond to the needs of
genetic lexicologists, regulators, students, and educators. In addition to test objects used and agents tested,
indexing has evolved to include ass,ay systems and end points, cells cultured, types of cells treated and
observed (somatic or germ), and agents used as controls and inducers.
The U. S. Environmental Protection Agency (EPA), with the help of the staff at EMIC, used the file as a
basis for the GENE-TOX Program, which continues to evaluate chemicals tested in validated assay systems.
EPA's Health Effects Research Laboratory in North Carolina has used EMIC as a source of data and exper-
tise for the generation of Graphic Activity Profiles.
244 "Access/Use Info Resources Assess Health Risk Chem Expos '93
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EMIC is funded by EPA and the National Toxicology Program of the National Institute of Environmental
Health Sciences through the National Library of Medicine. The file is available on the NLM's TOXNET
and TOXLINE systems.
12
Environmental Teratology Information Center File
Geraldine S. Danford, Shigeko Y. Uppuluri, and Florence M. Holland,
Oak Ridge National Laboratory
The thalidomide incident and the awareness of environmental effects on human health in the 1960s
resulted in a great increase in the volume of scientific papers dealing with teratology. The Environ-
mental Teratology Information Center (ETIC) was established in 1975 to collect, index, and comput-
erize systematically the literature in this research area. This work continued actively until the end of 1989.
The ETIC file that covers the literature published during the 1950-1989 era may be accessed via the
National Library of Medicine's TOXLINE and TOXNET systems. The ETIC file is still maintained and is
used to support several ongoing projects at the Laboratory. There are now more than 50,000 entries from
over 3700 sources in the ETIC file. Copies of complete original documents are available for each entry.
Each ETIC entry represents a publication from the open literature. For a paper to be accepted for the ETIC
database, it must discuss the testing and evaluation of the developmental toxicity or reproductive effects of
an agent whether the results are positive, negative, or inconclusive. Agents may be chemical, biological, or
physical, and may also include dietary deficiencies and disease conditions in the mother. ETIC focuses
mainly on the administration of an agent to a pregnant animal and the examination of the offspring at or
near birth for either structural or functional anomalies. Also contained in the ETIC file are reports of
epidemiological studies and clinical cases in humans, testing methods, in vitro studies, proposed rapid
screening methods, placental transfer studies, reproductive and/or fertility studies, and studies of the repro-
ductive effect of agents administered before pregnancy.
13
Gene-Tox Agent Registry File
Roswitha T. Haas, Oak Ridge National Laboratory, and
Angela E. Auletta, U.S. Environmental Protection Agency
The Gene-Tox Agent Registry File is the primary data compilation of the U.S. Environmental Protec-
tion Agency's Genetic Toxicology Program, a multiphase effort to evaluate the effects of chemical
agents in selected short-term bioassays for genotoxic activity. The file contains results for over 4600
chemicals, extracted from the literature published from 1968 to the present. Panels of scientists who are
authorities on particular test systems read publications in their respective fields and made decisions on the
effect of test agents. The file resides in the ORLOOK data management system, run by an IBM 3033 com-
puter.
Access/Use Info Resources Assess Health Risk Chem Expos '93 245
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13 continued
The biological information in the file is qualitative and is listed as positive, negative, or non-definitive
results for 73 bioassays. These 73 tests can be grouped by gene mutation, chromosome aberration, other
genotoxic effects, and in vitro cell transformation assays. The chemical information is contained in two
main classification schemes, one by functional groups and one by ring systems.
The file is used to determine the sensitivity of each bioassay in response to specific classes of chemicals and
to devise specialized batteries of assays that detect the various types of genetic damage induced by specific
classes of chemicals.
14
Genetic Toxicology Chemical Structure File
Roswitha T. Haas, Mary Ann C. Davidson, and K. S. Rao, Oak Ridge National Laboratory
The Genetic Toxicology Chemical Structure File is part of the U.S. Environmental Protection
Agency's Genetic Toxicology Program, a multiphase effort to evaluate the effect of chemical agents
in selected short-term bioassays for genotoxic activity. The database contains information on over
4600 chemicals.
The structure file uses the ChemBase database management software for personal computers from Molecu-
lar Design Limited to store chemical structure diagrams in addition to conventional database fields such as
Chemical Abstracts Service Registry numbers and names. For structure entry, the diagrams are drawn with a
mouse. The structure field can be searched for the occurrence of structure fragments.
The structure file is used to identify groups of chemicals with common substructures, to find structure-
activity relationships, to visualize structures, and to print structure diagrams and tables of structure diagrams
for viewgraphs, slides, and publications.
15
Environmental Restoration and Waste
Management Data Bases
Park T. Owen, Linda F. Coins, and Nancy P. Knox, Oak Ridge National Laboratory
In 1979 the U.S. Department of Energy (DOE) established the Remedial Action Program Information
Center (RAPIC) at Oak Ridge National Laboratory to provide technical information support to the U.S.
Department of Energy's Remedial Action Programs, which comprise Formerly Utilized Sites Remedial
Action Program (FUSRAP), Surplus Facilities Management Program (SFMP), and Uranium Mill Tailings
Remedial Action Program (UMTRA). In addition to these ongoing programs, RAPIC also serves the other
groups within the DOE Office of Environmental Restoration. Specific information activities that RAPIC
performs to support the DOE programs include maintaining a computerized bibliographic database contain-
ing approximately 7000 annotated references; publishing an annual bibliography, Nuclear Facility Decom-
246 Access/Use Info Resources Assess Health Risk Chem Expos '93
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15 continued
missioning and Site Remedial Actions, A Selected Bibliography, ORNL/EIS-154; maintaining a document
repository and providing copies of requested publications; and performing manual and computerized
searches of the technical literature. The most important RAPIC function is serving as a focal point for reme-
dial action information. With these extensive resources at its command, RAPIC is in a unique position to
provide a comprehensive information base to the remedial action and environmental restoration community.
16
Development of Applicable or Relevant and
Appropriate Requirements (ARARs) for
Remediation of Hazardous Waste Sites Under
Superfund
Elizabeth L. Etnier, Patricia S. Hovatter, Sylvia S. Talmage, Rose S. Weaver, Linda M. Houlberg,
Robert H. Ross, Oak Ridge National Laboratory, and
Robert Muhly, * U.S. Army, Toxic and Hazardous Agency
The U.S. Environmental Protection Agency (EPA) has established the National Priorities List (NPL)
to prioritize for the states and the public those waste sites in the United States that have known or
threatened releases of hazardous pollutants or contaminants into the environment. The U.S. Depart-
ment of Energy (DOE) Oak Ridge Reservation (ORR) was listed on the final NPL on November 21,1989.
The U.S. Army currently has 17 installations listed on the final NPL. As a result of this listing, remediation
at these sites must proceed according to the Comprehensive Environmental Response, Compensation, and
Liability Act (CERCLA) of 1980, the Superfund Amendments and Reauthorization Act (SARA) of 1986,
and the National Contingency Plan (NCP).
SARA specifies that remedial actions for cleanup of hazardous substances comply with applicable or rele-
vant and appropriate requirements (ARARs) or standards under federal and state environmental laws. Inher-
ent in the interpretation of ARARs is the assumption that protection of human health and the environment is
ensured. ARAR reports are currently being developed for the DOE ORR and the U.S. Army. These reports
highlight the chemical-, location-, and action-specific issues of concern for each waste site.
*Cunent organization Army Environmental Center
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Selection of Indicator Chemicals at Hazardous
Waste Sites
Patricia S. Hovatter and Robert E. Gibson, Oak Ridge National Laboratory,
and Robert Muhly, * U. S. Army
According to the Environmental Protection Agency (EPA) methodology outlined in the 1989 Risk
Assessment Guidance for Superfund the first step in the baseline risk assessment at Superfund sites
is data collection and evaluation, which involves the selection of indicator chemicals. This proce-
dure identifies the chemicals that pose the greatest potential public health risk at a site and is based on site
monitoring data, chemical toxicity information, and environmental persistence and mobility of the chemi-
cals. A computer program (CASIC), using Lotus 1-2-3 spreadsheets, was developed to automate the routine
features of the procedure. Initially, a concentration-toxicity screening method is used to obtain a ranking of
the relative risk for each detected chemical in a specific environmental medium. A risk factor for each
chemical is calculated as the maximum detected concentration in the particular medium times a toxicity fac-
tor, which is the reference dose for noncarcinogens or the carcinogen potency factor for carcinogens. The
most current toxicity factors are obtained from either the EPA Integrated Risk Information System (IRIS)
database or the quarterly EPA Health Effects Assessment Summary Tables. The top-scoring chemicals in
the screening procedure, along with any detected chemicals for which toxicity factors are currently unavail-
able, are subsequently analyzed to establish a potential list of indicators for final selection. Final selection of
indicators is then based on evidence of human carcinogenicity, frequency of occurrence in environmental
media, exceedance of acceptable intake values, exceedance of background levels, and the migration poten-
tial and environmental persistence of the chemicals.
