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T W Schultz

Publications and source records attributed to T W Schultz.

At least 37 records · Page 2Linked to original sources
PubMed2001

Reproducibility of toxicity across mode of toxic action in the Tetrahymena population growth impairment assay.

Toxicity data collected in a laboratory setting are the primary source of potency information used for regulatory, modeling, or risk assessment purposes. However, the relative reproducibility of such toxicity data is rarely discussed. This study investigated the reproducibility of growth impairment data for the freshwater ciliate Tetrahymena pyriformis exposed to a structurally diverse group of chemicals of varying hydrophobicity within different modes of toxic action, either non-covalent narcosis or covalent electro(nucleo)philicity. The proportions of chemicals representing each mode of toxic action, or mechanism of action within each mode, were not chosen to emulate the occurrence of manufactured chemicals or chemicals within the TETRATOX database. Chemicals for which prior toxicity data existed were re-tested and reproducibility was evaluated. The toxic potency values of the selected chemicals were largely reproducible after re-testing of the toxic potency, as 98% of the chemicals had re-test toxicity values within one log unit of the original potency value. To further scrutinize the reproducibility of toxicity values, differences between values were investigated by mode of toxic action. A stringent criterion for reproducibility was enforced, which dictated that the re-tested toxicity value must be encompassed by the fiducial interval (FI) of the original toxicity value and vice versa for the chemical to be considered reproducible. Toxicity values of 28 of the 50 re-tested chemicals conformed to the criterion set for reproducible values. Of the nonreproducible chemicals, seven were narcotics: four nonpolar or neutral narcotics and three other narcotics (e.g. polar narcotics). However, four of these seven narcotics did have toxicity values encompassed by one FI, but not the other FI. The remaining chemicals that did not have reproducible potency measurements were electro(nucleo)philic in nature. Certain toxicophores were highly represented among these chemicals. These included quinone derivatives, electron releasing amino and hydroxyl moieties, and electron withdrawing nitro substituents, often in tandem with strong leaving groups (i.e. halogens), and unsaturated alcohols. Lack of reproducibility was common among the chemicals that elicited toxicity after either abiotic or biotic transformation. There was no clear trend between hydrophobicity and lack of reproducibility. While data are limited, these results suggest that toxic potency values of chemicals acting via the electro(nucleo)philic mode of toxic action could be more susceptible to non-reproducibility. Ramifications of such lack of reproducibility could manifest in predictive toxicology models and their use in regulatory and risk assessment endeavors.

Animals↗
PubMed2001

Parametrization of electrophilicity for the prediction of the toxicity of aromatic compounds.

The aim of this study was to determine which descriptor best parametrized the electrophilicity of aromatic compounds with regard to their acute toxicity. To achieve this, toxicity data for 203 substituted aromatic compounds containing a nitro- or cyano group were evaluated in the 40-h Tetrahymena pyriformis population growth impairment assay. Quantitative structure-activity relationships (QSARs) were developed relating toxic potency [log(IGC(50)(-1))] with hydrophobicity quantified by the 1-octanol/water partition coefficient (log P) and electrophilic reactivity quantified by the molecular orbital parameters, either the energy of the lowest unoccupied molecular orbital (E(LUMO)) or maximum acceptor superdelocalizability (A(max)) was developed. For the full data set, E(LUMO) and A(max) were collinear (r = 0.87). A comparison of the QSARs [log(IGC(50)(-1)) = 0.40 log P - 0.94E(LUMO) - 1.27; n = 203, r(2) = 0.60, s = 0.49, F = 151] and [log(IGC(50)(-1)) = 0.37 log P + 13.1A(max) - 4.30; n = 203, r(2) = 0.70, s = 0.42, F = 237] reveals A(max) to be the better electrophilic parameter for modeling these data. Analysis of outliers indicates a preponderance of 4-subsituted nitrophenols and nitroanilines. Smaller datasets (51 and 102 compounds) selected in order to reduce the collinearity between A(max) and E(LUMO) were also evaluated. Results indicate A(max) to be the superior descriptor of electrophilicity for the purpose of toxicological QSARs for aromatic compounds. Development of QSARs using partial least-squares yielded similar results.

Aniline Compounds↗
PubMed2001

Development of quantitative structure-activity relationships for the toxicity of aromatic compounds to Tetrahymena pyriformis: comparative assessment of the methodologies.

The purpose of this study was to develop quantitative structure-activity relationships (QSARs) for the toxicity of 268 aromatic compounds in the Tetrahymena pyriformis growth inhibition assay. The QSARs were developed using the response-surface (or two-parameter) approach, which was also modified using linear free-energy parameters to account for outliers. Subsequently, the data set was analyzed using partial least-squares (PLS). The results of the modeling using different methodologies were compared to the use of a Bayesian regularized neural network (BRANN) trained on the same data. Both response surface approaches, and PLS explained between 75 and 80% of the variance in the data; BRANN gave a higher statistical fit. In terms of the transparency of the approaches, the response surface clearly provides the simplest and easiest to use QSAR, it is readily interpreted in terms of mechanism of toxic action. PLS and BRANN are respectively less transparent. The use of atomistic and fragment-based indexes as descriptors in QSARs is assessed also, these are found not to be as useful as whole molecule parameters for the prediction of toxicity for molecules outside of the training set. The relative merits of the different approaches to the development of QSARs are described.

