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QSAR for acute toxicity to fathead minnow
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03.09.2009
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03.09.2009
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Model is proprietary, but the training and test sets are available.
Algorithm is available.
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None to date
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Fathead Minnow
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EU test method C.1. Acute toxicity for fish (Fathead minnow)
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mg/MolWeight
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log(LC50) - logarithm of the median lethal concentration (LC50). The LC50
is the concentration that will kill 50% of the subjects after some
specified exposure time.
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Acute toxicity to fish was determined using the EU Test Method C.1. The
acute toxicity for fish is a method for investigating the discernible
adverse effects induced in an organism within a short time (days) of
exposure to a substance. Acute toxicity is expressed as the median lethal
concentration (LC50), that is the concentration in water which kills 50%
of a test batch of fish within 96h. The concentrations of the test
substance are given in millimoles per litre (mmol/L). The EPA Fathead
Minnow Acute Toxicity database was generated by the U.S. EPA
Mid-Continental Ecology Division (MED) for the purpose of developing an
expert system to predict acute toxicity from chemical structure based on
mode of action considerations. Hence, an important and unusual
characteristic of this toxicity database is that the 617 tested industrial
organic chemicals were expressly chosen to serve as a useful training set
for development of predictive quantitative structure-activity
relationships (QSARs). A second valuable aspect of this database, from a
QSAR modeling perspective, is the inclusion of general mode-of-action
(MOA) classifications of acute toxicity response for individual chemicals
derived from study results. Each chemical was classified into one of eight
modes of action: base-line narcosis or narcosis I, polar narcosis or
narcosis II, ester narcosis or narcosis III, oxidative phosphorylation
uncoupling, respiratory inhibition, electrophile/proelectrophile
reactivity, AChE inhibition, or several mechanisms of CNS seizure
responses. A detailed description of the biological and chemical test
protocols used for these exposures has been published [Brooke LT et al.
(1984), Geiger DL et al. (1985)]. Briefly, all tests were conducted using
Lake Superior water at 25 ± 10C. Aqueous toxicant concentrations were
measured in all tests with quality assurance criteria requiring 80%
agreement between duplicate samples and 90 to 110% spike recovery.
Flow-through exposures were conducted using cycling proportional, modified
Benoit, or electronic diluters. Tests conducted on the Benoit and
electronic diluters did not have replicate tank exposures. Median lethal
concentrations (LC50s) were calculated using the Trimmed Spearman–Karber
Method, with 95% confidence intervals being calculated when possible.
Information can be obtained from the EPA Fathead Minnow Acute Toxicity
Database (1) and references (2-4) are listed in Section 9.
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Statistics: max value: 2.96, min value: -6.38, standard deviation: 1.40,
skewness: -0.14
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QSAR
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Log(LC50) = 0.97 - 3.48*Average bond order (AM1) -0.32* Highest total
interaction (AM1) -2.21E-003* LPSA Low polarity (AM1) part of SASA -0.16*
count of H-acceptor sites (AM1) (all) -0.64* logP
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Initial pool of ~1000 descriptors. Stepwise descriptor selection based on
a set of statistical selection rules:
1-parameter equations: Fisher criterion and R<sup>2</sup> over threshold,
variance and t-test value over threshold, intercorrelation with another
descriptor not over threshold;
2 parameter equations: intercorrelation coefficient bellow threshold,
significant correlation with endpoint in terms of correlation coefficient
and t-test.
Stepwise trial of additional descriptors not significantly correlated to any
already in the model.
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1D, 2D, and 3D theoretical calculations quantum chemical descriptors
derived from MMFFs(vacuum) conformational search and AM1 calculation.
Model developed by using multilinear regression.
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84.6 (423 chemicals / 5 descriptors)
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Applicability domain based on training set:
By chemical identity: diverse set of organic compounds: amines, nitro
derivatives, nitriles, halogenated compounds, alcohols, phenols, organic
acids, aromatic compounds.
By descriptor value range: the model is suitable for compounds that have the
descriptors in the following range: Average bond order (AM1) (min: 0, max:
2.09), Highest total interaction(AM1)(min: -18.19, max: 0 ), LPSA Low
polarity (AM1) part of SASA (min: 0 , max: 713.28 ), count of H-acceptor
sites (AM1) (all)(min: 0 , max: 10 ), logP(min: -2.38 , max: 9.80).
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Presence of functional groups in structures.
Range of descriptor values in training set with ±30% confidence.
Descriptor values must fall between maximal and minimal descriptor values of
training set ± 30%.
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423 data points: 312 negative values; 111 positive values
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R<sup>2</sup> = 0. 76 (Correlation coefficient);
s = 0.47 (Standard error of the estimate);
F = 269.30 (Fisher function);
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R<sup>2</sup><sub>cv</sub> = 0.75 LOO;
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R<sup>2</sup><sub>cv</sub> = 0.76 LMO;
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ABC analysis (2:1 training : prediction) on sorted data divided into 3
subsets (A;B;C). .Training set formed with 2/3 of the compounds (set A+B,
A+C, B+C) and validation set consisted of 1/3 of the compounds (C, B, A)
average R<sup>2</sup> (fitting) = 0.76 average R<sup>2</sup> (prediction)
= 0.76
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46 data points: 34 negative values; 12 positive values
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The full experimental dataset was sorted according to increasing values of
log(LC50) and each tenth compound was assigned to the test set.
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R<sup>2</sup>= 0.70
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The descriptors for the test set are in the limits of applicability domain.
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The acute toxicity to Fathead Minnow increases with the solubility of the
compound in octanol (logP), this being a measure of the organic compound
penetration in the animal tissue. The acute toxicity to Fathead Minnow
also increases with increasing values of descriptor Count of H-acceptor
sites (AM1) (all). The presence of H acceptor sites makes possible the
binding of the molecule to the fish tissue and in this way increased
toxicity. The toxicity is further increased with the limited polarity of
the molecule (reflected by the descriptor LPSA Low polarity (AM1) part of
SASA). The increased unsaturation (reflected by descriptor Average bond
order (AM1)) and increased 2-center interaction (electrons and nuclei) in
the molecule (reflected by the descriptor Highest total interaction (AM1))
have as result an increased acute toxicity.
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A posteriori mechanistic interpretation
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The partition coefficient logP is the ratio of concentrations of a
compound in the two phases of a mixture of two miscible solvents at
equilibrium (usually water and octanol).
The descriptor Count of H acceptor sites (AM1) is a measure of the ability of
the compound to form H bonds.
The limited polarity of the molecule (LPSA Low polarity (AM1) part of SASA) is
an indication of mostly hydrophobic, but slightly polar compounds, and
increases the possibility of binding the molecule to the fish tissue.
An increased unsaturation (Average bond order (AM1)) and an increased 2-center
interaction (Highest total interaction (AM1)), indicate strong (multiple)
bonds in the molecule, causing some reactivity, and as a result render the
molecule more toxic.
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acute toxicity, fathead minnow, Molcode