*Current organization Army Environmental Center
18
Less-Than-Lifetime Risk Assessment: Estimation
of No-Effect Levels for Nonlethal Toxic End
Points by Analogy to Acute Toxicity
Cheryl B. Bast and Robert E. Gibson, Oak Ridge National Laboratory, and
Christopher H. Cubbison and Christopher T. DeRosa, * U.S. Environmental Protection Agency
Data necessary for establishing human no-observed-adverse-effect levels (NOAELs) are not available
for many chemicals, whereas acute toxicity data are often readily available. If the existence of a rela-
tionship between acute toxicity data and NOAELs were to be established for those chemicals for
which both types of data exist, it would then be possible to estimate a NOAEL for some chemicals for which
only the acute toxicity data exist. Over 1100 chemicals from the Chemical Unit Record Estimates (CURE)
database of the U.S. Environmental Protection Agency were classified according to the 30- or 69-class
scheme used for the Gene-Tox Program. No-effect levels and acute toxicity data (from the Registry of Toxic
248 Access/Use Info Resources Assess Health Risk Chein Expos '93
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18 continued
Effects of Chemical Substances) were incorporated into a less-than-lifetime database, and the
log(LD5o/NOAEL) was determined. The percentage of chemicals included by a given ratio was then calcu-
lated for various chemical classes for oral exposure in rats. Data suggest that both the LDsos and NOAELs
are normally and independently distributed. The upper limit for a NOAEL can be estimated by the use of a
factor of 10,000 to 100,000, but the probability is high that the no-effect level will be underestimated by sev-
eral orders of magnitude.
*Now affiliated with Agency for Toxic Substances and Disease Registry
19
PATS: Packaging and Transportation Safety
Program Data Base
Ruth M. Gave, Andrea A. Richmond, Miriam J. Welch, and Richard R. Rawl,
Oak Ridge National Laboratory
The Department of Energy Assistant Secretary for Environment, Safety, and Health is charged under
DOE Order 5480.3 with safety overview responsibilities for the packaging and transportation of haz-
ardous materials, substances, and wastes at all DOE facilities. The Packaging and Transportation
Safety (PATS) Program is the means by which these responsibilities are addressed. Oak Ridge National
Laboratory (ORNL) serves as the integrator for the PATS Program.
The PATS database was initiated in 1989 to organize information related to DOE packaging and transporta-
tion safety activities. It contains specific site information regarding DOE facilities, appraisal visit schedules
and reports, appraiser names, training, and expertise.
The database is maintained on a PC using dBase III and Clipper software. The user can select reports based
on such things as hazardous class, site/facility names, and appraiser name.
20
Toxicology Guide for Installation Restoration
Program Application
u
Robert A. Young, Po-Yung Lu, Mary W. Francis, and Robert H. Ross,
Oak Ridge National Laboratory, and
G. W. JepsonandJ. W. Fisher, Wright-Patterson Air Force Base, U.S. Air Force
nder the Installation Restoration Program, the U.S. Air Force is required to provide comprehensive
chemical profiles of toxic or hazardous chemicals commonly found at Air Force installations. Four
volumes (2500 pages) of peer-reviewed reports covering 70 chemicals will be used by all Air Force
Access/Use Info Resources Assess Health Risk Chem Expos '93 249
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20 continued
installations (both domestic and overseas), nearby communities, and state and local governments. This Toxi-
cology Guide provides two categories of information: (1) concise summaries and (2) in-depth evaluations.
The summaries include substance identification, air w/v conversion factors, reactivity and physico-chemical
data, pathways of exposure, persistence in soil/groundwater systems, health hazard data, handling precau-
tions, environmental and occupational standards and criteria, and regulatory status (federal, state, and Euro-
pean Economic Community directives). The evaluations include environmental fate, human health effects
(carcinogenicity, teratogenicity, genotoxicity, short- and long-term toxicity), and sampling and analysis
information. A fifth volume covering six metals of concern is in preparation.
21
Hypertext System Demonstration: Information on
the Symposium and BEIA
Gloria M. Caton and Suzanne E. Joy, Oak Ridge National Laboratory
A
hypertext demonstration provides information on the symposium on Access and Use of Informa-
tion Resources in Assessing Health Risks from Chemical Exposure, the Biomedical and Environ-
mental Information Analysis (BEIA) Section, and local area attractions.
The mission of BEIA and the expertise and capabilities of BEIA staff members are summarized. Informa-
tion is given on the following groups and their projects: the Human Genome and Toxicology Group, the
Chemical Hazard Evaluation and Communication Group, the Environmental Regulations and Remediation
Group, and the Information Management Technology area.
22
Activities of the Federal-State Toxicology and
Regulatory Alliance Committee
Robert Cantilli, U.S. Environmental Protection Agency
The Federal-State Toxicology and Regulatory Alliance Committee (FSTRAC) was formed in 1985 to
facilitate cooperation between federal and state regulators and risk assessors on drinking water
issues. FSTRAC is composed of representatives from state health and environmental agencies, the
U.S. Environmental Protection Agency (EPA), Office of Drinking Water, and EPA regional programs.
FSTRAC brings together professionals with many different areas of expertise to develop well-rounded, inte-
grated approaches to risk assessment and standard-setting issues. In a broad sense, EPA sponsors FSTRAC
to foster cooperation among states, and between states and EPA; provide a setting for informal and formal
discussions of common problems; improve consistency between federal and state approaches to setting
drinking water standards or guidance; obtain feedback on federal or state guidance and standards; and dis-
cuss factors influencing state risk assessment and regulatory programs. Specific activities and products of
FSTRAC include workshops on risk assessment methodologies commonly used by EPA and states; panel
250 Access/Use Info Resources Assess Health Risk Chem Expos '93
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22 continued
discussions between FSTRAC members on practical solutions to risk assessment problems; guidance docu-
ments on chemical mixtures in drinking water; a summary of state and federal drinking water guidelines and
standards; an electronic seminar series in which states and EPA share information on recent risk assessment
developments through teleconferencing; a guidance document on assessing noningestion exposures to drink-
ing water contaminants; and a risk communication bibliography and a number of nation-wide surveys on the
occurrence, regulations, and guidance for drinking water contaminants.
23
The Rodent Dominant Lethal Assay
Bradford L. Whitfield, Oak Ridge National Laboratory
The rodent dominant lethal assay is one of the short-term genotoxicity tests selected by the U.S. Envi-
ronmental Protection Agency for inclusion in the Gene-Tox Program (other posters at this meeting
describe the Gene-Tox Program). This poster provides details of the dominant lethal assay and uses
the Gene-Tox evaluation of this assay as an example of the ability of the Biomedical and Environmental
Information Analysis (BEIA) Section Human Genome and Toxicology (HGT) Group to provide scientific
and information support to other groups and government agencies.
The Environmental Mutagen Information Center (EMIC), one component of HGT, has for 21 years been
identifying, collecting, and extracting the technical information from the published literature in genetic toxi-
cology. This extensive computerized database and the expertise of the EMIC staff are instrumental in the
continuing success of the Gene-Tox Program.
Published literature on the dominant lethal assay had already been identified, and copies of the publications
were available at EMIC; thus it was quick and easy to obtain a subset of the literature dealing with this
assay. After an initial screening of the literature by the EMIC staff, copies of the pertinent papers were dis-
tributed to the Gene-Tox panel of experts for critical evaluation. The EMIC staff member assigned to the
panel contributed both as a scientist and as an information specialist. The final report of the panel was pub-
lished in open literature, and the results were entered into the Gene-Tox database at ORNL. Newly publish-
ed data are evaluated and added to the database on a continuing basis.
Access/Use Info Resources Assess Health Risk Chem Expos '93 251
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In Vivo Micronucleus Assay in Mammalian Bone
Marrow and Peripheral Blood
Kathleen H. Mavournin, Oak Ridge National Laboratory;
David H. Blakey, Department of National Health and Welfare, Canada;
Michael C. Cimino, U.S. Environmental Protection Agency;
Michael F. Salamone, Ontario Ministry of the Environment, Canada; and
John A. Heddle, York University, Canada
The protocol recommended for the micronucleus assay in mammalian bone marrow has been revised
and simplified. The number of sample times has been reduced to one or two, depending upon the dos-
ing protocol. The minimum number of cells to be scored per treatment group has been increased to
20,000 to increase the ability of the assay to detect a doubling of the control micronucleus frequency. Use of
both male and female animals is recommended. Scoring of micronuclei in polychromatic erythrocytes of
peripheral blood is included as a variation of the bone marrow assay. Published data on chemicals tested by
the micronucleus assay have been reviewed and are summarized.
25
Inhalation Reference Dose Methodology:
Development, Dosimetric Adjustments, and
Human Equivalent Concentrations
Chon R. Shoaf and Annie M. Jarabek, U.S. Environmental Protection Agency
Information resources are the critical basis for initiating inhalation reference dose (RfD;) development.
The information retrieval method includes a complete and current literature search, information abstrac-
tion, database construction, and compilation of the concentration-response data. When such an informa-
tion retrieval method is coupled with a physiologically-based dosimetry model, human equivalent concen-
trations integral to the RfDi development process can be derived. Critical studies chosen from the literature
searches provide the necessary information on health effects to which extrapolation methods for high-to-
low dose, animal-to-human extrapolations, and normal-to-susceptible subpopulations are applied. The con-
centration response database should yield the no-observed-adverse-effect level (NOAEL) or the lowest-
observed-adverse-effect level (LOAEL). Other necessary data include characteristics of the aerosol or gas
(mass medial aerodynamic diameter, particle distribution, temperature, pressure) and the appropriate respira-
tory tract region (extrathoracic, tracheobronchial, pulmonary, or total) or other organ manifesting the toxic
effect. Data bases of animal and human physiological, anatomical, and metabolic parameters will continue
to play an important role in reducing uncertainty in the RfD; by providing information for mathematical
models of empirical data and physiologically based pharmacokinetic models to support dosimetric adjust-
ments and more accurate risk estimates. (This abstract does not necessarily reflect EPA policy.)
252 Access/Use Info Resources Assess Health Risk Chem Expos '93
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26
Animal Testing Alternatives: A Selected
Annotated Bibliography
i
Robert S. Stafford and Po-Yung Lu, Oak Ridge National Laboratory,
and George J. Cosmides, National Library of Medicine
The scientific community is concerned about animal welfare and is also sensitive to public concerns
regarding how and why animals are used in biomedical research and lexicological testing. Although
it is unlikely that alternatives to animal methods or in vitro methods will ever satisfy all the require-
ments of research and testing, alternatives to the use of intact animals (vertebrates) are being developed.
