oEPA
United States
Environmental Protection
Agency
EPA-600/9-80-049
October 1980
Chemical Testing and
Assessment Research
Committee — Research
Strategy 1979 - 1985
-------
EPA-600/9-80-049
October 1980
CHEMICAL TESTING AND ASSESSMENT
RESEARCH COMMITTEE - RESEARCH STRATEGY
1979-1985
PREPARED JOINTLY BY:
Office of Research and Development
and
Office of Toxic Substances
U.S. ENVIRONMENTAL PROTECTION AGENCY
Washington, D.C. 20460
-------
PREFACE
The U.S. Environmental Protection Agency relies on thirteen Research
Committees to integrate the planning of the bulk of its research programs
with the research needs of EPA's regulatory and operational programs.
Each Committee addresses a specific portion of the programs managed and
implemented by the Agency's Office of Research and Development (ORD).
The overall structure of the Committees and corresponding ORD programs
are aligned to the organizational structure and function of EPA's
regulatory offices: the Office of Pesticides and Toxic Substances; the
Office of Air, Noise and Radiation; and the Office of Water and Waste
Management. EPA's ten Regional Offices, Office of Enforcement, and
Office of Planning and Management are represented on each Committee as
well.
Developed by the Chemical Testing and Assessment Research Committee,
this particular document presents a multi-year strategy for ORD's
programs on Toxic Substances. Like its twelve counterparts, this
strategy is intended to serve as a basis for preparing each fiscal year's
program proposals and for reviewing the progress of ORD's ongoing effort.
The document will be updated annually by the Research Committee to refine
the strategy and help assure the program's responsiveness to emerging
concerns and priorities.
APPROVED BY
Stephen . Gage
Assistant Administrator
for Research and Development
V
S'teven D. Jelinek
Assistant Administrator
for Pesticides and Toxic
Substances
AUGUST, 1980
-------
TABLE OF CONTENTS
Preface i
CHAPTER ONE (EXECUTIVE SUMMARY)
Section 1 Introduction 1
Section 2 Toxic Substances Control Act - A New Law 3
I. Regulation Under TSCA 4
II. Implementation of TSCA 6
Section 3 TSCA vs. Toxic Substances 7
Section 4 Chemical Testing and Assessment Research Committee .... 10
I. Committee Membership 10
II. Committee Charter 12
CHAPTER TWO (TSCA AND THE PROGRAM AND REGIONAL OFFICE STRATEGIES)
Section 1 Office of Pesticides and Toxic Substances Strategy .... 15
I. OPTS Organization and
Function Related to TSCA 15
II. Program Priorities 16
III. Program Strategy 17
iii
-------
Section 2 Office of Enforcement Strategy 20
I. Enforcement Strategy 20
II. Enforcement Objectives 22
Section 3 Regional Program Strategy 24
I. Regional Office Toxic
Substances Control Programs 24
CHAPTER THREE (RESEARCH STRATEGY)
Section 1 Overview 27
I. Testing Schemes 28
II. Hazard Assessment 30
Section 2 Technical Assistance 33
Section 3 Quality Assurance 35
I. Quality Assurance Program 35
II. FY-80 Planned Programs 36
Section 4 Health Effects Research Strategy 37
I. Overview 37
II. Testing and Assessment 40
A. Acute, Subchronic, and Chronic Testing 42
B. Teratogenesis Testing and Reproductive Toxicity. . 55
C. Neurotoxicology 66
D. Mutagenicity Testing 73
E. Carcinogenicity Testing 80
IV
-------
F. Metabolism • 89
G. Epidemiology 93
III. Chemical Specific Concerns 1°°
A. Evaluation of Asbestos
And Asbestos-Like Minerals 10°
Section 5 Environmental Research Strategy 104
I. Overview 104
A. Research Priorities 109
B. Program Structure 111
II. Testing and Assessment 112
A. Transport and Fate
(Exposure Assessment) 116
B. Environmental Effects
(Hazard Assessment). • 135
Section 6 Monitoring Research Strategy 161
I. Overview 161
A. Research Priorities 162
B. Implementing Structure 163
C. Program Structure 164
II. Testing and Assessment 164
A. Methodology Development And
Measurement System Research 166
B. Field Collection Methodology
And Monitoring Activities 178
III. Chemical Specific Concerns 184
A. Background and Status 184
B. Research Strategy 185
C. Research Program 186
Section 7 Environmental Engineering and
Technology Research Strategy 194
-------
I. Overview 194
II. Background and Status 195
III. Research Goals 195
IV. Research Approach 197
APPENDIX 200
VI
-------
Chapter One
Executive Summary
SECTION 1
INTRODUCTION
This document was prepared by the Chemical Testing and Assessment
Research Committee, established in March, 1979, by the Assistant
Administrator for the Office of Research and Development (ORD), U.S.
Environmental Protection Agency (EPA). The committee's main function is
to address the increased chemical testing and assessment needs resulting
from the enactment of the Toxic Substances Control Act of 1976 (TSCA).
Included in this responsibility are the establishment of a TSCA research
strategy and the provision of aid in developing a TSCA implementation
program which provides for g_uality assurance.
Over the last decade, concern about the impact of toxic substances
has resulted in the passage of a broad range of environmental
legislation. TSCA was promulgated as "back-up" legislation for these
acts. The Clean Air Act (CAA) and the Clean Water Act (CWA) provide for
regulation of emission or discharge of toxic substances to air and
surface waters. The Marine Protection Research and Sanctuaries Act
(MPRSA) controls disposal of toxic substances in the marine environment.
Protection of ground waters from toxic insult and control of toxic
substances in potable water is mandated by the Safe Drinking Water Act
(SDWA). The Federal Insecticide, Fungicide and Rodenticide Act (FIFRA)
regulates the use of pesticides, and the Resource Conservation and
Recovery Act (RCRA) will regulate the land-based disposal of hazardous
1
-------
waste materials. TSCA serves not only to reinforce all of these Acts,
but also to fill in the regulatory and data information gaps existing
among them.
The Office of Pesticides and Toxic Substances (OPTS), Office of
Enforcement (OE), and EPA Regional Offices reflect the Agency's focus on
toxic substances control in all of their program implementation
activities. This is seen in the ongoing Regional research efforts for
air, water, soild waste, water supply, pesticides, and especially toxic
substances media, and the OPTS annd OE efforts for TSCA implementation.
The Chemical Testing and Assessment Research Committee serves to advise
the Assistant Administrator concerning these research efforts.
-------
SECTION 2
TOXIC SUBSTANCES CONTROL ACT - A NEW LAW
The Toxic Substances Control Act is a major environmental statute
designed to help eliminate future detriments to the public or environment
caused by toxic substances. Several key provisions within TSCA permit
EPA to fill the gaps in earlier-promulgated mandates. EPA is currently
working to implement all of these provisions.
TSCA is significant in two major areas from the standpoint of toxics
control. First, it requires the screening of new chemicals prior to
manufacture and distribution in commerce, thereby preventing the
introduction of unreasonably hazardous chemicals into the environment.
Second, it provides for comprehensive control of existing chemicals shown
to pose unreasonable health or environmental risks; control options range
in severity from bans on manufacturing or use to strict disposal
requirements. However, TSCA control action can only be taken where
appropriate protection is not already afforded by other environmental and
health-related legislation. To insure that public health and the
environment are protected from unreasonable chemical risk, TSCA provides
broad information-gathering authority to EPA, including the authority to
require testing of chemicals by industry in cases where data are needed
to evaluate the risks posed by these compounds.
-------
I. REGULATION UNDER TSCA
Section 4 of TSCA provides EPA authority to require manufacturers
and/or processors to test their chemicals for health and environmental
effects. This authority is selective, applying only to those chemicals
for which the Agency can make certain findings as to the need for
testing. A Section 4 testing requirement cannot be applied to all new
chemicals. All testing requirements under Section 4 are imposed by rule;
each rule specifies not only the chemicals to be tested, but also the
nature and standards of the required tests.
The testing provisions of TSCA are designed to support the need of
other agencies and to supplement other statutes such as the Occupational
Safety and Health Act (OSHA) or the various consumer protection laws. In
fact, Section 4(e) establishes an Interagency Testing Committee (ITC)
which is to recommend priority chemicals for testing under TSCA.
Section 5 of TSCA establishes a premanufacture notification process
for all new chemicals and chemicals proposed for significant new uses (as
designated by rule). A new chemical is any chemical not contained in an
EPA-compiled inventory of existing chemicals. The manufacturers of these
chemicals are required to submit specified information to the Agency at
least 90 days prior to production. The Agency has an opportunity to
review the submission for 90 days (extendable to not more than 180 days).
Unless during this period EPA finds that the chemical poses an
unreasonable risk or demonstrates a need for additional testing, the
chemical is placed on the inventory without restriction.
-------
Sections 6 and 7 of TSCA provide the control authority for existing
chemicals: Section 6 is the general regulatory authority; Section 7
gives the Agency special powers to address imminent hazards. This
authority is tempered by Section 9, which requires EPA to determine that
regulation under other statutes (e.g. OSHA, CAA, RCRA, or CPSA) is not
more appropriate, before TSCA's authority can be invoked. Apart from
this limitation, TSCA empowers EPA to limit the production, distribution,
disposal, or use of chemicals to prevent unreasonable risks to health
or the environment.
The authority to require information reporting is given to EPA in
Section 8 of TSCA, and reflects the inadequacy of knowledge about which
chemicals are produced, in what amounts, for what purposes, and with
what consequences. The information required ranges from the submission
of commercial- to exposure- to hazard-related data.
Section 8(a) contains the general reporting authority provided by
TSCA. Section 8(b) is the mandate to collect and compile an inventory of
chemicals in commerce. Record-keeping and reporting of adverse effects
information are covered by Section 8(c). Section 8(d) empowers the
Agency to obtain industry and publicly-held health and safety data, and
Section 8(e) mandates the submission of information supporting the
conclusion that there may be a substantial risk to health or the
environment.
As for other TSCA authorities, Section 8 provisions are designed to
supplement other statutory mandates and to support the needs of addi-
tional programs in carrying out their responsibilities.
-------
The remaining sections of TSCA emphasize the need for coordination
of information and research on toxic substances.
II. IMPLEMENTATION OF TSCA
Since the passage of TSCA, preliminary test schemes and assessment
approaches have been developed. In the next five years, EPA will revise
and expand health and environmental test methods and will develop
standards for characterizing chemicals and their fates. Standards for
environmental effects testing will likewise be developed.
TSCA testing will most probably follow a tiered approach, beginning
with test procedures to determine whether a substance needs further
investigation. The main factors considered by ORD in developing a toxic
substances research program are: (1) provision of specialized technical
assistance to resolve complex problems; (2) development of research
capabilities to meet the time frames of TSCA implementation; (3) develop-
ment of a comprehensive long-range research program to refine continually
the test methods and logic assessment schemes; and (4) achievement of
continuity and stability in the research program in order to meet future
challenges.
-------
SECTION 3
TSCA vs. TOXIC SUBSTANCES
The commercial production of chemicals has followed a trend of
steady increase in the U.S., resulting in the present day production of
over 40,000 compounds. This increase in production has naturally
augmented the presence of toxic substances in the environment and an
increase in adverse effects resulting from their use and disposal. To
address the wide variety of problems inherent in toxic chemical usage,
extensive environmental legislation (as discussed in Section 1) has been
promulgated over the past decade. In relation to this legislation, TSCA
serves as an "umbrella" mandate, aimed at filling in the research and
data information gaps. Unfortunately, in proportion to the pervasiveness
of toxic substances in the environment, neither TSCA nor the other
promulgated legislation is sufficiently inclusive to solve all or even
most of the problems toxic substances present.
In November 1977, the American Chemical Society had a registry of
four and one half million distinct chemical substances (not including
compounds cited before 1965). Of the 40,000+ compounds currently being
produced in the U.S., the manufacture of at least 50 of them exceeds a
rate of 1.3 billion Ib/yr. Revenue collected from the production and
distribution of chemicals amounts to 7% of the U.S. Gross National
Product (GNP).
-------
The risks involved with toxic substances must be weighed against the
benefits derived in order to achieve a feasible and effective regulatory
strategy for toxic substances. As our society continues to become more
industry-oriented, chemical production and usage are predicted to
increase steadily, especially in the plastics industry. Although
increased production introduces more toxics into the environment, it also
offers many benefits: new and improved medicines; higher quality
consumer goods; better fertilizers for increased food production; etc.
The regulation dilemma is often referred to as determining "maximum
benefit at acceptable risk."
One of the major obstacles facing EPA regulatory programs is the
lack of sufficient data on which to base their regulatory decisions. The
production of chemicals has increased so rapidly over such a short period
of time that research, in effect, has not had time to "catch up." The
adverse environmental and human health effects resulting from the use of
most chemicals have yet to even be discovered.
Acute toxic effects have received the most attention to date. Out
of necessity, the study of long-term chronic effects, environmental
transport and fate, and biological pathways have received less attention,
both in terms of funds and time. Moreover, the Agency has in recent
years experienced a shortage of laboratory facilities and trained
professionals in the areas of toxicology, industrial hygiene, pathology,
and other relevant areas.
-------
Perhaps the greatest research need for toxic substances is the
development of methods for evaluating the ecological effects and chemical
fate of toxics in the environment. If such methods were made available,
hazardous chemicals could be identified prior to environmental incidents.
Latency periods for diseases caused by exposure to toxic substances may
often extend from 20 to 40 years. In the past, such delayed effects have
not been identified until well after the chemicals have been introduced
into the environment. For example, mercury, nitroso compounds,
chloroform, kepone, and the dioxins were manufactured in great quantities
until they were discovered to be extremely hazardous to both the environ-
ment and humans. Thus, the crux of toxics control is uncovering such
deleterious effects from unsuspected substances.
Although the environmental legislation currently in effect and the
authority allowed by TSCA for expanded control of industrial production
are doing much to solve the toxics dilemma, extensive research is still
required to prevent further hazard in the future. In addition, the
problems already apparent still require enormous effort to reach any
viable solution. This effort will require far more than what the present
legislation can offer, both in output of labor and availability of
funds.
-------
SECTION 4
CHEMICAL TESTING AND ASSESSMENT RESEARCH COMMITTEE
I. COMMITTEE MEMBERSHIP
The Chemical Testing and Assessment Research Committee (CTARC) is
one of thirteen research committees established by ORD under its revised
planning process. These committees were formed to explore the
effectiveness of joint committee strategy development for regulatory,
operational, and research programs. Each committee is responsible for
the development of a research strategy for one of the thirteen "research
modules" covered under the ORD program: Water Quality; Municipal
Wastewater and Spill Prevention; Drinking Water; Industrial Processes;
Solid Waste; Mobile Source Air Pollution; Oxidants; Gaseous and
Inhalation Particulate Pollutants; Hazardous Air Pollutants; Radiation;
Energy; Pesticides; and Chemical Testing and Assessment. As suggested
by its name, CTARC is responsible for the Chemical Testing and Assessment
module.
The Office of Pesticides and Toxic Substances is the regulatory
program office related to the Chemical Testing and Assessment module.
Thus, ORD and OPTS work in liaison through CTARC to develop a research
strategy. CTARC also works closely with the Office of Enforcement, which
works to enforce the implementation program adopted by OPTS.
10
-------
According to directives set forth by the Assistant Administrator of
ORD, CTARC is co-chaired by a senior OKD official and a senior OPTS
official. Dr. Michael Waters of ORD and Dr. Warren Muir o OPTS were
originally named co-chairmen of CTARC. In April 1980, these positions
were assumed by Dr. Vilma Hunt of ORD and Dr. James Reisa of OPTS. The
membership of the committee includes representatives from the Office of
Enforcement, Office of Pesticides and Toxic Substances, Office of
Research and Development, the EPA Regional Offices, and the Office of
Planning and Management.
At its organizational meeting in April 1979, CTARC established three
subcommittees to plan the research effort for the testing and assessment
of chemicals: (1) the health subcommittee; (2) the environmental
subcommittee; and (3) the monitoring subcommittee. Each subcommittee is
co-chaired by a senior member of ORD and of OPTS.
Until 1980 Dr. Ronald Baron (ORD) and Dr. Jerry Williams (OPTS)
served as co-chairmen of the health subcommittee, and Mr. Clinton Hall
(ORD) and Dr. James Reisa (OPTS) headed the environmental subcommittee.
Currently, Dr. Ronald Baron (ORD) and Dr. C. C. Lee (OPTS) serve as
co-chairmen of the health subcommittee, and Dr. William Murray (ORD) and
Dr. Michael Heeb (OPTS) head the environmental subcommittee. The
monitoring subcommittee is co-chaired by Ms. Phyllis Daly (ORD) and Mr.
Martin Halper (OPTS). A new subcommittee on Environmental Engineering
and Technology has recently been established and is co-chaired by Mr.
Carl Shaffer (ORD) and Dr. Roger Garrett (OPTS).
11
-------
In addition, ORD's program on Stratospheric Modification Impact
Research has been incorporated into CTARC's area of concern. The program
addresses the effects on health and ecosystems of increased exposure to
ultraviolet radiation due to ozone depletion in the stratosphere.
Although the addition of this program to CTARC's purview is too recent to
include the program in the present document, it will be included in the
next updating of the strategy in early 1981. In the interim, the reader
may obtain a specific description of the research and its findings from
the annual report to Congress, "Results of Research Related to Strato-
spheric Ozone Protection."
II. COMMITTEE CHARTER
The CTARC charter, as set forth by ORD, charges the committee with
five major tasks:
Review the current program to familiarize all members
with the status of ongoing work.
Review the upcoming year's plans and formulate
appropriate recommendations to improve those
plans.
Participate in the development of budget year plans.
Develop a multi-year research strategy with sufficient
detail for use as a primary planning document in sub-
sequent years.
Review the quality of ongoing and recently completed
research.
The committee works within the framework of the EPA and Federal Planning
and budgeting cycles to aid in making responsible resources allocations.
The mechanism by which the committee operates is within the annual Zero
12
-------
Base Budgeting (ZBB) process. CTARC reviews all Decision Units (DU's)
relevant to its research module, ranking them in importance and
suggesting alterations. ORD considers these recommendations in their
final budget decision-making process.
A major output of the committee is the present research strategy
document which expresses the committee's view of the kinds of research
needed to support a given regulatory strategy area and the general
approach which should be taken. The strategy is related to EPA's overall
planning process in two ways, through the Research Outlook, and through
impact on the budget process.
The Research Outlook, an annual publication describing EPA's plans
for research over a four to five year period, consolidates and describes
the strategic aspects of the plans developed by the research committee.
At the same time, it builds on the findings of ORD's Strategic Analysis
Group on emerging environmental trends, pertinent results from the
Exploratory Research Program, and the insights of senior ORD personnel
(both at Headquarters and the laboratories). Information contained in
the strategy, coupled with specific scientific results that become
available, serve as building blocks for the Research Outlook.
The second interface between the research strategies and ORD's
planning process concerns the document's relationship to budget year
planning. The strategies provide major direction for the annual
preparation of ORD's Decision Units. These documents describe the
annual program proposals which enter the ZBB process and form the basis
13
-------
for both EPA's yearly budget submission to Congress and eventually the
program operating plan.
CTARC also serves to assure quality for ongoing and recently
completed research. Quality assurance (QA) and quality control (QC) are
the joint responsibility of the regulatory (OPTS) and the research (ORD)
contingents of the committee.
14
-------
Chapter Two
TSCA and the Program and Regional Office Strategies
SECTION 1
OFFICE OF'PESTICIDES AND TOXIC SUBSTANCES STRATEGY
I. OPTS ORGANIZATION AND FUNCTION RELATED TO TSCA
To implement the many facets of TSCA, three offices have been
established within the Office of Pesticides and Toxic Substances (OPTS).
The Office of Program Integration and Information (OPII) was
established to implement Section 8 reporting provisions; to coordinate
toxic substances information collection and retrieval systems; determine
the sources of toxic substances entering the environment; carry out field
measurements; and coordinate the various federal, state, and regional
toxic substance control programs.
The Office of Testing and Evaluation (OTE) was established as the
scientific institution responsible for testing recommendations and
requirements as well as environmental and health hazard and risk
assessments of new and existing chemicals.
The Office of Chemical Control (OCC) was created to be the focal
point for regulatory policy for new and existing chemicals. This office
contains the engineering and economic expertise necessary to evaluate
technical feasibility and the economic consequences of contemplated
control actions.
15
-------
II. PROGRAM PRIORITIES
When TSCA was enacted, no significant organizational entity existed
to implement it. As a result, highest priority activities by OPTS since
passage have been those efforts necessary to build an institution capable
of undertaking the major task of implementation. These efforts have
included definition of organizational structure and function, staffing,
and establishing operating procedures and policies. Thus technical
service (obtained from ORD) has been one of the priorities of OPTS.
Considerable effort has also gone into establishing implementation
strategies for all of the key aspects of TSCA. Particular emphasis
during the early stages of implementation has been placed on those
program aspects that are relatively unique to TSCA. These include
evaluation aspects of TSCA (i.e. information collection and risk
assessment) and the Premanufacture Notification (PMN) provisions of
Section 5. Longer-term priorities include a greater emphasis on existing
chemical regulatory activity.
To evaluate chemicals, OPTS has established a multi-stage risk
assessment process designed both to take advantage of ad hoc information
(e.g. Section 8(e) substantial risk notices), and to systematically
select chemicals for the next level of analysis. In discrete stages,
chemicals undergo increasingly detailed analysis with judgments made
concerning the adequacy of the available information and the need for
regulatory or non-regulatory control action. In later stages, the
assessment process is designed to carry out the analysis of risks
16
-------
effectively enough to support regulatory actions under TSCA or other
statutes.
III. PROGRAM STRATEGY
Each of the tasks outlined above requires the development and
application of validated measures and techniques to assure quality. Data
base precision and accuracy used for risk assessment and regulatory
decisions will be achieved through a quality assurance program that
covers personnel, methods, equipment, and data handling procedures. The
quality assurance program is to be applied to each of these components
individually as they function in an integrated research system.
OPTS will use the Section 8(b) inventory and Section 8(a) reporting
information to provide sufficient information to systematically select
chemicals entering the assessment process. If at any time a chemical or
chemical class is deemed important enough to continue assessment,
although key information is lacking, a Section 8(a) and/or 8(d) reporting
rule, a monitoring study, and/or a Section 4 rule will be considered to
obtain the necessary data.
In FY 78 and 79, much effort went into defining this process and
initiating it for a selection of chemicals. In FY 80 and 81, the system
should reach a steady state with certain chemicals feeding into
regulatory processes as new ones enter evaluation.
To gather needed testing data, Section 8(d) rules are employed to
identify unpublished existing studies. If testing is needed, Section 4
17
-------
would generally be used to require industry to generate the necessary
data. To implement Section 4, a series of test standards will be
proposed through separate rulemaking for incorporation into test
rules. TSCA requires that these standards be reviewed and revised as
appropr a ely as possible, at least annually. Activities in FY 78 and FY
79 focused on an initial set of test standards for health effects
testing. Test standard activities in FY 80 and 81 will stress revision
and expansion of these health test methods, as well as the development of
standards for chemical characterization, fate, and environmental effects
testing.
The first test rules under Section 4 will be proposed in FY 80. The
scope of the initial rules will be those chemicals recommended by the
Section 4(e) Interagency Testing Committee (ITC). As soon as the Agency
"catches up" to ITC, it is expected that Section 4 will be used to
generate testing of those chemicals arising from the assessment process
and categories of chemicals important to other programs and agencies.
With publication of the Section 8(b) Inventory of Chemicals in
Commerce on June 1, 1979, the Section 5 new chemical premanufacture
notification requirement went into effect. Most of the Section 5 efforts
in FY 78 and 79 focused on laying the necessary procedural and policy
foundation for the notification process. Interpretative rules containing
a submission form have been proposed.
Although statutory authority to require testing is lacking, OPTS has
been considering issuing new chemical testing guidance to clarify what
18
-------
approach to testing the Agency would advocate for new chemical producers.
In FY 79 a pre-proposal discussion document was published in the Federal
Register. Proposed guidance is scheduled for FY 80.
19
-------
SECTION 2
OFFICE OF ENFORCEMENT STRATEGY
I. ENFORCEMENT STRAGEGY
The effective implementation of Section 4 is vital to the success of
almost all other TSCA programs. Data submitted pursuant to Section 4
rules will assist the Agency in determining which chemicals should become
subjects of further scrutiny through reporting or control regulations.
Inspection strategies are being prepared to assure that the testing
standards and rules are carried out properly by the testing facilities.
Violations will be detected during these inspections and submitted test
data performed by OPTS will be reviewed.
Section 5 represents an information-gathering mechanism crucial to
the overall success of the TSCA program. The focus of the Office of
Enforcement program concerning Premanufacture Notification regulations is
the detection of "failure to notify" or "noncompliance'1 violations.
Headquarters, acting with the assistance of OPTS, will target candidates
for inspection. Inspections will be conducted primarily by the Regions,
and enforcement actions will be directed primarily by Headquarters.
Section 6 rules are chemical-specific control regulations. To date,
three chemical control regulations have been promulgated. The rules
20
-------
pertain to polychlorinated biphenyls (PCBs) and chlorofluorocarbons
(CFCs). The major phases of the Section 6 enforcement program are as
follows:
Identify persons and facilities subject to the
regulations.
« Notify such persons of the requirements of the
rule and the potential consequences of violative
behavior.
• Establish criteria governing the position a particular
company occupies in an insepction-priority hierarchy.
o Develop guidelines for use by inspection personnel.
« Initiate compliance monitoring activities, including,
if applicable, inspections, market sampling, literature
review, and analysis of submitted data.
o Formulate a strategy for the prosecution of
violators, including the ranking of violations
and the development of penalty policy.
• Analyze data furnished through compliance monitoring
activities and adjust enforcement strategy.
Section 7 authorizes the Administrator to seize and/or apply for
equitable relief from imminently hazardous chemical substances or
mixtures. The Office of Enforcement will not conduct an affirmative
program to unearth emergency incidents. Rather, EPA will respond to
imminent hazard situations when they are reported to the Agency. OE's
involvement will focus on:
the rapid and efficient processing of imminent hazard
i nformation
the bringing of a Section 7 action
the enforcement of any orders handed down
by the appropriate judicial authorities
21
-------
In addition to ongoing PCB and CFC compliance programs, OE will
concentrate its FY 80 efforts on enforcing the inventory reporting
requirements, Section 8(e) substantial risk notification requirements,
Section 8(c) requirements regarding maintenance and reporting of
allegations of significant adverse reactions, and Section S(d) health and
safety reporting requirements.
OE is currently working on a Toxic Substances Control Act Penalty
System, which will serve to determine civil penalties against violators
of the Act. The primary goal of the TSCA penalty policy is to encourage
compliance with the Act, without setting penalties higher than is
necessary to do so. The general penalty system is designed to achieve
this goal while fulfilling the following requirements:
o Provide consideration of all of the penalty-affecting
factors required by TSCA.
• Be structured enough to treat violators consistently
and fairly.
Be flexible enough to accommodate new and varied
regulations to be promulgated under TSCA.
O Base penalty amounts on readily available facts and
data.
II. ENFORCEMENT OBJECTIVES
The six main objectives set forth by the Office of Enforcement are:
(1) defining methods for assigning priorities to chemical substances for
investigations and regulations, (2) establishing procedures for testing
and evaluating chemical hazards, (3) initiating actions for information
22
-------
gathering, (4) establishing mechanisms for the premanufacture
notification of new chemical substances, (5) conducting laboratory
inspections and case preparation in relation to data fraud, and (6)
developing a coherent Agency-wide approach to toxic substances.
To accomplish these goals which relate to the Headquarters programs
with oversight to the Regional programs, technical support from ORD will
be needed in two sections of TSCA.
To meet Section 4 requirements, OE will need the analytical
capability to analyze feed samples (obtained by inspectors while auditing
an ongoing study) for test substance concentration. Pathology services
for evaluation/interpretation of selected slides from a study will also
be required by OPTS.
To satisfy Section 6 requirements, OE will need technical assistance
from ORD in three main areas, namely:
The development of standard analytical protocols
for specific chemicals as they are identified for
regulation. For existing Section 6 regulations,
the development of methods for analyzing PCBs in
mineral oil, waste oils, pigments and other media,
and CFCs (fully halogenated chlorofluoroalkanes)
in aerosol products.
The development of multi-media environmental
field sampling methodologies for PCBs and
other controlled chemicals.
The development of a rapid biological screening
technique for PCBs and priority toxic chemicals.
23
-------
SECTION 3
REGIONAL PROGRAM STRATEGY
I. REGIONAL OFFICE TOXIC SUBSTANCES CONTROL PROGRAMS
The Regional Offices reflect the Agency's focus on toxic substances
control in all of their program implementation activities. This is seen
in the ongoing Regional efforts in the air, water, solid waste, water
supply, pesticides, and toxic substances media.
Direct TSCA-related activities include enforcement, information
gathering to assist the Office of Pesticides and Toxic Substance's review
of Premanufacture Notification, provision of technical assistance to
industry and other affected groups in complying with TSCA regulations and
voluntary chemical control programs, monitoring of TSCA Section 28 State
cooperative agreements, etc. The Regional Offices are integrating toxic
substances control activities in all media to maximize their program
impact and operational effectiveness.
