UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460

OFFICE OF
THE ADMINISTRATOR

EPA-EPEC-92-004

November 12, 1991

The Honorable William Re illy

Administrator

U.S.Environmental Protection Agency
401 M Street, S.W.

Washington, D.C. 20460

SUBJECT: Science Advisory Board Evaluation of EPA's Research on Expert
Systems to Predict the Fate and Effects of Chemicals

Dear Mr. Reilly:

The Fate and Effects Subcommittee of the Ecological Processes and Effects
Committee of the Science Advisory Board has completed its review of research in
progress on "expert systems for predicting the environmental fate and effects of
chemicals". The Subcommittee reviewed three research programs on "expert systems"
which are complementary and at different stages of development. Each of the
systems relies on the physical and chemical properties of molecules to predict
characteristics such as affinity for soil, water, or tissue and potential effects on biota,
mode of toxic action, or metabolic products.

The Subcommittee met once on January 9-11, 1991 at the Athens
Environmental Research Laboratoiy to review the research. The Subcommittee
reviewed research on three expert systems: 1) SPARC (Sparc Performs Automated
Reasoning in Chemistry) which estimates chemical and physical reactivity from
molecular structure; 2) CRAMS (Correlations of Reactivity and Molecular Spectra)
which predicts reactivity from spectroscopy analysis; and 3) QSAR (Quantitative
Structure Activity Relationships) which will predict the mode of toxic action. As part
of the review, the Subcommittee was asked to address the following charge:

1.	Assuming that one can use chemical properties to predict chemical fate and
environmental effects, does each system use chemical properties in a scientifically
valid manner to make these predictions?

2.	Is the documentation for using each system complete?

3.	How well does each system "learn"?

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3.	How well does each system "learn"?

4.	Are there other user needs that these systems could address?

The Subcommittee strongly endorses the present program of developing more
potent structure activity relationships and methods to predict physical and chemical
properties of compounds. However, the Agency should not rely solely on estimated
values. The current approach of using fundamental molecular and atomic level
information is an improvement over previous methods that used such information
only for specific molecular properties. EPA has a continuing need for rapid
estimation methods. This need is likely to increase rather than diminish in the near
term as a result of two factors: i) a growing emphasis on review and regulation of
existing chemicals by chemical class, rather than on a chemical-by-chemical basis as
in the past; and ii) the establishment of a streamlined existing chemicals process
capable of handling larger numbers of chemicals.

Documentation should be provided to assist the potential users of all three
systems. Before such documentation is completed, each system should be subjected
to rigorous testing, including representatives from EPA's toxics, pesticides, and
hazardous waste programs as well as potential users from the academic and industrial
research co as part of its development.

Two of the systems (SPARC and QSAR) can be "trained", however, due to the
lack of documentation and testing, they must currently be considered as systems not
capable of independent learning.

The overall approach seems to be state-of -the-art and should be useful not
only for EPA efforts but will likely find use in other sectors of science, i.e., academic
and industrial. The Subcommittee recommends that the SPARC, CRAMS, and QSAR
expert system research programs be continued with an adequate level of funding for
the initial development and testing.

The Subcommittee learned from the presentations by the Office of Pesticides
and Toxic Substances that TSCA has no minimum data requirement for applicants
in the Premanufacturing Notice program. It would be useful if the Agency were
provided with basic data of known quality for all PMN chemicals. One way to
achieve this would be for the Agency to issue guidelines relative to these data
requirements.

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The Subcommittee appreciates the opportunity to conduct this scientific review
and looks forward to receiving your response to the scientific advice we have offered.

Sincerely,

Dr. jfaymond^xfeErT^hairman
Executive Committee
Science Advisory Board

Drr Robepc Huggett, XDhairman
Fate and Effects Committee

£

D\]

—/A L—QtAr~*-

k Kenneth Dickson, Chairman
Ecological Processes and
Effects Committee

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United State*	IcImim Advisory	EPA-SAB-EPEC-92-004

Environmental	Board (A-101)	No*ambar 1991

Protection Apency

v>EPA AN SAB REPORT:

EVALUATION OF EPA'S
RESEARCH ON EXPERT
SYSTEMS TO PREDICT THE
FATE AND EFFECTS OF
CHEMICALS

PREPARED BY THE FATE AND
EFFECTS SUBCOMMITTEE OF THE
ECOLOGICAL PROCESSES AND
EFFECTS COMMITTEE

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abstract

This report presents the conclusions and recommendations of the U.S.
Environmental Protection Agency's Science Advisory Board following a review of
research in progress on "Expert Systems for Predicting the Environmental Fate and
Effects of Chemicals". Three research programs were reviewed. SPARC is an expert
system for estimating chemical and physical reactivity. CRAMS predicts reactivity
parameters of organic chemicals from spectroscopic data. The QSAR has several
expert systems within it, but for this review, the Subcommittee concentrated on the
"Single Integrated Language for Chemicals" and the plans for predicting mechanisms
of toxic action from chemical structure. The Subcommittee supports the continued
development and vigorous testing of each system. The SPARC and QSAR systems
were considered state-of-the-art. CRAMS is more preliminary and shows promise
particularly in the area of predicting metabolites. EPA was cautioned on the
premature designation of these as "expert" systems. Other comments and suggestions
are offered in the report.

Key Words; Expert Systems; Structure Activity Relationships; Predictive Toxicology;
Fate and Effects.

~
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U.S. ENVIRONMENTAL PROTECTION AGENCY

NOTICE

This report has been written as part of the activities of the Science Advisoiy Board,
a public advisoiy group providing extramural scientific information and advice to the
Administrator and other officials of the Environmental Protection Agency. The Board
is structured to provide a balanced expert assessment of scientific matters related to
problems facing the Agency. This report has not been reviewed for approval by the
Agency, and, hence, the contents of this report do not necessarily represent the views
and policies of the Environmental Protection Agency or other agencies in Federal
Government. Mention of trade names or commercial products does not constitute a
recommendation for use.

• •
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U.S. ENVIRONMENTAL PROTECTION AGENCY
SCIENCE ADVISORY BOARD
ECOLOGICAL PROCESSES AND EFFECT COMMITTEE
FATE AND EFFECTS SUBCOMMITTEE
ROSTER

CHAIRMAN

Dr. Robert Huggett, Professor, Virginia Institute of Marine, College of William
and Mary

MEMBERS and CONSULTANTS

Dr. Anders Andren, Professor, Water Chemistry Program, University of Wisconsin

Dr. Yoram Cohen, Associate Professor, Chemical Engineering Department, University
of California at Los Angeles

Dr. William Cooper, Chairman, Department of Zoology, Michigan State University

Dr. Steven Eisenreich, Professor, Department of Civil and Mineral Engineering,
University of Minnesota

Dr. Donald Mackay, Professor, Department Chemical Engineering and Applied
Chemistiy, University of Toronto

Dr. Calvin H. Ward, Chairman, Department Environmental Science and Engineering,
Rice University

FEDERAL AGENCY LIAISON

Dr. Ronald Mason, National Institute of Environment Health and Sciences

SCIENCE ADVISORY BOARD STAFF

Dr. Edward S. Bender, Designated Federal Official, U.S. Environmental Protection
Agency, Science Advisoiy Board, 401 M Street S.W., Washington, D.C. 20460

Mrs. Marcia K Jolly, Staff Secretary, U.S. Environmental Protection Agency, Science
Advisory Board, 401 M St., S.W., Washington, D.C. 20460

Mr. Robert Flaak, Assistant Staff Director, U.S. Environmental Protection Agency,
Science Advisoiy Board, 401 M St., S.W., Washington, D.C. 20460

•••
ill

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Dr. Donald G. Barnes, Staff Director, U.S. Environmental Protection Agency, Science
Advisory Board, 401 M St., S.W., Washington, D.C. 20460