Research on methodology is aimed at refinement of procedures to reduce pain and discomfort, reduction in
the number of experimental animals necessary for scientifically valid results, and replacement of intact ver-
tebrates when scientifically acceptable alternatives can be verified and validated.
The purpose of this series of quarterly bibliographies is to provide periodic literature surveys in a format
that facilitates easy scanning. Citations with annotations relating to the method are organized under catego-
ries such as cell culture or a specific target organ. The bibliographies feature selected citations that deal in
some predominant way with methods, assays, tests, or procedures that may be useful alternatives to intact
vertebrates. The citations are selected and compiled after monthly on-line searching of appropriate bibliog-
raphic databases on the computer system of the National Library of Medicine. These bibliographies are
available, free of charge, to interested organizations or individuals.
27
Superfund Technology Support Center for Health
Risk Assessment
Pei-Fung Hurst, W. Bruce Peirano, and Christopher T. DeRosa, *
U.S. Environmental Protection Agency
*,
In December 1989, the Office of Health and Environmental Assessment (OHEA) was designated, in a
memorandum of understanding between the Office of Research and Development (ORD) and the
Office of Solid Waste and Emergency Response (OSWER), as the location for the Superfund Technical
Support Center (TSC) for human health risk issues. The Environmental Criteria and Assessment Office
(ECAO) will function as the focal point to coordinate OHEA- or agency-wide assistance in this area. A hot
line has been established [FTS 684-7300 or (513) 569-7300] to facilitate the communication between the
TSC and the Superfund risk assessors.
OHEA has a long history of providing support to different regulatory programs, has experience with chemi-
cal review and toxicity evaluation, and has an excellent working relationship with other ORD labs and pro-
gram offices. These factors place OHEA in a unique position for providing assistance in health risk
assessment. This assistance will be conducted in conjunction with the Toxics Integration Branch (TIB) of
the Office of Emergency and Remedial Response (OERR) in order that future research and Superfund
Access/Use Info Resources Assess Health Risk Chem Expos '93 253
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27 continued
program issues may be identified and to ensure consistent responses to policy questions and specific situ-
ations with broad application. In order to encourage interaction and information exchange, OHEA and
T1B/OEKR will convene a risk assessment round table with the regions. Regional representatives are encour-
aged to participate in the monthly Risk Assessment Teleconference for Superfund (RATS) with TIB and
OHEA to ensure that consistent approaches are applied across all National Priority List (NPL) sites and to
identify policy issues.
The specific function of the health risk TSC is to provide a rapid response to specific questions by telephone
and written follow-up, when appropriate, to regional toxics integration coordinators (RTICs), remedial pro-
ject managers (RPMs), on-scene coordinators (OSCs) and regional Superfund staff relating to chemical-
specific health information. Contractors may also contact the TSC with site-specific Superfund questions,
but may be required to route the question through their RTIC, RPM, etc. In any event, these people will be
notified of the question and the response.
Clarification and interpretation of the Risk Assessment Guidance for Superfund (RAGS) will be coordinated
with the TIB. OHEA will also consult with other offices and programs, when necessary, to respond to multi-
faceted questions such as route-to-route extrapolation, dermal risk parameters, and less-than-lifetime expo-
sure. Coordinated responses will also be provided on health-based triggers and cleanup levels and
justification for surrogate cleanup levels based on default assumptions.
Utilization of the TSC is expected to be extensive. The TSC is already responding to between six and ten
calls per day prior to any extensive publicity. This TSC has been designed for maximum flexibility in order
to respond to a wide variety of assistance requests. With the help of the TIB, the Regional Forum and other
agency offices, the TSC should prove extremely valuable to the entire Superfund program by providing
timely, consistent, state-of-the-science answers to complex questions.
*Now affiliated with Agency for Toxic Substances and Disease Registry.
28
Chemical Hazard Assessment
Robert H. Ross, Cheryl L. Bast, Mary L. Daugherty, Kowetha A. Davidson, Rosmarie Faust,
Andrew A. Francis, Patricia S. Hovatter, Dennis M. Opresko, Sylvia S. Talmage and
Robert A. Young, Oak Ridge National Laboratory, and
Christopher T. DeRosa, * Harlal Choudhury, V. J. Cogliano, Christopher H. Cubbison, and
Bennett G. Smith, U.S. Environmental Protection Agency
The assessment of the health and environmental hazards posed by the environmental release of chemi-
cals is an information-intensive process. An assessment can be qualitative, quantitative, or a combi-
nation of both, the latter being most common. Qualitative assessments convey the risk of exposure to
a chemical to the extent that the potential hazards are clearly identified, but exposure levels of concern are
not derived. On the other hand, quantitative hazard assessments are processes by which levels of concern
are derived. The methodology for conducting hazard assessments involve computer-aided scans of the litera-
ture, selection of all relevant human and animal studies that make up the database, selection of key studies
that identify and characterize the critical effect and dose-response relationships, and use of dose-response
data points in specific equations or computer models to calculate the specific risk values. An example of a
qualitative hazard assessment is the carcinogen classification schemes used by the Environmental Protection
254 " Access/Use Info Resources Assess Health Risk Chem Expos '93
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28 continued
Agency and the International Agency for Research on Cancer. Examples of quantitative assessments include
reference doses, slope factors, reportable quantities, and water quality criteria. Because each of these quanti-
tative risk assessments can be derived on the basis of a single well-conducted study, access to all available
information is essential to ensure that all relevant studies have been considered.
*Now affiliated with Agency for Toxic Substances and Disease Registry
29
Mutagenicity Testing Guidelines for the U.S. EPA
Office of Toxic Substances (OTS)
Michael C. Cimino and Angela E. Auletta, U.S. Environmental Protection Agency
The U. S. Environmental Protection Agency (EPA) Office of Toxic Substance presently has 22
mutagenicity test guidelines, either existing, proposed or in draft. 20 have been published in the Fed-
eral Register (FR), and 19 appear in the Code of Federal Regulations (CFR). Eleven guidelines are
widely used by OTS. The Ames guideline is considered current state-of-the-art and it is not scheduled for
update. The in vitro gene mutation test is also widely-used; the L5178Y cell line is being split out as a sepa-
rate assay, and the CHO and AS52 cell lines are also likely to be split out. The Drosophila sex-linked reces-
sive lethal (SRL) test, used in Sect. 4 test rules, will likely be replaced with alternative test(s), and is not
scheduled for up-date. The visible SLT, the 3rd-tier test rule standard, is considered state-of-art; minor modi-
fications have been proposed in the FR. The biochemical SLT has been proposed as an alternative to the vis-
ible test; a final guideline should be published by January of 1990. The in vitro chromosome aberration test
is widely-used; these are currently undergoing revision. The in vivo spermatogonial chromosome aberration
test is new for OTS. The rodent dominant lethal is widely-used, and will be revised soon. The heritable
translocation test is a 3rd-tier standard in test rules, but is considered state-of-art and is not scheduled for
update. Although intended as recommendations for conducting the subject assay for submission of data to
EPA, OTS guidelines, along with relevant modifications, become test standards when cited in a test rule.
30
Material Safety Data Sheets for Hazard
Communication
SibyllM. Hubner, Betty W. Kline, Po-Yung Lu, and Linda B. Pierce,
Oak Ridge National Laboratory, and
James R. Crawl, Environmental Health Center, Norfolk, U.S. Navy
The Occupational Safety and Health Administration Hazard Communication Standard 29 CFR
1900.1200 requires manufacturers, distributors, users, and importers to communicate information to
employees on all hazardous chemicals used in the workplace in the form of Material Safety Data
Sheets (MSDS). Also, Superfund Amendment Reauthorization Act, Title III, Sections 311 and 312, cites
Access/Use Info Resources Assess Health Risk Chem Expos '93 255
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30 continued
MSDS as a means of fulfilling community right-to-know reporting requirements. The Oak Ridge National
Laboratory (ORNL) uses the Hazardous Substances Data Bank, the U.S. Environmental Protection Agency
Gene-Tox Data Base, other pertinent databases, reference books, and manufacturers' information to prepare
MSDS. Selected MSDS are peer-reviewed to ensure that they accurately reflect what is known about the
chemical or trade name products. Currently, information on 2661 pure chemicals and 5136 trade name prod-
ucts is available through a menu-driven retrieval system developed using INQUIRE on an IBM mainframe
computer, which allows on-site or off-site access. The MSDS at ORNL are kept current by updating such
selected data elements as threshold limit value, toxicity, and cancer rating. In addition, a total of 2000
MSDS have been prepared for the U.S. Navy and Army to be incorporated into the Department of Defense
Hazardous Materials Information System. Information obtained primarily from manufacturers' MSDS has
been enhanced to update threshold limit values, toxicity, and cancer ratings.
31
DART and Other Information Resources in
Developmental and Reproductive Toxicology
Carole A. Kimmel, Environmental Protection Agency, Stacey J. Arnesen and Henry M. Kissman,
National Library of Medicine, and
Bernard A. Schwetz, National Institute of Environmental Health Sciences
The DART (Developmental and Reproductive Toxicology) database is a new bibliographic database
intended to provide a comprehensive collection of the available literature in developmental and
reproductive toxicology. DART is a continuation and expansion of the ETIC (Environmental Teratol-
ogy Information Center) database, which was established originally by the National Institute of Environ-
mental Health Sciences (NIEHS) and produced by Oak Ridge National Laboratory (ORNL). Currently,
DART contains references to literature primarily in developmental toxicology dating from 1989; ETIC cov-
ers literature of similar scope from 1950 to 1988. Both DART and ETIC (as ETICBACK) are available on
line via the National Library of Medicine (NLM) TOXNET (Toxicology Data Network) system. DART is
currently funded by NIEHS, the Environmental Protection Agency (EPA), and the Agency for Toxic Sub-
stances and Disease Registry (ATSDR), through agreements with NLM, which provides support and over-
sees the maintenance of the database. The scope of DART will be expanded soon to include other areas of
reproductive and developmental toxicology that have not been covered previously; at least 3600 references
will be added each year, both from NLM's MEDLINE database (approx. 60%) and from non-MEDLINE
sources, such as books, meeting abstracts, technical reports, and journals not indexed for MEDLINE. These
records will contain abstracts, MeSH (Medical Subject Headings) indexing, and complete chemical index-
ing. A summary of other information resources available in developmental and reproductive toxicology
(e.g., REPROTOX, Shepard's Catalog, TERIS, etc.) also will be provided.