Effective enforcement of TSCA regulations, especially those
promulgated under Section 6, requires the development of standard
analytical methods for regulated substances in the specific media that
will be encountered (air, water, soils, oil, etc.). Vigorous quality
assurance is essential to ensure the validity of analytical data
generated. Accordingly, methods development and definition of
appropriate quality assurance considerations should commence at an early
24
-------
stage of regulation development to assure that they are fully established
when the regulations become effective.
A prominent activity that spans many program concerns is the
identification of and response to environmental and health related
situations involving chemical substances. These situations are
identified in any number of ways. They can be brought to the Agency's
attention by the public, private industry, other governmental agencies,
or our own activity in the Regional Office or at Headquarters. When
identified, these situations must be evaluated to determine the nature
and extent of the Agency's response. The Regional Office must decide if
action is warranted and how best to achieve control. The process is
similar to the analysis the Administrator must make to involve TSCA in a
hazardous situation.
Although these situations can usually be characterized as problems
with respect to one or more specific media such as air or water, they
invariably involve presently unregulated substances. The first decision
that must be made is whether or not the situation poses a health or
environmental threat sufficient to warrant control. The Regional Offices
often look to ORD and OPTS in this regard for technical assistance in the
areas of environmental and health effects assessment and environmental
monitoring. Where the appropriate surveillance and analysis capability
is provided, this monitoring can be effectively performed by the Regional
Offices. Often, however, resource limitations prevent extensive
monitoring, and assistance is needed from ORD and/or other Headquarters
program offices. This assistance could be in the form of direct ORD
25
-------
analytical support or ORD/OPTS contractor support. By close coordina-
tion of Headquarters contract and direct monitoring efforts and Regional
Office requirements, monitoring activities can serve multiple needs.
Once a decision on the need for control has been made, appropriate
action is taken. This action, when possible, will involve existing
regulatory authority under the Clean Air Act, Clean Water Act, Safe
Drinking Water Act, etc., where such action can effectively deal with the
situation. When existing authorities are inadequate, the Regional Office
will recommend consideration by the Administrator for such action under
TSCA.
Finally, the Regions are faced with many and varied situations
associated with disposal of toxic substances. Assistance from ORD for
development and assessment of toxic substances disposal alternatives will
be required.
26
-------
Chapter Three
Research Strategy
SECTION 1
OVERVIEW
This chapter presents a detailed review of the research needs,
strategies, and programs for the major areas of research conducted by EPA
in support of TSCA: health effects research; environmental effects
research; monitoring research; and environmental engineering technology
research.
Chemical testing and assessment are the major emphases of all
research efforts. For the health effects research component, the testing
and assessment needs, strategy, and program are concerned with seven
areas of study: (1) acute, subchronic, and chronic toxicity testing;
(2) teratology and reproduction; (3) neurotoxicology; (4) mutagenicity
testing; (5) carcinogenicity testing; (6) metabolism; and (7) epidemi-
ology. Testing and assessment research for the environmental component
will concentrate on environmental exposure and assessment techniques and
methodologies. Monitoring testing and assessment needs fall mainly in
the areas of toxic substance identification and control. Environmental
engineering and technology will provide research on direct exposure and
control options relative to the manufacturing, marketing, and use of
chemicals.
Chemical specific concerns are also included in the research
efforts, and are discussed, when applicable, at the end of each section.
27
-------
I. TESTING SCHEMES
In contrast to the battery approach traditionally employed for drugs
and pesticides, new chemical testing guidance and the generic approach to
Section 4 testing are anticipated to consist of a tiered testing scheme.
The tiered or step sequence approach to testing is the preferred
course, because unlike drugs and pesticides, commercial chemicals are not
designed to be biologically active and have high human or environmental
exposure. The tiered approach employs relatively quick and inexpensive
tests to determine the need for more thorough studies. This approach
offers the advantage of being able to direct scarce human financial
resources to those chemicals and circumstances for which the greatest
hazard or risk potential exists.
A subset of the tests in a generic tier scheme would probably be
most appropriate for specific chemicals (such as those recommended by the
Interagency Testing Committee) for which certain information generally
already exists. Unfortunately, for most effects, only less than optimal
tests are available which can be incorporated into a recommended or
required tiered testing scheme. A tiered approach implies the need for
two different types of tests, each with a specific set of
characteristics.
Tests of the first type are often referred to as screening tests.
The characteristics important for a screening test used under Section 4
or 5 of TSCA include:
28
-------
• defined protocol
• high sensitivity (few false negatives)
• at least moderate specificity (discriminating)
• relatively inexpensive
• relatively quick
• relatively easy to perform
• reproducible
• readily interpretable
• broad applicability
Often tests with such characteristics simply do not exist for
various effects. Fortunately, the state of toxicology is such that there
are numerous concepts or systems that are possible candidates for future
research. But, as described later, certain questions should be asked
before selecting which to pursue.
Tests of the second type are often called evaluation or assessment
tests. These tests logically follow screening tests and can be used to
evaluate a chemical sufficiently to support regulatory decisions under
Sections 5, 6, and 7 of TSCA and other statutes.
Evaluation tests should be reproducible, serve as a suitable model
of human or environmental exposure, and be useful for risk assessment
purposes (to the extent possible). For many, but not all effects, there
are evaluation tests that could be employed under TSCA. Unfortunately
these tests tend to be very expensive and time consuming. Few have
sufficient data bases to evaluate fully their relevance to humans or the
29
-------
environment. Thus, more work is often needed on the assessment science
for interpreting these tests than is needed for developing them. In some
cases, new or less expensive tests are needed as testing recommendations
are revised.
II. HAZARD ASSESSMENT
In its various assessment processes, OPTS faces a two-fold
scientific challenge. First, it must be able to evaluate for regulatory
purposes the results of tests that it prescribes. Second, it must be
able to carry out hazard assessments on data from the potpourri of
various tests that have been or will be performed on chemicals.
As much professional expertise as possible, both internal and
external, will be brought to bear on OPTS hazard assessments. However,
an enormous need still exists to improve our understanding of the meaning
of chemical tests results. Professional judgment needs to be superseded
by real data and fundamental knowledge.
In most instances, no good substitute for empirical information is
available to evaluate the relevance of a test system. For example, to
determine which professional judgment can be used to evaluate how
important a non-rodent species is as a supplement to a subchronic rodent
study, the best basis is actual experimental experience. Sometimes
partial studies compiled and evaluated are sufficient to make such a
judgment; however, preexisting information often needs to be supplemented
before confidence is placed on a judgment.
30
-------
Thus, OPTS sees the need to carry out additional experimental work
to better understand the significance of existing and proposed test
systems. OPTS suggests that an array of archetypal chemicals be agreed
upon from which chemicals would be chosen for validation, standardiza-
tion, and research studies on new and existing test systems. By doing so
there will be a better basis to cross correlate test systems.
ORD research to support hazard assessment science needs is required
by OPTS now and for the foreseeable future.
In some cases a sufficient basis exists to evaluate the dose-effect
curve in a hazard assessment and to relate the test system to humans or
the environment. Even in these cases, however, there is a need to evalu-
ate as best as possible human and environmental exposure and exposure
potential under a variety of different scenarios. This evaluation pro-
vides the basis for risk assessment and risk reduction analysis which are
a part of regulatory decision-making under TSCA and many other statutes.
Exposure assessment involves many different types of analyses,
including estimates and/or measurements of:
• environmental release
• environmental fate
• exposure through use
• exposure through distribution
• exposure through disposal
31
-------
Some aspects of these analyses can be handled through the develop-
ment and use of appropriate laboratory or field tests. Other aspects are
best handled by the development of suitable models. Field monitoring is
often needed to fill key data gaps and to evaluate the models used in
exposure assessments.
Thus, OPTS has a need for much research into exposure assessment
methodology, including:
• development and validation of certain fate test methods
• development and validation of certain monitoring methods
• development and validation of certain exposure and fate
models
32
-------
SECTION 2
TECHNICAL ASSISTANCE
Program needs for research and support from EPA's Office of Research
and Development fall into four categories: technical assistance; testing
methods; scientific foundations of risk assessment; and research on
certain chemicals of interest' The early years of TSCA implementation
will be building years, in which initial testing schemes and assessment
approaches are to be established. Thus, the greatest needs for ORD
support fall into the first three categories. As implementation matures
and a greater fraction of program resources flow into regulatory
activities under TSCA and other statutes, research and measurements on
certain chemicals for which Section 4 testing is not appropriate will be
increasingly important. Similarly, as more regulatory activities are
undertaken, greater needs for research and support will be generated by
the Regional programs and the Office of Enforcement, which will oversee
their implementation.
The Office of Pesticides and Toxic Substances' highest priority for
ORD support is for technical assistance. ORD has considerable experience
and expertise on many subjects relevant to OPTS program activities.
Included in these needs are technical input for and prior to Section 4
workgroup activities on test standard and test rule development. In
addition, technical input is desired on proposed approaches to testing,
monitoring, and various types of hazard and risk assessment under TSCA.
33
-------
Finally, ORD technical comment on specific assessments is needed to
assure the best possible product. This latter category may involve, for
example, input of particular experts on certain Section 5 premanufacture
notifications that raise issues related to their expertise.
We envision time and personal efforts of some of the best scientists
in ORD. Because much of the ORD expertise relevant to OPTS's needs is
located in laboratories remote from Washington, a significant allocation
of travel dollars will be required for scientists to attend key meetings
so that important details may be discussed directly.
ORD technical assistance in the areas of health/environmental
effects assessment and monitoring is also a high priority Regional
Office need. This assistance is often required to aid Regional
decision-making in response to potential problem situations involving
chemical substances.
34
-------
SECTION 3
QUALITY ASSURANCE
I. QUALITY ASSURANCE PROGRAM
The environmental monitoring research program plays a dual role with
quality assurance (QA) areas to provide both a review function for the
Agency's mandatory quality assurance program and a research effort in the
development of standardized methods andd protocols for monitoring testing
programs.
Consistent with the Administrator's policy statement of May 30,
1979, when instituting the mandatory quality assurance program for the
environmental monitoring program, all QA plans will be reviewed to assure
that appropriate practices are continued or, when necessary, implemented.
In addition to implementing the mandatory QA program and associated
research needs for environmental monitoring activities, the monitoring
research program will assist OPTS in developing suitable guidelines for
"Good Laboratory Practices" to guide industry in responding to testing
required by TSCA.
When required, assistance will also be provided in the development
of suitable quality assurance standards protocols. Many of the
standardized methods have or will be developed under other environmental
legislation. When such standards are unavailable for the purpose of
35
-------
TSCA, they will be developed under this program. As test standards and
guidelines are developed, quality assurance needs which are specific to
individual protocols will be developed in phase with protocol
development.
One immediately foreseeable need for FY-82 is the development of one
or more multimedia quality assurance centers to serve all EPA environ-
mental measurement programs. This need becomes increasingly evident as
other EPA programs branch out into multi-media investigations to meet
responsibilities under EPA legislative authorities. Other quality
control needs will be incorporated into the program as they are
identified.
II. FY-80 PLANNED PROGRAMS
• Develop a standardized protocol for sampling and
analyzing asbestos in bulk material such as ceilings.
Methods involve use of a polarized light microscope
for identification and counting and X-ray diffraction
for confirmatory analysis.
Develop quality control tools as needed for specific
protocols. Development needs to be phased with
protocol development.
36
-------
SECTION 4
HEALTH EFFECTS RESEARCH STRATEGY
I. OVERVIEW
The Toxic Substances Control Act of 1976 requires the Agency to
address questions dealing with methods to be used in the toxicological
evaluation of chemicals currently or potentially released to the
environment. Therefore, it is necessary for the Office of Health
Research (OHR) to work toward improving testing methodologies so that the
confidence placed on test results, both qualitative and quantitative, may
be increased.
Experimental animals have been used with a significant degree of
success in testing chemical substances or products to predict their
toxicity potential in humans. Historically, this testing has
concentrated on endpoints of acute lethality. However, as it has become
evident that the toxicity of chemicals may be delayed or cumulative in
many instances, morbidity as measured by systematic histopathological
examination has arisen as a consideration.
Toxic chemicals can impact a variety of target organs and a number
of physiological systems. As more chemicals are tested, it becomes
clearer that the systems which appear critical in acute toxicological
tests may not be those which are affected in chronic tests. Classic
incidences of this variation may be drawn from many chemicals, but the
37
-------
chlorinated hydrocarbons are perhaps the most pervasive examples.
Chloroform, a chemical commonly found in drinking water, became prominent
in medicine primarily for its effects on the central nervous system. The
depressant activity of chloroform on the nervous system made it one of
the first popular general anesthetics. Unfortunately, acute fatalities
due to chloroform are invariably a result of this same activity. Through
chloroform's continued use in medicine, however, it was soon found that
late fatalities from chloroform anesthesia were the result of liver and
kidney damage.
Chlorinated hydrocarbons used as pesticides are another example for
which acute disturbances of the central nervous system lead to tremors,
convulsions, and death, but long-term, low-level exposures result in
liver and kidney hyperplasia, nodular formation, and ultimate oncogenic
response. The bioaccumulation of many chlorinated hydrocarbons and the
accumulation of chlorinated hydrocarbons in storage depots lead to
continued toxic interactions long after acute or subacute exposure has
ended. These extended interactions give entirely different responses.
Animal experiments and human experience have repeatedly confirmed that
acute toxicity is a poor predictor of the chronic toxicity of a wide
variety of chemicals.
A second feature of chemical toxicity is that the route by which a
chemical contacts the animal can often dramatically affect the nature of
its toxicity. For example, the lung is often the target organ of
inhalation exposures to a chemical, whereas it would often not be a taget
organ if the same chemicl were encountered in the diet, drinking water,
38
-------
or other media. A chemical contacting the skin may produce a local
reaction rather than the systemic action which might occur if the
chemical were taken internally. Specific examples of the dramatic
influence the route of exposure can have on chemical toxicity include:
the pronounced central nervous system toxicity observed with inhaled
elemental mercury and the absence of such toxicity by the oral route; and
the lung proliferation noted on oral ingestion of paraquat and the
absence of such effects from dermal or inhalation exposure.
Results obtained from testing chemicals in different species have
made it increasingly evident that unexpected differences exist between
species and/or sex sensitivities and susceptibilities. In certain
instances, the bases for peculiar across-species or sex variability have
been resolved: different mechanisms may be involved in the metabolism of
a chemical in different species; or certain hormonal systems may be
involved in the toxicity observed. However, no general basis for such
differences has been established.
Finally, advancements in the understanding of certain types of
toxicity have allowed the development of presumptive tests for some types
of chronic toxicity. At present, these developments are best exemplified
in the area of chemicl carcinogenesis. The use of the somatic mutation
theory of chemical carcinogenesis has allowed the development of a number
of genetic assays in bacteria to be used as qualitative tests for
chemical carcinogens. The understanding of toxicological effects in
mechanistic terms is so poor in most areas, however, that such
methodologies have limited application outside the area of chemical
carcinogenesis and/or mutagenesis testing.
39
-------
II. TESTING AND ASSESSMENT
At the request of the Office of Testing and Evaluation (OTE), this
section has been organized in a manner corresponding to OTE's research
program. This organization leads to certain lapses in logic; for
example, the redundancy in discussing such issues as species differences
creates areas of artifactual overlap such as behavioral teratology, etc.
However, this organization does lend itself to more direct establishment
of functional contacts between OTE and the corresponding researchers
within OHR. Implicit in this organization is the weighing of priorities
across these research areas, allowing for (in extreme cases) the
abolition of one research area to meet a higher priority as perceived by
the Program Officer in another area.
The seven research areas discussed in this section are:
• Acute, subchronic, and chronic testing
• Teratology and reproduction
• Neurotoxicology
• Mutagenicity testing
® Carcinogenicity testing
• Metabolism
• Epidemiology
In the last analysis, the most cogent scientific evidence upon which
the regulatory function of OPTS can be predicated derives from direct
epidemiological study of the impact of a given exposure upon human
health. However, such an approach must be tempered by full appreciation
40
-------
of existing limitations in epidemiological technique when applied to the
problems confronting a regulatory agency. Nevertheless, in research
planning the pre-eminent role of epidemiological study merits full
emphasis.
Finally, this section addresses the question of toxicity testing
costs and effectiveness, which are of fundamental importance to the
enforcement of TSCA. As toxicological endpoints are increased in number
or the length of experiments is extended, the costs of testing chemicals
increase substantially. Since acute toxicity is not a predictor of
chronic toxicity, the question is whether or not subchronic toxicity is
an accurate predictor of chronic toxicity. If so, what mathematical
functions describe the differences between subchronic and chronic
toxicity to various organs? If a good fit can be achieved, what should
the minimum duration of subchronic testing be to predict adequately
toxicity observed over a lifetime in all target organs? Similar problems
exist in the more specialized areas of toxicological testing. In cases
where a latent period is definitely involved in the development of the
disease (e.g. cancer), the researcher would like to determine if some
constant relationship exists between precursor lesions and the
development of the life-threatening phase of the disease. There are
partial answers to some of these questions, but a data base has not been
developed which contains sufficient information to support testing
regulations and guidelines. Further work is needed to establish many of
the parameters required to establish an efficient means of assessing all
toxicological endpoints.
41
-------
A. ACUTE, SUBCHRONIC, AND CHRONIC TESTING
1. Background and Status
Toxicity testing falls into three basic categories, depending
primarily on the duration of exposure. Acute toxicity can be defined as
the adverse effects which occur following exposure to a test agent for 24
hours or less. This definition provides for the 24-hour exposure often
used in dermal procedures and the 1- to 8-hour exposures often used in
inhalation procedures. Subchronic toxicity procedures are designed to
detect adverse effects that may occur during repeated exposure over a few
days to a few months (usually to 90 days). The dosage levels used are
usually intended to be sublethal and directed towards detection of
specific target organ or system lesions. Subchronic studies are
considered essential to the design of lifetime studies (e.g. chronic
and/or oncogenicity studies). Chronic toxicity studies are generally
regarded as involving exposures ranging in duration from 6 months to the
lifetime of the test species. Generally, the classical chronic toxicity
test is supported as the only available experimental approach for
assessing long-term human health hazards. The basic tenets inherent to
all toxicological testing are: (1) use of multiple species; (2) long-
and short-term testing; and (3) consideration of the route(s) of
exposure. There is enough historical perspective on acute, Subchronic,
and chronic testing to justify the application of these testing
procedures to new chemicals and products immediately.
The major practical difficulty in acute, Subchronic, and chronic
testing is determining the point at which redundancy of testing becomes
42
-------
cost-ineffective. For example, given that species differences exist in
toxic responses to toxic chemicals, how many species must be tested in
acute, subchronic, and chronic phases before one gains a level of
confidence in the overall test results?
A second difficulty with utilizing historically-founded toxicologi-
cal testing methods is the question of what toxicity escapes detection.
In some respects, the historical record of the drug industry is not
comforting. Too often, toxicities dissociated from the desired
therapeutic effect of a drug (ruling out simple overdose or exaggerated
therapeutic effect as the mechanism) have been discovered in humans
rather than in pre-market toxicological testing. Such examples abound
and in large part are responsible for the development of some of the
specialized areas of toxicological study (with the notable exception of
mutagenesis since there are no known examples of a chemical mutagen in
humans). The current emphasis on teratology had its genesis in the
human experience with thalidomide. Liver and kidney damage associated
with halogenated organics such as those used as anesthetics or pesticides
serve as another example of toxicities first discovered in practice. The
toxicity of the anthracycline antibiotics for the heart was also first
discovered in humans, even though their use in medicine is quite recent.
Most of the problems associated with the use of oral contraceptives are
becoming evident through human epidemiology rather than through animal
experiments. More recently, the epidemiological literature has suggested
that a chemical used in the treatment of atherosclerosis improves the
symptoms of the disease but shortens the life span of patients. In view
of the vast number of chemicals entering the market as drugs, these and
43
-------
similar examples undoubtedly represent a small fraction of the chemicals
that are subjected to toxicological testing procedures. However, they do
demonstrate some of the limitations of the current methodology used in
toxicity testing.
Trade-offs between risks and benefits from environmental chemicals
are fundamentally different from those considered for drugs and
occupational exposures. The taking of drugs is for the individual's
personal benefit (i.e. therapeutic reasons) and is generally voluntary,
making some risk-taking acceptable. Occupationally, an individual does
at least receive compensation, which allows a personal means of weighing
risks and benefits. However, what level of risk-taking is acceptable
with environmental chemicals from which the individual may not derive any
direct personal benefit? Traditional toxicological tests will
undoubtedly still serve to define hazards; however, the demands for
accurate risk assessment have become more critical in the environmental
toxicology area because the impact of a chemical's effects on a large
population (as opposed to the individual) must be wieghed against
benefits attributable to the chemical. This difference makes the
definition of the dose-response characteristic of chemically-induced
disease processes and the responses of sensitive populations of much
greater importance. Thorough understanding of the quantitative and
qualitative variables operating in chemically-induced disease states is
essential for accurate and equitable risk/benefit analyses.
Much of the difficulty associated with general toxicological testing
is the question of how complete a picture is gained from the histopatho-
logical examination of major organs and tissues. Without doubt,
44
-------
histopathological examination is the most generalized and cost-effective
technique that can be applied to long-term testing procedures. However,
what is generally observed is simply evidence of cellular death and
resultant tissue necrosis. Such changes are late manifestations of
functional disturbances which can often be detected biochemically,
physiologically, and on an ultrastructural level far prior to and at
lower exposures than histopathological changes. The major source of
false negative results is the extent to which histopathological
techniques are insensitive to functional disturbances.
A second reason for false negatives is the inability to include
considerations of every possible endpoint in a testing protocol. The
pursuit of variables must often be based on consideration of the
documented toxicity of related chemicals to prevent the cost of a test
from being prohibitive. This technique has two weaknesses. First,
structure-activity relationships have very limited application in
toxicity testing since subtle changes in chemical structure often have
dramatic and unpredictable effects on toxicity. The only real successes
achieved with this technique have been situations in which pharmaco-
kinetics have limited biological effect or very specific chemical
receptor interactions were being dealt with. The second weakness is that
testing of analogues is rarely complete. For example, cardiovascular
diseases are the major cause of death in human populations, yet in
toxicological testing very little consideration is generally given to the
processes which give rise to cardiovascular disease. Depressed immune
function is a second example. Damage is undoubtedly done to the organism
45
-------
in this case, but the morbidity and mortality that result arise from
indirect causes. This damage would not be readily apparent
histopathologically. Neither is the damage likely to be recognized as
resulting from a chemical instead of a microbiological etiology, if it
does occur in a human population.
The opposite of the problem posed above (i.e. false negatives) is
the problem of false positives. Traditionally, when extrapolating data
to humans, only data obtained from the most sensitive species tested
(usually limited to mammalian) are utilized unless other ancillary data
clearly demonstrate the species inappropriate. In general, data are not
sufficiently complete to allow determination of the most appropriate
species at the time a decision is made. This in many cases undoubtedly
results in regulatory decisions being made on the basis of an exaggerated
risk estimation, distorting the cost/benefit ratio upon which the
regulatory decision must be made. However, in the absence of substantive
data to clearly establish the most appropriate species, the decision is
generally made to err on the side of increased public safety by using
data from the most sensitive species.
Thus the key questions surface as: (1) the appropriateness of
effects on biological and animal models to humans; and (2) how to
model accurately the extrapolation of these effects to humans. These
questions are of primary importance to the Agency. Unfortunately, no
basic scientific effort to design convenient models of toxicologically-
induced human disease processes has been undertaken outside of the
chemical ccarcinogenesis area. In general, what efforts have been made
46
-------
have been specific to the investigation of single chemicals. This area
of study has not developed because the substantial resources necessary to
develop this data base have not received a high priority. Instead,
resources for environmental toxicology research have been allocated along
the lines of pursuing the effects of single chemicals with the goal of
establishing maximum contaminant levels (MCL's). With TSCA legislation,
a coordinated effort to establish a generalized methodology for
across-species extrapolation in quantitative as well as qualitative terms
is of very high priority.
2. Research Strategy
The Office of Research and Development (ORD) research strategy on
health effects research supporting TSCA must be sharply focused in order
to be effective. Many nonscientific issues will be key considerations in
the regulatory posture ultimately arrived at by the Agency; for example,
economic considerations surrounding the particular chemical being tested,
the availability of suitable alternatives, and the size of the population
likely to be impacted. These considerations will and must be weighed
against harm to humans and the environment in order to arrive at a
sensible and defensible regulatory stance. Therefore, it is essential
that testing strategies in the health area produce the best possible
estimates of a chemical's ability to produce human disease. Furthermore,
this evaluation must be done in a cost-effective manner since, in many
cases, the cost of testing alone could exceed the projected economic
benefits that may be derived from a chemical.
47
-------
The fundamental questions which must be addressed over a wide area
of disciplines are:
• What is the full range of human disease states that could
result from exposure to environmental chemicals and chemical
classes?
• Can we define the appropriate test systems and/or animal
species that may be employed in a cost-effective manner
to detect reliably chemically-induced disease processes?
• What are the critical factors (e.g. metabolism, pharmaco-
kinetics, repair processes) in the handling of a chemical
or the responses of different species that impact quantita-
tive extrapolation between species?
« What is the place man occupies in the range of sensitivities
expressed by various species to particular types of toxicity
(i.e. interspecies comparisons of intrinsic sensitivity)?
Research must determine what the most significant endpoints
addressed in toxicological studies should be. In addition, it must
establish what types of toxicity are observed when representatives of
major chemical classes are given. The literature available today is not
particularly useful in answering these questions because in the past
chemicals have usually been studied for their effects on particular organ
systems (e.g. chlorinated hydrocarbons and liver necrosis), and the
pathology to other organs and tissues has generally been ignored.
Efforts should be directed at detecting damage at the biochemical,
physiological, and ultrastructural levels which can be correlated with
functional deficits as well as histopathological examination of major
organs. A critical assessment of what organs are specifically impacted
at lower doses than others will allow development of a maximally
cost-effective test protocol.
48
-------
The similarities and differences between humans and experimental
animals on a biochemical and physiological basis must be investigated.
Attention should focus primarily on animals which would fit logically
into testing protocols rather than simply on "man-like" animals. Most
man-like animals could never be employed in large-scale testing because
of their limited numbers and extremely high cost. This effort, then,
should be designed to uncover the actual physiological and biochemical
differences involved in the spurious results given by a particular
species, so that the required characteristics for a human response may be
specified. This type of information across multiple endpoints could
eventually allow specification of a single species for testing chemicals
with particular characteristics. These data could replace the arbitrary
specification of two to three species now utilized as a means of reducing
the risk of false negatives. In addition, these data would serve as a
basis for rejecting positive data developed in an inappropriate species
historically.
The appropriate species or test systems (in terms of the qualitative
similarity of their responses to toxic chemicals) must then be studied
with regard to the quantitative relationships between their responses and
those of man. This area has the largest impact on the regulatory process
and is the least well understood. At present, the arbitrary assignment
of a safety factor (ranging from 10- to 1000-fold) to results obtained in
the most sensitive species is the only defensible position and is the
most prudent course from a public health point of view. However, it is
highly probable that many very useful chemicals are and may be kept out
of commerce on this basis. Less probably, but still possibly, this lack
49
-------
of knowledge and the lack of quantitative extrapolation models could lead
to the acceptance of a substance more toxic to humans than substitute,
particularly if the two chemicals produce different toxic effects. Man
could be more sensitive than the test species to one type of toxic effect
and less sensitive to another, leading to false conclusions of the
relative hazards of two alternative chemicals.
To complete a risk assessment, some critical knowledge is necessary
concerning the development of a disease process with doses, particularly
with low doses. Is the process simply linear with dose as is assumed
with cancer, or is there a threshold below which no effects occur? In
either of these cases, how can the variability in sensitivities produced
by predisposing risk factors be taken into account in extrapolation?
3. Research Program
The research and development (R & D) toxicology program supporting
the Agency's toxic substances regulatory efforts will concentrate on the
development and validation of test systems and animal models that serve
as predictors of human disease processes which may be potentially
impacted (directly or indirectly) by environmental chemicals. The major
areas of research will investigate: (1) the development of methods
capable of evaluating the responses of entire systems to a toxicant
insult (i.e. the cardiovascular system, the immune system, the
reproductive system, the gastrointestinal system, etc.); and (2) the
development of methods sensitive to specific target organ toxicity (i.e.
liver, kidney, heart, lung, skin, etc.). Since the former are the
broader tests, it is anticipated they will eventually form the core of
50
-------
screening or first level tests, whereas the latter tests would be more
specific and confirmatory in nature. In each of these cases it may be
necessary to develop a data base to establish the most appropriate
species. Specific research needs may be divided into those needed in
acute toxicity testing, subchronic toxicity testing, and chronic toxicity
testing.
a. Acute Toxicity
Code # Immediate Research Goals OPTS Priority*
A-1 • Need to standardize the acute inhalation
toxicity protocol so that is is compar-
able to the acute oral, dermal, and eye
models.
Intermediate Research Goals
A-2 • Continue "Round-Robin" testing of all
acute procedures to determine if across
laboratory variation falls into an
acceptable range.
A-3 • Support program for enhancing sensitiv-
ity of classical approaches (e.g. use of
pathological bacteria introduced into
animal lungs following exposure to
common pollutants as adjunctive studies).
A-4 • Develop methodologies for detection of
asthmatic type sensitization.