iv

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TABLE OF CONTENTS

1.	EXECUTIVE SUMMARY 	1*

2.	INTRODUCTION		3

2.1	Subcommittee Review Procedures 		3

2.2	Charge to the Subcommittee 	4

3.	SUBCOMMITTEE RESPONSE TO THE CHARGE	5

3.1	Scientific Basis for the Systems 		5

3.2	Adequacy of the Documentation	6

3.3	System Performance 		7

3.4	Agency's Need for Chemical Properties Data 		8

4.	SUMMARY OF RECOMMENDATIONS	11

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1. EXECUTIVE SUMMARY

Under existing laws (Toxic Substances Control Act, Federal Insecticide,
Fungicide, and Rodenticide Act, and others), the EPA is responsible for predicting
and evaluating the environmental fate and effects of chemicals. Multimedia
assessments (air, water, soil) are needed to adequately evaluate the potential risks
to human health and the environment from exposure to chemicals. Assessments
must include the potential for effects due to specific properties of chemicals and to
both short and long term exposures. Hence, detailed knowledge of chemical
properties and reactivity is required to provide a rational scientific basis for the
assessment process. Research being conducted at EPA's Environmental Research
Laboratories at Athens and Duluth is designed to provide predictive capabilities for
these chemical and biological fate and effect parameters. Three expert systems
were presented for this review, SPARC, CRAMS, and QSAR. Expert systems, in
this context are interactive PC-based programs that can be queried by
professionals to examine the chemical characteristics of unknown compounds to
make predictions about their fate in the environment. In practice, expert systems
should be able to recognize patterns and 'learn" from each problem that it
analyzes. The following are some of the mqjor points concluded by the
Subcommittee in their review of this research:

1.	The Subcommittee strongly endorses the present program of developing
more potent Structure Activity Relationships (SAR) and methods to predict
physical and chemical properties. However, the agency should not rely
solely, at the present state-of-the-art, on estimated chemical, physical, and
biological properties in its evaluation of toxic chemicals.

2.	The over-all approach being used in developing SAR tools seems to be state-
of-the-art and should be useful not only for EPA efforts but will most likely
find wide use in other sectors of science, i.e. academic and industrial.

3.	The Subcommittee recommends that EPA modify issue a Guideline to
require the submission of basic physical and chemical data with statements
of their quality during the PMN application process.

4.	The Subcommittee recommends that the programs be continued with
adequate funding.

5.	The evaluation of CRAMS should focus on the development of model
equations. The state-of-the-art is a long way from being able to incorporate
all of the necessary state variables into models. Therefore, the model and
its outputs should be subjected to vigorous field testing.

6.	EPA should complete the documentation for the QSAR system. If not
already available, EPA should develop information on the thermodynamics,

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theory, etc. necessary to evaluate the underpinnings of the estimation
method.

7.	The models and their outputs should be subjected to vigorous field testing
as soon as possible.

8.	The concept of molecular properties prediction via structural correlation is
an old idea which has been used in various branches of chemistry and
chemical engineering. The current approach of using fundamental molecular
and atomic level information in SPARC is an improvement over previous
methods that used such information only for specific molecular properties.

9.	The SPARC system has been labeled as an expert system but it is not with
respect to teaching itself. The system has to be "trained" using hundreds of
compounds. The so called "training" (which is equivalent to conducting a
regression to obtain the various correlation parameters) requires precise
empirical data and it has not been demonstrated that predictions can be
accurately made for compounds that are outside the range of the chemicals
used to "train" the system.

10.	Care must be taken not to abuse the SPARC system by requiring it to
perform functions for which it has not been "trained" or tested.

11.	For biologically mediated reactions, state variables involving substrate
concentrations, biological history of the population, impacts on biological
rates and genetic shifts in the populations must all be considered.

12.	User friendly expert systems for predicting chemical reactivity and
environmental fate and effects of chemicals are needed now and they will
play even more important roles in the future.

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2. INTRODUCTION

The EPA administers several statutes (notably the Toxic Substances Control
Act (TSCA) and the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA))
which require the Agency to estimate the fate and effects of chemicals. These
assessments of fate and effects are often based on estimated values for specific
properties of the chemicals. The Office of Research and Development (ORD) has
been systematically working with the Office of Pesticides and Toxic Substances to
assemble and integrate models that can predict specific chemical properties to
estimate the environmental fate and effects of chemicals for inclusion in the Toxic
Substances Inventory and for pesticide registration. This research has been an
adjunct to other mainline programs and is centered in two laboratories: Athens,
Georgia and Duluth, Minnesota.