256 Access/Use Info Resources Assess Health Risk Chem Expos '93
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32
The Ames/Salmonella Microsome Assay for
Genotoxicity
Mary M. Brown and Elizabeth S. Von Halle, Oak Ridge National Laboratory, and
Angela E. Auletta, U.S. Environmental Protection Agency
The number of chemicals for which published data in the Salmonella assay (SAL) have been evalu-
ated and entered into the GENE-TOX EPA database is 2469. Of these, 666 are reported to be SAL+
(positive), 416 SAL+-* (positive with metabolic activation), and 18 SAL+ (positive without metabo-
lic activation and negative with metabolic activation). Collectively, 1100 chemicals were positive in the
SAL assay, 880 negative, and 489 were inconclusive. Comparative results between chemicals tested in SAL
and a variety of other test are available in Gene-Tox database. For example, of the 2469 compounds tested
in SAL, 326 results for animal carcinogenicity (CCG), 108 for mutations in Chinese hamster lung cells
(V79), 122 for sex-linked recessive lethals in Drosophila (SRL), 156 for cell transformation in mammalian
cell systems (CT). The number of noncarcinogens reported in the Salmonella database increased from 14 in
the original Gene-Tox review to 58 in the present update. These data are used to compare sensitivity, speci-
ficity, concordance, and predictivity in the different test systems with carcinogenicity in animals. Compari-
sons are also made of test results of genotoxicity in Salmonella with genotoxicity in eucaryotes.
When the limited positive and negative results for animal carcinogenicity (CCG+L and CCG-L) are
removed from the calculations, the sensitivity (78.36 to 82.93%) and concordance (76.07 to 80.00%) of the
Salmonella test increased without a significant decrease in specificity (65.52 to 65.00%). Elimination of
these data from the comparisons results in values for sensitivity, concordance, and specificity values similar
to those obtained with pre-1979 data when only 14 noncarcinogens were available for comparison.
Combining genotoxicity data obtained from the V79 and SRL test systems with the Salmonella data does
not improve the correlation with carcinogenicity. The cell transformation data do not correlate as well as the
Salmonella data with carcinogenicity but do have a higher predictivity for noncarcinogens, although this
value is only in the 50% range.
33
Proposed Changes to the Toxic Substances
Control Act (TSCA) Tier Testing Scheme for
Mutagenicity
Angela E. Auletta and Michael C. Cimino, U.S. Environmental Protection Agency
Under the Toxic Substances Control Act (TSCA) EPA may require testing in the areas of "carcino-
genesis, mutagenesis,... and unreasonable risk... to health or the environment." Chemicals are
tested for gene and chromosomal mutation using tier schemes designed to detect intrinsic mutagenic-
ity, determine if the chemical reaches the gonad and interacts with germ cell DNA, and detect the induction
of heritable mutations in mammals. Positive responses in key tests also serve as triggers to a bioassay. The
Access/Use Info Resources Assess Health Risk Chem Expos '93 257
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33 continued
gene mutation scheme begins with an Ames assay. An in vitro test for gene mutation is performed if the
Ames assay is negative. A positive response in either test triggers a Drosophila sex-linked recessive lethal
(SRL) test; a positive SRL response triggers a visible or biochemical-specific locus test. The cytogenetics
scheme begins with an in vitro cytogenetics test. An in vivo cytogenetics test is performed if the in vitro
assay is negative. A positive response in either test leads to a dominant lethal test; a positive dominant lethal
response leads to a rodent heritable translocation test. A bioassay is triggered if both the Ames and the SRL
tests are positive or if the in vitro gene mutation test or the in vitro or in vivo cytogenetics tests are positive.
It is proposed to combine the first tier of both schemes, to replace the SRL test with a test or tests for direct
effects on gonadal DNA such as the induction of UDS or SCE in testicular tissue, to eliminate the single test
trigger to a bioassay, and to have any combination of tests leading to a bioassay include a positive response
in an in vivo test for chromosomal damage.
34
Radiological Site Characterization Surveys and
Data Analyses
Mary S. Uziel, Lois M. Floyd, and Judy W. Crutcher, Oak Ridge National Laboratory
The Measurement Applications and Development (MAD) Task Group of the Biomedical and Environ-
mental Information Analysis Section, Oak Ridge National Laboratory, has the primary responsibility
of writing technical reports based on radiological characterization surveys conducted by the Environ-
mental Measurements and Applications Section. At the request of the U.S. Department of Energy (DOE),
these investigative surveys are performed to determine whether a site is currently contaminated with radio-
active residues derived from activities related to past projects of DOE or its predecessors.
The surveys may encompass both indoor and outdoor examination of the site with direct and transferable
measurements of alpha, beta, and gamma radiation levels; gamma scans; and collection of samples for
radionuclide analyses.
Responsibilities of the MAD Task Group include participation in field surveys, analyses of site data, inter-
pretation of results, digitization of survey site maps using CAD programs, development of computer pro-
grams to facilitate statistical analyses and graphical presentation of data, and recommendations for
corrective actions where appropriate.
'DOE programs supporting the MAD Task Group include the Formerly Utilized Sites Remedial Action Program, the Remote Surplus Facilities Man-
agement Program, the Environmental Restoration Program, and the Environmental Regulations Program.
258 e Access/Use Info Resources Assess Health Risk Chem Expos '93
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35
Biomedical and Environmental Information
Analysis Section Communication Resources:
Printed and Electronic
Gloria M. Caton, Linda M. Houlberg, Marilyn E. Langston, and Judy M. Wyrick,
Oak Ridge National Laboratory
Biomedical and Environmental Information Analysis (BEIA) personnel from different groups work
together using technical, editing, and desktop publishing skills to produce scientific publications for
a variety of projects and sponsors (internal and external). Technical information, research results,
and research news are prepared and summarized in readily accessible formats for investigators, managers,
and other interested parties. Examples of products from these integrated efforts include the following:
• Newsletters: Radon Research Notes, Human Genome News, ESHNEWS, and Ceramic Technology for
Advanced Heat Engines',
• Reports: Environmental Regulatory Update Table, Weekly Federal Register Digest, 1990 Inventory of
Federal Hazardous Waste Activities at ORNL, Spill Prevention Control Countermeasures and Contin-
gency Plans at ORNL, and ORNL Part B RCRA Permit Application for Remote-Handled Transuranic
Concrete Cask Storage Facility;
• Books and Manuals: Environmental Guidance Reference Books, and VP-Expert: Rule-Based Expert Sys-
tem Development Tool for Personal Computers, Course Workbook',
• Regulatory Posters: "Drinking Water Regulations" (with federal current/proposed drinking water crite-
ria and the stricter state criteria); and
• Hypertext Interactive Communication (see demonstration describing symposium, BEIA, and local
area attractions).
36
Environmental Guidance Program: Reference
Books and Regulatory Update Table
Cynthia G. Heckman, Linda M. Houlberg, Marilyn E. Langston, Patricia A. Nikbakht,
Marti S. Salk, and Julia M. Stockstill, Oak Ridge National Laboratory
The mission of the Environmental Guidance Program, based at Department of Energy (DOE) head-
quarters in Washington, D.C., is to provide guidance to DOE in complying with various environ-
mental laws and regulations. The Reference Books and Regulatory Update Table are two tools used
to provide this guidance. The Reference Books provide information on major environmental statutes and
their implementing regulations that appear to be most relevant to DOE activities. The 14 books are revised
Access/Use Info Resources Assess Health Risk Chem Expos '93 259
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36 continued
and distributed to DOE and contractor staff annually, although this may occur more often when required by
major new developments in statute regulatory programs. The books are divided into four sections: Sum-
mary, Legislative History and Statutes, Implementing Regulations, and Updates. These reference books pro-
vide a convenient up-to-date source of information on each of the major environmental statutes. The
Regulatory Update Table provides information on regulatory initiatives of interest to DOE operations and
contractor staff with environmental management responsibilities. The table tracks regulatory developments
and is updated each month with information from the Federal Register and other sources, including direct
contact with regulatory agencies. Each table entry provides a chronological record of the rulemaking process
for that initiative with an abstract and a projection of further action.
37
Air Risk Information Support Center (Air
RISC)—Technical Support to State and Local
Agencies for Risk Assessment
Chon R. Shoaf and Daniel 3. Guth, U.S. Environmental Protection Agency
The Air Risk Information Support Center (Air RISC) was initiated in early 1988 by the Environ-
mental Protection Agency (EPA) Office of Health and Environmental Assessment and the Office of
Air Quality Planning and Standards (OAQPS) as a technology transfer effort that would focus on
providing information to state and local environmental agencies and to Environmental Protection Agency
(EPA) regional offices in the areas of health, risk, and exposure assessment for toxic air pollutants. Provi-
sion of technical assistance to the state and local agencies is key to supporting their greater regulatory role
as envisioned in the EPA's National Air Toxics Strategy announced in 1985. Technical information is fos-
tered and disseminated by Air RISC's two primary activities—technical assistance and guidance projects on
air toxic, health, and educational issues and staffing a "hot line" to provide immediate response to state and
local inquiries. Technical assistance and guidance projects have included a wide variety of activities in risk
assessment and risk communication, short-term assessments of hydrogen chloride, a glossary of terms
related to risk assessment, a directory of information resources related to risk assessment, and training
courses on risk assessment. In the 2 years since inception, the scientists at the Environmental Criteria and
Assessment Office and OAQPS have responded to 1131 calls from state and local agencies. (This abstract
does not necessarily reflect EPA policy.)
