Abstract
Using Quantitative Structure-Activity Relationships (QSAR) to
Establish
Toxicity/Environmental Scores (TES)
The Agency for Toxic Substances and Disease Registry (ATSDR)
uses
Reportable Quantities (RQs) established by the Environmental
Protection
Agency (EPA) in order to prioritize substances subject to
Toxicological Profile
development. RQs are calculated using two distinct criteria. The
first criteria is
based on the intrinsic physicochemical (ignitability/reactivity)
and toxicological
properties (aquatic toxicity, acute mammalian toxicity, chronic
toxicity, and
potential carcinogenicity) of each chemical. The second criteria is
based on a
chemical's susceptibility to biodegradation, hydrolysis, and
photolysis (BHP).
When an RQ is not available, ATSDR uses the same criteria to
develop a
Toxicity/Environmental Score (TES). Sufficient original data are
not available to
assign a TES to many candidate chemicals. However, Quantitative
Structure-
Activity Relationship (QSAR) methods can be used to computationally
predict the
physicochemical, toxicological and biodegradability properties
needed to
calculate TESs. To evaluate the potential use of QSAR methods to
estimate
TESs, the physicochemical, toxicological and biodegradability
properties of 102
chemicals were computationally-predicted, and QSAR TESs estimated.
QSAR
rat oral LD50, fathead minnow LC50, and BHP models predicted TESs
that
correlated strongly (71%, 53%, and 67%, respectively) with original
TESs.
QSAR could not predict a dose-response relationship needed to score
chronic
toxicity. However, an alternate approach combining developmental
toxicity and
chronic LOAELs was used to estimate chronic toxicity values. Using
1 of 4
proposed methods, QSAR-derived TESs were identical to original TESs
for 57%
of the chemicals evaluated. 89% of predicted TESs were within 1
tier of original
TESs. Thus, QSAR methods may be used as an alternative approach to
fill in
data gaps needed for calculation of TESs. To optimize the use of
In Silico
prediction, an integrated approach for the use of multiple QSAR
models, tools
and approaches is needed.
Using Quantitative Structure-Activity Relationships (QSAR) to
Establish
Toxicity/Environmental Scores (TES)
B.S., Environmental Health Science
The University of Georgia
2009
Thesis Committee Chair: W. Michael Caudle, PhD
A thesis submitted to the Faculty of the
Rollins School of Public Health of Emory University
in partial fulfillment of the requirements for the degree of
Master of Public Health
in Environmental Health
2012
Table of Contents
Table of Contents
INTRODUCTION
..........................................................................................................................
1
METHODS
.....................................................................................................................................
5
DATASET
..................................................................................................................................
5
QSAR
PROTOCOL
..................................................................................................................
5
Carcinogenicity
.....................................................................................................................
6
Acute
Toxicity
........................................................................................................................
7
Chronic
Toxicity
....................................................................................................................
9
Aquatic
Toxicity
...................................................................................................................
11
Biodegradability
..................................................................................................................
12
Ignitability/Reactivity
...........................................................................................................
13
RESULTS
....................................................................................................................................
14
ANAYLSIS OF INTRA-CRITERIA
AGREEMENT
..............................................................
14
ANALYSIS OF SCORING
METHODS
................................................................................
21
DISCUSSION
..............................................................................................................................
23
REFERENCES
...........................................................................................................................
27
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About this Master's Thesis
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