Long-Range and Basic Research Goals
A-5 Conduct basic research on animal and
human skin which would lead to a
fundamental understanding of factors
which influence permeability and/or
irritation.
* Ranking of priority: (1) High - (5) Low
51
-------
A-6 Conduct basic research on animal and
human lungs which would lead to
fundamental understanding of factors
which influence local effect and/or
absorption (e.g. particle size,
solubility, reactivity, etc).
b. Subchronic Toxicity
Immediate Research Needs
A-7 • Review existing data on various parameters
used in present protocol for reliability
and predictability (e.g. urine analysis,
certain elements of the hemogram, and
clinical chemistry). The aim of this
review would be to evaluate the usefulness
of certain commonly used tests.
A-8 • Introduce new parameters for inclusion
in protocols (e.g. Serum Ornithine Carbamyl
Transferase (OCT) as a liver response test
for exposure to certain organic solvents).
A-9 • Determine how much useful information a
90-day test would contribute as opposed
to a 28-day test or a 7-day test.
Intermediate Research Needs
A-10 • Establish the minimum duration of
subchronic toxicity tests which can
be utilized to predict chronic toxicity
for chemicals. (Shorter-term tests
must account for decreased lifespan from
nonspecific organ toxicity).
A-11 • Determine the relevance and dependability
of in vitro systems as predictors of target
organ toxicity in vivo.
A-12 * Provide a scientific basis for making
quantitative extrapolations from data
obtained with experimental animals to
effects predicted in man.
52
-------
A-13 • Characterize toxicity to different organ
systems. Also characterize toxicity in-
duced by different mechanisms with respect
to those mechanisms' reversibility, cum-
ulative nature, characteristics of bio-
chemical interactions, and the mathematical
relationships involved in the damage func-
tion at different levels of organization.
A-14 • Provide systematic investigation and
characterization of representative
chemicals from major classes of environ-
mental chemicals concerning their target
tissues, organs, or systems. Test models
used for extrapolation of data to man for
their generality.
A-15 • Systematically investigate the effects
of chemicals on target organs or systems
involved in major human diseases to
determine the extent to which toxic
chemicals may impact those disease
processes (e.g. cardiovascular diseases
and the immune system)-
A-16 • Develop organ function tests applicable
to subchronic tests (e.g kidney and liver
function as opposed to static tests). The
sensitivity of the glucose tolerance test
versus blood glucose and/or urine glucose
have been amply demonstrated.
A-17 • Expand the test protocol to include
endocrine effects (e.g. thyroid effects
through measurement of PBI, T^, TSH, etc.).
A-18 • Review diagnostic procedures used in
human medicine for applicability to
animal protocols.
A-19 • Examine pre-existing studies to determine
how helpful nonrodent data are.
Long-Term and Basic Research Needs
A-20 • Develop predictive models for safety
evaluation in certain subpopulations at
high risk (e.g. persons with inborn
errors of metabolism, the chronic kidney
53
-------
diseased population which has approximately
10 million members in the U.S., and persons
having sensitivity to kidney toxicants).
A-21 • Determine relevance and dependability of
in vitro systems as predictors of target
organ toxicity in vivo.
A-22 • Provide systematic investigation and
characterization of representative
chemicals from major classes of environ-
mental chemicals to identify target organs
and to test the generalities of models
used for extrapolation of data to man.
Is the use of a nonrodent species essential
for proper safety evaluation? Is the use
of the NOEL proper in determining margin of
safety (M.O.S.)?
c. Chronic Toxicity
Immediate Research Needs
A-23 • Initiate discussions with NTP/NCI for
investigating feasibility of expanding
their chemical carcinogenesis bioassay
to include non-oncogenic chronic effects
(primarily additional dosage levels).
Intermediate Research Needs
A-24 • Clarify those parameters in Levels I and 1
II which would trigger need of chronic
testing.
A-25 • Undertake analysis of the NCI bioassay 1.5
data base and other data bases which
may support TSCA chronic health effects
standards.
Long-Term and Basic Research Needs
A-26 • Develop altered protocols for Level III 3.5
testing using stressed animals (e.g.
lower target organ function).
54
-------
A-27 • Research into the mechanism of action 2.5
of target organ pathology.
A-28 • Research to validate the ability to 3
predict the qualitative and quantitative
response to Level III tests and human
populations from Level I and II tests.
A-29 • Epidemiologically validate non-oncogenic 4
chronic toxic responses in human popula-
tions.
B. TERATOGENESIS TESTING AND REPRODUCTIVE TOXICITY
1. Background and Status
The developing embryo and/or fetus is known to be vulnerable to a
wide variety of agents which effectively interfere with normal
development and function. This vulnerability has been demonstrated both
in the laboratory and in the environment. A series of tests have been
standardized and are currently utilized to assess the potential of agents
to induce prenatal toxicity. These tests involve the response of
pregnant mammals to the test agents during the period of greatest
embryonic organogenesis. The pregnant animals are sacrificed shortly
before term, and the fetuses are examined for soft tissue and skeletal
anomalies. These standard tests suffer from several significant
shortcomings, including the time and expense involved in performing them:
the difficulties in assessing the importance of experimental effects in
terms of the human population; the problem of extrapolating test data to
form some estimate of potential risk to the human population; and the
lack of a testing framework which will identify functional deficits which
may only appear postnatally.
55
-------
The reproductive system is known to undergo several critical periods
during development. These include organogenesis, sexual imprinting, mor-
phological development, puberty, functional reproduction, and decline in
reproductive activity. The hypothalamic-pituitarygonadal axis is vulner-
able to a wide variety of agents. Assessment of the reproductive system
in the past has generally been limited either to the dominant-lethal
evaluation in males, or evaluation by output from "three generation" type
data, (such as fertility index, gestational index, viability index, and
lactational index) in females. These types of assessment fail to
evaluate specific physiological alterations. In addition, they are
time-consuming, expensive, insensitive, and not necessarily predictive
of effects in humans.
2. Research Strategy
a. Teratology
A primary aim of research in teratology is the scientific support
for and development of tests for evaluating chemicals for human terato-
genic potential. Faced with the task of screening large numbers of
chemicals for teratogenic potential, current testing methodology suffers
from some severe drawbacks. No cost-effective screening tests are
available for the assessment of this health effect, since the
"definitive" test used for teratogenic hazard assessment is the two-
species animal study. This study is expensive, time-consuming, and
measures only structural anomalies which must be extrapolated to indicate
an impact on humans. Clearly, additional research in the area of
teratology testing is required.
56
-------
Of primary importance in teratogenicity testing is the development
of a Level I (i.e. screening) test for teratogenic potential. The
demands on such a test are great since teratogenicity may be the
consequence of one or more separate effects of a chemical agent on a
biological system during a "critical" period of development. Possible
solutions to this need may be in the development of a battery of
short-term tests for various suspected mechanisms of teratogeneis. This
battery would include tests for mutation, chromosomal non-disjunction,
altered nucleic acid integrity or function, lack of chemical precursors
of substrates, altered energy sources, change in membrane character-
istics, etc. These tests might involve in vitro cell, organ, or embryo
culture techniques. This approach is a complex one; however, the
potential for missing a true human teratogen will have to be weighed
against the possible savings of time and resources by use of such a
screening battery.
Although desirable in a tier scheme, no Level II (i.e. confirmatory)
test is available for use at this time. A possible candidate for this
level of testing is an in vivo embryo/fetal toxicity test which is now
in the process of being validated with known animal teratogens. This
test requires breeding and dosing regimes similar to a two-species study,
but requires only the weighing and counting of offspring at birth and 3
days later. Positive results in this test (a decrease in viable litter
size after 3 days) would be taken as evidence for teratogenic potential,
requiring a two-species study for hazard assessment. Preliminary
evaluation of this test indicates a high percentage of "true positives,"
57
-------
but an indepth evaluation of this test will be required to recommend its
use in an EPA tier scheme.
At present, EPA's test scheme suggests a two-species teratogenicity
study on all chemicals for which exposure, production, structure and/or
biological activity relationships, epidemiology, or other existing
biological data dictate further tests toward the evaluation of this
endpoint. Other data supporting the use of this type of study come from
reproduction or metabolism studies where biological effects or chemical
products (metabolites) might increase suspicion of teratogenic
potential. Further research is needed to strengthen these aforementioned
correlations. In addition, the development of extensions of this test
for the evaluation of "late" effects including growth retardation,
behavioral effects, and perinatal carcinogenicity have been recommended.
The research strategy in the area of teratology will address a
number of basic problems faced in any attempt to formulate regulatory
policy based on experimental data.
Interpretative Problems; A variety of embryonic and fetal changes
observed in experimental data derived from current test protocols,
although shown to be clearly compound-induced, are not understood in
terms of their biological significance. Examples of these non-
teratogenic effects include decreased fetal weight, the occurrence of
wavy and/or supernumerary ribs, and delays in the development of various
organ systems (e.g. enlarged renal pelvis and enlarged cerebral
ventricles). These types of data are currently being submitted to the
58
-------
Agency, and the use of these data depends on the understanding of their
toxicological significance. Research should therefore be directed
towards optimal utilization of the data derived from current testing
procedures.
Extrapolation Problems; In any governmental agency with a
regulatory mandate, the most important endpoint of many toxicology
studies should be the significance of the experiment's effects to the
human population. In the field of teratology, relatively little
attention has been paid to problems associated with extrapolation of data
between mammalian species, in both the quantitative and qualitative
sense. In order to assess comparative species sensitivities to different
agents in terms of the types of defects seen and their relative
incidences, research should be directed toward dose-response
relationships in diverse laboratory species. A key part of such an
effort should be the detailed analyses of human data and the comparison
of such data with data developed in the laboratory setting.
Method Improvement Problems; Current standard test procedures are
not concerned with the fate of the animal after parturition. It has been
demonstrated that several compounds, when administered during the
prenatal phase of development, produce toxicological manifestation
apparent only in the postnatal animal. Research is needed for postnatal
sequelae of in utero exposure to compounds. This research should be
directed at assessing permanent alterations in the hemostatic functioning
and reserve capacity of all major organ systems.
59
-------
Resource Utilization Problems; Current teratogenic screening
procedures require the input of scientists and highly skilled technicians
and 3 to 5 months of experimental work. In addition, the cost of a
standard test in two species is approximately $35,000. As such, our
current capability for assessing the teratogenic potential of compounds
could quickly be outstripped by the testing that may be required under
TSCA. There is a need, therefore, to develop test systems which will
enable regulatory personnel to prioritize the testing of compounds by
standard procedures. These tests should ideally reduce the requirements
of technical expertise, as well as time and financial commitments
involved in the standard assays. Research should be directed into the
development, validation, and utilization of short-term test systems which
will accomplish the above objectives.
b. Reproduction
Certain chemicals will have no data available from which
reproductive hazards can be assessed. Innovative chemicals for which
production figures cannot be projected adequately and high exposure
chemicals of low production could possibly be inhibited by requirements
for testing. Inexpensive tests are necessary for the testing of these
types of chemicals under Sections 4 and 5 of TSCA.
Testing for Section 4 and 5 chemicals is organized in a tier-wise
fashion, progressing from general evaluation tests which are least
predictive (such as structure/activity relationship tests) to tests which
are of more predictive value (such as a reproductive test in an animal
species).
60
-------
In the lowest tier, structure/activity relationships and biological
activity of known or suspected potential are used to predict potential
for reproductive effects. Improvements in available testing methods are
needed to detect these relationships. The next higher level of tests
should include a screening test (not currently in the tier testing
scheme, but projected if suitable tests become available). A screen
should be predictive of effects on fecundity; however, because of the
lack of suitable methods, the screen may be limited to fertility or other
specific factors in reproduction. Positive results from the test should
either trigger reproductive testing or be of sufficient validity to be
useful in hazard evaluation or in risk assessment and regulations. The
reproductive test which could be triggered by the screen needs consider-
able improvement. Subchronic and chronic tests can trigger reproductive
testing. Subchronic studies are not always predictive of physiological
effects which may disrupt reproduction and which may be detected by the
pathologist associated with the study. Improvements in the predict-
ability of these tests for reproductive effects are needed.
The research approach in developing and assessing rapid, sensitive,
and cost-effective reproductive tests must address a number of basic
problems.
Interpretative Problems; Compound-induced alterations with no
apparent functional reproductive effects have been observed in sperm
count, morphology, viability, and motility. In addition, changes in the
normal serum hormone concentration during development have been seen
without apparent changes in functional reproduction. The significance of
61
-------
these and other subclinical. indices in the reproductive life of the
animal have yet to be evaluated. Research efforts should be directed
toward optimal utilization of these data.
Resource Utilization Problems; Current procedures to assess
reproductive function require 6 months to 1 year and highly skilled
technical assistance. The reproductive testing that may be required
under TSCA would be unrealistic using these current test procedures.
Therefore, the research effort should be directed toward the development
and validation of test systems which require a minimum of time and
resources and allow prioritization of compounds for the standard
reproductive test procedures.
Method Development/Assessment Problems; Concomitant changes in
other functional systems should be evaluated for their potential to
predict reproductive effects. Sexually dimorphic behavior patterns in
model species is an area where further investigation into the possible
predictive value of deviations from the norm may be of value. The role
of postnatal exposure to toxic agents through the milk should also
receive attention since it is known that this route of exposure may be of
considerable importance in the toxicity of lipophilic compounds.
3. Research Program
a. Teratology
Code # Immediate Research Goals OPTS Priority
B-1 • Validate the proposed short-term in vivo
screen by the testing of a significant
number of diverse compounds of known
teratogenic potential.
62
-------
B-2 • Evaluate other proposed short-term
screens, including the growth of an
embryo and/or embryonic tissues in
culture.
B-3 • Compare the responses of rodent and
nonrodent species to agents administered
during gestation. Data from humans
should be included.
B-4 • Conduct studies of dose-response
relationships to specific agents in
different species.
B-5 • Develop and validate behavioral
teratology testing procedures in rodents.
B-6 • Acquire data on the background malforma-
tion rates, inherent susceptibilities,
and resistance to certain chemicals for
the various species and strains.
Intermediate Research Goals
B-7 • Conduct studies to determine the signifi-
cance of various manifestations of fetal
toxicity (excluding gross terata) on peri-
natal viability and function. These experi-
ments will attempt to measure the potential
of agents to prenatally induce postnatal
functional alterations in the absence of
gross terata. Areas of study will include:
hepatic function and metabolic patterns;
central nervous system growth and function
including selected behavorial parameters;
cardiac function, renal function, and
resistance to stress.
B-8 • Evaluate the effects of maternal toxicity
on the outcome of embryonic and fetal
development.
B-9 • Study the potential of diverse agents
to act synergistically and result in
perinatal function. An example of this
type of study would be the simultaneous
administration of fetotoxic agent and a
teratogen.
B-10 • Develop biochemical markers of postnatal
development that may be used to assess
63
-------
developmental delays of major organ
systems.
Long-Range Goals and Basic Research
B-11 • Conduct studies to elucidate the basic 1
mechanism's response for perinatal
dysfunction. Specific areas of investi-
gation would include: histopathological
development of terata; correlation of
biological actions of agents with perinatal
effects; and biochemical and physiological
causes of perinatal dysfunction.
B-12 • Study the potential of agents to induce 2
dominant non-lethal mutations during the
male spermatogenic cycle as evidenced
by the production of terata after breed-
ing with untreated females.
B-13 • Assess the utilization of ultrasonic 2
vocolizations in neonatal rodents as
an indicator of the general health status
of animals to toxic substances during
in utero development.
B-14 • Study the effects of diet, including 4
selected deficiencies, on perinatal
response to agents.
B-15 « Study the effects of in utero exposure 3
on the ontogeny of senescence.
b. Reproduction
In the area of reproductive toxicity, efforts will continue to
develop an acute (14-day) and a subchronic (30-day) reproductive screen-
ing procedure applicable for regulatory programs. These efforts will
incorporate modern and sophisticated reproduction, physiological,
biochemical, morphological, and functional methodologies.
64
-------
Immediate Research Goals
B-16 • Develop a reproductive screen which is
value-effective in screening for: sperm
motility, number, and viability; and
ovarian cyclic function, ovum viability,
and uterine impairment.
Intermediate Research Goals
Using current acute dosing regimens and selected compounds, studies
will evaluate short-term response of the hypophyseal-gonadal axis through
the use of the:
B-17 • FSH, LH, FSH-RH, LH-RH, and steroid hormone 1
(testosterone, estrogen, etc.) profiles in
males and females
B-18 • In vivo and in vitro HCG stimulated Leydig 1
cell testosterone production
B-19 o in vivo and in vitro pituitary extract 2
stimulated testosterone production
B-20 • Alterations in sexually dimorphic patterns 1
including anatomical and behavioral differen-
tiation, fertility, fecundity, and the on-
togeny of infertility
B-21 • Morphologic parameters, i.e. testes, ovarian, 1
and accessory gland weight
B-22 « Histological parameters, i.e. pituitary, 1
gonodotrophocytic, and hypothalamic
cytologic alterations
B-23 • Effects on sperm production and quality, 1
i.e. number (vas deferens and epididymal),
viability, morphology, motility, and
capicitation
B-24 • Physiology of lactation and the transport 1
of toxic compounds to sucklings
B-25 • Evaluation of the effects on the estrus 2
cycle
65
-------
Long-Range Goals and Basic Research
Short-term response of the hypophyseal-gonadal axis will be
evaluated through the use of:
B-26 • Interaction of other endocrine physiology
with reproductive function
B-27 • Identification of optimal species for specific
reproductive testing procedures
C. NEUROTOXICOLOGY
1. Background and Status
Despite man"s long association with chemicals which adversely
affect the nervous system, regulatory agencies are just now focusing
attention on the study of neurotoxicology. This focus includes the
recognition that neurotoxicological evaluation is an essential component
in a comprehensive toxicology program. Many chemicals, which are derived
from a variety of sources (environmental, occupational, food and drugs,
etc.) and have a variety of intended uses (additives, pesticides,
industrial chemicals, and which enter the body by a variety of routes
(air, water, food) exert toxic effects on the nervous system.
Therefore, a systematic investigation of neurotoxicity, including the
development of short-term tests, is essential to all government agencies
concerned with the protection of human health. Section 4 of TSCA
specifically calls for such research; "the health and environmental
effects for which standards for the development of test data may be
prescribed include .... Behavioral Disorders, cumulative or
synergistic effects and any other effect which may present an
66
-------
unreasonable risk or injury to health or the environment." A comprehen-
sive neurotoxicology program is needed to investigate chemically-induced
changes in nervous system function at all levels of organization,
including functional and structural. This multi-disciplinary approach is
essential, especially for the cross-validation process which will allow
for the development of short-term tests which are rapid, sensitive, and
cost-effective. The data base for implementing such testing procedures,
including validation, does not exist.
The development of a tier testing scheme for multi-disciplinary
neurotoxicity testing is in its early stages of development. The current
tier testing scheme consists of acute and repeated exposure dose-response
experiments. In the absence of specific knowledge about a chemical's
targets within the nervous system, acute tests will consist of an 1-hour
locomotor activity test and a functional observational battery. Where
existing data or acute test results indicate, specific behavioral or
neurophysiological function tests (e.g. motor nerve conduction velocity)
will be combined with general neuropathology tests in the repeated
exposure testing. Where warranted, neurochemical tests will also be
included in the repeated exposure testing. Other special tests warranted
by existing information on specific chemical classes will be required
on a case or class basis.
The status and source of the proposed tests illustrate the problems
in this area that EPA's Research Program should address. These problems
include the following:
67
-------
• General types of tests have been proposed, e.g.
tests of locomotor activity or functional test
batteries, but specific tests for these cate-
gories have not been systematically evaluated
or validated for chemical toxicants. Our need,
then, is both to validate explicit tests of
locomotor activity and to evaluate empirically
the relative sensitivities of different tests
of locomotor activity.
• Specific tests of general functions referred to
above, or tests of more specific neurological
functions (e.g. conditioned reflexes or motor
nerve conduction velocity), have generally been
used to evaluate drugs often designed for
neurological effects or to evaluate one
chemical class such as aryl phosphates.
* Thirdly, many existing tests have not been
designed for efficient use on a broad scale, so
they require systematic development.
Development of test standards, a statutory requirement under TSCA
for rule-making, will be the culmination of an evaluative-research
process; our success in this effort will rely a great deal on the
personnel in ORD laboratories and their research. In summary, the
regulatory needs of OTE can be stated as: expansion of the data base on
screening tests of general and specific function to facilitate the
empirical determination of which tests and parameters to standardize; the
determination of relative specificity, sensitivity, and utility of tests
in different disciplines; and the refinement of the broad array of
existing neuropharmacological tests for use in neurotoxicological
testing.
2. Research Strategy
The area of neurotoxicology is very appropriate to illustrate the
problems encountered in evaluating target organ toxicity. The incredible
68
-------
complexity of the nervous system has become in a sense a cliche, but it
is also a fact. Owing to this complexity, it is extremely difficult to
perform simple evaluations of toxicant-induced changes in nervous system
function. The broad range of approaches which have historically been
utilized in neurobiology, from morphology and biochemistry to behavioral
analysis, must also be incorporated into the development of
neurotoxicological test methods. Otherwise the efficiency of any
screening method to detect damage simply cannot be evaluated.
By incorporating multi-disciplinary testing into the tier structure,
we can maximize the likelihood that neurotoxicity will be detected,
characterized, and quantified. At the first level of testing, the
screening level, toxicant-induced neurobehavioral alterations will be the
primary test methods. At the second level, the evaluation level, testing
will determine the exact nature of this toxicity and will more thoroughly
define dose-response relationships which are essential for risk
assessment.
To be useful for screening, a test must be sensitive, reliable with
respect to a minimum of false negatives, and cost-effective. Recently,
considerable attention has focused on the use of locomotor activity as a
primary screen. This test has a demonstrated sensitivity to a variety of
substances including pesticides, heavy metals, solvents, and psychoactive
drugs. However, a number of factors influence locomotor activity levels
as well as chemically-induced changes in these levels. This is also true
for most neurobehavioral measures, and therefore, consideration is being
given to defining more clearly the organismic and environmental factors
69
-------
which influence these measurements. Data are being collected using both
acute and subacute exposure to a variety of neurotoxicants. In addition
to measures of locomotor activity, other neurobehavioral indices being
evaluated as primary tests include measures of acquired behavior
learning, memory, and performance), neurophysiology (evoked and
spontaneous electrical activity), and neurochemistry (neurotransmitters
and neuroenergetics).
Once neurotoxicity is indicated, testing is needed to: (1) rule
out false positives in the screening level, and (2) more extensively
define this toxicity in both a quantitative and qualitative manner.
Therefore, specific functional tests are being evaluated for their
reliability and sensitivity at the second and third levels of testing.
Tests currently being investigated in the Agency include: measurements
of learning and memory (using visual discrimination-taste preferences,
spatial alternation, and spatial memory); performance acquisition
(utilizing operant techniques under a variety of schedule control condi-
tions); neuromotor function tests (including locomotor patterns such as
gait andd stride); social behavior (including sexual and aggressive
behaviors); neurophysiological techniques (including sensory evoked
potentials, nerve condition, velocity, and both chemically- and
electrically-induced seizure patterns); sensory motor function (as
measured by optokinetic nystagmus); and neurochemical parameters (inclu-
ding measurements of specific enzymes, neurotransmitter substances, and
neuroenergetics).
70
-------
With few exceptions, the neurobehavioral programs described have
also been applied to the developing organism. The importance of these
studies derives from the fact that perinatal exposure to toxic substances
is widespread in our society, and that in many instances the developing
nervous system is especially vulnerable to the deleterious effects of
chemicals. Developmental neurotoxicology studies (behavioral teratology)
with rodent models have also included postnatal exposures because of the
extensive development the central nervous system undergoes during this
period. There are many unique methodological problems associated with
this area of research, i.e. the need for "between groups" comparisons,
longitudinal testing, etc., which are currently being addressed in the
neurotoxicology program.
The initial efforts in the neurotoxicological program are aimed at
evaluating such specific chemicals as methylmercury, various alkyl tin
compounds, and a variety of insecticides and rodenticides because of
their known or suspected neurotoxic properties. These compounds are
suitable for initial studies which will allow exploration of the
relationships between acute, subchronic, and chronic exposures. These
initial studies should also provide information on the specific
neurobehavioral alterations and the general means by which dose-response
data may be used for risk extrapolation to humans. The neurotoxicology
research effort will concentrate on implementing the most promising test
methods to gather sufficient data for assessing their relative utility
and sensitivity and ultimately for selecting those tests which are most
appropriate to the regulatory settings.
71
-------
3. Research Program
Code # Immediate Research Goals OPTS Priority
C-1 « Select and validate the best means of
assessing locomotor activity.
C-2 • Develop and validate tests suitable for
incorporation into a functional observational
(or minimally equipment-dependent) test
battery; (e.g. seizure thresholds, motor tests
of stride and gait, and acoustic startle
reflex).
C-3 • Develop and validate tests suitable for
assessment of specific functions and
comparison of alternative techniques for
similar functions (e.g. rapid training and
testing methods for operant conditioning
studies of cognitive and discriminative
functions, and comparison of visual evoked
response to visual discrimination performance).
C-4 o Develop and validate the same kinds of tests
and special tests for perinatally exposed
organisms.
Intermediate Research Goals
C-5 • Evaluate and implement procedure to measure
alterations in specific behaviors as indicators
of exposure and of potential toxic effects in
man.
C-6 e Correlate sexual dimorphic behavior with the
reproductive development effects of toxic
substances on the development of social
behavior in rodents.
C-7 • Evaluate a series of electrophysiological
procedures (i.e. EEC, evoked potentials, etc.)
as indicators of neurotoxicity.
C-8 « Develop more quantifiable and less subjective
means of evaluating neuropathological lesions,
including automated morphometric analysis
techniques.
72
-------
C-9 • Develop and validate screening tests for
neuroenergetics and the correlation of
neurochemical with functional data.
C-10 « Develop biochemical indicators of neurotoxic
responses.
C-11 • Assess the validity and usefulness of tests
for sensory-motor function (Optokinetic
Nystagmus).
C-12 • Evaluate macroelectrode neurophysiological
techniques.
C-13 • Evaluate effects of toxicant exposure on
tests of specific temporal response patterns,
learning, and sensory discrimination in
animals.
C-14 • Evaluate olfactory effects of airborne
toxicants.
Long-Range Goals and Basic Research
C-15 • Develop an EPA laboratory capibility to
execute the OTE Tier Testing Program when
needed by the Agency.
C-16 • Develop class-specific (e.g. chlorinated
solvents) comprehensive test programs
utilizing multi-disciplinary teams of
neuroscientists.
C-17 • Develop toxicological support for neurotoxi-
cological testing (e.g. inhalation exposure
facilities).
D. MUTAGENICITY TESTING
1. Background and Status
The primary objective of mutagenicity testing is to determine
the potential of a chemical agent to induce mutations in humans.
Quantitative assessment of this potential genetic risk is an ultimate
73
-------
objective of a regulatory agency concerned with controlling mutagens in
the environment. Health related endpoints which are of interest in
genetic toxicology are point (gene) mutation and chromosomal
alterations.
Point mutations are alterations which affect single genes. These
alterations include base pair substitutions and frameshift mutations, as
well as other small deletions and insertions. Existing in vitro test
systems include both forward and reverse mutation assays in bacteria,
yeast, fungi, and mammalian cells in culture. The prokaryotic (e.g.
bacterial systems detect only point mutation, whereas eukaryotic systems
detect both point mutation and chromosomal alterations. Also, most in
vitro assays must employ an exogenous source of metabolic activation in
the form of a mammalian liver microsomal preparation. The majority of
genetic toxicants must be converted into reactive forms before their
effects can be detected. This metabolic conversion is thought to be
mediated by oxidative enzymes and to involve the formation of
electrophilic metabolities which bind covalently to DNA.
Short-term in vitro assays for gene mutations include tests in
insects, plants, and intact animals. The sex-linked recessive lethal
test in the fruit fly Drosophila melanogaster has been the most widely
used in vivo gene mutation assay to the present time. However, higher
plants offer special advantages as in situ monitoring systems, which may
be of particular utility in environmental studies.
Chromosomal alterations include the loss or gain of entire
chromosomes, chromosome breaks, non-disjunctions, and translocations.
74
-------
Tests for these abnormalities involve searching for chromosomal
aberrations in somatic and germinal cells usually obtained from insects
and mammals. Chromosomal aberrations observed in the germinal tissues of
mammals provide important evidence of the accessibility of the test
chemical to the reproductive organs. Thus, positive evidence of specific
gene mutation seen in jji vitro tests, along with observations of
chemically-induced chromosomal damage in germinal tissues of rodents,
suggests that the chemical under evaluation has the potential to produce
heritable effects.
DNA damage and repair bioassays do not measure mutation per se, but
do measure direct damage to DNA and other macromolecules by chemical
agents and the subsequent repair of that damage. Bioassays to detect
macromolecular damage and repair are available using bacteria, yeast,
mammalian cells, and whole animals.
The present tier schemes for mutagenicity are divided into two
parts: a scheme for the detection of gene (point) mutations and a
scheme for the identification of chromosomal mutations.
Both schemes are directed toward an estimation of risk to man from a
potential mutation. To assess risk, it must be shown that the suspect
chemical reaches the germ cells and that once there it interacts with DNA
to cause a heritable mutation. Both tier schemes have three levels:
Level I — Identification; Level II — Confirmation; and Level III —
Risk Assessment.