2.1 Subcommittee Review Procedures

The Ecological Processes and Effects Committee (EPEC) of the Science
Advisory Board received a request for this review from Dr. Michael Slimak,

Deputy Director of the Office of Ecological Processes and Effects Research, ORD
in June, 1990. After discussion by the committee, a proposal for a research in
progress review of "Expert Systems for Predicting Fate and Effects of Chemicals"
was submitted to the Executive Committee of the SAB. The Executive Committee
assigned the review to EPEC. EPEC formed a Fate and Effects Subcommittee,
which included a member of the Environmental Engineering Committee, and
scheduled the review.

The Subcommittee received a research summary and scientific publications
which described three "expert systems" (or systems intended to become experts
systems): 1) SPARC (Sparc Performs Automated Reasoning in Chemistry), 2)
CRAMS (Correlations of Reactivity and Molecular Spectra), and 3) QSAR
(Quantitative Structure Activity Relationship). SPARC is an "expert" system for
estimating chemical and physical reactivity. CRAMS predicts reactivity parameters
of organic chemicals from spectroscopic data. The QSAR has several expert
systems within it, but for this review, the Subcommittee concentrated on the
"Single Integrated Language for Chemicals" and the plans for predicting
mechanisms of toxic action from chemical structure.

The Subcommittee met January 9-11, 1991 at the EPA and USDA facilities
in Athens, Georgia to receive briefings and a demonstration of the SPARC system.
Following the meeting, the Subcommittee prepared a draft report. Unfortunately,
none of these systems were available for testing by the Subcommittee members in
their own laboratories.

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2.2 Charge to the Subcommittee

Following the discussion of EPEC with Dr. Slimak, a formal charge for the
review was developed and provided in December, 1990. The Subcommittee was
asked to address the following questions:

1.	Assuming that one can use chemical properties to predict chemical fate and
environmental effects, does each system use chemical properties in a scientifically
valid approach to make these predictions?

2.	Is the documentation of the use and performance of each system complete? Is
additional guidance needed to indicate under what circumstances the system may
fail to accurately predict a value?

3.	How well does each system "learn"? Are additional algorithms needed to back
correct the estimates? Are additional approaches needed to identify outliers?

4.	Are there other user needs that these systems could address?

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3. THE SUBCOMMITTEE'S RESPONSE TO THE CHARGE

3.1 Scientific Basis for the Systems

The 1988 U.S. EPA document "FUTURE RISK: Research Strategies for the
1990's" (SAB-EC-88-040), contains a special section on sources, transport, and fate
research of environmental contaminants. The document describes the importance
of understanding fundamental environmental processes, improving the accuracy
which with they can be modeled, and identifying emerging environmental
problems. It further recognizes that one of the most effective approaches used in
modeling environmental behavior of chemicals integrates data on physicochemical
properties of the compound in question with hydrodynamic or aerodynamic
transport models. This approach, which in large measure was formalized by the
ERL-Athens, uses results from such laboratory measurements as aqueous
solubilities, saturation vapor pressures, liquid and vapor molecular diffusivities,
Henry's law constants, photolysis rates, UV absorption, octanol-water partition
coefficients, etc. These data are then incorporated into various steady-state and
time-dependent transport models. The fields of synthetic chemistry, chemical
engineering, and pharmacology have, for quite sometime, successfully incorporated
information on chemical properties in designing new chemicals, unit processes, and
drugs. Additionally, studies aimed at understanding mechanisms of action at the
molecular level of toxicity, carcinogenicity, mutagenicity, etc. clearly show that a
knowledge of physical and chemical properties of both chemicals and targets is
required. It is thus clear to the Subcommittee that the development of an ability
to predict chemical properties for biological effects and environmental transport
evaluations must be of high priority to EPA.

The Subcommittee thus strongly endorses the present program of developing
more potent SARs and methods to predict physical and chemical properties.
However, the agency should not relv solely, at the present state-of-the-art, on
estimated chemical and physical properties in its evaluation of toxic chemicals.
SARs and chemical property estimation methods should ideally be used to check
experimental data for reasonableness, to pre-screen chemicals, to organize
chemicals into different reaction or biological effects categories, and to generally
improve the agency's capability of dealing with thousands of chemicals. A
complete reliance on "desk exercises" is dangerous and will put EPA scientists in
the position of making heroic estimations.