260 Access/Use Info Resources Assess Health Risk Chem Expos '93
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38
Risk Assistant
John Schaum, Environmental Protection Agency and
John Young, Hampshire Research
Risk Assistant is a microcomputer-based software system being developed by the Environmental Pro-
tection Agency (EPA) in conjunction with Hampshire Research for the purpose of conducting risk
assessments. It is designed to be applied to specific sites and chemicals. The user inputs the chemi-
cal concentration data at the point of exposure, and the system retrieves the relevant toxicological data, pro-
vides defaults for the various exposure parameters, and produces a report summarizing the results and
important assumptions. The system uses a pull-down menu interface with on-screen help covering both
operational and scientific information. It requires an IBM-XT equivalent or higher machine. The currently
available version is a Beta-type, and a final release is scheduled for late 1990.
39
Development and Application of Numeric Files
Derived from Toxicologic Experimentation
Sidney Siegel, National Library of Medicine
P
I resented as a poster session will be rationale for the development and maintenance of information
resources to be supportive of the efficient and cost-effective accomplishment of the assessment and
management of risk.
Identified and outlined are issues relevant to the development, use, and acceptance of numeric files derived
from published toxicologic experimentation.
Access/Use Info Resources Assess Health Risk Chem Expos '93 261
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Agenda
(All platform sessions for the symposium will be held in the Auditorium of the American Museum
of Science & Energy. Poster sessions will be held in the Ballroom of the Garden Plaza Hotel. The
American Museum of Science & Energy is located behind the Garden Plaza Hotel.)
Tuesday Evening, June 26,1990
5:00-8:00 Registration (Garden Plaza Hotel)
Wilma J. Barnard, Conference Secretary, ORNL
Poster Setup
Entertainment
Moon Miller, Spring City, Tennessee
Wednesday Morning, June 27,1990
7:00-8:00 Registration (Garden Plaza Hotel)
Wilma J. Barnard, Conference Secretary, ORNL
8:00 Symposium Introduction and Overview,
Po-Yung Lu, ORNL
(American Museum of Science & Energy)
Welcome Stephen V Kaye, ORNL;
William H. Farland, EPA
8:10
Introduction, rrieeting overview, and purpose
Po-Yung Lu, ORNL
8:25-10:30 Chemicals, Health Effects, and Information Needs
Introduction Po-Yung Lu, ORNL, Chair
8:30 The problem of living in a world contaminated with
chemicals
Robert L Metcalf, University of Illinois
9:00 The environmental laws regulating chemicals
Jeffrey M. Gaba, Southern Methodist University
9:30 Information needs for risk assessment
Christopher T. DeRosa and Rita S. Schoeny, EPA
10:00 Information needs for risk management/communication
David A. Bennett, EPA
Access/Use Info Resources Assess Health Risk Chem Expos '93 263
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10:30-10:45 Break
10:45-12:15 Toxicology Information Resources, Challenges, and Needs
Introduction John S. Wassom, ORNL, Chair
10:45 Evolution of toxicology information systems
John S. Wassom, ORNL
11:15 Information and technology: a coexistence without limits,
a beginning with no apparent ending...
David J. Reisman, EPA
11:45 The challenge of information access
Linda A. Trovers, EPA.
Wednesday Afternoon, June 27,1990
12:15-1:30 Lunch
1:30-3:05 Application of Toxicology Information for Establishing
Priorities for Chemical Testing, Hazard Ranking, and
Assessment
Introduction Babasaheb R. Sonawane, EPA, Chair
1:35 Structure-activity relationships (SARs) to assess new
chemicals under TSCA
Angela E. Auletta, EPA
2:05 Quantitative genetic activity graphical profiles for use in
chemical evaluation
Michael D. Waters, EPA
2:35 Interagency Testing Committee chemical selection process
John D. Walker, ITC
3:05-3:20 Break
3:20-5:30 Guidelines Used to Assess Toxicological Hazards
Dorothy E. Patton, EPA, Chair
3:30 EPA's program for risk assessment guidelines: Overview
Dorothy E. Patton, EPA
4:00 Cancer classification issues
Jeanette Wiltse, EPA
4:30 Quantification issues
Michael L Dourson, EPA
5:00 Exposure issues
Michael A. Callahan,EPA
264 Access/Use Info Resources Assess Health Risk Chem Expos '93
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Wednesday Evening, June 27,1990
5:45-7:30 Poster Session/Demonstrations (Garden Plaza Ballroom)
Refreshments and Entertainment
Moon Miller, Spring City, Tennessee
Thursday Morning, June 28,1990
8:00-10:00 Poster Session/Demonstrations (Garden Plaza Ballroom)
10:15-10:45 Rapporteur Summary Sidney Siegel, NLM
(American Museum of Science & Energy)
10:45-5:30 Information Applications
Introduction Christopher T. DeRosa, EPA, Chair
11:00-3:00 Panel discussion on how information resources are used
by federal agencies in risk assessment applications
Penny Fenner-Crisp, EPA, Rapporteur
ATSDR Deborah A. Barsotti
DOD-US Army William E. Legg
DOE-ORO Timothy W. Joseph
EPA-Region III Richard Brunker
FDA Angela Turturro
Thursday Afternoon, June 28,1990
12:00-1:30 Lunch
NIOSH Leslie T. Stayner
NTP James K. Selkirk
USDA-FS Dennis R. Hamel
USDA-FSIS Wesley A. Johnson
2:20-3:00 Questions from audience
3:00-3:30 Break
3:30-5:30 Panel discussion on how information resources are used
by state agencies in risk assessment applications
Stephen M. Dizio, California, Rapporteur
California
Connecticut
Illinois
Louisiana
Massachusetts
Stephen M. Dizio
David R. Brown
Clark S. Olson
Suzanne M. Gardner
Carol Rowan West
265
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New Jersey Gloria B. Post
Tennessee Bonnie S. Bashor
5:00-5:30 Questions from audience
Friday Morning, June 29,1990
8:00-9:25 Information Files and Data Base for Evaluating Health
Hazards From Chemical Agents (American Museum
of Science & Energy)
Introduction Linda A. Trovers, EPA, Chair
8:05 Rapporteur summary of session on information
applications
Federal agency perspective: Penny Fenner-Crisp, EPA
State agency perspective: Stephen M. Dizio, California
8:45 EPA data bases for risk assessment
Linda Tuxen, EPA
9:05 ORNL data bases for health effects assessment
Po-Yung Lu, ORNL
9:25-12:30 Information Resource Development/Integration/
Communication/ Transfer for Assessing Health.Effects
from Chemical Exposure
Introduction Robert H. Ross, ORNL, Chair
9:30 Application of the Federal Technology Transfer Act to
health risk assessment
Larry Fradkin and Christopher T. DeRosa, EPA
10:00-10:10 Break
10:10-12:00 Panel discussion on information resources for assessing
health effects from chemical exposure: Challenges,
priorities, and future issues
William H. Farland, EPA, Moderator
Deborah A. Barsotti, ATSDR
Penny Fenner-Crisp, EPA
Chon R. Shoaf, EPA
11:00-11:15 Break
Bonnie S. Bashor, Tennessee
Robert O. Beauchamp, Jr., CITE
Heinrich V. Mailing, NIEHS
Sidney Siegel, NLM
Linda A. Travers, EPA
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Friday Afternoon, June 29,1990
12:00-12:30 Questions from audience
12:30-1:00 Concluding Remarks: Where Do We Go From Here?