75
-------
In the tier scheme for gene mutations, Level I includes tests for
bacterial mutations, mutation in mammalian cells in culture, and DNA
damage and repair. Confirmatory assays include sex-linked recessive
lethal tests in Drosophila melanogaster, and under the appropriate
circumstances, tests for point mutation in mammalian cells in culture.
Level III includes the mouse specific locus test, a test for sperm
alkylation in mice, Drosophila, and mammalian cells in culture.
To date, the proposed tier schemes have not called for a mouse
specific locus test as a basis for risk estimation. Rather they have
relied upon molecular dosimetry as a bridge between mammalian germ cell
involvement (as evidenced by mouse sperm alkylation) and mutational dose
response as determined in Drosophila or mammalian cells in culture.
2. Research Strategy
The mutagenesis research strategy plan will focus on: (1) the
development and validation of systems for detection and confirmation of
potential mutagenicity, especially those tests which will demonstrate the
mutagenicity of a chemical in human and animal germinal tissues; (2) the
continuation of longer-range research programs which provide a firm base
from which new bioassays in genetic toxicology can be developed for
aneuploidy detection and risk assessment; and (3) the establishment of a
major effort in the development, use, application, and interpretation of
hazard assessment methodology in the regulatory process.
The use of tier testing schemes to identify and quantitate the
hazard due to environmental mutagens for regulatory purposes has placed
76
-------
great emphasis on existing state-of-the-art methodology in this field.
Unfortunately, bioassay systems which were originally designed for
mechanistic and exploratory research have been placed in the regulatory
process without much regard for system design, applicability, validity,
and availability. To meet regulatory needs, existing test systems need
to be redefined and realigned so that the desirable characteristics of
reproducibility, high sensitivity, specificity, and ease of performance
can be acquired.
The ideal tier scheme requires a lower tier which is sensitive and
which does not generate false negative results. First level tests for
mutagenicity can include bacterial mutation bioassays, mammalian cell
mutation bioassays, DNA damage and repair bioassays, and in vitro and in
vivo cytogenetics bioassays. Second level tests which confirm mutagenic
activity for gene mutation can include the sex-linked recessive lethal
in Drosophila; those for chromosomal aberration can use the mouse
dominant lethal. Third level tests which provide data for quantitative
risk assessment can use the mouse specific locus and germinal dosimetry
or mouse heritable translocation bioassays for gene mutations and
chromosomal aberrations respectively.
The research emphasis will be in the development of improved methods
for all three levels of testing and will be concerned with the
development of test systems which detect endpoints, such as aneuploidy,
for which there are no bioassays available. The improvement of existing
bioassays to increase their sensitivity and accuracy will also be
stressed.
77
-------
Research in the area of hazard assessment will be directed at risk
estimation by application of existing bioassays, by the modification of
these bioassays to give highly reproducible and accurate data, and by the
development of new test methodologies and mathematical models for hazard
assessment of mutagens.
3. Research Program
Code # Immediate Research Goals OPTS Priority
D-1 • Develop methodologies to detect mutagens
in germinal tissue under the conditions
of environmental exposure
D-2 • Develop methods for testing volatile
substances in _in vitro test systems.
D-3 • Validate the YFF sperm morphology test
to monitor human exposure.
D-4 • Validate the microlesion assay for gene
mutations.
D-5 • Develop criteria for determination of what
constitutes a positive or negative test
result in mutagenicity assays.
D-6 • Develop statistical models for test
evaluation.
D-7 • Conceptualize and develop a program to
assure quality of regulatory data obtained
under TSCA.
Intermediate Research Goals
D-8 • Expand the data base for all assays to
include a wide range of chemicals that
can be used for validation of each system.
78
-------
D-9 • Develop more sensitive and alternative
indicators of gene mutation, chromosome
breaks, rearrangement, and non-disjunction,
especially for tests relating to hazard
assessment.
D-10 • Expand the data base on the mouse specific
locus test by testing individual chemicals.
Long-Range Goals and Basic Research
D-11 • Determine the cost of genetic defects in
the human population.
D-12 • Develop mathematical models for risk
assessment.
D-13 • Improve test methods and standardize
procedures for assays in all levels of
the mutation scheme.
D-14 • Improve activation systems for all
in vitro assays.
D-15 • Develop in vitro human cell lines for
gene mutation, DNA damage and repair,
and in vitro cytogenetics.
D-16 • Develop markers of any kind for specific
locus and translocation assays.
D-17 • Conduct research on mutagenesis assays
with female animals.
D-18 • Determine alkylation in sperm DNA as an
indicator of genetic hazard.
D-19 • Determine the dominance of non-sex-linked
traits.
D-20 • Develop biochemical methods for monitoring
the human population for exposure to
mutagenic agents (e.g. circulating RBC,
HGPRT mutants, alkylated hemoglobin,
immunologic techniques for mutagen-DNA
adducts).
D-21 • Examine the genetic basis of gene mutation
at the thymidine kinase and ouabain loci.
79
-------
D-22 o Develop appropriate bioassay for aneuploidy. 2
E. CARCINOGENICITY TESTING
1. Background and Status
Cancer is the second leading cause of death in the United States,
resulting in the death of one out of every five Americans. Thousands of
new chemicals are introduced yearly into the environment that have the
potential of greatly increasing the cancer hazard. The prudent way to
reduce the cancer risk to humans would be to identify environmental
carcinogens so that they can be removed from use and to screen new
chemicals for carcinogenic potential prior to their introduction into the
environment.
Environmental chemicals can affect human cancer rates by several
distinct mechanisms. Chemicals may act as tumor initiators, promotors,
or carcinogens. Tumor initiators are capable of producing a change in
the genotype of cells which can be irreversible and can eventually
progress to a tumor. The ability to initiate tumors has been closely
associated with somatic mutation, allowing the use of simple in vitro and
bacterial systems as a qualitative means of detecting tumorigenic
chemicals. Tumor promoters act subsequent to the initiating carcinogen
to decrease the latent period of tumor development, and/or lead to higher
incidences of cancer. Tumor promoters have been identified in humans and
laboratory animals for almost all organs and tissues including the skin,
liver, colon, bladder, lung, and mammary gland. Chemicals which are
capable of both tumor initiation and promotion are referred to as
80
-------
complete carcinogens. Modifiers of the carcinogen progression that act
during the initiation stage (i.e. when the carcinogen is administered)
are called cocarcinogens. Fluoranthrene, the most abundant environmental
polycyclic aromatic hydrocarbon, is the prototype cocarcinogen. Tumor
promoters and cocarcinogens represent a health hazard since they can
increase both chemical-induced and viral-induced tumors and the rate of
"spontaneous" malignancies.
Epidemiological studies have associated a limited number of
chemicals with human cancer. However, it is infeasible to rely on
epidemiological studies for the determination of the carcinogenic potency
of new chemicals because of the 15- to 30-year delay in the appearance of
most tumors after the exposure of humans to a carcinogen. Regulation of
new chemicals for carcinogenicity will have to be made on animal
bioassays instead of waiting for people to be exposed for many decades.
Many environmental carcinogens and promoters have been identified in
laboratory animals. Because of the similarity of the carcinogenic
progression in man and animals, it is reasonable to assume that at least
some of those animal carcinogens are also human carcinogens. All human
carcinogens except arsenite have been shown to be animal carcinogens.
The extrapolation of the animal carcinogenicity data to man is required
for a risk-benefit analysis.
In order to provide a consistent, cost-effective approach to testing
and evaluation of data for the purposes of TSCA, it is necessary to
develop and validate those tests which are reasonable predictors of
oncogenicity in humans and to place them in the most appropriate
81
-------
positions in a testing and evaluation scheme. The scheme will help
determine the weight of different types of evidence EPA will receive and
help provide a sound approach to the evaluation of that evidence.
In the tier scheme, the first group of tests (initial biological
tests) presently includes mutagenicity assays such as the Ames test and
mammalian cell tests, DNA damage and repair assays, and in vivo and in
vitro cytogenetics. These tests mainly detect a chemical's ability to
interact with DNA in the cell. Ongoing research on these tests includes
validation of predictors of oncogenicity, development of consistent
guidelines for assessment of results, and improvement of current tests
and/or development of new tests that do not overlap the effectiveness of
the current ones. At this level, false negatives should be kept at a
minimum. As a result, a number of false positives will sift through to
the next group of tests.
The second group of tests (confirmatory biological tests) contains
additional in vitro or in vivo assays which will confirm the results of
the previous tests. These tests' results tend to be more accurately
extrapolated to the human situation. Thus, most of these tests involve
the use of whole animals. It is important here to have a low level of
false positives. The tests that are currently being considered for this
group are in vitro cell transformation studies, a lung adenoma
bioassay, a skin painting bioassay, a mammary carcinogen bioassay, and
the liver microfoci bioassay. All of these tests need further validation
and improvement in order to eliminate the high incidence of false
negatives in some of them.
82
-------
The third group of tests is the most relevant to the human
situation. These tests are whole animal studies and are of longer
duration (normally at least 2 years in a rodent study) than the previous
two groups. They give more credible results in terms of oncogenic
potential and are usually considered by EPA to be substantial evidence.
When coupled with positive epidemiological results, a positive 2-year
animal bioassay is considered by EPA to be the best evidence possible.
Presently, the primary goal for the completion of the oncogenicity
testing and evaluation scheme is the validation of the tests mentioned
above as predictors of oncogenicity in humans. This will involve an
immediate and extensive investigation and evaluation of the
literature. The secondary goal is to develop and evaluate methods for
detecting promoters and cocarcinogens. The present scheme does not take
these into account. These methods should follow a basic scheme similar
to the one outlined above.
2. Research Strategy
It has been proposed that chemical carcinogens initiate
carcinogenesis by altering DNA, which results in somatic mutations and
chromosomal aberrations. The similarity in the mechanism of mutagenesis
in prokaryotes and eukaryotes has permitted the use of rapid and
inexpensive bacterial and other in vitro systems to screen for mutagens.
The first level of testing in the carcinogenesis area utilizes the same
bioassays used in the mutagenesis area as a result of a close relation-
ship between chemicals which induce cancer and those producing mutations
83
-------
in lower animals. The primary requirement at this level of testing is
that false negatives be kept at a minimum. Consequently, redundant tests
must be eliminated from this level in order to maintain the cost-
effectiveness.
The non-carcinogenic mutagens and clastogens can be operational
false positives, so they should be eliminated from the decision tree by a
set of second level bioassays. Implicit in target organ susceptibility
to particular carcinogens is that there is a condition for carcinogenesis
beyond the initial biochemical lesion presumed to involve DNA. Numerous
chemicals lacking carcinogenic potency bind and damage the DNA of a
given organ to extents greater than carcinogens. The properties that
distinguish carcinogens from other DNA-altering chemicals are those which
can discriminate between carcinogenic positives and false positives
observed at the lower level of testing.
False positives in the first testing level can result from any
pharmacokinetic or metabolic factors not taken into account in lower
level test systems. Chemicals giving false positives might not be
systemically absorbed and metabolized in intact animals, rendering lower
level test results irrelevant. The differences in metabolism need not be
qualitative. Quantitative differences can be such, that in the higher
order tests, the amount of the biochemical lesion that initiates the
carcinogenic process is low enough to be repaired. Other mechanisms by
which false positives would be detected in first level tests are
differences in the rates of detoxification of the chemical and/or the
repair of the biochemical lesion of initiation.
84
-------
A research strategy to establish second level test methods requires
the development of target organ bioassays that are sensitive to
carcinogens of all chemical types and that take into account factors such
as differences in pharmacokinetics. Prime candidates for this level of
testing are the short-term bioassays that employ benign lesions as a
determinant of carcinogenesis and tumor promoters to decrease the
latency. The spectrum of chemicals to which each test is sensitive must
be determined in order to insure an acceptable level of false negatives
without redundancy. Quantitative relationships that might exist between
the results of these short-term bioassays and Level III lifetime exposure
should be determined.
Other second level tests available are those which measure the
malignant transformation of rodent or human cells in culture. These
oncogenic transformation bioassays are rapid, relatively low in cost
compared to in vivo tests, and have been able to detect a wide variety of
classes of chemical carcinogens. Cells which have been transformed in
culture will grow unhindered when implanted into animals, and thus the
test measures true malignancy. Some types of oncogenic transformation
tests give quantitative dose-response information; however, it is not
clear that these results reflect in vivo potency. The disadvantages of
these tests are limited activation systems, omission of pharmacokinetic
considerations, lack of standardization, and incapability of quantitative
reproducibility.
Third level bioassays involve chronic exposure of a chemical to
intact animals with extensive pathological examination to detect the
85
-------
occurrence and onset of tumors. Usually, testing is done in two species
by the route of major exposure in humans. The ultimate assay is
expensive, takes approximately 3 years for completion, and requires
elaborate animal facilities and highly trained professionals. Both
facilities and trained personnel are in limited supply. The established
correlation of the third level bioassay with human epidemiology must
remain the basis for carcinogenesis risk assessment.
It is important to realize that the testing strategies outlined
above and those currently in use primarily address the initiation of
tumors. It is the policy of EPA to consider that tumor promoters are
carcinogens. Therefore, the synthesis of tests to detect promoters and
cocarcinogens into the current tiered testing scheme is essential to
assess carcinogenic risk. Research into the essential characteristics of
promoters must be performed. The observed actions of promoters, such as
DNA replication, cell division, and hyperplasla should be explored.
Research to determine the mechanism underlying tumor promotion is
necessary for the development of short-term and inexpensive Level I
bioassays.
The process of tumor promotion is reversible and in laboratory
animals would appear to have a threshold dose of no effect. The
extrapolation of the animal data to humans, however, requires the
development of models. These models will have to be validated with
epidemiological evidences of tumor promoters. Therefore, a major
research effort is required in the determination of the dose-response
86
-------
relationship of tumor promoters in animals and in the epidemiological
establishment of tumor promoters in man.
3. Research Program
Code I Immediate Research Goals OPTS Priority
E-1 • Establish a matrix for oncogenicity
bioassays at Level II.
E-2 • Establish the level of confidence in
the matrix by systematic testing with
known carcinogens of different class
and target organ specificity (test
systems in the matrix to include,
among others, systems indicated below).
E-3 • Develop and validate the SENCAR mouse
as a Level II bioassay, defining its
responsiveness to chemicals applied
topically, parentally, and orally.
E-4 • Document the influence of different
experimental procedures possible in
the liver microfoci assay on the response
to known chemical carcinogens.
E-5 • Test the strain A mouse as a Level II
assay using multiple routes of exposure
(i.e. intraperitoneal, oral, and inhala-
tion) .
E-6 • Evaluate the mammary gland carcinoma
bioassay as a Level II oncogenic test
system.
E-7 • Evaluate the available in vivo molecular
markers for tumor promoters and develop
new ones if current ones prove unsatis-
factory.
E-8 • Investigate the utility of using un-
scheduled DNA synthesis as a means of
detecting compounds poorly detected by
current Level I bioassays.
E-9 • Develop and evaluate in vitro tests
for tumor promoters.
87
-------
E-10 o Negotiate with the NCINTP carcinogenesis
bioassay program to include archetypal
chemicals in long-term assays to better
establish carcinogenic potencies.
Intermediate Research Goals
E-11 • Assess the ability of measures of DNA
damage (alkaline-labile sites, endonuclease
recognized damage, etc.) produced by a
chemical _in vivo to predict its carcinogenic
potency.
E-12 • Determine if a matrix of short-term in vivo
bioassays can be used as a surrogate for the
much more expensive and time consuming life-
time carcinogenesis bioassays.
E-13 ® Correlate the response of in vivo molecular
markers of tumor promotion in various organs
with tumor promoting activity of chemicals
in target organs.
E-14 ® Improve the methods for metabolic activation,
reproducibility of results, sensitivity of
systems, and methods for data analysis of
oncogenic transformation assays.
E-15 • Determine if in vivo unscheduled DNA synthesis
can serve as an indicator of carcinogenic
potency.
Long-Range Goals and Basic Research
E-16 • Conduct research to elucidate the mechanism(s)
involved in tumor promotion of different
target organs.
E-17 e Define mechanisms which operate in cocarcino-
genesis with the aim of establishing short-
term bioassays for these phenomena.
88
-------
F. METABOLISM
1. Background and Status
Metabolism of toxic chemicals here refers collectively to the
processes of absorption, distribution, metabolic alteration, and
excretion of chemicals from the body. One of the basic principles of
toxicology is that the processes by which chemicals are handled
metabolically greatly influence both the quantitative and qualitative
characteristics of a chemical's toxic effects. Although standards cannot
be established based on metabolic data, metabolic data can provide
critical information in three areas:
• Where conflicting data exist concerning the
toxicity of several species, metabolic data
may be able to establish the species most
proximate to man. This presumes that the
metabolism of the compound is known.
• Metabolic interactions are often involved in
synergisms and antagonisms.
o The generation of certain electrophilic
intermediates capable of entering into
covalent interactions with DNA can serve
as presumptive evidence of carcinogenic
or mutagenic activity at the first level
of testing.
The metabolism of toxic chemicals represents only one possible basis
for interspecies differences in response to toxic chemicals. In the case
of chemical carcinogens and mutagens, the biological response can vary
according to the ability to repair DNA damage induced by the chemical and
the presence or absence of exogenous or dietary promoting agents.
Genetic factors in xenobiotic metabolism also indicate differences in the
89
-------
intrinsic sensitivity of a species to these chemicals. Similarly,
species variability in teratogenic responses is sometimes traceable to
differences in placental type and function. Consequently, it is
essential that any research directed at species differences in response
to toxic chemicals include studies of intrinsic sensitivity as well as
xenobiotic metabolism.
2. Research Strategy
In only very special circumstances would it be likely that a
chemical would be regulated solely on the basis of metabolic data. Thus
it is essential that the metabolism of toxic chemicals be studied in the
same context as the toxicity of a compound. Nevertheless, it is likely
that the success of regulatory actions on specific chemicals will
increasingly involve consideration of a chemical's metabolism. In fact,
the principal substantive challenges in the recently proposed water
quality criteria have been based on interspecies differences in the
metabolism of chemicals. The principal difficulty involved in accepting
such arguments is simply the absence of comparable data in humans.
Consequently, the general approach has been to accept the premise that
the most sensitive species tested best represents man.
To accommodate the diverse need for metabolic data, the adoption of
a two-fold strategy is suggested; one approach applied, the second
somewhat more basic or anticipatory. The applied approach is taken in
the course of studying any toxicological endpoint in which metabolism is
a likely basis for interspecies response differences. Documenting
differences in metabolism should be either an integral part of the
90
-------
experiments or performed in retrospect as a means of establishing whether
metabolic differences are responsible. It is only by meticulous study of
individual cases that a sufficient data base can be established to allow
generalizations concerning what the most appropriate data might be.
A more basic program in metabolism, however, is necessary for the
Agency to remain in an authoritative position in future regulatory
activities. Industry is making considerable investment in the area of
comparative metabolism. To establish an Agency capability to evaluate
the significance of metabolic differences accounting for species
differences in toxicity, a base program needs to be established. The key
problem that must be considered in establishing such a program is that
without some means of studying metabolism in man, the utility of the
results will be virtually nil. The program planned will essentially
pursue two questions:
• Does metabolism of foreign compounds by cells in
organ or cell culture accurately reflect metabolism
in vivo in commonly employed laboratory animals?
• If the first point can be established, can the com-
parison of a chemical's metabolism in human organ or
cell culture vs. that in cultures derived from experi-
mental animals provide the means whereby meaningful
across-species comparisons can be made?
The main value of this effort will be realized as data are obtained
from these essentially separate efforts. Comparison of across-species
differences in sensitivity to particular toxic effects with comparative
metabolic work will establish the data bank upon which predictions can be
made concerning the relative importance metabolism plays in a chemical's
91
-------
toxicity. This data bank will be based on experience with related
compounds and a basic knowledge of the metabolic pathways involved.
Throughout this effort, however, it should be kept in mind that
metabolic differences between species must be considered in relation to
other factors which can account for differences in a toxic effect between
species. When metabolism cannot be shown responsible for such
differences, active pursuit of alternative factors is essential to put
across-species toxicological response variation in proper perspective.
3. Research Program
Code # Immediate Research Goals OPTS Priority
F-1 • Investigate the ability of pharmacokinetic
models to account for across-species differ-
ences in sensitivity.
F-2 • Develop predictive models for comparing the
impact of differing routes of exposure based
upon physical-chemical characteristics and
structural analogs.
F-3 o Develop systems for interspecies extrapolation
of metabolism/pharmacokinetics data.
F-4 • Determine whether covalent binding of electro-
philic intermediates to proteins and/or nucleic
acids in critical organs can be correlated with
chronic toxicity, carcinogenesis, and terato-
genesis.
F-5 • Develop predictive models for the pharmaco-
kinetic and metabolic characteristics of
different placental types. Determine to
what extent data can account for across-
species differences in teratogenic responses.
F-6 • Determine the extent to which DNA damage
induced by chemical carcinogens can be
correlated with carcinogenic responses
in target organs.
92
-------
Intermediate Research Goals
F-7 • Develop in vivo integrating dosimeters for
chemicals which are reactive or metabolized
to reactive intermediates (carcinogens and
mutagens), and which are suitable for use
as a means of correcting for across-species
differences in pharmacokinetics and metabolism.
Long-Range Goals and Basic Research
F-8 • Determine specific carcinogen-DNA adduct
and nonspecific DNA damage occurrence in
human lymphocytes using radio-immunoassay
techniques•
F-9 • Determine if primary cell and/or organ
cultures from different species accurately
represent the metabolic and damage and
repair characteristics of the tissue
in vivo.
F-10 • Determine the relative reactivity and
stability of reactive metabolic inter-
mediates.
F-11 • Determine the transport mechanisms by which
reactive intermediates reach sites of
attack.
F-12 • Determine the metabolism in specific organs
and tissues to clarify expressions of toxic
effects.
F-13 • Establish a data bank of chemical inter-
actions analogous to drug interactions.
6. EPIDEMIOLOGY
1. Background and Status
Epidemiology atempts to explain disease causation by examining the
distribution and determinants of disease in human populations. In
93
-------
contrast to usual toxicology approaches, epidemiology is opportunistic in
nature, utilizing existing human exposure situations to gather health
data. When dealing with chemical agents causing irreversible effects,
such as teratogens, mutagens, and carcinogens, any experimental approach
to study humans is precluded and available human studies are limited to
existing circumstances. This does not imply that sound epidemiology
studies are not feasible. However, it does mean that only selected
chemical compounds will be amenable to study since the exposed group must
meet requirements of adequate size and duration and level of exposure.
Epidemiology studies will therefore be complimentary to toxicology
testing, conducted in parallel, and will provide a general data base for
extrapolation from animals to humans.
In this context, epidemiology assumes a vital role; only through
this approach can animal testing systems be validated to determine how
accurately they qualitatively and quantitatively resemble man in their
biological response.
The relationship of man-made chemicals in the environment to human
morbidity and mortality is essentially unknown at the present time.
Relatively few epidemiologic investigations have been conducted to test
the hypothesis that environmental chemicals contribute significantly to
human disease. Studies that have been carried out have been generally
either purely descriptive or ecologic in design. In an ecological
approach, the unit of exposure and analysis is the group rather than the
individual. Such studies can provide evidence of increased risk;
however, a quantitative risk estimate is usually best derived from more
94
-------
sophisticated studies which are organized on an individual basis and
utilize case-control or cohort designs. Some form of cohort design is
usually best suited if the focus is directed towards a specific chemical
exposure and if an identified exposed group is available. In a cohort
design, the population at risk is followed through time, either
retrospectively in an historical cohort analysis or prospectively. The
incidence of particular pathologic conditions is determined, and disease
rates are compared between exposure groups to develop dose-response
relationships or are compared to other standard populations. This
approach has been used widely in occupational settings to quantify human
carcinogenic risk.
If a particular disease rather than an exposed population is the
orientation, a case-control design is usually more appropriate. Cases
with a specified pathologic condition are matched with suitable controls
and individuals are then studied to determine the occurrence of the
primary hypothesized risk factor and other known risk factors in both
groups. Relative risks are calculated to determine if an association is
present.
Since epidemiology is a methodology, its categorical placement in a
tiered testing scheme is not practical. The following justifications
support this consensus: the long duration and uncertain outcomes of
feasibility studies; the long duration of epidemiologic studies; the
possibility that relevant health effects may be overlooked; and the
detection capabilities of studies may be limited by known biological
endpoints. As a result of the inability to incorporate directly
95
-------
epidemiologic studies in a tiered system, several alternative roles are
being considered. These roles, which are outlined below, include ad hoc/
specific uses, use for information gathering with Sections 8(a) and 4 (a)
of TSCA, generic epidemiologic screening, and proportionate mortality or
morbidity.
Ad Hoc/Specific Uses - There may be specific situa-
tions in which analytical epidemiologic studies
would be highly useful and practical, or in which
TSCA's Section 4 authority could enable EPA or
some other party to initiate or complete a planned
or ongoing study. Such studies will be conducted
on an ad hoc basis, rather than being triggered
within the tier system.
Information Gathering with TSCA's Sections 8(a)
and 4(a) - Under Section 8(a), EPA may obtain a
wide range of existing data and information from
the files of chemical manufacturers and processors
(e.g. exposure monitoring and medical record systems)
The development of an 9(a) rule specifically for
epidemiology is being considered. Section 4(a)
may be used to obtain new data or data which are
not "reasonably ascertainable" from industry files.
Section 4(a) and 8(a) information may be useful in
determining the feasibility of epidemiologic studies,
which may be conducted on an ad hoc basis, as pre-
viously described.
Generic Epidemiological Screening - Information
obtained through screening populations under
Section 4 authority may supply Level I suggestive
information and be useful in analytical studies
conducted either by EPA or other organizations.
A battery of suitable human effect indicators
should be developed for each health effect area.
Proportionate Mortality or Morbidity Ratio (PMR)
Analyses - PMR analyses, which may be conducted
quickly and at small expense, may be useful
in supplying Level I type information. In a PMR
analysis, the fraction of deaths or cause of
disease over all deaths or illnesses in a study
population is compared to the fraction in a
standard population. PMR analyses may give
96
-------
misleading results since this calculation does
not deal with rates. It is, however, relatively
easy to conduct by utilizing data from such sources
as medical and death records. The feasibility of
requiring industry to conduct such studies is being
investigated. The usefulness of such studies in
general is also being assessed through a literature
review.
2. Research Strategy
Epidemiology has several roles in chemical testing and assessment.
The first study types to be considered are descriptive or ecologic
investigations, generally categorized as hypothesis generating
studies. These studies are important because they are often a logical
first approach to identify problems, because they provide impetus and
information for designing more specific analytic investigations, and
because they tend to be quick and relatively inexpensive. In this
category are descriptive studies such as cancer mapping, international
disease comparisons, and other broad ecologic designs. The information
obtained tends to be suggestive evidence rather than strongly conclusive,
thus when circumstances allow, more definitive studies would be conducted
to follow up the results.
Hypothesis testing investigations include analytic epidemiologic
studies in which a quantitative risk estimate is derived. The
methodologies employed include the standard case-control, cohort, and
cross-sectional designs. Data are collected usually on an individual
basis, and all known potentially confounding variables are accounted for
to the extent possible. Dose-response relationships are pursued whenever
feasible since they often provide the strongest etiologic evidence.
97
-------
These types of investigations are commonly utilized in occupational
settings, but they have been applied much less frequently to
environmental exposures of the general community. These studies serve
the dual purpose of establishing effects of specific chemicals on humans
and providing the data base for validating toxicological models.
Methodology development is an important area where additional
epidemiological research is needed. Although new designs and analytical
techniques are a consideration, the emphasis in this area will be
directed towards (1) developing more sensitive and accurate measures of
pathologic damage than can be applied to population studies, and (2)
applying proven epidemiologic methods to new situations. An example of
the latter would be the adaptation of historical cohort designs (commonly
used in occupational studies) to the general community. Such an
application could provide direct risk estimates for the general
population.
Epidemiologic support of toxicologic dose monitoring techniques is
necessary to confirm methods developed to measure doses of toxins,
particularly carcinogens, in human populations. After refinement of the
methods in animal experiments, exposed human populations would be sampled
to validate the technique. The ultimate objective is to develop the
capability for screening exposed groups to identify high risk groups and
to quantitate dose in epidemiologic investigations.
98
-------
3. Research Program
Code # Immediate Research Goals OPTS Priority
G-1 • Determine the usefulness of proportionate
mortality or morbidity analyses as an
initial screen for health effects.
G-2 • Conduct analytical epidemiological studies
of adverse health effects to estimate human
risks.
Intermediate Research Goals
G-3 • Develop more accurate and sensitive indica-
tors of pathologic changes that can be
feasibly applied in epidemiologic studies.
Refine selected clinical laboratory testing
methods to better quantitate interpreta-
tion of results that might indicate mild
functional impairments due to chronic low-
dose exposures.
G-4 • Conduct studies to determine the adverse
effects of chemical compounds on the male
and female reproductive system. In the
male, effects directly on the germ cells
will be studied through semen analysis.
Toxicity to the female and embryo will
be studied through reproductive outcomes,
spontaneous abortion, and congenital mal-
formation. Fertility is a major concern.
