v-xEPA
United States
Environmental Protection
Agency
Environmental Research
Laboratory
Duluth MN 55804
Research and Development
EPA-600/S3-81 -029 June 1981
Project Summary
State-of-the-Art of
Structure Activity Methods
Development
Oilman D. Veith
The overall objective of this project
is to provide the Agency with the tech-
nical basis for estimating the toxicity
and environmental behavior of
organic chemicals from molecular
structure. The .project is directed
toward the evaluation of quantitative
structure-activity relationships
(QSAR) for use by EPA Program
Offices and toward the development
of new data and QSAR methods to
extend the technique to meet Agency
needs.
Specifically, the objective of the
Structure-Activity Project is to
develop methods to predict the toxic-
ity, persistence, and treatability of
large numbers of untested chemicals
using QSAR based on structural,
chemical, and biological properties of
representative reference data bases.
Development of QSAR is being tai-
lored of use in the (1) initial screening
of chemicals under the Toxic Sub-
stances Control Act (TSCA), (2) devel-
opment of risk assessment strategies,
(3) prioritization of chemicals for
Water Quality Criteria development,
and (4) the optimization of national
monitoring programs for toxic
chemicals.
This report summarizes the prog-
ress during the first six months of the
project. The report provides a litera-
ture review and perspective for apply-
ing structure-activity methods to
aquatic toxicity of industrial
chemicals. Experimental work
centered on developing methods for
estimating molecular descriptors
such as log P and connectivity indexes
and on the development of a system-
atic structure-activity data base for
aquatic toxicity. A new program for
entering structures into a computer
and calculating connectivity indexes
is discussed. A general model for pre-
dicting 96-hour LC50 for narcotic
chemicals is presented.
This Project Summary was develop-
ed by EPA's Environmental Research
Laboratory, Duluth, MN, to announce
key findings of the research project
that is fully documented in a separate
report of the same title (see Project
Report ordering information at back).
Introduction
Developing technology to predict the
toxicity or reactivity of new and existing
industrial chemicals from structure re-
quires the simultaneous generation
and compilation of endpoints to
measure toxicity, etc. and of molecular
descriptors for representative struc-
tures as well as the development of
statistical methods of relating the two to
form the predictive model. This report
includes a literature review of statistical
methods which indicates that methods
are available for most models for
QSAR deemed necessary for EPA pur-
poses. A small effort by this project is
aimed at compiling computer programs
for the most useful statistical methods
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into a QSAR modeling library which
uses common input/output formats.
The limiting factor for use of QSAR in
screening chemicals, therefore, is the
availability of data on endpoints and
molecular descriptors for industrial
chemicals. Consequently, this project
placed major emphasis on generating a
systematic aquatic toxicity data base
using the 96-hour LC50 for fathead
minnows, and on generating a data
base of important molecular descriptors
such as the n-octanol water partition
coefficients and molecular connectivity
indexes.
Experimental Procedures
The chemicals initially selected for
this study include a wide variety of
alcohols, ketones, aldehydes, ethers,
phenols, and chlorinated aliphatic and
aromatic hydrocarbons. Toxicity tests
were conducted in proportional diluters
(Mount and Brungs, 1967) each with a
dilution factor of 0.6. Test chambers
were glass aquaria measuring 20 x 35 x
25 cm with a 9 cm standpipe, providing
a 6.3 L volume. A 16-hr light, 8-hr dark
photoperiod with no transition was
used.
All tests were conducted with fathead
minnows (Pimephales promelas) from
the Environmental Research Labora-
tory—Duluth culture units. Fish were
hatched and reared in Lake Superior
water and fed live brine shrimp at least
twice daily. Typical fish tested were 30
days old and weighed 0.12 g. Twenty-
five fish were randomly assigned to
each of 12 tanks in lots of five. Fish were
not fed during the 96-hour tests. Deaths
were recorded at hours 1, 3, 6, 12, and
24, and every 24 hours thereafter.
Concentrations for toxicity in each test
tank were determined by chemical
measurements throughout the test.
can be grouped together in QSAR
models and that the chemical activity
needed to produce narcosis in fish is
similar to that which causes narcosis in
mammals. The data showed that the
96-hour LC50 for industrial alcohols,
ethers, alkyl halides, ketones, and
benzene derivatives can be estimated
by the equation:
log 1 - 1.17 + 0.94 log P
LC50
where log P is the logarithm of the n-
octanol/water partition coefficient.
However, this model is limited to chem-
icals with a log P less than 4.0 until
more data can be generated. The data
also showed that chemicals which do
not behave as narcotics at lethal con-
centrations require additional QSAR for
their specific mode of action.
An extensive computer program was
developed which permits entry of
chemical structure through either a
graphics terminal or conventional TTY
and calculations of 134 connectivity
indexes for even polycyclic chemicals
were developed. Preliminary results
indicate that the toxicity of narcotics
can be estimated from structure by the
QSAR:
log LC50 = 0.28 - 1XV
where 1XV is the first order valence con-
nectivity index of the chemical.
This approach has the advantage that
the connectivity indexes are computed
rather than measured values, which
eliminates experimental error and the
need for data other than structure. It has
the potential for discriminating chemi-
cals in terms of expected mode of action
of lethality, other biological effects and
chemical reactivity through cluster
analysis in a multi-dimensional struc-
ture space.
Results
During the initial six months of this
project, toxicity tests with more than 50
organic chemicals indicated that the
majority of the chemicals caused death
by non-specific physical toxicity-termed
narcosis. The literature review on
narcosis presented in the report
showed that the toxicity data for fish are
consistent with literature data in mam-
malian tests in that homologous series
Conclusion
QSAR can provide cost-effective
methods of screening new and existing
chemicals for potential hazards in the
aquatic environment. The development
of a comprehensive QSAR system for
evaluating the 45,000 chemicals in the
TSCA inventory is limited largely by the
time needed to generate the training
sets of toxicity data for the numerous
classes of chemicals.
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This Project Summary was authored by GilmanD. Veith who was also the EPA
Project Officer (see below).
The complete report, entitled "State-of-the-Art of Structure Activity Methods
Development," /Order No. PB 81-187 239; Cost: $11.00, subject to change)
will be available only from:
National Technical Information Service
5285 Port Royal Road
Springfield. VA 22161
Telephone: 703-487-4650
The EPA Project Officer can be contacted at:
Environmental Research Laboratory
U.S. Environmental Protection Agency
Duluth, MN 55804
1 US GOVERNMENT PRINTING OFFICE: 1W1-757-OU/7149
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Environmental Protection
Agency
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Information
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