The chemical, engineering and pharmacological literature contains many
techniques designed to estimate such properties as molar volume, boiling points,
aqueous and multi-solvent solubilities, and vapor pressures. In addition, numerous
investigations on chemical reaction rates and methods to predict these, especially
in homogeneous gas and liquid phases, exist. These methods are often a blend of
empirical, semi-empirical and thermodynamic approaches and each method may do
particularly well (or poorly) for a selected subset of chemicals. It is probably fair
to say that the above mentioned properties are veiy hard to predict a priori for
chemicals that are very insoluble, have a low vapor pressure, exhibit moderate to

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strong hydrogen bonding, and/or dissociate in liquids. Complicated molecular
models, such as those that incorporate force field theory exist. However, a large
dose of additional insight into fluid phase equilibria on a molecular level is needed.

Research developments at Athens and Duluth recognize all these past efforts
and are designed to bring state-of-the-art insight into biological and environmental
science applications. The Subcommittee agrees with the arguments presented on
the need for these efforts and recommends that these be continued. Additionally,
it appears that funding levels in the past have been rather uneven. The
Subcommittee recommends that the programs be continued with adequate funding.

The effort for SPARC at Athens, although called an expert system, contains
too many multivariate regression algorithms to be an expert system in the sense
that it does not teach itself. The approach recognizes and uses formulations for
basic intermodular forces (electrostatic, induction, dispersion, and hydrogen
bonding) to predict properties. However, although reduced in number over most
present approaches, there still are several "adjustable" parameters which must be
derived from learning sets. The functional group contribution approach combined
with use of the reaction center concept is logical and is the only practical way to
deal with thousands of chemicals. Thus the over-all approach seems to be state-of-
the-art and should be useful not only for EPA efforts but will most likely find
wide use in other sectors of science, i.e. academic and industrial. EPA should
include members of this community in its beta testing of the SPARC system.

The biologically mediated reactions related to CRAMS involve a whole new
set of model equations. State variables involving substrate concentrations,
biological history of the population, impacts on biological rates and frenetic shifts
in the populations must all be considered. The state-of-the-art is a long way from
being able to incorporate all of these state variables into models. Therefore,
models generated in the near future will probably not be "smart" models that can
mechanistically internalize error signals. The models and their outputs should be
subjected to vigorous field testing as soon as possible. The individual modules
could be placed on line as they are developed.

3.2 Adequacy of Documentation

The expert system for estimation of toxic effects reported on by ERL-Duluth
is still under development. Therefore, this review must be seen as a review of
research in progress. The documentation was complete in providing an overview
of the knowledge-based system, especially in the form of output. However, the
documentation available to the Subcommittee was incomplete for evaluating the
performance of the expert system itself. For example, the SILC program and the
SMILES program for establishing an appropriate computer code describing unique
chemical strings addressable by other programs are very well described. But, the
thermodynamics, theory, and other background information necessary to evaluate
the underpinnings of the estimation method was not reviewed by the
Subcommittee. However, it appears to the Subcommittee that the systems of

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estimation are valid and represent the state-of-the-art.

The expert system (SPARC) for predicting chemical reactivity by computer
is also still under development. The documentation for predicting UV-VIS
absorption and ionization pKa is complete, rigorous and well done. The SPARC
manual describes the steps and a minute part of the reasoning for the estimation
of chemical and physical reactivity. SPARC is designed to estimate any reactivity
parameter that depends on molecular structure. SPARC can estimate more than
fifty different parameters but the theoretical and thermodynamic frameworks were
only presented for UV-VIS absorption spectra. The ionization pKa's were not
presented. We urge publication of these so that the approach can be subjected to
additional peer review. There are still problems to be worked out. For example,
better temperature functionalities and better ability to deal with nonideal systems
(high ionic strength and multisolvent systems) are needed. The documentation
offered does not permit an examination of the underpinning of the estimation
procedures. However, the predictive capability of the software, as presented at the
program review, is both state-of-the-art and comprehensive. For a program still in
development, progress is excellent. Resources should be made available to
complete the documentation and conduct extensive testing of the model.

3.3 System Performance

Subcommittee members were not provided with the opportunity to work
with the software and individually evaluate the SPARC system. Therefore, some
of the following comments are based only on the short demonstration that was
presented.