G-5 • Improve the statistical techniques used in
epidemiology. Examples:
— Refine statistical tests used to obtain
confidence limits on relative risks from
paired case-control studies.
— Compare available techniques for taking
into account characteristics of a popula-
tion which may not be balanced between
cases and controls. Determine which of
the techniques are best or develop new
methods for adjusting for these
characteristics.
99
-------
G-6 ® Conduct epidemiologic research to determine
the impact of specific chemical compounds
in the environment on general community
morbidity and mortality. Both broad
spectrum ecologic studies and specific
analytic investigations are needed. New
applications of methodologic approaches
such as the higtorical cohort design to new
situations, such as the general community
population, might enable more precise
quantification of risk to the community
from low level exposures.
G-7 • Conduct studies of known high risk groups to
determine if certain diseases that appear
environmentally-related are associated with
specific toxic exposures.
G-8 » Validate toxicologic dose monitoring
techniques in human populations.
Long-Range and Basic Research Goals
G-9 ® Improve and attempt to standardize the
study techniques used in epidemiologic
research. Examples:
— Establish standards for selective
appropriate methodologies to be
utilized. For example, examine
the usefulness of case-control
studies within a cohort design.
— Develop better capabilities for
controlling confounding variables
through study design.
III. CHEMICAL SPECIFIC CONCERNS
A. EVALUATION OF ASBESTOS AND ASBESTOS-LIKE MINERALS
1. Background and Status
Asbestos is a well known hazard to human health, and the Agency is
actively concerned with controlling its possible environmental impacts.
100
-------
Asbestos-like minerals are commonly found in large areas of American
bedrocks (Figure 4-1). Therefore, rock fibers for which the hazards are
as yet undetermined are found in many mines and quarries. The existing
uncertainty concerning the toxicity of these materials make development
of rational regulatory actions impossible. Thus, an understanding of the
health effects potential of these minerals and its relationship to their
mineralogical characteristics is needed before it can be determined if
control measures are needed, and if so, what the design and application
of those measures should be.
The development of a safe asbestos substitute, or a means of
treating asbestos fibers to render them harmless to man is becoming
increasingly important. The only sure means of testing these substitutes
is by long-term animal experiments. However, since these tests may take
years to complete, shorter-term tests are urgently needed now.
2. Research Strategy
The proposed project for control of asbestos and asbestos-like
minerals addresses the following problems:
• Determination of the relative toxicity
and carcinogenicity of asbestiform
amphibole mineral fibers
• Detection of mineralogical determinants
in carcinogenesis
• Development of simpler means of obtaining
valid biological parameters
• Application of these principles to the
evaluation of real world hazards posed
by asbestos and its substitutes and
other asbestos-like minerals.
101
-------
o
NJ
FIGURE 4-1.
REGIONS OF THE UNITED STATES (SHADED AREA) REPORTED
BY EPA TO CONTAIN ASBESTIFORM MINERALS IN THE BEDROCKS,
-------
Research Program
Immediate Research Goal
• To complete the ongoing in vivo and
in vitro studies of evaluating re-
lative toxicity and tumorogenesis
of mineral amphiboles.
Intermediate Research Goal
• To validate the in vivo splitting to
fibers and correlate the phenomenon with
carcinogenesis.
Long-Range and Basic Research Goals
• To develop a short-term system to predict
potential toxicity and tumorogenesis of
mineral fibers.
• To establish a "representative" sample
and establish its toxicity and tumorogenesis
as a model for a health and safety evalua-
tion of mixed amphibole mineral fibers.
103
-------
SECTION 5
ENVIRONMENTAL RESEARCH STRATEGY
I. OVERVIEW
To fulfill the operational dictates of TSCA, test rules and
standards, assessment methodologies, and testing schemes regarding the
ecological effects and fate of chemicals in the environment must be
promulgated. The Office of Testing and Evaluation is responsible
for the scientific applications and interpretations that generate these
test rules and standards. OTE is supported in this effort by the Office
of Environmental Processes and Effects Research (OEPER). Through a
comprehensive research and development program, OEPER provides OTE with a
scientific foundation for their operations, including the basic science
and its applications in test methodologies, interpretative models, and
support documentation.
As provided in Section 4 of TSCA, test rules specify the chemicals
to be tested as well as the nature and standards of the required tests.
The Support Documents for Test Rules should provide an assessment of the
environmental fate and effects of the chemical. Thus, a trial assessment
of each chemical considered as a candidate for Test Rule promulgation is
necessary. This process includes an evaluation of the scientific
validity of information sources, an assessment of the potential for
environmental impact, and an assessment of the need for further testing
104
-------
to fill in gaps in the information available. Recommended additional
testing must provide the necessary information to determine whether or
not the suspect chemical would cause an unreasonable environmental
impact.
Test standards (or protocols for testing the ecological effects and
fate of chemicals) are necessary to implement both Sections 4 and 5 of
TSCA. The test standards and the accompanying rationale for the
particular test standard (the test standard support document) together
provide a guide for new chemical testing (Section 5).
In order to establish a basis for risk assessment and testing
decisions, the Office of Pesticides and Toxic Substances has developed an
integrated tiered testing and assessment scheme. This testing and
assessment scheme will be employed to define the relationships between
the various information elements which may be germane to chemical risk
assessment. In this capacity, the scheme can be used to help identify
potential risks based on analysis of the existing information, as well as
to indicate the additional testing necessary for a complete risk
assessment.
The testing and assessment schemes for environmental effects will
couple information on the production, use, and disposal characteristics
of a chemical with data on its physical and chemical properties to
formulate a preliminary partitioning analysis. The environmental media
and compartments identified in the partitioning analysis will help direct
the toxicity testing to appropriate species. Following the partition
105
-------
analysis, an analysis of the chemical's degradation characteristics
(e.g. probable persistence in the identified media or compartment) will
be performed. This analysis is used to determine whether short-term
exposure (acute toxicity tests) or additional long-term exposure (chronic
toxicity tests) effects need to be investigated. If the threshold effect
levels obtained in the toxicity tests are near the estimated or field-
measured environmental concentrations of the chemical, additional
chemical fate tests may be needed. In addition, biological uptake
analyses may be needed for chemicals which demonstrate chronic toxic
effects, or which lead to important non-toxic effects such as flesh
tainting.
In summary, the testing and assessment scheme relies on the
identification of test data, interpretation of the relationships between
effects and environmental concentrations, and the criteria relevant to
risk assessment for interpreting the data on the basis of these
relationships.
Various means are available to support OTE's operational approach to
the implementation of TSCA. Existing information and known relationships
provide the primary foundation. New data and new relationships from
both the new and already available data (supplied by laboratory and field
research) must be obtained. In regard to their role in establishing
environmental concentrations of concern (exposure assessment), these data
must be organized and interpreted and the value of their relationships
documented and validated. The criteria for synthesizing the exposure
106
-------
and hazard assessment data, into a risk assessment must then similarly be
documented.
Since the scope of TSCA exerts severe pressure on the operation of
OTE, the role of research in testing and evaluation becomes complex.
Approaches which have proven successful in the limited case for
pesticides and certain other known toxicants must now be extrapolated to
a multitude of chemicals (the estimated number of which is 7 x 10^). The
difficulty inherent in this extrapolation is that for known toxicants/
toxic hazard is well-defined and environmental dispersal may be
anticipated, whereas for the greater multitude of chemicals, toxic hazard
is still undefined and environmental dispersal may or may not occur.
Although this difficulty is present, past experience suggests that
environmental protection (e.g. risk assessment) may be achieved by
judiciously examining the ambient concentration in the environment
through a careful exposure assessment, and comparing the effects of the
chemical (through a dose-response relationship) to the environmental
concentration. Selection of the appropriate effects to be evaluated and
the criteria by which these might be employed form the basis of hazard
assessment. The actual synthesis of exposure and hazard assessment is
called the risk assessment process.
As hazard and exposure assessment are not completely separated, both
are also linked with health hazard assessment in many phases. On a
practical level, however, research to provide the data and relationships
must be segregated into parcels and packages of closely associated
subject matter and methodology. Exposure assessment consists of
107
-------
determining or estimating the environmental loading, the physical/
chemical properties of the chemicals, the nature of the chemical
and biological transformations, the nature of the transport processes,
and the nature of the significant environmental characteristics impinging
on these processes. These data and processes must then be integrated
into validated models which provide the estimates of environmental
concentration in time and space. Environmental concentration estimates
must have the form of projected surfaces which will enable the
operational office staff to examine the implications of environmental
partitioning and transport processes over time and under various
environmental conditions. The estimation models must be user-acceptable
and user-accessible and be supplied with adequate documentation. More-
over, the validity of the models in regard to actual field situations
depends on the understanding and agreement of all parties concerning the
implications of the data and the criteria applied to the utilization of
the models.
Hazard assessment must take into account important species effects,
since these are known to be the principal drivers of the legislation and
its effective implementation. Hazard assessment must be cognizant of the
effects on community function, abiotic effects (e.g. stratospheric
modification), the interactions between chemicals regarding various
effects, and finally the dose-response relationships which can be applied
in the overall hazard assessment. The dose-response relationship,
supported and documented by knowledge obtained in the field concerning
the significance of these effects, is then coupled with the estimated
108
-------
environmental concentrations (the aforementioned surfaces) to provide the
risk assessment. The risk assessment can take into account safety
margins, multiple pathways of exposure, and other significant variables
in establishing risk.
The operational assessment approaches of OTE and the research and
development approaches of OEPER serve as complimentary functions. OEPER
provides the test methodologies, the evaluation criteria, and the
interpretative relationships for OTE; OTE in turn helps guide the
priorities and most practical approach within that research and
development program to achieve their operational ends. OTE's approach
can be adjusted and updated as new research provides the tools and
technologies; adjustments in the research and development program can be
made to adequately accommodate some shifts in priorities to meet the
demands of administrative law or other interpretations of TSCA.
Informational needs and future research for the environmental
program are outlined in Figure 5-1.
A. RESEARCH PRIORITIES
During the initial phase of TSCA implementation, the greatest
emphasis of the research will be placed on providing technical assistance
to OTE in developing testing protocols and models for determining the
ecological effects of toxic chemicals. As the implementation program
matures, emphasis will shift to validation of testing models and
protocols, refinement of the methodologies, and maintenance of
cost-effectiveness and simplicity. In general, the test protocols will
be incorporated into test rule development and testing guidelines.
109
-------
RESEARCH STRATEGY INFORMATIONAL NEEDS
Testing and
Assessment
(Environment)
Transport Fate
Exposure Assessment
Ecological Effects.
Hazard Assessment
(1) Environmental Loading
(2) Physical/Chemical
Properties
(3) Transport Processes
(4) Transformation Processes
(5) Characterization of
Environment
(6) Integration of 1,2,3,4, and 5
Exposure Assessment
(7) Validation
1) Important Species Effects
2) Community Function
(3) Structure-Activity Relationship
(4) Interaction
(5) Abiotic
(6J Dose-Response
(7) Integration of 1,2,3,4,5, and 6
in Hazard Assessment
(8) Validation
FIGURE 5-1. RESEARCH STRATEGY ENVIRONMENTAL INFORMATIONAL NEEDS AND FUTURE RESEARCH
-------
The research program will also take into consideration the needs of
the Office of Enforcement and particular problems experienced by the EPA
Regional Offices. Thus the program must develop a capability for
handling special problems and emergency situations related to toxic
chemicals in Regions throughout the United States.
B. PROGRAM STRUCTURE
Environmental research on toxic substances is being carried out
under two categories: Toxics - Transport and Fate; and Toxics -
Ecological Effects. The goal of transport and fate research is to
provide cost-effective and improved methodologies for predicting
transport, transformation, movement, and persistence of toxic chemicals
in the environment. Transport and fate methodologies will be used to
develop testing protocols and exposure assessment models for defining
environmental concentration of toxic chemicals. The Toxics - Ecological
Effects research goal is to develop cost-effective and improved
methodologies for measuring the effects of toxic chemicals on the
environment. Ecological effects research will lead to the development of
testing protocols and hazard assessment models for defining toxic hazard.
In early FY 80, research on the development of measurement techniques for
defining human exposure to toxic chemicals in the ambient environment was
initiated under the Public Health Initiative.
Transport and fate and ecological effects research in ORD is
administered by OEPER and is being carried out in its seven laboratories.
These seven laboratories provide capability for research in various
media:
111
-------
• Freshwater - Athens, GA; Corvallis, OR;
and Duluth, MN
o Marine - Gulf Breeze, FL; Narragansett, RI;
and Corvallis, OR
o Terrestrial - Corvallis, OR; and Ada, OK
« Ground Water - Ada. OK
® Air - Research Triangle Park, NC
In addition, the work on methodologies for human exposure to ambient
toxics is being conducted by the Environmental Monitoring and Systems
Laboratories in Las Vegas, NV; Cincinnati, OH; and Research Triangle
Park, NC; and the Health Effects Research Laboratories at Research
Triangle Park, NC, and Cincinnati, OH.
II. TESTING AND ASSESSMENT
The Toxic Substances Control Act contains several features which
implicitly require the acquisition of chemical fate information. Such
information is useful in conducting fate assessments for both existing
and new chemicals. One of the key determinations, in either case, will
be the exposure assessment or estimated environmental concentration
(EEC).
One of the many elements which determines EEC is the fate of the
chemical in the environments) under consideration. Fate, in turn, may
be viewed as consisting of transport and transformation characteristics.
An analysis of potential transport mechanisms leads to the conclusion
that certain physical and chemical data should be considered.
112
-------
Recent research on aquatic transport and transformation processes
for trace chemicals; the development of hypotheses, concepts, and
strategies for conducting exposure assessments; and the development of
new and improved analytical methods have greatly advanced the
state-of-the-art for exposure assessment. Unfortunately, the level of
knowledge is not uniformly distributed across the various environments.
In addition, the concepts and procedures developed for determining or
predicting the fate of toxic chemicals have not been in use long enough
to gain general acceptance by the scientific community or the various
regulatory authorities.
Thus, the objectives of the testing and assessment portion of the
research strategy for environmental exposure are as follows:
• Describe the scientific concepts, technology, and
information required in environmental exposure
analyses for toxic chemicals.
• Identify the current state-of-the-art and information
gaps in exposure analysis.
• Outline the research and development strategy for
extending, improving, and simplifying the concepts,
methods, and information bases required.
Releases of hazardous chemical substances into the environment
during manufacturing processes, distribution, use, or disposal (whether
accidental or planned) can have adverse impacts on both natural and
man-modified ecosystems and their components. The social costs may
include degradation of the environment; losses in sport, commercial
fishery, and wildlife resources; decreases in agricultural production,
113
-------
losses in tourism and devaluation of property values, and other adverse
impacts.
The potential ecological effects of chemical substances are exerted
differently upon diverse life forms, as well as at various levels of
biological organization including subcellular, cellular, organismal,
population, community, and ecosystem levels. Testing for such effects
requires the selection of indicators (i.e. indicative parameters) that
provide for wide taxonomic representation and include a range of
biological processes, or that have validated application (productive
capability) to these parameters.
Levels of ecological organization above the individual species can
provide information directly related to ecological consequences of the
release of a hazardous chemical. However, the development and
standardization of tests for such effects is difficult due to the
complexity of the species interactions that characterize ecosystems. A
major thrust for the research program for ecological effects, therefore,
will be the development of test methods that address interactions such
as those which occur between predator and prey, among competitors for
habitat or food, and between disease and host organisms. As methods such
as microcosm studies and other laboratory model systems are developed and
validated they will help to address these ecological testing needs.
Laboratory testing below the level of the organism is also
potentially useful, generally rapid, and readily amenable to
standardization. The majority of such testing, however, needs further
development to be usable for ecological impact assessment. Since many
114
-------
cellular and subcellular functions are common to a wide range of
organisms, they have the potential of being applicable to many sets of
ecological circumstances. Therefore, the development and validation of a
number of cellular and subcellular tests are being considered for
inclusion in the research program;
Most ecological effects tests currently in use employ single species
test populations of vertebrates, invertebrates, or plants. Individual
species represent an intermediate level of biological organization
between cellular and subcellular functions and community/ecosystem
interactions. Many single species tests are considered to be
state-of-the-art methods and have correlated well with actual ecological
effects of chemicals. As a consequence, the continued development and
validation of single species tests will be important components of the
research program for ecological effects.
An important emphasis of the hazard assessment research program,
working in concert with the research program for chemical fate, will be
upon the determination of which system(s) of hazard evaluation, exposure
evaluation, and risk assessment provide the necessary and sufficient
information for recommending possible regulation. This includes the
identification of the best available criteria to be applied in utilizing
these approaches, and how scientifically-defensible risk assessments may
be accomplished in the most cost-effective manner.
All aspects of testing and assessment development to be supported by
the hazard assessment research program must include in the research
design a demonstration(s) of linkage with effects of toxic substances
115
-------
upon elements of the real environment, thus establishing a measure of the
predictive capability of the research product. This approach will
produce legally-defensible tools with which the mandates of TSCA may be
implemented.
A. TRANSPORT AND FATE (EXPOSURE ASSESSMENT)
1. Background and Status
The determination of environmental exposures is an integral step in
any risk analysis or toxic substance regulatory/control decision which
attempts to tie the volumes and distribution of materials entering the
environment to specific adverse human health or environmental effects.
As a corollary, reliable exposure analyses require valid estimates of
the loading rates of toxic materials into the various environmental
media.
Once in the environment, the distribution, concentrations, and
persistence of a toxic substance at any point in time are the net result
of physical, chemical, and biological processes that transport and
transform the pollutant either simultaneously or in sequence. The rates
at which these processes actually affect a material are functions of its
physical/chemical properties and the biotic and abiotic conditions
present in the receiving environments. Although a number of processes
can theoretically affect a chemical's fate, only a few may be significant
for any particular chemical and/or environment. It is important to note
that both the identity and magnitude of the predominant "fate" processes
116
-------
affecting a chemical can change drastically from one environmental system
to another.
For many existing chemicals whose loading patterns have been
established, properly designed monitoring programs can provide
environmental concentrations and exposure estimates. In order to
extrapolate from monitoring data, minimal knowledge of (1) the dominant
fate processes involved, (2) the physical/chemical properties of the
materials, and (3) the characteristics of the receiving environment must
be available. For new chemicals, estimates of environmental loadings must
be based on projected production, use, and disposal patterns.
The most important aspect in predicting environmental exposure is
the development and application of valid strategies, techniques, or
models to assemble, integrate, and assess the various complex data sets
required.
Thus, the research activities required to provide the scientific
basis for making valid quantitative estimates of human and ecological
exposure to toxic substances entering various environmental media
include:
• Development of improved concepts and techniques to
determine or estimate environmental loadings.
• Development of improved concepts and methods to
characterize the dominant transport processes.
• Development of improved concepts and methods to
characterize the dominant transformation processes.
• Development of improved laboratory methods to determine
the physical/chemical properties of toxic substances.
117
-------
• Development of concepts and methods for optimum
characterization of environments.
• Integration of the above in developing exposure assessment
models.
• Development of concepts, methods, and information
requirements for testing and validating exposure
assessment models, laboratory methods, and
field observations.
• There is a need to make available analytical
techniques to be used in carrying out fate, effects,
and exposure assessment studies for many toxic chemicals
in their fresh-water, estuarine, terrestrial, and biota
environments. For many toxic chemicals, measurement
techniques for identification and quantification are
not available.
2. Research Strategy
a. Environmental Loading (Emissions) Estimates
Chemicals may enter the environment: (1) at the time of production
through direct losses from the production process (i.e. discarded solid,
liquid, or gaseous waste products); (2) when the principal manufactured
material is packaged, transported, and/or delivered to intermediate or
final users (accidental spills, etc.); or (3) when the product or
products containing the materials of concern are used and discarded.
For some materials, precise information may be available on the
rates of discharge into various compartments of the environment. For most
materials, however, estimates must be made which consider the projected
volumes produced or imported and the anticipated distribution, use, and
disposal patterns. Regardless of the type of data, the procedures or
models used for loading analysis should integrate and reduce the
118
-------
pollutant inputs to time-series concentrations at specific locations for
the aquatic, atmospheric, or terrestrial media. The accuracy of the time
functions is extremely important and is dependent on both the fate and
the effects of the chemical in the environment.
b. Transport Processes Characterization
To obtain valid exposure estimates, an understanding of and
characterization of the significant transport processes which impact
chemical distribution and exposure in any environment are essential.
Characterization in this sense requires that (1) the process be
identified, (2) cost-effective laboratory procedures be developed to
determine the rate and extent of the process within anticipated ranges of
environmental conditions, (3) protocols be written describing the
laboratory characterization procedures; and (4) interlaboratory testing
and evaluation of the protocols be conducted prior to final acceptance
and general application.
As the dominant transport processes in general environments are
characterized and protocols completed, other processes which may
dominate selected exceptional environments will be investigated.
Processes which may be important in the environmental transport of a
chemical include volatilization, partitioning adsorption/desorption with <
soils and sediments, solutions/disolution, advection, dispersion,
precipitation, sedimentation, deposition, and scour.
Suitable methods for the determination of octanol/water partition
coefficients, soil thin layer chromatography (TLC), and soil adsorption
119
-------
isotherms are currently under development. Methodologies also need to be
developed for measuring volatilization rates, leaching potential, and the
uptake of chemicals by biota.
Identification of those circumstances in which expensive laboratory
testing can be avoided through the use of structure/activity
relationships (SAR) or estimation techniques by which existing chemical
and physical data can be used to calculate some other parameter is highly
desirable.
Most of the test methods which appear suitable for the development
of transport data are not standardized. Thus, evaluations and
validations of these procedures through mechanisms such as inter-
laboratory testing ("Round-Robins") are needed.
The effects of salinity and other constituents present in marine
water on transport processes is poorly understood. Transport and fate
protocols need to be tested for freshwater vs. marine systems.
The atmospheric fate of hazardous and toxic chemicals is determined
by competing physical and chemical processes. Physical processes
responsible for the transport and removal of chemical compounds include
dilution, dry deposition, adsorption to particulates, and rainouts. A
rapid reduction in the concentration of gaseous emissions is a result of
dilution; however, dilution does not cause any loss from the atmosphere
in the chemical's mass. Dilution affects all chemical compounds equally,
whereas other physical processes are compound-specific. Dry deposition
is important for those chemical compounds which react with or are
120
-------
adsorbed on surfaces such as soils, plants, bodies of water, and man-made
structures. The fate of the chemical compound adsorbed on a particulate
is determined mostly by the fate of the particulate, which is subject to
rainout, conglomeration, and fallout. Desorption of the chemical
compound from the particulate is also possible, because dilution reduces
the concentration of free compound around the particulate. Rainout
affects chemical compounds which are highly soluble, thus resulting in
contaminants deposited in water bodies or on land.
c. Transformation Process Characterizations
Exposure analysis procedures must also include quantitative
descriptions of the significant physical, chemical, and biological
transformation processes. The significant processes must be identified;
cost-effective laboratory procedures must be developed to obtain the
rates and extent of the processes within anticipated ranges of
environmental conditions; protocols must be developed describing the
laboratory characterization procedures; and interlaboratory testing and
evaluation of the protocols must be conducted prior to final acceptance
and general application. These transformation process protocols may be
very complicated since several different analytical procedures may be
required to quantify the same reaction kinetics. How many different
procedures are needed depends on the physical/chemical properties of the
toxic substance and the environmental media of interest. Thus,
successful application of these protocols may depend on the analyst's
ability to select an appropriate set of standard laboratory procedures.
121
-------
The significant mechanisms for the environmental transformation of
synthetic chemicals are hydrolysis, photolysis, biodegradation, and
abiotic oxidation/reduction reactions.
Suitable methods exist for the evaluation of hydrolysis and aqueous
photolysis. However, appropriate methodologies or improved procedures
need to be established for atmospheric photolysis, biodegradation, and
atmospheric oxidations. A need is also apparent for research on the
significance of abiotic reduction and free-radical oxidation in water and
soils. With respect to biodegradation reactions, there is a need to
determine the importance of anaerobic biodegradation in the environment,
and to develop and refine laboratory methods which can be used to predict
environmentally relevant biodegradation rates.
Studies should be conducted to ascertain the extent to which
structure/activity relationships can be used to predict hydrolysis,
photolysis, and free-radical oxidation reactions.
The test methods currently available for the development of
transformation data and those which will be developed are not yet
standardized and will need to be evaluated and validated. Hydrolysis and
photolysis tests are at such developmental stages where Round-Robin
testing may be initiated. The overall importance of anaerobic
biodegradations in the environment needs to be determined, and the
ability to determine biodegradation rates or rate constants in the
laboratory which can be related to real world conditions needs to be
improved. Studies need to be conducted on the importance of acclimation
and the role of concentration vs. biodegradation. Another important
122
-------
research need is for a "toxicity screen" procedure. This procedure will
permit the introduction of some appropriate species into a test chamber
where biodegradation (or some other transformation process) has occurred,
and will "screen" for the loss, continuation, or enhancement of original
toxicity. Round-Robin studies are needed for most state-of-the-art
methodologies.
New methods on aquatic and atmospheric systems need to be developed
and current methods improved to define better the significance of
reactions on water and soils, and to develop structure/activity
relationships between chemicals and their susceptibility to free-radical
reactions.
Since the effects of salinity and other marine water constituents
are not well-defined, a comparative evaluation of the rate constants for
hydrolysis, photolysis, biodegradation complexation, and oxidation/
reduction in freshwater vs. marine systems should be carried out.
Chemical transformation processes important in the troposphere
include reaction of compounds with OH radicals, with ozone, (03) and to a
much lesser extent with species such as RO2, HC>2, atomic oxygen, singlet
molecular oxygen and oxides of nitrogen (NOX). Data needed to assess the
lifetimes of toxic compounds in the troposhere are now obtained from
estimates or measurements of OH radical and ozonolysis reaction rates.
The need exists for better estimates and for a means of actually
measuring the OH radical and ozonolysis reaction rates for various toxic
compounds. Also to be identified are reaction products.
123
-------
Those chemical compounds which are reactive, that is, have
half-lives of a day or less, can occur at elevated concentrations only
within the boundary layer of the atmosphere. For these compounds, it
would be necessary to investigate the possibility that degradation
products of a toxic nature might form at levels problematic to human
health.
Certain chemicals absorb sunlight directly and undergo photolysis
reactions. To assess tropospheric photolysis, solar radiation intensity
and spectral character must be estimated or measured along with the
adsorption efficiencies of compounds at various wavelengths. The gas
phase photolysis rate and reaction products need to be established to
estimate atmospheric photolysis lifetimes in the troposphere. Additional
research is needed to establish photolysis rates of compounds on
adsorbed materials and to determine if any synergistics such as the
photolysis of copollutants can induce the decomposition or transforma-
tion of original toxic compounds.
In the stratosphere, important processes involve reaction of toxic
compounds with atomic oxygen O(1D), and photolysis in the 150 nm to
300 nm region of the solar spectrum. Significant in stratospheric
photolysis are solar radiation intensity and spectral character, and the
adsorption efficiencies of absorbing compounds at various wavelengths.
d. Physical/Chemical Properties of Toxic Chemicals
Simple physical/chemical properties of toxic compounds are important
and may provide good information on the potential fate of chemicals in
124
-------
the environment. Physical/chemical properties provide an initial
indication of which of the various transport, transformation, and human
and environmental test protocols should be utilized. Such shortcut
procedures may be useful in the cost-effective testing of large numbers
of chemicals; however, each decision procedure must be thoroughly
evaluated and tested to assure that significant exposure and/or effects
are not overlooked.
Standard laboratory methods for measuring many of these
physical/chemical properties are well accepted by the scientific and
industrial community; yet, the selection of appropriate analytical
methods may depend upon the magnitude of the constants and the precision
and accuracy of the methods. Important properties include water
solubility, vapor pressure, boiling point, melting point, particle size,
molecular dimension, molecular diffusivity, and partition coefficient.
For the purpose of defining environmental transport of chemicals, the
data on water solubility, vapor pressure, and partition coefficients are
especially important. Although satisfactory methods exist for most of
the physical/chemical properties measurement, Round-Robin validation of
such methods is needed.
e. Environmental Characterizations
Both the rates and extent of transport and transformation processes
are impacted by the physical, chemical, and biological characteristics
of the receiving environments (e.g. air, water, soil, temperature, pH,
biomass, volume, area, depth, etc.). Thus, new and improved concepts and
125
-------
methods must be developed to identify, measure, and catalogue these
parameters in the simplest detail required to describe quantitatively
the environments of interests. Since many of these parameters fluctuate
at least seasonally, maximum, minimum, and time-averaged values become
important.
Previous ecosystem studies and environmental monitoring programs
provide the basis for characterizing site specific environments (e.g. a
particular air shed, river beach, lake, estuary, etc.). However, new
methods must be developed, evaluated, and tested to reduce the
characteristics of a large number of environments into a minimum set of
simple hypothetical (canonical) descriptions for calibrating exposure
assessment models.
f. Exposure Assessment Models
The state-of-the-art of exposure assessment models is not
well-developed. Attempts are underway to integrate loading information
with data on transport and transformation of chemicals to produce
suitable models. An Exposure Analysis Modeling System (EXAMS) developed
by the Agency predicts concentrations of toxic chemicals in water. EXAMS
is being tested for various chemicals and is also being refined to
improve its resolution. Corresponding models need to be created for air
and terrestrial environments. To date, most air models are based on
simple dispersion and transport characteristics. These models should be
replaced by site specific and generic models. Finally, models describing
concentrations of toxic chemicals in multimedia environments must be
developed.