Animals↗
PubMed2001

Structure-toxicity analyses of Tetrahymena pyriformis exposed to pyridines -- an examination into extension of surface-response domains.

A selection of mechanistically diverse substituted pyridines were tested in the Tetrahymena pyriformis population growth impairment assay. The response-surface approach was used to derive multiple-regression type structure-toxicity relationships between T. pyriformis population growth impairment toxicity data (log(IGC(-1)(50)) and the 1-octanol/water partition coefficient (log K(ow)) and one of two different descriptors of molecular orbital interaction: energy of the lowest unoccupied molecular orbital (E(LUMO)) and maximum acceptor superdelocalizability (S(MAX)). A statistically robust model (log(IGC(-1)(50)) = -3.91 + 0.50(logK(ow)) + 10.70(S(MAX)); n=83, r(2) =0.756, s=0.38, F=124, Pr>F=0.0001) was developed with S(MAX) as the indicator of reactivity. This model was not statistically different in fit from the model (log(IGC(-1)(50)) = -1.19 = 0.56(logK(ow)) - 0.61(E(LUMO)); n=86, r(2) =0.749, s=0.38, F=124, Pr>F=0.0001) derived using the alternative descriptor of electrophilic interaction. Compounds with high residual values were removed. An examination of these outliers from both response-surfaces, revealed that pyridines substituted in the 2-position with electron-releasing groups and halogenated nitro-substituted pyridines did not fit the above models well. A third group of outliers, the mono-halogenated pyridines, was unique to the S(MAX) response-surface, which are neutral narcotics with potentially high volatility. A comparison of observed and predicted toxicities for a validation set of pyridines for the S(MAX) surface (log(observed IGC(-1)(50) = 0.10 + 0.75(log(predicted IGC(-1)(50)); n=10, r(2) =0.662, s=0.49, F=15.7, Pr>F=0.004) and the E(LUMO) surface (log(observed IGC(-1)(50)) = 0.17 + 0.80(log(predicted IGC(-1)(50)); n=10, r(2) =0.707, s=0.45, F=19.3, Pr>F=0.002) validated the above models, with the fit in the same range as the parent model. The model derived with S(MAX) was compared to the response-surface derived for substituted benzenes (log(IGC(-1)(50)) = -3.47 + 0.50(logK(ow)) + 9.85(S(MAX)); n=197, r(2) =0.816, s=0.34, F=429, Pr>F=0.0001) revealing the similarities in slope and intercept between the two response-surfaces. The model fit was poorer for the pyridine surface, which may be a factor of increased reactivity due to the presence of nitrogen and the associated pair of unshared electrons in the ring not present in benzene. However, the similarity of the pyridine and benzene response-surfaces suggests that the domain defined for benzenes may be extended to encompass nitrogen heterocyclic pyridines.

Animals↗
PubMed2001

Correlation of Tetrahymena and Pimephales toxicity: evaluation of 100 additional compounds.

In the summary/recommendations for the Ecotoxicology Session of TestSmart--A Humane and Efficient Approach to Screening Information Data Sets (SIDS) Data Workshop, it was recommended that more population growth impairment data using Tetrahymena be generated and compared with available lethality data for the fathead minnow. To comply with this recommendation, 100 additional chemicals were tested in the ciliate assay. Toxicity values for the 96-h Pimephales promelas mortality assay (log[LC50(-1)]) and the 2-d Tetrahymena pyriformis growth assay (log[IGC50(-1)]) were compared. Each chemical was a priori assigned a mode of action. The majority of compounds were classified as either narcotics (n = 46) or direct-acting electro(nucleo)philes (n = 43), while 11 chemicals were listed as carboxylic acids, diesters, proelectrophiles, or weak acid respiratory uncouplers. Toxicities for narcotics showed an excellent relationship between endpoints with the coefficient of determination (r2) being 0.93. A weaker relationship, r2 = 0.78, was observed for the electro(nucleo)philes. The poorer fit for the covalent-reacting electro(nucleo)philes is attributed to differences in protocol, in particular, to test-medium composition and exposure scheme. Those chemicals whose potency is mediated by metabolism in fish (diesters and proelectrophiles) as well as the acids exhibited poor correlation between endpoints, with toxicity in the fish assay being greater than that predicted from the ciliate data. The regression analysis between endpoints, regardless of mode or mechanism of toxic action, yielded the model log(LC50(-1)) = 1.12(log[IGC50(-1)]) + 0.46, with n = 92, r2 = 0.82, s (root of the mean square error) = 0.87, F = 399, and p > F = 0.0001. A result for the present investigation supports earlier findings that, with noted exceptions, there is a strong relationship between toxicity potency as quantified by P. promelas mortality and T. pyriformis growth impairment.

Animals↗
PubMed2001

Structure-activity relationships for aquatic toxicity to Tetrahymena: halogen-substituted aliphatic esters.