William H. Farland, EPA
1:00 Adjournment
2:30 ORNL Overview (Optional)
Truman D. Anderson, ORNL
267
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Author Index
Adamson, Anne E. 243
Arnesen, Stacey J. 256
Auletta, Angela E. 53,245,255,
257
Baratta, Maria 163
Bashor, Bonnie S. 169
Bast, Cheryl B. 244,248,254
Beauchamp, Jr., Robert O. 211
Bennet, David A. 31
Blakely, David H. 252
Brown, Mary M. 257
Callahan, Michael A. 107
Campbell, Sherry J. 239
Cantilli, Robert 250
Caton, Gloria M. 250,259
Choudhury, Hartal 21,254
Cimino, Michael C. 252, 255, 257
Cogliano, V. J. 254
Cosmides, George J. 253
Crawl, James R. 255
Crutcher, Judy W. 258
Cubbison, Christopher H. 241, 248,
254
Danford, Geraldine S. 245
Darr, James F. 240
Daugherty, Mary L. 254
Davidson, Mary Ann C. 244,246
Davidson, Kowetha A. 254
DeRosa, Christopher T. iii, 21, 244,
248,253,254
DiZio, Stephen M. 145
Dourson, Michael L. 103
Ehrlich,Alan 195
Etnier, Elizabeth L. 247
Farland, William H. iii, 231
Faust, Rosemarie 254
Fenner-Crisp, Penelope 141, 203
Fisher, J.W. 249
Floyd, Lois M. 258
Fradkin, Larry 195
Francis, Mary W. 241,244,249
Francis, Andrew A. 244,254
Gaba, Jeffrey M. 13
Gardner, Suzanne 155
Garrett, Neil E. 61
Gatchett, Annette M. 195
Gibson, Robert E. 248
Coins, Linda F. 246
Gorman, Thomas 195
Gove,RuthM. 249
Guth, Daniel J. 205,260
Haas, Roswitha T. 239,243,245,
246
Hamel, Dennis R. 133
Hardin, Bryan 123
Heckman, Cynthia G. 259
Heddle, John A. 252
Holland, Florence M. 245
Houlberg, Linda M. 247, 259
Hovatter, Patricia S. 247, 248,254
Hubner, Sibyll M. 255
Hurst, Pei-Fung 253
Jackson, Marcus A. 61,242
Jarabek, Annie M. 252
Jepson, G.W. 249
Johnson, Wesley A. 135
Joseph, Timothy W. 115
Access/Use Info Resources Assess Health Risk Chem Expos '93
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Joy, Suzanne E. 250
Kavlock, Robert J. 242
Kilgore, Donald G. 239,243
Kimmel, Carole A. 256
Kissman, Henry M. 256
Kline, Betty W. 255
Knox, Nancy P. 246
Langston, Marilyn E. 259
Legg, William E. 113
Leitzke, John S. 240
Lu, Po-Yung iii, v, 35, 179, 244,
249, 253, 255
Mailing, Heinrich V. 219
Mansfield, Betty K. 243
Mavournin, Kathleen H. 244, 252
Mayes, Michael D. 243
McGeorge, Leslie 163
Meinhardt, Theodore 123
Metcalf, Robert L. 1
Miller, Kathy C. 239
Miller, Ida C. 241,244
Moore, Michael 195
Muhly, Robert 247,248
Nikbakht, Patricia A. 259
Olson, Clark S. 151
Opresko, Dennis M. 254
Owen, Park T. 246
Owens, Elizabeth T. 242, 243
Patterson, Jacqueline 242
Patton, Dorothy E. 95
Peirano, W. Bruce 253
Pfuderer, Helen A. 239
Pierce, Linda B. 255
Post, Gloria B. 163
Rao.K. S. 246
Rawl, Richard R. 249 '
Reisman, David J. 43,244
Richmond, Andrea A. 249
Ross, Robert H. 247, 249, 254
Salamone, Michael F. 252
Salk, Marti S. 259
Schaum, John 261
Schoeny,R. S. 21
Schwetz, Bernard A. 256
Selkirk, James K. 129
Shoaf, Chon R. 205,252, 260
Siegel, Sidney 109, 227, 261
Slusher, Kimberly G. 241
Smith, Bennett G. 254
Stack, H.Frank 61, 242
Stafford, Robert S. 244,253
Stayner, Leslie T. 123
Stockstill, Julia M. 259
Talmage, Sylvia S. 247,254
Travers, Linda A. 49,240
Turturro, Angelo 119
Tuxen, Linda 173,242
Uppuluri, Shigeko Y. 245
UzieLMaiyS. 258
Vaughan, T. Owens 242
Von Halle, Elizabeth S. 244, 257
Walker, John D. 71
Wassom, John S. iii, 35, 179, 219,
244
Waters, Michael D. 61,242
Weaver, Karen A. 244
Weaver, Rose S. 247
Welch, Miriam J. 249
West, Carol Rowan 159
Whitfield, Bradford L. 244, 251
Wiltse, Jeanette 97
Wolfson, Sharon 163
Wyrick, Judy M. 243,259
Young, John 261
Young, Robert A. 249,254
Yust, Laura N. 243
270 Access/Use Info Resources Assess Health Risk Chem Expos '93
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Addresses
Adamson, Anne E.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
Aebischer, Judith A.
226 Hendrix Drive
Oak Ridge, TN 37830
Auletta, Angela E.
Health and Environmental Review
Division
Office of Toxic Substances
U.S. Environmental Protection Agency
Washington, DC 20460
Barnard, Wilma J.
Oak Ridge National Laboratory
RO. Box 2008, MS 6050
Oak Ridge, TN 37831
Barnthouse, Lawrence W.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6036
Oak Ridge, TN 37831
Barsotti, Deborah A.
Division of Toxicology (MS E-29)
Agency for Toxic Substances and
Disease Registry
1600 Clifton Road N.E.
Atlanta, GA 30333
Bashor, Bonnie S.
Environmental Epidemiology
Cordell Hull Building
Nashville, TN 27247-4912
Bast, Cheryl B.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
Beauchamp, R. O. Jr.
1608 Green Pine Court
Raleigh, NC 27614
Bennett, David A.
Toxics Integration Branch (OS-230)
Office of Emergency and Remedial
Response
U.S. Environmental Protection Agency
Washington, DC 20460
Ben ton, Mary
Oak Ridge Associated Universities
P.O. Box 117
Oak Ridge, TN 37830
Bishop, Jack B.
National Toxicology Program
National Institute of Environmental
Health Sciences
P.O. Box 12233
Research Triangle Park, NC 27709
Blevins, John, Jr.
601 Jackson Elementary School
Kingsport, TN 37660
Brazell, Thomas L.
Martin Marietta Energy Systems, Inc.
Building C710, MS 8398
P.O. Box 1410
Paducah.KY 42001
Brown, David R.
Preventable Diseases Division
Department of Health Services
State of Connecticut
119 Washington Street
Hartford, CT 06106
Brown, Elise A.
USDA-Food Safety Inspection Service
68 UNesbitt Place
McLean, VA 22101
Brown, Mary M.
St. Eustatius
Netherlands Antilles
Brumback, Vicki J.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6383
Oak Ridge, TN 37831
Brunker, Richard
Remedial Support Section (3HW15)
U.S. Environmental Protection Agency
Region in
841 Chestnut Building
Philadelphia, PA 19107
Buchan, Leca
Bechtel National, Inc.
P.O. Box 350
Oak Ridge, TN 37830-0350
Access/Use Info Resources Assess Health Risk Chem Expos '93 271
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Burnett, Bonnie H.
550 Old Wagon Road
Seymour, TN 37865
Callahan, Michael A.
Exposure Assessment Group
Office of Health and Environmental
Assessment (RD-689)
U.S. Environmental Protection Agency
401 M. Street, SW
Washington, DC 20460
Campbell, Sherry
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
Cantilli, Robert E.
Office of Drinking Water (WH-5501)
U.S. Environmental Protection Agency
401 M Street, SW
Washington, DC 20460
Caton, Gloria M.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
Cheng, Jing-Jy
Argonne National Laboratory, EID
809 Columbia Lane
Darien.IL 60559
Choudhury, Harlul
Environmental Criteria and Assessment
Office
U.S. Environmental Protection Agency
Cincinnati, OH 45268
Cimino, Michael C.
Office of Toxic Substances
Health and Environmental Review
Division (TS-796)
U.S. Environmental Protection Agency
401 M Street, SW
Washington, DC 20460
Coffey, Mike
PAI Corporation
116 Milan Way
Oak Ridge, TN 37830
Cogliano, James
Carcinogen Assessment Statistics
and Epidemiology Branch
Human Health Assessment Group
OHEA (RD-689)
U.S. Environmental Protection Agency
401 M Street, SW
Washington, DC 20460
Cole, Deborah
Oak Ridge National Laboratory
P.O. Box 2008, MS 6191
Oak Ridge, TN 37831
Conrad, Daniel E.
Martin Marietta Energy Systems, Inc.
P.O. Box 2009
Oak Ridge, TN 37831-8103
Copeland, Kimberly D.
Publication Division
105 Inn Lane Apt. #104
Oak Ridge, TN 37830
Cosmides, George J.
Toxicology Information Program
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
Cowne, Robert W.
Alabama Dept. of Environmental Mgt. -
Air Div.
1751 Cong. W.L. Dickinson Drive
Montgomery, AL 36130
Crutcher, Judy W.
701SCA, MS 8240
Oak Ridge, TN 37830
Cubbison, Christopher H.
Environmental Criteria and Assessment
Office
U.S. Environmental Protection Agency
26 West Martin Luther King Drive
Cincinnati, OH 45268
Gumming, Robert B.
Martin Marietta Energy Systems, Inc.
P.O. Box 2009
Oak Ridge, TN 37831-8103
Danford, Geraldine S.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
Daugherty, Mary L.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
Davidson, Mary Ann C.
117 Orange Lane
Oak Ridge, TN 37830
Davidson, Kowetha A.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
272 Access/Use Info Resources Assess Health Risk Chem Expos '93
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Davis, Charles D.
Martin Marietta Energy Systems, Inc.
Bldg. 9201-5, MS 8156
Oak Ridge, TN. 37830
Deck,KathyS.
U.S. Centers for Disease Control
Chamblee 27 F-29
Atlanta, GA 30333
DeLucia, Anthony J.
East Tennessee State University, College
of Medicine
Box 19750-A
Johnson City, TN 37614
DeRosa, Christopher T.
Agency for Toxic Substances and
Disease Registry
1600 Clifton Road
Atlanta, GA 30333
Dickey, Mark W.
Martin Marietta Energy Systems, Inc.
Bldg. 9733-1
Oak Ridge, TN 37830
DiZio, Stephen M.
Department of Toxic Substances Control
California Environmental Protection
Agency
P.O. Box 942732
Sacramento, CA 94234-7320
Dolan, Linda C.
Martin Marietta Energy Systems, Inc.
Bldg. 9115, MS 8223
Oak Ridge, TN 37830
Dorsey, G. F.
Martin Marietta Energy Systems, Inc.
P.O. Box 2009
Oak Ridge, TN 37831-8097
Douglas, Terence A.
General Electric Co., Neutron Devices
. Dept
P.O. Box 2908
Largo, FL 34649
Dourson, Michael L.
U.S. Environmental Protection Agency
26 Martin Luther King Drive
Cincinnati, OH 45268
Dupuy, Carolyn J.