126
-------
Screening procedures based on structure/activity relationships,
representative groups, and pattern recognition methods are needed to
provide rapid estimation of exposure and fate of chemicals in the
environment. These models will be particularly helpful in evaluating new
chemicals under Section (5) of TSCA.
Models describing pathways and concentrations of toxic chemicals are
also needed to assess the total exposure of toxic chemicals to the
environment. Finally, the exposure assessment models must be coupled
with ecological effects data in order to develop risk models.
g. Validation
A model is a logical and/or mathematical simplification of a
real-world system. Models may be either predictive or descriptive in
nature and can be used for designing environmental monitoring systems and
clean-up procedures for pollutant spills, or for evaluating potential
hazards of new chemicals. In the first stage of validation, it must be
verified that the logic and/or mathematics of the model do not contradict
any principle of the subject field. In the second stage of model
validation, field collected data are used to exercise the model. Model
derived output values are then compared to actual measurements of ambient
conditions. The following factors should be considered in the third
stage of model validation:
Determine those areas for which modeling can provide a more
cost-effective means of acquiring needed information.
Determine the criteria for evaluation of the model, i.e. the
level of confidence that will be acceptable for the intended
use.
127
-------
• Review and evaluate existing models and identify further
developmental requirements.
• Obtain good reaction rate constants which are measured and
verified. It is essential also to have good reaction product
characterization. Local area model validation can use wind-
tunnel/water-channel simulations. Microcosms and laboratory
ecosystems are needed for testing of models. Microcosm test-
ing may provide first indication of the validity of the model.
Field validation of models is also necessary before a model can be
used by the Agency in the regulatory decision-making process. When
field-study data are used to validate models, quality assurance must be
emphasized to obtain good quality data. If methods change with time,
full-fledged comparisons and validations of old and new methods must be
undertaken. Field studies should be undertaken to provide background
concentrations for all models (local, regional, and global).
3. Research Program
Research in the area of exposure is designed to meet the immediate
needs arising from TSCA implementation as well as from the development of
methodologies for controlling long-term environmental pollution problems.
Some of the important needs identified by OEPER as resulting from TSCA
requirements are: (1) technical assistance to OTE so that the
implementation of TSCA can be carried out on a sound, credible, and
scientifically-defensible basis; (2) testing methodologies for
predicting the fate of chemicals in the environment (such tests must be
cost-effective, simple to perform, and based on scientifically-sound
principles); and (3) models for estimating or predicting exposure
concentrations of toxic chemicals in the environment (such exposure data
128
-------
are essential in defining the risk toxic chemicals may pose to humans and
the environment).
One portion of the ORD resources allocated for exposure assessment
is designated for the provision of direct technical support to OPTS.
Technical support is a critical service because OPTS in its initial
stages of operation must develop guidelines, evaluation schemes, and
other testing and assessment documents. Since the area of exposure
assessment is still in a developmental stage, it is essential that ORD
work closely with OPTS to develop guidelines and testing schemes that are
scientifically-defensible. Technical assistance may include aid in the
development of the scientfic logic for testing and assessment, technical
support in document preparation and/or review, workgroup participation,
chemical evaluation support, special testing, site visits, serving as
expert witnesses, and computer model document and user support.
Testing methodologies for predicting the fate of chemicals in the
environment are necessary to provide data for exposure assessment. Pate
tests provide critical information on what happens to a chemical once it
is introduced into the environment, in which part of the environment
(air, water, soil, and/or biota) the chemical may accumulate, and for how
long and in what form the chemical may persist. Chemical fate testing
methodologies are currently being developed for incorporation into
testing schemes under Sections 4 and 5 of TSCA. In developing such
methodologies, emphasis is placed on scientific soundness, cost-
effectiveness, rapidness, and relative ease of performance.
The most important areas for which testing methodologies are needed
include: atmospheric reactions; the transport, transformation, and
129
-------
movement of chemicals in soils/sediments; biodegradation of chemicals;
photolysis; range-finding screening methods; transport and transformation
via the food chain system; and structure/activity concepts for fate
prediction. Work on the atmospheric fate of chemicals involves the
development of predictive techniques and laboratory test methods, as well
as environmental sampling techniques. Effort in the area of transport,
transformation, and movement of chemicals is concerned with the
development of improved methodologies for predicting adsorption/
desorption and leaching of chemicals in soils/sediments. Biodegradation
studies are designed to define the half-lives and transformation of toxic
chemicals in terrestrial, fresh-water, estuarine, and marine
environments.
ORD has initiated several projects to define the fate of toxics in
the food chain. The information obtained will be used to develop food
chain models and testing methods. ORD has also initiated a program to
develop structure/activity concepts for predicting the fate of chemicals
based on physical/chemical properties and structural characteristics.
Mathematical models also need to be developed and improved which can
be used to integrate and validate the testing methodologies. Mathemati-
cal models for estimating the environmental loadings, exposure, and
effects of chemicals are being developed, improved, and evaluated by
ORD. These models represent quantitative hypotheses of chemical entrance
into various environmental media, their transport, degradation and
distribution, and human and environmental impacts.
130
-------
Exposure assessment models are being developed to predict the
concentrations of chemicals in air, surface waters, sub-surface waters,
marine environments, soils, and sediments. A program which closely
parallels OPTS needs is being initiated under the Public Health
Initiative to develop models for defining the movement and concentration
of chemicals in the food web and to develop methodologies for measuring
human exposure to toxic chemicals present in the ambient environment.
Specific investigations under the Public Health Initiative include the
development of an air model, water model, terrestrial model, multi-media
models, food chain models, transport and transformation models, exposure
assessment methodology, and microcosms for the validation of models.
Basic Research Goals
• Development of laboratory methods for determining
atmospheric reaction rates of organic chemicals
with free radicals. (Highest Priority)
• Work to determine the effects of halocarbons on
ozone levels in the troposphere/stratosphere.
The dispersal and removal of man-made halocarbons
will be described by a mathematical model that
combines the atmospheric chemical transforma-
tion with physical transport mechanisms. This
model will be able to predict the impact of
substitutes for freons on stratospheric ozone
and will be able to aid in designing various
control options. The photodissociation rates
and mechanisms of halogenated compounds under
stratospheric conditions will be examined.
(Highest Priority)
• Determine of the distribution of halogenated
compounds in the troposphere by sampling of
selected urban, rural, and maritime areas.
Another project will focus on developing degrada-
tion models from an analysis of photolysis rates
and reaction products under laboratory condi-
tions. (High Priority)
131
-------
Evaluate sorption properties of soil/sediments
as they relate to the correlation of adsorption
with organic content, cation exchange capacity,
solubility, and the n-octanol-water partition
coefficient. (Highest Priority)
Develop protocols for leaching of chemicals in
soils. These protocols will provide a metho-
dology for testing chemicals for leaching in soils
and for their potential as groundwater contami-
nants. Procedural modifications required to
adapt these protocols for use with toxics will
be identified and documented in detail*
Procedural and operator variability will be
identified and procedures developed to reduce
their impact. (Highest Priority)
Investigate the adsorption of charged and
protonated organics in natural sediments.
Emphasis is on relating the sorbent properties
with cation exchange capacity, particle size,
organic carbon, ionic strength, and pH.
Sorbate properties include solubility,
molecular structure, and size. (High
Priority)
Conduct studies on the biodegradation properties
of estuarine microorganisms and their impact on
the fate of toxic chemicals. (Highest Priority)
Determine the rate of degradation of chemicals
under conditions of anaerobiosis with emphasis
on defining microbial kinetics for degradation.
(Highest Priority)
Evaluate the importance of co-metabolism in the
microbial degradation of chemicals under varying
environmental conditions. (High Priority)
Define the role of sensitizers as well as the
effect of sediments on solar radiation in
water. (Highest Priority)
Develop, evaluate, and validate, for differing
environmental simulations, range-finding systems
(e.g. Eco-core) for determining the transport
and transformation of organic chemicals in
laboratory-maintained environmental samples
which integrate all fate processes into one
aquatic system. (Highest Priority)
132
-------
Bioaccumulation models must be developed which
employ basic physico-chemical and biochemical
measurements to predict bioaccumulations and
potential residues. (Highest Priority)
Transformation processes in plants and animals,
particularly conjugation and covalent reaction
can result in retained residues or bioactive
products. Investigation of the major components
of food chains will be based on studies in both
large and small scale microcosms and modular
food chain systems. After early studies on simple
(primary producer/herbivore; herbivore/carnivore)
systems/ studies on more complex systems involving
birds and fish will be attempted for multi-media
assessment. (Higher Priority)
Predict degradation based on the structure of
toxic chemicals. Coordinate studies of
structure/activity relationships between
various microsomal (plants, insects, mammals)
and chemical (free radical, UV, peroxide)
oxidation systems. Predict plant uptake and
transport and transformation based on structure/
activity relationships. (Highest Priority)
Water Model: Some progress has been made in
the development of water models.
— The Exposure Analysis Modeling System
(EXAMS) has been developed to predict
the concentration of chemicals in fresh-
water systems. (Highest Priority)
— Continue development of models to predict
movement of toxic chemicals in the Great
Lakes. (Highest Priority)
Estuarine Models: Continue efforts to develop
mathematical sub-models generated from other
projects which can be appropriately inserted
into existing estuarine hydrodynamic models.
(Highest Priority)
Continue development of models to predict transport
amd transformation of chemicals in estuarine and
marine environments. Initial emphasis will be
placed on defining the rate parameters followed
by development and validation of the models.
(Highest Priority)
133
-------
Air Model: Continue development of a numerical
model for predicting concentration of toxic
chemicals in air. The model is based on trans-
formation of chemicals coupled with transport
and diffusion data. (Highest Priority)
Terrestrial Model: Continue work to develop
T-EXAMS (analogous to EXAMS for water) for
predicting concentrations of chemicals in
terrestrial environments. (Highest Priority)
Develop mathematical models for transport
and transformation of chemicals in saturated
and unsaturated soils. Mathematical models
will be developed to describe selected
mechanisms for chemical attenuation for
both steady state and transient hydraulic
conditions for one-and-two dimensional flow
geometries. (High Priority)
Multimedia Models: Continue attempts to
develop a first generation model for defining
exposure concentrations of toxic chemicals
in multi-media environments. The development
of a comprehensive integrated multi-media
model will require a long-term research
approach with considerable resources.
(Highest Priority)
Food Chain Models: Continue work on defining
pathways and concentrations of toxics in food
chain systems. This work involves the measure-
ment of uptake of chemicals in plants, studies
of bioaccumulation of chemicals in fish, marine
animals, avian species, etc., and finally, in-
tegration of this information with transformation
parameters to develop a model. (Higher Priority)
Exposure Assessment Methodology: Continue work
under the funding of the Public Health Initiative
on developing methodologies to measure human and
environmental exposure to toxic chemicals present
in the environment. This work involves the measure-
ment of ambient concentrations of toxic chemicals
in air, water, soil, and the food chain. (Higher
Priority)
Microcosms for Validation of Models: Continue
development of laboratory microcosms (aquatic,
terrestrial, and estuarine) for the validation
of mathematical models. Specific work includes:
134
-------
The use of large and small microcosms in the
validation of models to be complemented by
field studies on a limited number of chemicals.
These systems will be tested using existing
field data, where possible.
Microcosms will be designed to simulate ter-
restrial, surface freshwater, ground water,
estuarine, and wetland environments.
Field studies may include the continued use
of existing field channels. (Highest
Priority)
Future Research Goals
• Interlaboratory validation of methodologies
for measuring physical/chemical properties of
toxic chemicals.
• Interlaboratory validation of tests for
defining transport and transformation of
chemicals in the environment.
• Validation of exposure assessment models using
laboratory model ecosystems, mocrocosms, and
field studies.
o Increase emphasis on structure/activity
relationships and other estimation techniques
for predicting the fate of chemicals.
• Refinement of the methodologies for predicting
transport and transformation of chemicals.
• Development of a long-range research program
to meet the future needs of TSCA.
B. ENVIRONMENTAL EFFECTS (HAZARD ASSESSMENT)
1. Background and Status
As recognized in numerous sections of several Congressional acts
(including TSCA) EPA is charged with the responsibility to protect public
135
-------
resources as well as biological integrity, e.g. "balanced indigenous
populations" and the like. To protect specific components of natural
systems, a different data set is required than for cases where an
"ecosystem" is to be preserved. For example, the data needed to control
air emissions to protect agricultural crops are more specific and
restricted than the data needed to protect northern coniferous forests or
grasslands. Similarly, information needed to protect trout populations
for sport fishing is more specific than information needed to protect the
balanced indigenous populations of a water body.
Past regulatory efforts have relied heavily on data sets for one or
a few species, assuming that if these species are protected the necessary
supporting organisms will be able to thrive under similar conditions.
However, unless adequate data are developed to assure protection of those
specific processes required to protect the selected species, their
protection will not be assured even though the community is healthy. The
concern here is with population protection as distinguished from
community protection.
To achieve our goal requires us to identify the species important
to man as objects of regulatory decision-making before we can decide the
necessary data sets. This task is simple for domestic organisms such as
White Pine, corn, salmon, and sheep. Likewise protection of endangered
species such as the golden eagle and snail darter is mandated by law.
Many decisions are much more difficult, e.g. how does one decide if
Pocket Gophers or Wild Roses are among the important species? Once a
list of important species is estabblished, "indicator" species and
136
-------
surrogates must be identified since resources are not available to test
them all.
Communities are viewed by many in a manner analogous to the view of
an organism, i.e. they have functions such as primary production,
respiration, decomposition, and aging just as organisms have metabolism,
breathing, and growth. Community functions are dependent on many species
and species interactions which are complexly intertwined, so that a
change in one place may have a ripple effect throughout the whole
community. For communities, individual species are less important than
the community functions, regardless of which subset of species may
accomplish that function. For example, instead of the mortality rate,
growth rate and number of eggs produced, biomass, R/P ratios , and
predation rates may be used to measure community response. Protection of
biological integrity and similar goals can only be achieved by community
protection, but these goals do not ensure that an aesthetically desirable
species to man will thrive.
The number of communities is probably as large as the number of
different species, so the first problem (as for single species) is to
decide which species can be used as indicator or "type" communities and
which can be used as surrogates since all cannot be tested. However
single species and microcosm tests cannot be equated with protection of
important species and communities. The protection of species and
communities are objectives, whereas single species and microcosm tests
are techniques.
137
-------
In addition, judgment of the effects of a chemical placed in the
environment cannot be made as though the chemical were the only stress to
be considered. In nearly every locale, other man-made contaminants as
well as natural stress will exist. The impact of these other stresses on
the effect of concern must be included in the final evaluation.
Some effects may occur that are abiotic (e.g. damage to structures
from acid rain) or that have indirect biological effects such as ozone
depletion and subsequent radiation effects. These effects also need to
be identified and included in the decision-making process.
As practical decision-making proceeds, experience likely will show
that there will not be a single environmental concentration, but
many. The expected ambient concentrations will vary over time. There-
fore, effect concentrations expressed as single numbers may be an in-
adequate basis on which to judge the safety of expected ambient concen-
trations. Rather, a family of curves or response surfaces will be
required to integrate time of exposure into acute, sub-chronic, and
chronic toxicity as well as behavioral changes, bioaccumulation, and
seasonal considerations.
The generation of such response surfaces requires different data
which are more difficult to obtain than data needed for threshold values
for use under worst case conditions. The state-of-the-art to generate
such information is poorly developed.
The above generic informational needs appear to be the more
important ones that must be fulfilled for decision-making under TSCA.
138
-------
For new chemicals, reliance will have to be placed on laboratory tests
and predictive techniques such as models, whereas for existing chemicals,
experience and monitoring data can substantially increase the basis for
decision-making.
2. Research Strategy
a. Important Species Effects
A number of reliable single species tests have been developed for
important organisms such as sport and commercial fishes and a select few
of their food organisms. Similar tests are available for measuring
stimulatory or inhibitory effects for aquatic algae and a few terrestrial
plants. Some species such as the salmonid fishes are obviously important
and have been shown to be quite sensitive to toxicants. With the
invertebrates, it is not so evident that we have the most sensitive
species in the test protocols. In fact, some would suggest that the
species which have been tested are most amenable to being raised in
captivity. Present research concentrates on three areas: (1) Round-
Robin testing of those tests which are well developed to ascertain
whether the methods are adequate and to give an idea of the variability
which might be expected among laboratories; (2) development of new tests
for species which represent special niches such as sediment-dwelling
aquatic organisms; and (3) development and validation of shortcut
methods to reduce the time and cost of testing. Important factors
influencing the definition of informational needs in this area are
(1) the number and kinds of species, (2) significance of end points,
(3) estimating species sensitivity, and (4) residues, tainting, etc.
139
-------
(1) Number and Kinds of Species
Resource constraints will allow testing of only a few important
species. A principal need is to identify which species should be tested,
based upon the utility of the data that would be obtained, and to verify
that these choices adequately represent the species to be protected.
To date, except for cultivated species, those species most used for
testing have been chosen based upon laboratory adaptability, curiosity,
or availability. The number of important species among plants and
«
animals is highly variable within and between terrestrial, freshwater,
and marine habitats.
Suitable test conditions are most easily developed for species that have
been cultured, domesticated, or managed in some manner. For others, such
as marine invertebrates, the problems are more numerous.
(2) Significance of Endpoints
A myriad of endpoints have been proposed or used to assess effects
in toxicity tests. Increased mortality or reduced growth have been more
useful for regulation purposes than more subtle changes in physiology or
behavior. Any change from normal, however, may be detrimental. This is
more apparent for communities than for single species. In fact, many
practices in domestic animal production, such as using growth hormones,
depend on a change from normal to improve utility.
Whatever the effect measured in a toxicity test, the ultimate
concern is the impact on the population and its quality (size, taste,
140
-------
vigor, etc.), and the effects of this input at the ecosystem level. To
date, little concern has been given to the population significance of
small mortality differences or reproductive impairment, to say nothing of
physiological changes or alterations in behavior.
Establishing the significance of commonly used or potentially
convenient endpoints to populations is a high priority. In this area,
dose-response significance is needed rather than "all or none" judgments
if the expected effects are to be related to ambient concentration
predictions. Such evaluations will require use of large experimental
systems in which whole populations can be tested. For bacteria, the size
of the system needed is not large; however, for larger plants and
animals, systems of acres or square miles in size may be necessary. Data
for these evaluations may be obtained more efficiently from chemicals
already in use rather than in experimental systems. A good example of
this approach is the demonstration of the significance of egg shell
thinning caused by DDE.
A high priority is to focus effort towards the goal of validating
the populational significance of currently used endpoints.
(3) Estimating Species Sensitivity
As a result of examining the large data base for the toxicity of
consent decree chemicals to aquatic life, the range of sensitivity to a
given chemical among aquatic life species was frequently observed to be
much larger than the difference observed between acute and chronic
toxicity. If the total range of species sensitivity due to terrestrial
141
-------
organisms and bacteria could be included the difference would be even
greater.
Since only a few species can be tested, a method for estimating the
spread in species sensitivity is far more important than the estimation
of chronic toxicity. We have virtually no ability to make any guess
concerning the species range, except when sufficient data are available
to make an extrapolation from our sample set. No theories as to the
shape of such curves exist.
Progress in the area of comparative species sensitivity might yield
a larger return than most areas of endeavor because such a capability
would be as applicable to community judgments as to important species
judgments.
(4) Residues, Tainting, Etc.
Some effects of exposure to chemicals cause no apparent harm to the
population1s viability, but lessen the value of individuals for man1s
use (e.g. formation of unacceptable residue and production of off-
flavor) .
Methods for measuring residues are well developed but usually
measure only equilibrium, ignoring variable exposure and depuration. A
larger deficiency is the frequent absence of data on what constitutes an
unacceptable residue (i.e. a residue which impairs use). To obtain such
data often requires expensive and lengthy tests on higher animals (such
as primates) or predators (such as eagles). The prediction of direct
accumulation from an ambient medium on an organism has been developed to
142
-------
a point of usefulness, but prediction from one trophic level to the next
is not yet usable.
Methods for assessing off-flavor are insufficiently objective, and
recent safety precautions prohibit use of test panels for evaluation.
Methods development, especially in the area of prediction (as opposed to
actual testing) needs to be improved.
b. Community Function Effects
In dealing with communities of organisms within an ecosystem, one of
the primary needs is knowledge of the species interactions. The effects
of perturbations on a system are reflected to a greater or lesser extent
throughout the entire community. The extent to which we can measure
these effects depends on our knowledge of these species interactions and
the role of the species on the system function. Methods for assessing
contaminants which cause immediate low-level response to stress are
particularly important. Research must determine the sensitive indicators
(including organismic, chemical, or biochemical indicators) which can act
as rapid prognosticators for determination of effects on community
function. Mechanisms of stress, resistance to stress, and recovery from
stress are major areas of concern.
Community relationships involve complex interactions and processes
between biotic and abiotic constituents. A ranking of the stress-
sensitivity of major processes and their constituents may help to
define the most sensitive indicators of stress. The major processes
which contribute to community funtion and may be used to measure stress
143
-------
on a community are respiration, metabolic assimilation, primary
productivity, growth and development, reproduction, behavior, and
decomposition.
Organisms in any community produce gas and other byproducts as part
of their life process (i.e. respiration). Quantitation of the levels at
which the products are present during normal and perturbed states should
provide an understanding of the relationships of the dose-response
concept. To date, however, direct measurement of respiration appears to
be among the least sensitive indicators of toxic organic stress. This
may be due to the multiplicity of factors affecting differential
analysis.
Since certain toxic organics are known to inhibit selectively
macromolecular synthesis in some organisms, metabolic assimilation or
biosynthesis could serve as indicators of stress effects on a known
function.
Primary production at both higher and lower plant levels has been
investigated by single species tests because of extensive herbicide
usage. The photosynthesis process itself is not usually sensitive to
stress, but the number of ways in which its efficiency can be reduced and
the consequent drastic ecosystem repercussions suggest the need for
particular attention.
At the community and ecosystem levels, growth must be considered to
include genetic diversity and ecological succession. The community can
accommodate some loss in diversity caused by stress; however, precaution
144
-------
must be taken that predominant species loss does not change the basic
relationship and therefore function of that community.
Behavior is certainly central to the existence of any community of
organisms, thus, behavior may be viewed as a community process. Mating
and social behaviors, feeding motions, homing, phototropism, avoidance,
and aggression are examples of a variety of responses at many trophic
levels which may offer some measure of stress.
Information developed for the fate of chemicals may eventually allow
us to determine where a chemical will ultimately reside in a community.
Very little is known about the inhibition or disruption of the degrada-
tion process in nature by toxic organics. The fundamental ecological
importance of these processes make them important as indicators of stress
for community function. Nutrient cycles also may be included here.
Since these cycles are necessary for the stable functioning of
communities, they could serve as sensitive indicators of stress.
Bioaccumulation of chemicals by components of a natural community
can lead to stress within the system or simple innocuous storage.
Certain types of bioaccumulation are necessary for life processes (e.g.
hydrocarbons in plankton), but accumulation of certain toxic chemicals by
species within the system can lead to stress of a particular
function. Also innocuous bioaccumulation, by some species, can through
food chain magnification result in a stressful situation for some species
of the community.
145
-------
The exposure of potentially toxic chemicals to humans through their
environment is a result of a complex web of physical, chemical, and
biological processes. Prediction of hazard to man and the environment is
possible only through integration of the discussed processes. Mathe-
matical models provide a convenient tool for this purpose. Informational
needs include sources, fate and transport, toxic effects, population
dynamics, and environmental conditions. The development of chemical fate
data and transport models is discussed under the section concerning
estimating ambient concentrations. The kinetics of population dynamics,
impact of toxic chemicals on communities, and bioaccumulation/
bioconcentration data are discussed in this section. The integration of
these data with exposure concentration models will provide ecosystem
hazard prediction capability.
In the natural environment, the concentration of any substance
varies in a continuous fashion. To model adequately the effect of the
substance at any point in the environment, a continuous functional
relationship between exposure concentration and the studied effect is
necessary. From this relationship, a deterministic equation is derived
for inclusion in the model. Needed toxicity information can be obtained
from acute and chronic tests on important species. Population studies to
quantify the effects of the potential toxicant on community structure and
on predator-prey relationships as a function of the chemical concentra-
tion need to be developed. The effect of the chemical on rates of
predation on prey populations and the consequences of severe reductions
in certain classes of the community structure can then be quantitated.
146
-------
The accumulation of toxic chemicals in various levels of the food
chain is the result of both interaction with the surrounding environment
and biomagnification through consumption. The major processes involved
include uptake, assimilation, depuration, loss due to reproduction, and
biotransformation. Each of these processes is complex, and all are
intertwined. Research aimed at describing bioaccumulation should be as
simple a representation as possible. Research needs will depend on the
complexity necessary to describe the bioaccumulation process.
Tests for community function are not well developed, largely because
in the past, emphasis has been placed on single species toxicity
tests. There is a strong need to develop tests which will measure
community responses to the effects of a toxicant on ecosystem
processes. The most likely tests in this category are on simple
microcosms and are designed to duplicate a process such as nutrient
cycling or breakdown of leaf litter. Such tests are in planning stages,
but still some time away from the final method and validation stages for
standard use.
c. Interactions
Chemical substances are rarely found in their pure form, in uniform
concentrations, or unmodified by natural physical, chemical, and*
biological factors in the environment. Natural environments may refer to
either a perturbed state, i.e. man-made or modified environments such as
the agro-ecosystem or urban communities, or to the unperturbed condition
such as might be associated with a stream, a wetland, a forest, or a
147
-------
desert range land. Current scientific understanding of the interactions
of chemical substances in a variable uncontrolled natural environment is
primitive at best when compared to available knowledge of the effects
pure chemical substances exhibit in laboratory tests. There are a few
exceptions; for example, DDT has been well studied in both the laboratory
and in the field and its ecological effects are relatively well
understood. The basic understanding of how chemical substances affect
human health directly is much better than the understanding of how these
substances affect and interact with the natural environment.
Relatively little work has been done on the interactions of
pollutants with the exception of the effort to define the synergistic
actions of metal combinations. However, research is now underway to
define the interactions of mixtures and toxicants with other
environmental factors. Research has been initiated on toxicants present
in complex waste effluents and the effect of the actions of various
components. Tests have been conducted to determine the effect of
toxicant-imposed stress on the susceptibility of salmonid fishes to
naturally occurring diseases. These tests have demonstrated the effect
of toxicant-imposed stress on the ability of salmonid fishes to adapt to
salt water in their seaward migrations. They have also demonstrated
that often suspected interactions may have vital consequences in the
ecosystem. Such research on complex mixtures needs to be expanded in the
future if any degree of confidence in "safe level" predictions is to be
developed.
If EPA is to regulate chemical substances effectively and reasonably
under TSCA, then the interactions of chemical substances introduced into
148
-------
the environment must be understood. The presently available knowledge of
chemical risk and hazard assessment is derived through the use of simple
laboratory test schemes and general action models which use pure chemical
substances. The assessment of physical/chemical effects, biological
effects, and fate in the natural environment remains largely unknown.
The four principal areas of "interactions" research needed to relate
laboratory test models with field realities are as follows: (1) the
synergistic and antagonistic ecological effects of chemical substances;
(2) multiple chemical exposure in the ecosystems; (3) complex chemical
mixture effects on ecosystems; and (4) the physical, chemical, and
biological factors affecting the action of chemical substances or
chemical mixtures in the environment. This research should be conducted
in all media (air, water, and land) and in the laboratory, and should be
validated in the field. The results are expected to be vital in the
assessment of long-term and cumulative damage to the ecosystem.
d. Abiotic Effects
Important abiotic effects of chemicals on the environment may include
material damage, atmospheric modifications, acid precipitation, and
aesthetic loss.
(1) Material Damage
The contribution of trace gaseous materials (which includes toxic
compounds in the atmosphere) may have significant effects associated
with damage to materials. However, a wealth of information does not
exist on this subject. Thus, there is a need to define possible material
149
-------
damage due to chemicals either as single compounds or in association with
other compounds.
(2) Atmospheric Modifications
Gaseous toxic substances and/or their reaction products which contain
halogen atoms having sufficiently long lifetimes to be transported out
of the troposphere into the stratosphere could result in depletion of
the ozone layer. Research must recognize such long-term global effects
associated with long-lived gaseous compounds.
(3) Acid Precipitation
Of particular interest is the effect of acid precipitation which
results in changes in the acidity of lakes and streams. Outside, the area
of acid precipitation, few studies on the nature and concentrations of
organic chemicals in rainfall within the United States have been
conducted. Research is needed to measure the concentration of chemicals
both in rainwater and the ambient air to elucidate the extent of removal
of chemicals by precipitation. The validation of regional and
continental models is important because of the impact of long-range
transport of pollutants on acid rain problems.
(4) Aesthetic Loss
The possible result of aesthetic loss associated with visibility
reduction from chemicals is virtually unknown. The main areas of
research needs in aesthetic loss are associated with visibility reduction
and odor.