The SMILES string code is well organized and the graphics software
appears to be user-friendly and useful in viewing molecular structures. The
molecular editor appears to be efficient and with sufficient flexibility to
accommodate the experienced as well as the novice user. This system should
prove itself useful in a variety of applications that make use of molecular structure
information.

The concept of molecular properties prediction via structural correlation is
an old idea which has been used in various branches of chemistry and chemical
engineering. The current approach of using fundamental molecular and atomic
level information is an improvement over previous methods that used such
information only for specific molecular properties. The correlation of molecular
reactivity parameters is a difficult task and the SPARC approach has thus far
progressed to determining pKa values.

The SPARC system has been labeled as an expert system but this
description is misleading in one sense, because SPARC does not learn without
external stimulus. The system has to be "trained" using hundreds of compounds.
The so called "training" (which is equivalent to conducting a regression to obtain
the various correlation parameters) requires precise empirical data and it has not
been demonstrated that predictions can be accurately made for compounds that are

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outside the range of the chemicals used to "train" the system. The system is built
with a reasonable user interface but it does not automatically learn as new runs
are being conducted. The system appears to be one that, at present, requires
handling by experts although running the system is not in itself a difficult task.

A robust system must be able to handle temperature dependence of various
chemical properties. Thus, the robustness of the system should be tested by
"training" the system using information from a few specific temperatures and
subsequently attempting predictions at temperatures for which the system was not
"trained". Similarly, predictions for compounds outside the range of those used to
obtain the regression parameters should be used to test the performance of the
system.

It appears that the system will execute on a standard desk top computer
with a 386 or 486 processor (including a numeric co-processor). The regression
(or system training) has not been ported to the desk top computer level and
currently must be run on a mainframe. (This may have changed since our
review). The Subcommittee cannot offer comments regarding the reliability, speed,
or ease of use of the SPARC and CRAMS systems since it did not have the chance
to test them. The EPA researchers hope that, in time, these estimation
techniques will prove to be not only the nmost expedient, but also the most
reliable means of chemical characterization.

As mentioned elsewhere, care must be taken not to abuse the system bv
requiring it to perform functions for which it has not been "trained" or tested.
The main incentive for SPARC, at this time, should be to improve our
understanding and check the reasonableness of reported values. To go any further
would be a scientific mistake. The experience gained to date with the use of
structure activity relations indicates that such correlations can often yield
erroneous results if misused. Despite these concerns, the SPARC system as well
as CRAMS could be potentially useful in determining trends and signalling
problems when significant deviation is seen between the proposed prediction
methods and other estimation methods and/or experimental data.

3.4 Agency's Need for Chemical Properties Data

Under existing laws (TSCA, FIFRA, and others), the EPA is responsible for
predicting and evaluating the environmental fate and effects of chemicals.
Multimedia assessments (air, water, soil) are needed to adequately evaluate the
potential risks to human health and the environment from exposure to chemicals.
Assessments must include the potential for effects due to specific properties of
chemicals and to both short and long term exposures. Hence, detailed knowledge
of chemical properties and reactivity is required to provide a rational scientific
basis for the assessment process.

Approximately 70,000 industrial chemicals are listed by the EPA's Office of
Toxic Substances (OTS). Parametric values for such properties as photolysis,
hydrolysis, melting point and partitioning have actually been measured for only

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about one percent of the chemicals in the OTS inventoiy. The cost of
measurements required for the complete assessment of the probable behavior of a
chemical in the environment has been estimated to range from $20,000 to
$100,000. However, a basic physical/chemical data set would cost much less and
most developed countries require manufacturers to measure and report elementary
chemical properties such as solubility, Kq^, UV absorption, pKa, etc. The United
States; however, does not require submission of the chemical characteristics data
needed for initial risk screen.

The Toxic Substances Control Act (TSCA) clearly distinguishes between new
and existing chemicals. Under TSCA, premanufacture notices (PMNs) must be
submitted to (OTS) for review before new chemicals can be manufactured or
imported in commercial quantities. TSCA requires the submission of all relevant
data "known or to be reasonably ascertainable" by the submitter, but there is no
statutory requirement for any kind of testing as a precondition for approval. As a
result, PMNs seldom contain all the data necessary for a screening level
assessment of environmental fate, and often contain little or no useful information
beyond the name and structure of the chemical. The Subcommittee believes that
these data (molecular formulation, melting point and boiling point, aqueous
solubility, vapor pressure, and octanol/water partition coefficient) are "reasonably
ascertainable" and should be a minimum requirement.