Preventable Diseases Division
Department of Health Services
State of Connecticut
119 Washington Street
Hartford, CT 06106
Ehrenshaft, Anne R.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6352
Oak Ridge, TN 37831
El-hawari, Monaem
Midwest Research Institute (MRI)
425 Volker Blvd.
Kansas City, MO 64110
Emison, John A.
The Oak Ridger
785 Oak Ridge Turnpike
Oak Ridge, TN 37830
England, M. W.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6123
Oak Ridge, TN 37831
Ensminger, John T.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6200
Oak Ridge, TN 37831
Etnier, Elizabeth L.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
Fagin, Roy
United Airlines
36 Tanager Lane
Levittown, NY 11756
Farland, William H.
Office of Health and Environmental
Assessment
U.S. Environmental Protection Agency
Washington, DC 20460
Farmer, Geraldine T.
Tennessee Department of Education
4th Floor-North Wing, Cordell Hull
Building
Nashville, TN 37243-0279
Faust, Rosemaric
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
Fehr,Jo-AnnS.
P.O. Box 423
Norris, TN 37828
Feker,A. Estes
Tennessee Valley Authority
Chattanooga, TN 37412
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Fenner-Crisp, Penny
Health Effects Division
Office of Pesticides Programs
U.S. Environmental Protection Agency
Washington, DC 20460
Ferrell, Wanda R.
Office of Scientific and Technical
Information
U.S. Department of Energy
P.O. Box 62
Oak Ridge, TN 37831
Floyd, Lois M.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
Fore, Cathy
Martin Marietta Energy Systems, Inc.
HAZWRAP
MS 7606
Oliver Springs, TN 37840
Fradkin, Larry
Office of Technology Transfer and
Regulatory Support (H-8105)
U.S. Environmental Protection Agency
401 M Street, SW
Washington, DC 20460
Francis, Andy A.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
Francis, Mary W.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
Frank, Marilyn L.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6036
Oak Ridge, TN 37831
Gaba, Jeffrey M.
Southern Methodist University
School of Law
Dallas, TX 75275
Gardner, D. O.
Martin Marietta Energy Systems, Inc.
Bldg. 9201-5, MS 8156
Oak Ridge, TN 37830
Gardner, Suzanne M.
Policy Analysis and Planning
State of Louisiana
Department of Environmental Quality
P.O. Box 44066
Baton Rouge, Louisiana 70804
Garrett, Janice K.
Oak Ridge National Laboratory
P.O. 2008, MS 6109
Oak Ridge, TN 37831
Gentile, Chris C.
Allied-Signal Inc.
Kansas City Division
P.O. Box 419159
Kansas City, MO 64141-6159
Gibson, Robert E.
701SCA, MS 8240
Oak Ridge, TN 37830
Coins, Linda F.
Martin Marietta Energy Systems, Inc.
Building K1210, MS 7256
Oak Ridge, TN 37831
Gove, Ruth M.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
Gray, Thomas M.
The Dial Corporation
15101 N. Scottsdale Road
Scottsdale, AZ 85254
Greer, Jack K., Jr.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6395
Oak Ridge, TN 37831
Gupta, R. K.
Martin Marietta Energy Systems, Inc.
K-1001.MS7139
Oak Ridge, TN 37830
Guth, Daniel J.
Environmental Criteria and Assessment
Office (MD-52)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Haas, Roswitha T.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
Hamel, Dennis R.
Pesticide Specialist
U.S. Department of Agriculture - Forest
Service
P.O. Box 96090
Washington, DC 20090
Harris, Wilbur C.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6390
Oak Ridge, TN 37831
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Hastings, Constance M.
Consulting Technical Editea/Technical
Writer
1641 West Forest Blvd.
Knoxville, TN 37909
Hattemer-Frey, Holly A.
Advanced Sciences, Inc.
120 S. Jefferson Circle, Suite 101
Oak Ridge, TN 37830
Hawthorne, Alan A.
Route 1, Box 308G
Rural Retreat, VA 24368
Hawthorne, Sherry W.
Route 1, Box 308G
Rural Retreat, VA 24368
Hayes, Lisa A.
Exxon Biomedical Sciences
Mettlers Road, CN2350
East Millstone, NJ 08875-2350
Hayes, William P.
Indiana Department of Environmental
Management
5500 West Bradbury Avenue
Indianapolis, IN 46241
Heckman, Cindy G.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
Hoffmeister, John A.
Martin Marietta Energy Systems, Inc.
P.O. Box 2003
Oak Ridge, TN 37831-7212
Holder, Brenda W.
U.S. Department of Energy
Gennantown, MD
Holland, Florence M.
107 Carnegie Drive
Oak Ridge, TN 37830
Honea, Robert B.
Oak Ridge National Laboratory
P.O. Box 2008, MS-6179
Oak Ridge, TN 37831-6179
Horakova, Zdenka Z.
USDA-Forest Service
5508 Oakmont Avenue
Bethesda, MD 20817 ,
Houlberg, Linda M.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
Hovatter, Patricia S.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
Hubner, Sibyll M.
500 Mellen Road
Knoxville, TN 37919
Hurst, Pei-Fung
U.S. Environmental Protection Agency
Environmental Criteria and Assessment
Office
26 West Martin Luther King Drive
Cincinnati, OH 45268
Infante, Peter F.
OSHA Department of Labor
RoomN3718
200 Constitution Avenue
Washington, DC 20210
Ironside, Kevin S.
Health and Safety Research Division
Oak Ridge National Laboratory
Oak Ridge, TN 37831
Jackson, Marcus A.
Environmental Health and Testing
P.O. Box 12199
Research Triangle Park, NC 27709
Jeffers, Linda J.
Oak Ridge National Laboratory
P.O. 2008, MS 6145
Oak Ridge, TN 37831
Jepson, G. W.
Toxic-Hazards Division
Armstrong Laboratory
Wright-Patterson AFB, OH 45433-6573
Jeter, Nancy Jo
Cherokee Middle School
2016 Cedar Lane
Kingston, TN 37763
Johnson, Glenda J.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
Johnson, Wesley A.
Food and Drug Adminstration
Beltsville, MD
Joseph, Timothy W.
U.S. Department of Energy/Oak Ridge
Field Office
Oak Ridge, Tennessee 37831
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Joy, Suzanne E.
Oak Ridge National Laboratory
P.O. 2008, MS 6050
Oak Ridge, TN 37831
Just, Robert A.
Martin Marietta Energy Systems, Inc.
Bldg.9115,MS-8223
Oak Ridge, TN 37831
Karger, Eva R.
Polaroid Corp.
1265 Main Street
Waltham, MA 02254
Kaye, Stephen V.
Analyses Corporation
101-A East Tennessee Avenue
Oak Ridge, TN 37830
Kilgore, Donald G.
Martin Marietta Energy Systems, Inc.
MAXIMA, MS 8227
Oak Ridge, TN 37830
Kimmcl, Carole A.
U.S. Environmental Protection Agency
Office of Health and Environmental As-
sessment (RD-689)
401 Main St., SW
Washington, DC 20460
Kline, Betty W.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
Knox, Nancy P.
Martin Marietta Energy Systems, Inc.
Building K1210, MS 7256
Oak Ridge, TN 37831
Langs ton, Marilyn E.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
Larsen, Fred N.
Allied-Signal Inc., Kansas City Division
Dept. 837-XD43
P.O. Box 1159
Kansas City, MO 64141
Lcgg, William E.
Health Risk Assessment Branch
U.S. Army Environmental Hygiene
Agency
Department of Defense
Aberdeen Proving Ground, MD 21010-
5422
Leitzke, John S.
U.S. Environmental Protection Agency
Chemical Screening Branch (TS-778)
Washington, DC 20460
Loebl, Andrew S.
Martin Marietta Energy Systems, Inc.
P.O. Box 2003
Bldg. K-1001, MS-7170
Oak Ridge, TN 37831
Lu, Po-Yung
Oak Ridge National Laboratory
P.O. 2008, MS 6050
Oak Ridge, TN 37831
Lux, C. J.
Martin Marietta Energy Systems, Inc.
Quality and Technical Services
Portsmouth, OH
Mailing, Heinrich V.
National Institute of Environmental
Health Sciences
P.O. Box 12233
Research Triangle Park, NC 27709
Mansfield, Betty K.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
Mavournin, Kathleen H.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
May, Larry
Martin Marietta Energy Systems, Inc.
P.O. Box 2003, Bldg. 1310H
Oak Ridge, TN 37831
Ma yes, Michael D.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37830
McNeely, Brooks N.
Oak Ridge National Laboratory
P.O. Box 2008, MS-6396
Oak Ridge, TN 37831
Metcalf, Robert L.
320 Merrill Hall
University of Illinois
Dept. of Entomology
Urbana.IL 61801
Miller, Ida C.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
276 Access/Use Info Resources Assess Health Risk Chem Expos '93
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Miller, Kathy C.
701SCA, MS 8240
Oak Ridge, TN 37830
Mora-Applegate, Ligia I.
FDER/BWC
2600 Blairstone Road
Tallahassee, FL 32301
Morris, Stanton R.
California Dept. of Food & Agriculture
1601 12th Street, #16
Sacramento, CA 95814
Mower, L. Marie
Martin Marietta Energy Systems, Inc.
P.O. Box 2009
Oak Ridge, TN 37831
Munger, Frank
The Knoxville News Sentinel
204 West Clinch Avenue
P.O. Box 59038
Knoxville, TN 37950-9038
Nikbakht,A.
1505 Michaux Road
Chapel Hill,NC 27514
Olson, Clark S.
Illinois Environmental Protection Agency
2200 Churchill Road
Springfield, IL 62706
Opresko, Dennis M.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
Owen, Park T.
Martin Marietta Energy Systems, Inc.
Building K1210, MS 7256
Oak Ridge, TN 37831
Owens, Elizabeth T.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
Patton, Dorothy E.