150
-------
e. Dose-Response Relationships
It has been known for some time that "dosage makes the difference"
in regard to toxicity. The dose-response relationship can take many
forms (linear, exponential, biphasic, etc.), but the application of that
relationship is critical to the utilization of all the foregoing effects
(single species and community) in hazard assessment. This relationship
is assumed to allow the hazard assessment to be related to exposure
assessment in order to determine risk. Primary information for these
relationships is derived from acute, subchronic, and chronic exposures
and measurements of the resultant effects. Since realistic exposures
seldom take the form of the idealized continuous concentration and even
exposure in the laboratory, the role of intermittent and stochastic
exposure concentrations must be considered in developing the
relationships. The methodology must be supported by valid statistical
techniques and models which account for natural variations in response.
Finally, the "population-at-risk" must be established through models
which can connect the environmental concentration response surfaces to
the response function with respect to concentration (considering other
relevant factors) to provide a damage index or environmental impact
(risk) assessment.
(1) Acute, Subchronic, and Chronic Exposures
Short-term exposure needs are being met in test method development
to the extent that each assay procedure calls for output in the form of a
dose-response relationship (e.g. EC-50). In some instances, for example
151
-------
terrestrial plants, problems are being experienced in obtaining such
relationships.
The extent to which short-term exposures (acute and subchronic)
permit chronic and intermittent exposure assessment needs to be
determined. The relationship of chronicity of action for generic
chemical classes (linearity of time x concentration re effect) must be
known to determine dose-response relationships.
A stronger theroretical basis for understanding the relationships of
exposure for different types of tests must be derived.
(2) Intermittent Exposures
Studies of the effects of intermittent, discontinuous, or stochastic
exposures for significant effects are needed to supply a basis for
realistic exposure-response relationships.
The relationship of chronicity of action for generic classes of
chemical functions must be determined, and a means of ascertaining the
theoretical relationships of different exposure patterns must be devised
and applied.
(3) Statistical Methods and Models
Each test method must have appropriate statistical procedures for
its use or derive such procedures for that application. Difficult areas
include terrestrial plant responses, non-quantal responses (e.g. growth),
and interactions between chemicals, species, and environmental
factors in polyfactorial environmental tests.
152
-------
New statistical models for dose-response application (and their
computerized forms) are needed for the complex situations encountered in
community studies and other systems functioning above the level of
species.
The theoretical basis for statistical modeling and computer
simulation of population/community interactions, with chemical concentra-
tion surfaces of exposure assessment model projections will be needed.
(4) Response Function or Damage Function Models
Simple cases which demonstrate the validity of linear dose-response
models with respect to ambient concentrations under a variety of
environmental conditions must be applied to show the usefulness of this
approach in more complex exposures or responses. These simple models
must be tested against actual situations in the field. More complex
relationships must be examined which take into account environmental
factors and population distributions of vulnerability with respect to
age, class, or geographical distribution, so that estimates of impact can
be made on a broader basis.
The final formulation of damage function or response function
models, taking into account such factors as variable or intermittent
exposure, interactions with other chemicals or environmental factors; and
statistical models of response must be validated by explicit studies in
the field (within a biome or watershed). These field studies must be on
a large enough scale to justify generalization to large biomes or
populations. The damage response model(s) must be examined for a large
153
-------
variety of chemicals and types of responses. When incorporated into
computer simulations for hazard assessment, these models must be user-
accessible and user-acceptable and of uniform language and format
compatible with exposure assessment models.
3. Research Program
The ongoing toxics research program on ecological effects focuses
primarily upon the development and verification of standard tests for
defining environmental hazard to aquatic animals and plants. The
repeatability of standard tests is being verified through a Round-Robin
testing scheme, and several standard tests are near completion. These
tests will be incorporated into testing guidelines and will be used by
the Agency and industry in generating data for defining environmental
hazards.
The development of structure/activity concepts for predicting the
toxicity of chemicals is also a high priority of the program.
Structure/activity concepts will be used as a screening tool for
evaluating new chemicals. In order to observe plants and animals in a
more realistic context, the development of laboratory ecosystems and
microcosms is being emphasized. Microcosms are being developed to
predict the effects and fates of toxic chemicals, as well as to test
exposure models.
Research in the areas of food chain toxicology and behavioral
toxicology is relatively new to the toxics program. Food chain research
involves work on defining uptake, accumulation, and movement of chemicals
in plant systems and in marine animals. Behavioral research is aimed at
154
-------
defining effects at the community level. Providing technical assistance
to OTE on complex ecological problems is a major activity under this
program.
The specifics of the research program include the continuation and
initiation of work in the areas of single species tests, community level
tests, interaction studies, abiotic studies, and dose-response
relationships.
The development of tests for defining the toxicity of chemicals at
community and system levels is lagging as compared to single species
tests. Research is underway to design tests for aquatic and terrestrial
communities. Microcosms are being developed as one of the tools to study
the effect of chemicals on communities.
No immediate studies on interactions are underway, but the
methodologic evaluation of several tests (germination, stress, ethylene,
etc.) requires the testing of solvents and other materials used in
suspending hydrophobia agents. These often have bioactivity and
complicate interpretation of results.
Environmental factors in toxicologic response are an important part
of the development of a support document for OTE and for application of
the dose-response model to concentration models. In both community and
single species testing, a variety of environmental factors (temperature,
moisture, ventilation, etc.) are under study in microcosms and green-
houses. Quantitative relationships will be developed.
155
-------
Extensive studies on the effects of acid precipitation are underway
for crop loss estimates, soil community effects, and other significant
factors under Air Ecology. Work on the effect of chemicals on ozone
concentration in the stratosphere is also being carried out.
All dose-response assays under development are being established to
provide a dose-response relationship which can be used in hazard
assessment. Difficulties are being encountered with terrestrial plants
because "death" is a much less clear endpoint for plants than for
animals. Combinations of events and more complex decision trees are
therefore being developed. New statistical and computer-based methods
are being developed for plant responses to toxic substances. These will
be incorporated into the support documents for the assays.
Each class of responses will require a set of tests and an
evaluative model which will be used to provide a "response surface,"
which in turn will be used with the exposure assessment model "response
surface" to determine the limits within which a vulnerable population
might be adversely affected. These models will be developed at a later
stage of toxicological testing.
Since ongoing ecological effects research is mainly devoted to the
development of testing methodologes, many important areas are either
addressed at a low level or ignored altogether. For example, our
understanding of system level toxicity is inadequate, the synergetic and
antagonistic properties of toxic chemicals and their role in defining
hazard is not very well known, and little information is available on
comparative toxicology as it relates to various ecological species.
156
-------
These and other problems must be addressed in order to meet adequately
the needs of TSCA.
Research Goals
Continue development of several single species
bioassays tests by a Round-Robin scheme in ORD
Laboratory(ies) and contractor laboratories.
These tests will be available for inclusion in
testing guidelines and for use by the Agency
and industry. (Highest Priority)
Continue development of methods to evaluate
acute, subacute, and chronic effects on
organisms, including wild terrestrial verte-
brates such as avian wildlife. (Highest Priority)
Continue development of methods to evaluate acute
and chronic effects and fate of chemical substances
on benthic fauna. Tests include whole life cycle
tests with benthic crustacean and tests for effects
on reproduction and bioaccumulation in food-webs.
(Highest Priority)
Continue validation of a vertebrate cell assay.
This assay is designed to detect carcinogens,
mutagens, and teratogens in tissue, water, and
sediment. (Highest Priority)
Continue development of a toxicity/fate screening
method to monitor disappearance of the parent
compound with toxicity to an appropriate water
or sediment organism. The fate screening will
provide rates for adsorption, desorption,
biodegradation, and hydrolysis in sterile and
nonsterile systems. The toxicity test is designed
to monitor toxic metabolites. (Highest Priority)
Develop and conduct interlaboratory testing on
various species for seed germination and stress.
Ethylene stress tests have been or will be com-
pleted within the year. These tests provide a
spectrum of important agronomic species regard-
ing a critical phase of early development and
growth. For life cycle studies, the Arabidopsis
spp. have been identified by Air Ecology as
candidates for short-term (28-day) tests from
seed-to-seed. A life cycle test for Duck weed
is nearing completion. (Highest Priority)
157
-------
o Evaluate seedling root elongation as a more
sensitive and reliable response to phytotoxicity
to the young plant. This method will be used
to define the phytotoxicity of chemicals.
(Higher Priority)
• Continue development of a screening method
based on the Microtox microbial bioassay
using photobacteria. This method involves
inhibition of bioluminescence as a function
of toxicant concentration. At present, this
method is being refined to increase the sensi-
tivity. If it appears promising, then the next
step will be to determine its repeatability via
Round-Robin testing. (Higher Priority)
• Continue development of structure/activity
concepts to predict toxicity of chemicals.
The structure/activity concept is based on
the correlation of toxicity with the octanol/
water partition coefficient and structural
characteristics of a series of chemicals in
a homologous series. To date, toxicity,
partition coefficients, and bioenergetic
parameters are being collected to be used
in structure/activity development. This
concept, once developed, will be used as a
screening tool for evaluating the toxicity
of new chemicals under Section (5) of TSCA.
(Highest Priority)
• Continue several projets already underway
to study behavioral interactions at species
and community levels in the presence of
toxicants. Qualitative determinations of
effects between known toxicants and other
chemicals are being quantified. (Highest
Priority)
• Conduct studies on the effects of chemicals
on primary productivity. (Highest Priority)
• Continue studies on decomposition and
recycling processes in microcosms as a
part of efforts to develop a means for
using standard microbial studies in
holistic methods. These systems also
will be involved in food chain transforma-
tion. Continue studies on stability resis-
tance and resilience in soil core and soil-
litter microcosms. (Highest Priority)
158
-------
Continue development of methods to deter-
mine the effects of toxicants on ecosystem
processes in laboratory aquatic microcosms.
(Highest Priority)
Continue to assess the food chain effects
of water borne toxicants. The work involves
survey of field situations in order to deter-
mine key species and interactions affecting
food chain processes. These will later be
studied in laboratory microcosms. These studies
will provide ecological effects data and the
extent of biotransformation, bioaccumulation,
transport, and retention of toxic chemicals
through the food chain. Biological fate data
will be combined with ecological effects
data in order to assess hazard to humans.
(Highest Priority)
Continue development of nitrogen flux
methods to define transport of nitrogen
in soil-plant-animal systems. Selected
tests are anticipated to reveal system
dysfunction indicative of stress from
a toxic chemical. Attempts will be
made to correlate individual in vitro
assays and the disruption of nitrogen flux.
(Higher Priority)
Continue to link ecological effects data
with human health effects data as related
to food chain problems. (Higher Priority)
Future Research
Continue development of single species tests
and accelerate the development of testing
protocols for community and system level
responses. Emphasis also will be placed
on multiple species tests. (Highest Priority)
Expand the work on food chain toxicology and
behavorial toxicology. (Highest Priority)
Initiate work on comparative toxicology.
This area is important since it may lead to
identification of indicator species as related
to evaluating toxic chemicals' effects on
humans. (Highest Priority)
159
-------
Continue ecosystem research with emphasis on
identifying important processes, ecological
effects, and selected species as indicators
of ecosystem stress. Research also will
include work on a better understanding of the
ability of ecosystems to withstand contaminant
stress. (Higher Priority)
The following additional research areas are strongly recommended:
Initiate field validation to assess the capability
of all existing and prospective testing protocols
to predict responses in various real world environ-
ments. (Highest Priority)
Initiate development of pathobiological methods
for possible incorporation into predictive and
descriptive models for structural and functional
effects and as a documentary tool in chronic
test protocols and in tier testing schemes.
(Highest Priority)
160
-------
SECTION 6
MONITORING RESEARCH STRATEGY
I. OVERVIEW
Toxic substances can enter the environment at the source of pro-
duction, and/or during product use, transport, and disposal. Monitoring
is used to help identify which of these entry points, if any, should be
controlled and to determine the extent of control needed. Once a control
strategy is adopted, monitoring is used for enforcement. Finally,
monitoring is used to assess the effectivenesss of the regulatory
strategy chosen.
In regard to identification or problem definition monitoring, TSCA
is to be invoked as umbrella legislation in only those cases where other
environmental legislation, such as the Air or Water Quality Acts, is not
appropriate. Accordingly, a considerable amount of monitoring data
relevant to TSCA will be collected by monitoring programs supported by
other environmental legislation. Further, much of the data collected
under TSCA will be provided by industry in response to specific testing
protocols for the regulation of chemicals. Thus, the problem definition
monitoring effort under TSCA should be limited to filling in the data
gaps for existing chemicals in cases where industry is not required to
submit data and/or data are not available from other regulatory programs.
In all cases, the Monitoring Research Program manual under TSCA will be
161
-------
consistent with the Integrated Toxic Monitoring Strategy currently being
developed by the Agency.
A. RESEARCH PRIORITIES
During the initial implementation of TSCA, the focus of the
research program in the monitoring area will be directed towards
activities of a technical support nature. Effort will be concentrated on
developing and validating field collection and analytical methodologies
needed to:
• Fill in the gaps in the data base on existing
chemicals.
• Assist in the development of appropriate testing
protocols and environmental and exposure assessment
models.
• Develop suitable guidelines/procedures for the
validation and verification of predictive
models for future assessment activities.
• Enforce existing and planned TSCA control regula-
tions.
• Assure that appropriate Quality Assurance guidelines
and protocols are developed and implemented for all
monitoring activities.
For all of the above efforts, the underlying philosophy is to deliver the
research product in such a form that eventually much of the routine
collection of data can be performed extramurally.
In addition, the research capability will be used to assist the
Regions where appropriate. From a Regional perspective, TSCA's testing
and evaluation monitoring activity is focused on the areas of enforcement
and problem identification/evaluation. Regional Offices are required to
162
-------
respond to a variety of situations involving potentially toxic
substances. In order to evaluate the hazard involved in these situations
and the need for control action, monitoring activity is often necessary.
Where the appropriate surveillance and analysis capability exists, this
monitoring can be performed by the Regional Offices themselves. Often,
however, resource limitations prevent extensive monitoring, and assistance
is needed from ORD and/or other Headquarters' program offices. Monitoring
assistance could be in the form of direct analytical support or contractor
support. By close coordination of Headquarters contract and direct
monitoring efforts and Regional Office requirements, monitoring activities
can serve multiple needs.
B. IMPLEMENTING STRUCTURE
The TSCA implementation program falls under the planning purview of
the Office of Monitoring and Technical Support (OMTS). The majority of
the monitoring and field related activities are implemented by the
Environmental Monitoring Systems Laboratory (EMSL) at Research Triangle
Park, North Carolina, and Las Vegas, Nevada. The Environmental Monitoring
and Support Laboratory at Cincinnati, Ohio, provides relevant support in
the water area.
Advanced Methodology Development activities are implemented by the
Environmental Research Laboratory (ERL) at Athens, Georgia, and the
Environmental Sciences Research Laboratory (ESRL) at Research Triangle
Park, North Carolina.
163
-------
C. PROGRAM STRUCTURE
The monitoring program can be divided into two major subactivities;
research in support of Testing and Assessment and research in support of
Chemical Specifics. These categories correspond to the two major
responsibilities under TSCA, namely: (1) the development of suitable
tests and assessment methods for industry to follow in submitting the data
required for existing chemicals or requested for new chemicals; and (2)
the development of analytical methods and associated Quality Assurance for
the regulation of specific chemicals. The testing and assessment program
is further broken down into: (a) research required to develop laboratory
analytical methods, utilizing both chemical/physical characteristics and
biological reactions; and (b) research to develop and apply suitable field
monitoring methodology. The chemical specific program is devoted to
research on specific products identified by OPTS as possible candidates
for regulation.
II. TESTING AND ASSESSMENT
In the testing and assessment area, the primary goal of the
monitoring program is to support the assessment function. Except for
peripheral assistance from the monitoring program, the test protocols for
industry will be developed under the health and environmental programs.
Monitoring research in support of the assessment responsibility is
aimed at identifying toxics, determining the extent to which they are
currently present in the environment, and assessing the effectiveness of
TSCA regulations in controlling them. The former information is needed to
164
-------
help establish priorities for addressing the numerous existing chemicals
which pose possible hazards to man or the environment. The latter
category involves developing suitable monitoring techniques to assess
whether the test results required from industry do, in fact, effectively
control the release of hazardous chemicals into the environment.
Research to meet these objectives falls largely into two areas; the
analytical or laboratory methods development program and field
monitoring.
Methods development is a broad, all-inclusive area which includes
development of: (1) general and specific analytical methods for
pollutants (on a matrix-specific basis); (2) continuous and grab sampling
methodologies by matrix, media, and pollutants; (3) QC/QA techniques
which are most cost-effective based on the eventual use of the data; and
(4) the expansion of analytical methods, allowing a broader range of
pollutants to be identified and quantified by a single method.
The second major activity supporting the testing and assessment
program is field monitoring. Field monitoring studies will be conducted
in order to apply, assess, and refine newly developed monitoring
techniques, to obtain data needed for validating exposure assessment
models, and to help define the extent to which toxics are present in the
environment. Additionally, field studies will be conducted at industrial
sites identified by OPTS to collect data needed to validate environmental
system models for assessing pollutant exposure. Included in these models
are fenceline monitoring methods for air and multi-media sampling
165
-------
methodologies, for example, environmental field sampling methodologies
useful for collecting data needed for exposure assessments. The intent of
these methodologies is to develop standardized sampling protocols for
specific pollutants or classes of pollutants in all media.
OPTS has established the following priorities for monitoring
research:
• Develop analytical methods in the ppb and ppt range
for a range of chemical classes.
• Refine existing analytical methods.
* Develop non-invasive human sampling techniques.
« Collect base-line data for tissue bank establishment
refinement.
O Characterize the transport and fate mechanisms of a range
of chemical classes.
Develop and operate QA/QC activities to support the above.
• Provide expert technical assistance as required.
A. METHODOLOGY DEVELOPMENT AND MEASUREMENT SYSTEM RESEARCH
A major area of research activity in the monitoring area is
concerned with the development of methodologies for identifying and
quantifying new and existing toxic chemicals or their major degradation
products in biological matrices, in air, water, soil and sediments, and
in commercial products. These toxicants vary widely in their chemical
characteristics and detectability and without doubt will continue to
present detection and analytical complexities well beyond the foreseeable
future. Therefore, it is important that a vigorous, broadly-based program
in the analytical chemistry of toxic substances be pursued. Thousands of
166
-------
organic and inorganic chemicals in the broadest possible matrices will
require measurement by standardized methods with good quality control.
This monumental task will involve great expense; thus, cost-effectiveness
must be an essential objective of the methodology development and
measurement system research program.
1. Chemical/Physical Measurement Capability
(a) Background and Status
At the present time, our knowledge of the kinds and quantities of
organic chemicals present in the environment, many of which may be toxic,
is limited. Therefore, it is necessary to develop methods that are
broadly applicable to the wide varieties of chemical properties they
represent.
The methods currently available for the collection and analysis of
toxic organics have not been adequately validated. In addition,
collection and analysis methods do not exist for many toxic organics.
Different collection systems are needed for different media as well as
for different chemicals. Similarly, laboratory analysis techniques for
samples must be appropriate to the volatility and chemical nature of the
toxic organics collected. Various types of gas chromatographic
separation columns must be evaluated to determine their suitability for
the separation of toxic organics. Lastly, the detector system for
identifying individual toxic organics after separation must also be
evaluated.
167
-------
(1) Sampling Methodology and Preparation
It is important to keep in mind that regardless of the analytical
technique chosen, the data obtained can be no better than the sample
collected. Proper sample collection is critical for a good analysis.
In air, gaseous air samples are collected by a variety of
techniques, such as solid sorbents, plastic bags, cryogenic traps, and
evacuated containers. Particulate samples are collected by various types
of filters, impactors, and electrostatic precipitators. No one sample
collection method is universally valid for all chemical species.
Therefore, a variety of sampling techniques must be used. Tenax, for
example, shows low capacity for hydrocarbons less than 05 and low
recovery efficiency for high boiling compounds. The validity of sampling
methods is affected to a greater or lesser extent by such factors as
collection efficiency, desorption efficiency, shelf life, sample
capacity, chemical interactions, volatilization, and condensation of
chemical species. The various sample collection methods in use today have
not been fully evaluated or optimized for these variables. Tenax, as well
as other collection techniques for both gases and particulates, need to
be evaluated for interferences arising from reactions with SC>2, 03, and
NO2, and other reactive components in the atmosphere. Volatilization and
condensation of chemical species on particular filters must be evaluated
to determine the extent to which the phase of a chemical species may be
altered during sampling. Methods for transferring and interfacing air
samples to the particular analytical instrument being employed need to be
168
-------
optimized. The factors involved include sample concentration, sample
volume, and removal of interfering compounds.
In the area of sediment analysis, work is only recently being
initiated. A difficult task in this area is the development of separation
techniques which allow accurate identification and quantification of both
volatile and involatile organics.
(2) Analytical Instrumentation
The state-of-the-art for the analysis of toxic and/or hazardous
organic compounds generally involves the analytical techniques listed
below:
• Gas chromatography (GC) with selective detectors
- Mass Spectrometry (MS)
- Flame lonization Detector (FID)
- Electron Capture Detector (ECD)
- Fourier-Transform Infra-Red (FTIR)
- Ultra Violet (UV)
• High Pressure Liquid Chromatography (HPLC) with selective
detectors
- Ultra-Violet (UV)
- Refractive Index (RI)
- Fluorescence
- Mass Spectrometry (MS)
- Droplet Electrification (prototype)
• Visible, UV, and IR spectrum measurements
• Electrochemical techniques
All of these techniques have been and are being used successfully
for the analysis of organic compounds. Many are useful for both screening
or qualitative determinations.
169
-------
(a) Gas Chromatography with Selective Detectors
Gas chromatography coupled with one or more detectors is frequently
applied in the measurement of organic pollutants.
Gas chromatography/mass spectrometry (GC/MS) is the most widely used
technique because of its capability for identification of specific
pollutants of interest in complex mixtures. Recently, the GC/MS approach
has been useful in determining the 129 priority pollutants in industrial
effluents and in screening chemicals present in atmospheric samples.
Effort must now be focused on extending this tool to analyze for
organics in soils and sediments. Although the mass spectrometer is a
highly versatile detector, identification based on gas chromatographic
retention times and mass spectral data sometimes may not be definitive.
In these cases, Fourier-Transform Infra-Red (FTIR) Spectroscopy provides
the additional data for definitive identification. GC/MS systems are
costly; moreover, accurate identification and measurement of unresolved
chromatographic peaks require time-consuming manual data analysis
methods. Samples of certain classes of organic compounds require only
limited analysis. Thus, the high cost and complexity of GC/MS make it
imperative that simpler and less costly methods such as GC and HPLC be
developed for these compounds.
To date, GC/FTIR has been used mainly for identification of the
so-called volatile organic compounds in simple matrices. The term
volatile organic compounds is applied to those compounds that are
separated, can be separated, or can be caused (by derivatization) to
separate by gas chromatography. Although the data base for the
170
-------
identification of volatile organics by mass spectrometry for some media
is adequate, the corresponding data base for vapor phase infra-red
spectroscopy is only a fraction of that required.
Fourier-Transform Infra-Red spectrometry has been employed to study
organic species in photochemical smog reaction. Ultraviolet (UV) and
infra-red (IR) spectra and fluorescence have been used to identify
atmospheric organics. Work is underway to apply the FTIR technique in the
water and sediment area.
(b) High Pressure Liquid Chromatograph (HPLC) with Selected Detectors
The non-volatile organics, including refractory organics, comprise
a large fraction of the organic compounds whose occurrence for the most
part has not been well documented or investigated. HPLC advances should
assist in this area.
Some success has been achieved in interfacing a liquid chromatograph
with a mass spectrometer in the analysis of a few compounds. A HPLC/MS
instrument (Varian) is commercially available but has not as yet been
proven to be a useful analytical tool. Since the state-of-the-art has
not permitted the routine coupling of a liquid chromatograph with a mass
spectrometer (as can readily be accomplished with a gas chromatograph),
broad scale survey type analyses have not been carried out. Therefore, a
much more intensive effort is needed in this area.
Although the new prototype universal HPLC detector based on droplet
electrification is feasible, it is still in the process of development
and is not ready for general use in the scientific community.
171
-------
Methods for analyzing the non-volatile organics absorbed on
sediments must also be developed.
The interfacing of liquid chromatographs with molecular
spectroscopic techniques is also needed in order to provide the same
positive identification that is required for gas chromatography.
(c) Other Techniques
It appears that the chromatographic/mass spectrometry or FTIR
approach is the most cost-effective for monitoring a large number and
variety of compounds. However, in some cases and in particular for the
non-volatile compounds, group-specific detectors which may depend on
electrochemical properties or rapid screening UV absorption may be
desirable. In addition, direct mass spectra analysis of environmental
samples without preseparation of components by GC is needed to simplify
and accelerate the analytical process and to avoid the problems and
limitations encountered in GC analysis.
The toxic inorganic elements are determined by multi-element
techniques such as inductively coupled plasma emission or X-ray
spectroscopy. Of these two techniques, plasma emission spectroscopy is
more suited to the analysis of solids. Other approaches may be taken in
plasma emission spectroscopy which allow a simultaneous multi-element
analysis on solids, tissues, etc., and which require no sample
preparation. These approaches should be investigated.
It is well recognized that the oxidation state of a metal ion is
critical to its toxicity. Furthermore, complexing agents, such as humic
172
-------
acids, may be a critical factor in the transport of certain metallic
ions. The toxic anions, arsenate, selenate, etc., have received very
little attention, yet ion chromatographic techniques have been shown to
be useful in determining such species.
An electrochemical technique called potential sweep cyclic
voltammetry has been studied for sulfides and amines. Ion chromatography
is also being studied for the analysis of organic acids and aromatic
amines.
b. Research Strategy
As indicated earlier, we will rely mainly on methods being
developed through media programs set up primarily under the Air and Water
Quality Acts. TSCA resources will be used to study areas which are not
addressed under other media, or which are addressed on a time frame
inconsistent with TSCA requirements. Our present program addresses only
the most immediate problems and highest priorities of TSCA. Existing
chemical screening methodologies will be examined to streamline
operations and reduce costs per sample for specific chemicals or classes
of chemicals as specified by OPTS. Automation and streamlining of
equipment are also included. We expect that this directly responsive
"reaction" mode will continue for several years, until instrumentation
and analytical techniques developed for this and other programs broaden
sufficiently to allow detection of almost any type of chemical residue
in almost any medium and matrix.
173
-------
c. Research Program
Immediate Research Goals
• Develop new detector for high pressure liquid chroma-
tography using charged electrostatic droplets.
Feasibility will be demonstrated in FY-79; emphasis
in FY-80 will be on interface of detector with
HPLC and on improving sensitivity and resolution.
• Continue program to develop system for collection,
characterization, and quantification of volatile
organic compounds in ambient air environments
using GC/MS. Emphasis in FY-80 will focus on the
extent, if any, of artifact formation with Tenax
cartridges and the development of improved computer
techniques for analysis of GC/MS data.
• Investigate methods for separation, characterization,
and quantification of toxic chemicals bound to
sediments. Effort in FY-80 will focus on separating
volatile organics from sediments in quantitative fashion.
• Conduct research to optimize methods for collection of
PCBs in ambient air. Solid sorbent collection
techniques will be developed and evaluated for the
selective collection of halogenated biphenyls.
• Develop simplified, quick analysis of methods for
sampling particular classes of toxic compounds
in ambient air, using for example, GC and HPLC with
class optimized columns and detectors. Optimize sample
collection and transfer techniques with Tenax
cartridges.
• Conduct research to apply and streamline a combined
GC/FTIR system. Tests to determine sensitivity of
the system for dioxin measurements will be made.
Upon completion of this phase, additional studies
will be performed to determine the feasibility of
using a manifold of gas chromatographs to provide
"production type" dioxin analyses.
• Conduct a problem definition study to determine the
state-of-the-art for routine multi-element analysis
of environmental samples. An objective of the study
will be to evaluate various techniques for conducting
multi-elemental analysis of samples without sample
pretreatment.
174
-------
• Maintain MSS Library access for water spectra.
Intermediate and Long-Range Research Goals
Continue program to collect, characterize, and
quantify volatile organic compounds in ambient
air. Effort will focus on:
- determining in jitu reactions on Tenax GC
Cartridges
- investigating alternative sorbent materials
for Tenax
- further development of capillary technology
- extensive field validation of field collection
methodology developed under this effort
Assess the effects of particle/vapor interaction
on atmospheric sampling for vaporous toxic
compounds. A gas particle separator for the
collection of gaseous atmospheric samples will
be designed for the separation of particles of
0.1 micrometer and above. Compounds to be
assessed include high molecular aliphatic
hydrocarbons polyaromatic hydrocarbons including
benzo(a)pyrene, and phthalic acid esters.
Continue program to develop methodology for
measuring organics in sediments.
Conduct research to optimize methods for
chromatographic separations of organic pol-
lutants in complex mixtures. Techniques
employing blended chromatographic phases
and modified carrier gases to improve
separation will be examined.
2. Methods for Measuring Organics in Biological Matrices
a. Background and Status
The availability of analytical methods for identification and
quantification of toxic chemicals in biological matrices is critical to
the implementation of TSCA, both from the standpoint of estimating
exposure and as a monitoring tool.
175
-------
In the case of estimating exposure, data are obtained either by
analysis of biological samples or by using predictive models. Since
predictive models must be validated from available data, both methods
depend upon the availability of a credible measurement method.