The basic steps in the PMN process include the Chemical Review and
Search Strategy (CRSS) meeting where chemical nomenclature, structure,
properties, reactions and use are reviewed. The CRSS review is followed by the
Structure Activity Team (SAT) screening level assessment of environmental
transport and transformation and then a review of human health and ecological
hazards. Easily accessed databases such as the Environmental Fate Data Base are
routinely searched prior to CRSS for data on analogs of the PMN chemical as well
as the chemical itself, but data are seldom found. Moreover, even when data are
submitted with the PMN or located in a pre-CRSS search, they are often of
uncertain quality. Thus, early in the PMN process there is a need for reliable
estimate of key physical/chemical properties and chemical reactivity, including
biodegradability. In this regard, it would be useful if the Agency were provided
with basic data of known quality for all PMN chemicals. One way to achieve this
would be for the Agency to issue Guidelines relative to these data requirements.

From a technical standpoint, it would be favorable for the Agency to receive data
during the PMN application and reivew process to allow better use of models.

EPA has a continuing need for rapid estimation methods. This need is
likely to increase rather than diminish in the near term as a result of two factors:
i) a growing emphasis on review and regulation of existing chemicals by chemical
class, rather than on a chemical-by-chemical basis as in the past; and ii) the
establishment of a streamlined existing chemicals process capable of handling
larger numbers of chemicals.

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Because of the inadequacy of existing physical/chemical properties databases
and the lack of a requirement for industry submission of data required for initial
risk screen of the potential adverse effects of new and existing chemicals, the
Agency must develop and depend on methods for estimation of the parameters
needed. At present, much of the chemical properties data used in chemical risk
assessment is highly questionable and often obtained by "back-of-the-envelope"
methods. Individual experience and scientific expertise, both of which are highly
variable, play too large a role in the process. Hence, user friendly expert systems
for predicting chemical reactivity and environmental fate and effects of chemicals
are needed now and will plav increasingly important roles in the future. Methods
must be developed to scientifically determine whether compound A or B is a better
analog of compound C. Otherwise, chemical risk assessment will never progress
past chemical specific analysis, and the sheer numbers of chemicals will prevent
the Agency from accomplishing its public mandate.

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4.0 SUMMARY OF RECOMMENDATIONS

It is clear to the Subcommittee that the development of an ability to predict
chemical properties for biological effects and environmental transport evaluations
must be of high priority to EPA. The Subcommittee thus strongly endorses the
present program of developing more potent SAR and methods to predict physical
and chemical properties. The following list of recommendations should be pursued
as part of the continuing development of these expert systems.

1.	The Subcommittee recommends that the agency not rely solely, at the present
state-of-the-art, on estimated chemical and physical properties for which the
systems have not been trained, but rather to use the estimated values to improve
understanding of the system capabilities and to check the reasonableness of
reported values in their evaluation of toxic chemicals.

2.	The Subcommittee recommends that EPA modify issue a Guideline to require
the submission of basic physical and chemical data with statements of their quality
during the PMN application process.

3.	The Subcommittee recommends that the programs be continued with adequate
funding.

4.	EPA should involve other sectors of science, i.e. academic and industrial, in a
broad review and testing of these systems.

5.	The evaluation of CRAMS should focus on the development of model
equations. The state-of-the-art is a long way from being able to incorporate all of
the necessary state variables into models. Therefore, the model and its outputs
should be subjected to vigorous field testing.

6.	EPA should complete the documentation for the QSAR system. If not already
available, EPA should develop information on the thermodynamics, theory, etc.
necessary to evaluate the underpinnings of the estimation method.

7.	The Subcommittee urges the EPA to complete its testing of the SPARC
system and develop full documentation on the mechanistic underpinnings for each
of the systems.

8.	EPA should develop user friendly expert systems for predicting chemical
reactivity and environmental fate and effects of chemicals that include methods to
scientifically determine whether a known compound A or B is a better analog of
the fate and effects of an unknown compound C.

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