U.S. Environmental Protection Agency
Risk Assessment Forum (RD-689)
401 M Street, SW
Washington, DC 20460
Peddicord, Jerry L.
Martin Marietta Energy, Systems, Inc.
Lithium Opr. Div.
P.O. Box 2009
Bldg. 9204-2, MS-8128
Oak Ridge, TN 37831
Pfuderer, H.A
701SCA, MS 8240
Oak Ridge, TN 37830
Phillips, Mary H.
Martin Marietta Energy Systems, Inc.
Central HAZWRAP, MS 7606
Oliver Springs, TN 37840
Pierce, Linda B.
Oak Ridge National Laboratory
P.O. Box 2008
Oak Ridge, TN 37831
PoIifka,JanineE.
TERIS-University of Washington
Dept. of Pediatrics, WJ-10
Seattle, WA 98195
Porter, Randy L.
Allied-Signal Inc., Kansas City Division
P.O. Box 41959
Kansas City, MO 64141-6159
Post, Gloria B.
Division of Science and Research
New Jersey Department of Environ-
mental Protection CN409
Trenton, NJ 08625
Rao, K. S.
1144 Lovell View Drive
Knoxville, TN 37922
Rawl, Richard R.
Martin Marietta Energy Systems, Inc.
Chinn Building, Room 203, MS 6495
Oak Ridge, TN 37830
Reichle, David E.
Oak Ridge National Laboratory
P.O. Box 2008, MS-6253
Oak Ridge, TN 37831
Reisrnan, David J.
Environmental Criteria and Assessment
Office
U.S. Environmental Protection Agency
26 West Martin Luther King Drive
Cincinnati, OH 45268
Ress, John F.
Eastman Chemicals Company
B-54D
Kingsport, TN 37665
Rich, Joe L.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6035
Oak Ridge, TN 37831
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Richmond, Andrea A.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6235
Oak Ridge, TN 37831
Richmond, Robert S.
2912 Glendale Road
Knoxville, TN. 37917
Rivera, Rommel L.
Oregon Dept. of Environmental Quality
811SW Sixth Avenue
Portland, OR 97007
Roberts, Suzan L.
Martin Marietta Energy Systems, Inc.
Building K1210, MS 7256
Oak Ridge, TN 37831
Robinson, Allen
Kentucky Natural Resources & Environ-
mental Protection Cabinet
Dept. of Environmental Protection, Divi-
sion of Water
1800 Rielly Road
Frankfort, KY 40601
Ross, Robert H.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
Rubinstein, Rona L.
Martin Marietta Energy Systems, Inc.
Environmental Restoration Division
P.O. Box 2003
Oak Ridge, TN 37831-7256
Sabins, Dugan
Department of Environmental Quality
Office of Water Resources
P.O. Box 44091
Baton Rouge, LA 70804^091
Sakalosky, George P.
PAI Corp.
116 Milan Way
Oak Ridge, TN 37830
Schaum, John L.
Exposure Assessment Methods Branch
U.S. Environmental Protection Agency
401 M Street, SW
Washington, DC 20460
Schoeny, R. S.
Environmental Criteria and Assessment
Office
U.S. Environmental Protection Agency
26 West Martin Luther King Drive
Cincinnati, OH 45268
Scott, Shermonica E.
North Carolina A&T State University
106 Inn Lane Apt W
Oak Ridge, TN 37830
Selkirk, James K.
Carcinogenesis and Toxicology
Evaluation Branch
National Institute of Environmental
Health Sciences
P.O. Box 12233
Research Triangle Park, NC 27709
Shelton, Jean
Martin Marietta Energy Systems, Inc.
Lithium Opr Div.
P.O. Box 2009
Bldg. 9119.MS-8236
Oak Ridge, TN 37831
Shoaf, Chon R.
Environmental Criteria and Assessment
Office (MD-52)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Siegel, Sidney
Building 38A, Room 4S406 (MS 47)
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
SI usher, Kimberly G.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
Smith, Bennett G.
Environmental Criteria and Assessment
Office
U.S. Environmental Protection Agency
26 West Martin Luther King Drive
Cincinnati, OH 45268
Solti, Judith
Exxon Biomedical Sciences, Inc.
Mettlers Road
East Millstone, NJ 08875
Sonowane, Babasaheb R.
U.S. Environmental Protection Agency
Environmental Criteria and Assessment
Office
26 West Martin Luther King Drive
Cincinnati, OH 45268
Stack, H. F.
Environmental Health Research and Test-
ing (MD-69)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27709
278 Access/Use Info Resources Assess HealUi Risk Chem Expos '93
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Stafford, Robert S.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
Stayner, Leslie T.
Division of Standards Development &
Technology Transfer
National Institute for Occupational
Safety and Health
Cincinnati, OH 45 626
Stief, Stan S.
PAI Corp.
116 Milan Way
Oak Ridge, TN. 37830
Stiefel, Michael B.
Martin Marietta Energy Systems, Inc.
Environmental Restoration Division
P.O. Box 2003
Oak Ridge, TN 37831-7256
Stivers, Jr., Robert M.
Martin Marietta Energy Systems, Inc.
P.O. Box 2009
Oak Ridge, TN 37831-8014
Stockstill, Julia M.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
Swindle, David W.
Martin Marietta Energy Systems, Inc.
Environmental Restoration Division
P.O. Box 2003
Oak Ridge, TN 37831-7256
Talmage, Sylvia S.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
Teves, Mary R.
Public Participation Coordinator
Environmental Planning Office
Department of Health .
Five Waterfront Plaza, Suite 250
500 Ala Moana Boulevard
Honolulu, HI 96813
Thompson, Rod B.
Indiana Dept. of Environmental Manage-
ment
5500 West Bradbury Avenue
Indianapolis, IN 46241 ,
Tobler, Jack
Integrated Laboratory Systems
P.O. Box 13501
Research Triangle Park, NC 27709
Travers, Linda A., Director
Information Management Division
Office of Toxic Substances
U.S. Environmental Protection Agency
401 M Street, SW
Washington, D.C. 20460
Traylor, Dennis
U.S. Department of Energy
Office of Scientific and Technical
Information
Building 1916-T1, Room 134
Oak Ridge, TN 37831
Trinker, D. W.
Westinghouse Savannah River Company
Aiken, SC 29801
Turturro.Angelo
National Center for Toxicological
Research
Jefferson, AR 72079
Tuxen, Linda
Office of Health and Environmental
Assessment (RD-689)
U.S. Environmental Protection Agency
401 M St., SW
Washington, DC 20460
Uppuluri, Shigeko Y.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
Uziel, Mary S.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6382
Oak Ridge, TN 37831
Vaughan, T. O.
Genetic Toxicology Division (MD-68)
Health Effects Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Veach, Lynn H.
Martin Marietta Energy System, Inc.
Information Services
P.O. Box 2009, MS-8079
Oak Ridge, TN 37831
Von Halle, Elizabeth S.
113 Wendover Circle
Oak Ridge, TN 37830
Vowell, Rachel H.
Cherokee Middle School
17 Cooper Lane
Oak Ridge, TN 37831
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Walker, John D.
Office of Toxic Substances (TS-792)
Interagency Testing Committee
U.S. Environmental Protection Agency
401 M Street, SW
Washington, DC 20460
Wassom, John S.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
Waters, Michael D.
Genetic Toxicology Division (MD-68)
Health Effects Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Weaver, Karen A.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
Weaver, Rose S.
Martin Marietta Energy Systems, Inc.
Building K1001, MS 7117
Oak Ridge, TN 37831
Welch, Miriam J.
Martin Marietta Energy Systems, Inc.
Chinn Building, MS 6495
Oak Ridge, TN 37830
West, Carol Rowan
Office of Research and Standards
Department of Environmental Protection
1 Winter Street
Boston, MA 02108
Westerman, Albert
Kentucky Natural Resources & Environ-
mental Protection Cabinet
Dept. of Environmental Protection, Div.
of Water
1800 Rielly Road
Frankfort, KY 40601
Whitfield, Brad L.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
Wilkinson, Vance K.
Oak Ridge National Laboratory
P.O. Box 2008, MS-8088
Oak Ridge, TN 37831
Wilson, Carl
Martin Marietta Energy Systems, Inc.
Engineering Division
Building 9201-2. MS 8072
Oak Ridge, TN 37831
Wilson, Jeffrey David
Martin Marietta Energy Systems, Inc.
HAZWRAP
Bldg.TRCOMS-7606
Oak Ridge, TN 37831
Wilson, Karen T.
Oak Ridge National Laboratory
P.O. Box 2008, MS-6035
Oak Ridge, TN 37831
Wilson, Lee Ann
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
Wilson, Marialice
Science Applications International Corp.
P.O. Box 2501
Oak Ridge, TN 37831
Wiltse,Jeanette
Office of Health and Environmental
Assessment
U.S. Environmental Protection Agency
401 M Street, SW
Washington, DC 20460
Wong, Jeffrey J.
State of California
Department of Health Services
Toxic Substances Control Program
714-744 p Street
P.O. Box 942732
Sacramento, CA 94234-7320
Woodall, Steve
Georgia Hazardous Waste Management
Program
Athens, GA 30601
Wormell, Richard L.
Health and Environmental Review Divi-
sion
Office of Toxic Substances
U.S. Environmental Protection Agency
Washington, DC 20460
Wyrick, Judy M.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
Young, John S.
The Hampshire Research Institute
1600 Cameron Street, Suite 100
Alexandria, VA 22314
Young, Robert A.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
280 Access/Use Info Resources Assess Health Risk Chem Expos '93
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Yust, Laura N.
Oak Ridge National Laboratory
P.O. Box 2008, MS 6050
Oak Ridge, TN 37831
Zenick, H.
Health Effects Research Laboratory
(MD-51)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27709
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