Measurement methodology is also critical in carrying out certain fate and
effects tests needed for estimating the hazard of toxic chemicals.
Finally, biological matrices such as plants or marine animals are major
components of food chain models.
Biological organisms and biological media offer unique advantages in
monitoring for toxic chemicals in the environment and at the same time
present a complex set of problems inherent in their use. Two major
advantages are that: (1) detection of a compound in a target organism or
a biological medium is a direct confirmation of exposure which may reduce
the need for extended ambient monitoring to arrive at the same
conclusion; and (2) biological systems have been in place for long
periods of time and therefore offer an opportunity for retrospective
assessments of pollutant levels which is extremely important when
attempting to determine the cause of such effects as cancers occurring 20
to 30 years after exposure.
The present state-of-the-art for measuring chemicals in a biological
matrix is inadequate. Methodologies for assessing exposure concentrations
of toxics in biological matrices such as plants and animals is also
poorly developed.
Research is needed to adapt exposure methodologies to monitoring.
Biological monitoring includes using the biological media as a collector
176
-------
and as a sensor. When used as a collector, additional sample preparation
and analysis are required to determine the presence and concentration of
a chemical. The biological matrix itself can produce major interferences
in present analytical techniques and therefore usually requires careful
and complex extraction and separation procedures prior to analysis. This
is probably the most serious disadvantage to using biological media as
collectors. On the other hand, when using biological organisms as sensors
(such as tradescantia, AMES, and radio-immunoassay), the detection of a
compound is related to the observation of a change in the organism or
media and no special extraction or analysis is necessarily required.
However, the results are only qualitative and the techniques still may
require large initial investments to develop sensitive strains of
organisms responsive to compounds of concern.
Research needs to be conducted to develop a series of simple
false/positive biological monitoring methods for specific pollutants.
For example, the state-of-the-art for analyzing dioxin is minimal and
confined to: (1) gas chromatography combined with low or medium
resolution mass spectrometry; and (2) radio-immunoassay techniques.
Although these analytical methods are excellent for detecting dioxin in
environmental samples, the relative cost, the complexity of GC/MS
instrumentation, the preparation of antibodies from dioxin derivatives,
etc., make such techniques accessible to only a limited number of
laboratories. Rapid and inexpensive biomonitoring methods are needed to
initially screen for the presence of dioxin and other toxics in the
environment.
177
-------
b. Research Strategy
Emphasis will be placed on developing rapid biological screening
methods for those chemicals of immediate regulatory and enforcement
concern. Efforts will focus on applying bacterial and/or enzymatic
reactions to specific chemicals or classes of chemicals to produce
non-extractive, qualitative chemical analyses techniques. In addition, a
biological methodology will be developed for the identification and
quantification of specific pollutants. First priority will be given to
the development of a suitable method for testing dioxin.
c. Research Program
Immediate Research Goals
Determine the feasibility of developing a bio-
monitoring microbial test system for dioxin. This
approach will include screening strains of micro-
organisms for both "specificity" and "sensitivity"
to dioxin.
Intermediate and Long-Range Research Goals
• Continue development of biological monitoring methods
for pollutants specified by OPTS.
B. FIELD COLLECTION METHODOLOGY AND MONITORING ACTIVITIES
1. Background and Status
In addition to analytical methods development and laboratory
advances, field studies are needed to develop and/or apply improved
178
-------
techniques for collecting representative data in field
situations. Whenever possible, field methodology studies will be
conducted to expand the data base for pollutants of specific interest to
TSCA. Monitoring studies will also be conducted in support of chemical
characterization, transport and fate studies, and assessment activities.
Current effort in the area of field methodologies falls mainly in
two categories: (1) the development and validation of field methods in
support of assessing the extent of toxics present in air; and (2) studies
to develop and validate multi-media field techniques. In addition, the
monitoring effort is supplemented by the work being carried out under the
Public Health Initiative which is funded under the Environmental and
Health Sections.
a. Field Studies in Support of Assessing the Extent
to Which Toxics are Present in Air
Field studies of toxics in air are needed to determine the impact of
selected emission sources on air quality. This information is used in
risk assessment models, which provide scientific support of regulatory
actions. Methods used in developing basic intelligence for a regulatory
standard and those used to determine the effectiveness of the standard
must have a known precision and accuracy as well as sufficient
sensitivity and selectivity. For these reasons, it is important that
methods used for assessing the extent to which toxics are present in air
are initially evaluated under the conditions of use, and that procedures
for sampling and analysis be carefully documented, including provisions
179
-------
for quality assurance. In ambient air assessment, ancillary measurements
of meteorological conditions are also needed to demonstrate the
representativeness of the samples collected. In short, before a method is
used for assessing the extent to which toxics are present in air, it is
first examined in the laboratory and in the field to determine its
validity. The method is then improved if necessary, and detailed written
procedures are prepared. During the course of the field study, a quality
assurance plan is implemented to assure and document the precision and
accuracy of the data reported.
For the past two years, the field monitoring effort has focused on
developing field collection and sample preparation procedures for
applying GC/MS to screen for some 70 to 100 organic compounds in air
samples collected at various industrial facilities. Air sampling has been
conducted in Lake Charles and New Orleans, Louisiana; Beaumont and
Houston, Texas, Niagara and Buffalo, New York; and Newark and East
Rutherford, New Jersey.
Other techniques need to be evaluated for the measurement of polar
organic compounds in ambient air and of organics in the molecular weight
range of below C^ and above C2Q- Avenues of approach include use of other
polymeric sorbents, vacuum thermal desorption or solvent extraction of
Tenax, and cryogenic sampling. Also, the current Tenax GC/MS technique
needs to be optimized for quantitative analysis of selected high priority
toxic substances. The technique as currently applied is qualitative or
semiquantitative at best and is used for broad-spectrum identification of
volatile organic compounds in air.
180
-------
OPTS is currently interested in chemicals used by the dyestuff and
textile industries, including benzidine, substituted benzidine, and
dyestuffs derived from benzidine. High molecular weight organometallics
produced or used by these industries are also of interest. Determination
of these substances in ambient air will require methodologies different
from the GC/MS techniques used for volatile organics. Particulate
sampling devices, including low and high volume samples and high pressure
liquid chromatography, are the most promising techniques presently
available.
Research is also needed to develop improved methods for tracing the
source of toxic pollutants in air. When toxic materials are present in
atmospheric particulates in amounts which represent an unacceptable
health risk, it is important to identify the sources of these pollutants
so that appropriate control measures can be taken. By assessing the
contribution of individual emission source categories to pollutant
concentrations in the atmosphere, control strategies can be selectively
directed toward those sources found to contribute significantly to the
health risk.
Research is needed to determine the feasibility of developing data
analysis methods capable of relating toxic organic pollutants occurring
in atmospheric particulates (or in the gaseous phase) to their orgins.
Some success has already been achieved with source apportionment of
chemical elements found in particulate air samples and also with certain
stable gaseous components of the atmosphere. Some factors, such as
inplant variability of emissions, similarity of emissions from a given
181
-------
class of sources, meteorology, atmospheric transformation of pollutants,
particle size distribution and chemical composition, relationships
between organic particulates, organic gases, chemical elements, and
the quality and availability of required data still need to be
investigated.
b. Multi-media Field Activities
TSCA holds a unique place in the scope of EPA's responsibility
because of its charter to approach pollution problems on a multi-media
basis. OPTS is currently evaluating various models capable of predicting
the transport and fate of pollutants and human exposure to pollutants.
These models will be used to assess risks associated with the manufacture
and use of selected chemicals. Before these models can be used they must
be validated. Validation entails comparing model predictions with actual
field data and determining model precision or accuracy. Therefore, it is
very important that the field data be at least as precise as the
resolution capability of the model. Guideline documents need to be
developed on how to collect field data for the purpose of model
validation.
c. Public Health Initiative
A major objective of the Public Health Initiative, discussed in
greater detail under the Environmental Program, is the development of
exposure monitoring methodology to permit the systematic measurement of
actual exposure to individuals to a select set of chemicals by all major
routes of exposure.
182
-------
An intensive exposure monitoring field study will be carried out in
FY-80 to provide the first definitive set of integrated exposure
measurements of chlorinated hydrocarbons for a large sample of
population. The study should also result in a series of protocols for
sampling design and exposure monitoring methods and measurements useful
for further analysis of exposure to other pollutants.
Future monitoring work under the Public Health Initiative will be
directed toward: (1) instrumentation and methods development for
chemical, physical, and physiological monitoring; and (2) field testing
and validation of work being carried out under the Transport and Fate
portion of the Public Health Initiative.
2. Research Strategy
Field studies will be conducted to develop suitable guidelines or
protocols for the collection of data both in ambient air and in multi-
media situations. The primary objective of these studies will be to
develop methodology (or "how to manuals") that can be transferred to the
private sector, so that in the future monitoring activities can be
routinely conducted on a contract basis. As a secondary objective, the
studies will be designed to collect data on pollutants of specific
interest to OPTS, which can be used to establish a monitoring data bank
on these substances. The pollutants selected and the models which will
be validated first will depend on the requirements of the testing and
assessment program of OPTS.
183
-------
3. Research Program
Immediate Research Goals
Complete analysis of air samples collected at the
fenceline of chemical plants using a GC/MS organic
screening technique. Compounds identified by this
technique fall in the range of C4 to C2Q carbon
numbers.
Adapt field sampling techniques and analytical
methods for use in determining atmospheric levels
of pollutants of concern to OPTS relatable to
textile and pigment manufacturer. Compounds
of concern include azobenzene, 4-aminobiphenyl,
benzidine, and 3,3' dichlorobenzidine.
Develop stream sampling procedures that can be used
for model validation. Provide field data on several
toxic substances that can also be used for further
model validation. The study will entail reviewing
the models OPTS is considering, selecting a stream
and pollutants, field sampling over a one-year
period, analyzing the data, and writing reports.
Conduct an exposure monitoring field study as part
of the Public Health Initiative. Integrated exposure
measurements for chlorinated hydrocarbons will be
taken for a large sample of population. Protocols
will be developed for sampling of design and exposure
monitoring methods. Personal monitors for exposure
measurements will be tested.
III. CHEMICAL SPECIFIC CONCERNS
A. BACKGROUND AND STATUS
The chemical specific area is concerned with specific chemicals
which have been identified as requiring TSCA regulations of some type, or
for which additional chemical specific monitoring information beyond the
general laboratory tests prescribed under Section 4 is required. In the
latter case, research will be required to provide chemical specific
184
-------
monitoring programs to be included in test rules for industry to follow
in providing the required monitoring data on specific chemicals.
Enforcement of TSCA regulations, especially those promulgated under
Section 6, requires the development of standard analytical methods for
regulated substances in the specific media that will be encountered.
Analytical methodology here includes all activities associated with
sample collection, preparation, analysis, and quality assurance
provision. Vigorous quality assurance is essential to assure the
validity of analytical data generated. Accordingly, quality assurance
considerations should commence as soon as the Agency decides to take a
control action. This will assure that QA considerations are fully
applicable when the regulations become effective.
Since in most cases the Regional Offices have primary responsibility
with respect to TSCA compliance monitoring and associated enforcement,
regional TSCA needs in the chemical specific area are identical to those
of the Office of Enforcement.
B. RESEARCH STRATEGY
Top priority is being given to the development and improvement of
methods for chemicals already under regulation by the Agency.
At present, there is an immediate need for analytical methods for
PCBs in oil. Compliance monitoring with respect to final PCB manufactur-
ing, processing, distribution in commerce, and usage regulations
effective July 2, 1979, require PCB analysis in mineral oil and waste
185
-------
oils. Additional analytical methods are needed for PCBs which appear as
impurities or byproducts in the production of chemical substances and the
monochlorinated biphenyl species. In this area the methods should either
be developed by EPA or validated by EPA if they are developed by
industry.
Next in order of priority are chemicals for which regulatory options
are currently under development. Table 6-5 is a list of chemicals that
the Interagency Testing Committee has identified as potentially hazardous
to human health and the environment. Some 21 substances have been
identified in the four reports issued to date. The chemicals listed in
Table 1 have been identified for early action.
C. RESEARCH PROGRAM
Immediate Research Goals
Direct research toward developing methods to identify
trace organics in various commercial products. In
FY-80, effort will focus on determination of trace
levels of PCBs in an oil matrix. Various separation
techniques such as solvent extraction ion exchange,
selective absorption, and volatilization will be
evaluated. These impurities will subsequently be
separated for identification and measurement by the
most applicable technique (GC/MS, HPLC/MS, GC/FTIR, or
Ramon Spectroscopy).
Conduct research to examine the control of asbestos
and freon from automobiles. Ambient measurement
methods will be used to determine the effectiveness of
wet vacuum and other brake drum cleaning methods for
the control of the asbestos-containing debris from
worn brake lining, and to determine the effectiveness
of techniques for recovering freon from the air con-
ditioning systems of junked cars. The effectiveness
of non-freon substitutes in automobiles' air condi-
tioning systems will also be evaluated.
186
-------
Intermediate and Long-Range Goals
Identify and measure bituminous road surface emissions
in atmospheric samples. Sampling techniques will be
devised to collect roadway air samples enriched in
emissions resulting from frictional forces between
tires and bituminous road surfaces. Gaseous and
particulate samples will be analyzed to determine the
nature and amounts of toxic organic materials in the
emissions. The toxic components shall be related to
the composition of the tires and pavements tested.
187
-------
CD
CO
MONITORING STRATEGY-
TESTING AND ASSESSMENT
METHOD DEVELOPMENT AND
MEASUREMENT SYSTEM RESEARCH
CHEMICAL
BIOLOGICAL
FIELD COLLECTION METHODOLOGY
AND MONITORING ACTIVITIES
CHEMICAL SPECIFIC
PCBs IN OIL
FREON/ASBESTOS IN CARS
FIGURE 6-1. MONITORING STRATEGY FLOW DIAGRAM
-------
TABLE 6-1. THE TSCA SECTION 4(e) PRIORITY LIST
COMPOUND
DESIGNATED FOR
ACTION BY: *
Acetonitrile
Acrylamide
Alkyl epoxides
Alkyl phthalates
Aniline and bromo-, chloro-, and/or nitroanilines
Antimony (metal)
Antimony sulfide
Antimony trioxide
Aryl phosphates
Chlorinated benzenes, mono- and di-
Chlorinated benzenes, tri-, tetra- and penta-
Chlorinated naphthalenes
Chlorinated paraffins
Chloromethane
Cresols
Dichloromethane
1,2-Dichloropropane
Cyclohexanone
Glycidol and its derivatives
Halogenated alkyl epoxides
Hexachloro-1,3-butadiene
Hexachlorocyclopentadiene
Hydroquinone
Isophorone
Mesityl oxide
4,4-Methylenedianiline
Methyl ethyl ketone
Methyl isobutyl ketone
N i troben zene
0-Tolidine-based dyes
Polychlorinated terphenyls
Pyridine
Quinone
Toluene
1,1,1-Trichloroethane
Xylenes
April 1980
April 1979
(October 1978)
(October 1978)
April 1980
April 1980
April 1980
April 1980
April 1979
(October 1978)
October 1979
April 1979
(October 1978)
(October 1978)
(October 1978)
April 1979
October 1979
April 1980
October 1979
April 1979
(October 1978)
April 1980
April 1980
April 1980
April 1980
April 1980
April 1980
April 1980
(October 1978)
April 1979
April 1979
(October 1978)
April 1979
(October 1978)
*Chemicals followed by dates in parentheses were designated by the Committee
(Ref. 2) and responded to by the Administrator in 43 FR 50 134-50138.
189
-------
TABLE 6-2.
PROGRAM AREAS FY-80
Methodology Development n^tfirmlno rffretlvr.
(r Measurement System ness of brake clean-
Research Ing methods in limit-
ing asbestos exposures.
Determine effective-
ness of dye tracers
for detecting freon
leaks from automobile
MONITORING SUPPORT PLANNED OUTPUTS
FY-81
Publish method for
routine analysis
of aldlcarb.
Study the feasibility
microbial systems
for rapid detection
of dioxln.
FY-82
Extend "production type
GC/FTIR system to
pollutants specified by
OPTS.
Publish methods for
measuring OPTS specified
organics In sediments.
FY-83
Publish method for
measuring organlca
Study the feaslbll-
mlcroblal systems
for rapid detection
of organic compounds
FY-84
Publish methods for
measuring toxics In
OPTS.
Publish Methods for
OTS specified organlcs
in sediments.
air conditioners.
Develop method for
measuring PCB's in
oil.
Complete "production
type" GC/FTIR system
and protocol for
analysis of dloxin in
environmental samples.
Publish streamlined
method for multi-element
analysis.
specified by OPTS.
Publish nethod for use
of microblal system
for rapid detection of
pollutants specified
by OPTS.
Field Collection Methodology Publish field methods
and Monitoring Activities for three specific
chromophoric compounds
Including benrldene
(air measurements).
Publish field methods
for separation and
analysis of polar and
hydrophilic compounds
(air measurements).
Publish field methods
for screening toxic
air pollutants
specified by OPTS.
Collect monitoring
data at sites
selected by OPTS for
assessment studies.
Publish protocol on
multi-media field pro-
cedures to validate a
stream model.
Collect monitoring data
at sites selected by OPTS
for assessment studies.
Publish field
methods tor screen-
Ing toxic air
pollutants speci-
fied by OPTS.
Collect monitoring
data at sites
selected by OPTS
for assessment
studies.
Publish protocol on
multl-nedla field
procedures to validate
model selected by OPTS.
Collect monitoring
data sites selected
by OPTS for assessment
studies.
Quality Assurance
Publish good laboratory Implement mandatory
practices guidelines quality assurance
for transport and fate program.
and environmental pro-
cesses.
Develop guidelines
and protocols as
required.
Develop guidelines
and protocols as
required.
Develop guidelines
and protocols as
required.
Publish quality assur-
ance protocol for
measuring asbestos in
ceilings.
-------
TABLE 6-3. METHODOLOGY DEVELOPMENT AND MEASUREMENT SYSTEM RESEARCH
RESEARCH
PROGRAM
AREAS
FY-80 PROJECTS
RESOURCES
FY-80 FY-81
CHEMICAL
Air
Water
Soil/Sediments
Develop HPLC detector charac-
terization methods using GCMS/
HPLC optimization of methods
for collecting PCBs.
Maintain access to Mass Spec-
trometry Search (MSS) library.
Refine separation, charact-
erization and quantification
methods.
$351,000 $618,000
50,000
129,000
BIOLOGICAL
Efficiency
Improvements
Characterization
in marine animals
and plants
Biological Moni-
tors
Refine multiple GC, FTIR,
interface routine multi-
element analysis techniques.
70,000
Develop screening methods
for dioxin.
80,000
100,000
-0-
200,000
-------
TABLE 6-4. FIELD METHODS AND MONITORING SUPPORT
PROGRAM
GOAL
PROGRAM
AREAS
PROGRAM
FY-80
RESOURCES
FY-80
FY-81
Methodology Development
and Model Validation
Mr
Multi-Media
Public Health
Fenceline Monitoring $ 480,000 $ 504.00
Methods/Benzidene Focus
Stream Model Validation 865,000 949,000
Study
Exposure Assessment Methods -0- 1,011,000
Integrated Assessment Field -*
TOTAL $1,345,000 $2,464,000
Funded in environmental program
-------
TABLE 6-5. CHEMICAL SPECIFIC RESEARCH
1980 PROGRAM RESOURCES
AREAS FY-80
PCBs in Oil $40,000
Freon/Asbestos in Cars $50 ,000
TOTAL $90,000
-------
SECTION 7
ENVIRONMENTAL ENGINEERING AND TECHNOLOGY RESEARCH STRATEGY
The subcommittee for Environmental Engineering and Technology was
recently established to plan the research and provide experience and
expertise in subjects relevant to OPTS program activities. The sub-
committee is co-chaired by Mr. Carl Schafer (ORD) and Dr. Roger Garrett
(OPTS).
I. OVERVIEW
OPTS actions under Sections 5 and 6 of TSCA require support in the
assessment of potential risks involved in the manufacture, use, and
ultimate disposal of new and existing chemical products. Engineering
analysis provides the basis for assessing human and environmental
exposures to products of concern by identifying the modes, physical
form, extent, and points of generation and release of harmful or
potentially harmful substances to the environment within the product life
cycle. Environmental assessment (including consideration of health and
ecological exposure impacts) of such substances will only be as valid as
the engineering analysis. This analysis is therefore central to the
support of a sound toxics research and assessment program.
194
-------
II. BACKGROUND AND STATUS
The establishment of the Environmental Engineering and Technology
Research subcommittee creates the impetus for a significant shift in
researh emphasis. For three years the environmental engineering program
element in the toxics research and development decision unit has centered
on support evaluation of PMN and engineering analysis of certain
hazardous activities (i.e. asbestos removal, PCB's destruction,
etc.). This past effort is characterized as short-term technical support
rather than as research. Formation of the new research subcommittee
will enable ORD to conduct long-term research to establish a knowledge
base for engineering analysis of a wide spectrum of environmental
concerns. In addition, it will broaden the ORD capability to support
OPTS in assessing the risks of a multiplicity of toxic substances.
III. RESEARCH GOALS
The Environmental Engineering and Technology subcommittee has four
overall goals.
• To provide specialized technical assistance to resolve
complex problems.
• To develop research capabilities to meet long-term
implementation time frames.
• To develop a comprehensive long-range program to
refine continually assessment schemes.
• To build continuity and stability into the program
to meet future challenges.
ORD will support EPA's toxic substances program by providing the
expertise and methodology for toxic hazard and exposure assessment.
195
-------
OPTS will require improved hazard assessment test evaluation procedures,
both to analyze data from industrial sources and to support its own re-
sults for regulatory purposes. Enhanced exposure assessment methodology
will provide additional depth to the program by allowing EPA toeva;iate
better exposure levels of a variety of harmful and potentially harmful
substances and the potential risks they pose to humans and the environ-
ment. Exposure parameters to be documented include toxic chemical
generation, use, distribution, and disposal.
ORD will continue to aid OPTS with short-term projects not
necessarily covered under TSCA. Chemicals of specific regulatory and
research interest will be studied. Pilot efforts to initiate a long-
range research program will be carried out to build the framework for the
new subcommittee's planning. Thus, ORD's research program will
effectively converge with EPA's effort within OPTS to implement TSCA with
respect to the study, evaluation, and documentation of the health and
environmental impacts of toxic substances.
The program will be designed to support OPTS efforts by:
* Determining the occurence of selected toxic
substances through engineering analysis of
their sources in the products
« Recommending alternative manufacturing process
options for the processing and/or production
of potentially hazardous or toxic materials
9 Providing technical expertise and specialized
engineering for toxics regulatory actions
196
-------
FY 80 research activities supporting TSCA will be redirected, to the
extent possible, to establish toxics program elements for future long-
term research.
IV. RESEARCH APPROACH
EPA will continue to carry out systematic assessments to identify
the toxic product contaminants and pollutants discharged to air, water,
and land by the chemical inustry. This work originally focused on
product-specific commercial processes, such as those to produce aniline,
alkyl amines, and acrylonitrile. However, emphasis has been recently
shifted to achieve broader industry coverage by focusing on the toxic
discharges and product contaminants from generic processes. Toxic
discharges for allied chemical process industries including pesticides,
Pharmaceuticals, food activities, petroleum refining, textile fibers, and
dyes and inks will be assessed. The outputs from these assessments will
be managed through the establishment of an engineering analysis data
base, a knowledge resource which will receive increased use by the toxics
regulatory offices of the Agency. Recently, the Organic Chemical
Producers Data Base (OCPDB) has been expanded to include information on
potential risks involved in the production and use of some 600 organic
chemicals. Further OCPDB expansion will include data on the various
satellite industries such as plastics, dyes and pigments, and pharma-
ceuticals. Data on the exposure potential inherent in various
chemicals or chemical processes will be developed. These data will be
of particular value to OPTS in assessing the potential risk involved in a
new or existing chemical's manufacture and use.
197
-------
Through in-process evaluations of specific manufacturing processes,
the toxic chemical(s) inadvertently generated and introduced into
products will be identified. Such evaluations can also pinpoint those
in-process toxics sources that will require regulation under TSCA and
other applicable statutes. Over the next five years, ORD will focus on
developing alternative manufacturing methods and process conditions to
reduce the occurrence of toxic product contaminants. Additionally, ORD
will evaluate the possibility of developing substitutes for chemicals
that pose toxic threats.
This broadened approach to toxics engineering analysis will greatly
expand OPTS's potential for regulatory action under TSCA.
ORD thus anticipates the imposition of new, more rigorous
regulations for the reduction of toxic effluents from operations
producing major organic chemicals. Projected economic impacts of these
regulations have been based on the premise that capital and operating
costs of newly required control or modified facilities will be added to
the price of the materials produced and passed on to the ultimate
consumers.
However, in reality, plant owners have a number of alternative
responses to the imposition of new effluent control requirements. Their
choices will be dictated by their preception of their best business
judgment as well as the analysis of the data available to them. In this
respect, these decisions can be made exactly as other business decisions
unrelated to environmental concerns.
198
-------
In order to assess the most probable economic impacts of the
introduction of any particular regulation, the toxics program must
anticipate the nature of industry decisions. Effects on employment
import levels, and cost to the U.S. economy, in fact any change imposed
by industry actions, must be estimated.
The various options open to chemical industry management will in
many cases interact with one another. There will usually be secondary
and tertiary effects of any decision. Optimum strategies will vary from
company to company, and often from plant to plant, because of their
specific circumstances or philosophies. Thus the overall industry
response to any requirement will often be a mixture of several strate-
gies. The questions that industry should consider are:
Shifts In Feedstocks; What possibilities are there to
to shift to a more expensive feedstock to eliminate
formation of noxious effluents? At what cost would
this be economical?
Alternate Processes; Are there alternate processes
that could produce the same product without produc-
ing the prescribed effluent? What are the relative
economics of the alternatives?
This research program effort directed at predicting industry
response to regulations will enable OPTS to develop realistic toxics
regulatory strategies and to promulgate regulations that will effect
realization of OPTS legislative objectives.
199
-------
APPENDIX
TABLE A-l. FUNDING FOR THE PROGRAMS COVERED IN THE CHEMICAL TESTING
& ASSESSMENT RESEARCH STRATEGY - AUGUST, 1980
Program FY 19791 FY 19802
Health Effects $ 6,609.6 $ 9,252.4
NCTR5 4,500.0 4,500.0
Environmental
Processes and
Effects 4,798.3 11,515.7
O
O Monitoring Systems
FY 19813 FY 1982"
($000) ($000)
$12,798.3 $14,078.1
4,500.0 4,500.0
15,730.9 17,304.0
FY 1983
($000)
$15,485.9
4,500.0
19,034.4
FY 1984
($000)
$17,034.5
4,500.0
20,937.8
FY 1985
$18,737.9
4,500.0
23,031.5
and Quality
Assurance
Environmental
Engineering
and Technology
Stratospheric
Modification
Total
2,977.8
459.9
3,510.7
1,636.1
3,782.0
1,771.7
4,160.2
1,948.9
4,576.2
2,143.8
5,033.8
2,358.2
5,537.2
2,594.0
FY 79 Actual Expenditures
FY 80 Operating Plan
FY 81 Request to Congress
Funds for FY 82-85 are projected at 10% per year. This is the percentage used for the "moderate growth scenario" in ORD's
..Research Outlook, an annual report to Congress.
NCTR—National Center for Toxicologic Research. Funds shown are EPA's annual support to NCTR through agreement with the Food and Drug
Administration.
-------
TECHNICAL REPORT DATA
(Please read Instructions on the reverse before completing)
REPORT NO.
EPA-600/9-80-049
3. RECIPIENT'S ACCESSION NO.
TITLE ANDSUBTITLE
CHEMICAL TESTING AND ASSESSMENT
RESEARCH COMMITTEE RESEARCH STRATEGY 1979-1985
5. REPORT DATE
October 1980
6. PERFORMING ORGANIZATION CODE
AUTHOR(S)
8. PERFORMING ORGANIZATION REPORT NO.
PERFORMING ORGANIZATION NAME AND ADDRESS
Office of Research and Development
and
Office of Toxic Substances
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME AND ADDRESS
U.S. Environmental Protection Agency
Washington, D.C. 20460
13. TYPE OF REPORT AND PERIOD COVERED
14. SPONSORING AGENCY CODE
15. SUPPLEMENTARY NOTES
16. ABSTRACT
This document was developed by the Chemical Testing and Assessment Research
Committee and it presents a multi-year strategy for ORD's programs on Toxic
Substances. This strategy is intended to serve as a basis for preparing each
fiscal year's program proposals and for reviewing the progress of ORD's on-
going effort. The document will be updated annually by the Research
Committee to refine the strategy and help assure the program's responsive-
ness to emerging concerns and priorities.
17.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.lDENTIFIERS/OPEN ENDED TERMS C. COSATI Field/Group
18. DISTRIBUTION STATEMEN1
RELEASE TO PUBLIC
19. SECURITY CLASS (This Report)
21. NO. OF PAGES
207
20. SECURITY CLASS (This page)
22. PRICE
EPA Form 2220-1 (Rev. 4-77) PREVIOUS EDITION is OBSOLETE
201
U.S. GOVERNMENT PRINTING OFFICE: 19BO--757-064/0175
------- |