The toxicity of a series of 21 mono- and dihalogenated aliphatic monoesters has been evaluated using a Tetrahymena pyriformis population growth impairment assay. A structure-activity model has been developed for toxicity data (log(IGC50(-1))), using the 1-octanol/water partition coefficient (logKow) and the energy of the lowest unoccupied molecular orbital (ELUMO) as descriptors. A statistically robust plane (log of the inverse of the 50% growth inhibitory concentration (IGC50(-1)) = 0.34logKow - 0.84 (ELUMO) + 0.04; n = 15, r2 = 0.85, s = 0.26, F = 33, Pr > F = 0.0001) was found for monohalogen-substituted derivatives. These substances are thought to exhibit toxicity via the soft electrophilic mode of toxic action. This toxicity is imparted by the leaving ability of the halogen, which is enhanced when it is placed in close proximity to the carbonyl group. This leaving ability allows haloesters, especially alpha-haloesters, to undergo an SN2, addition-elimination substitution electro(nucleo)philic reaction. Outliers to the above model broadly fell into two groups: small reactive molecules (e.g., propylbromoacetate) that were more toxic than predicted and molecules in which the reactive center was sterically hindered by an alkyl group (e.g., ethyl-2-bromoisovalerate), which were less toxic than predicted.

Animals↗
PubMed2001

Population growth impairment of sulfur-containing compounds to Tetrahymena pyriformis.

A series of 37 aliphatic and aromatic sulfur-containing compounds were evaluated in 2-day Tetrahymena pyriformis population growth impairment assay. The results indicate that, except for select compounds, the in-ring sulfur-containing compounds, sulfates, sulfites, thiols, sulfones, and sulfoxides model as neutral and noncovalent-reacting narcotics. Abiotic loss due to volatility appears to interfere in accurate model prediction because actual toxicity was less than predicted. Vinyl sulfones and sulfoxides are more toxic than predicted using neutral narcosis. Tetrahymena exposed to methyl vinyl sulfone exhibits a direct relationship between the exposure concentration and the generation times with no lag phase in growth. As such, these population growth kinetics mimic those reported for hydrophilic neutral narcotics (i.e., ethanol and acetone). Tetrahymena exposed to phenyl vinyl sulfone exhibit a long concentration-dependent lag phase, which is followed by population growth at rates not different from controls. These population growth kinetics are similar but more dramatic than those reported for hydrophobic neutral narcotics (i.e., butylbenzene and 2-decanone). These results are useful in that they imply that sulfur-containing compounds for the most part act as simple narcotics. Therefore, their toxicity can be modeled with simple structure-toxicity relationships without much fear of underestimation of potency.

Animals↗
PubMed2000

Health-effects related structure-toxicity relationships: a paradigm for the first decade of the new millennium.

Prediction of the effects of industrial chemicals to humans will be an area of increasing concern in the next century. The role of quantitative structure-activity relationships (QSARs) is to aid in the prediction of effects by determination of the limits of variation in structure that are consistent with the production of a specific toxic effect and define the ways in which alterations in structure influences toxicity. The paradigm followed in the development of QSARs for ecotoxic-endpoints has been successful as a direct result of the availability of in vivo toxicity data in which to build initial QSARs and validate surrogate test systems. However, the lack of quantitative in vivo toxicity data means this paradigm cannot be used in the prediction of human health-effect endpoints. Therefore, a new paradigm, which provides guidance in the use of predictive QSARs for health-effects that serves to circumvent the problems associated with the lack of whole-mammal toxicity data must be established. A scenario is given that provides for the development, standardization, and validation of health-effects related QSARs in the first decade of the 21st century. Due to the structural diversity and sheer number of industrial organic chemicals, assays used to garner health-effects data must be based on quantifiable, rapid, reliable, and inexpensive surrogate endpoints. New 'biotools' developed using modern molecular techniques will aid in the circumvention of in vivo health-effects data and provide measurable endpoints, which can be used as surrogates for health-effects endpoints. This has particular application in receptor-mediated toxicity and gene expression. The lack of whole-mammal health-effects data means that the standardization and validation, of these endpoints will be accomplished in novel ways. Databases garnered using modern biotools will allow the derivation of QSARs developed for validated surrogate health-effect endpoints. If QSARs are to be useful in bridging gaps in health-effects data, they must be based on accurate, reproducible data for a robust series of non-congeneric chemicals. The latter applies to both toxicity and descriptor values. Because health-effects are often the result of metabolic activation, if these new QSARs are to be meaningful, validated software for predicting metabolite formation must be incorporated. Lastly, once QSARs and software are developed and validated, they will need to be linked into some type of expert system.

Animals↗
PubMed2000

Modeling the toxicity of chemicals to Tetrahymena pyriformis using molecular fragment descriptors and probabilistic neural networks.

The results of an investigation into the use of a probabilistic neural network (PNN)-based methodology to model the 48-h ICG50 (inhibitory concentration for population growth) sublethal toxicity of 825 chemicals to the ciliate Tetrahymena pyriformis are presented. The information fed into the neural networks is solely based on simple molecular descriptors as can be derived from the chemical structure. In contrast to most other toxicological models, the octanol/water partition coefficient is not used as an input parameter, and no rules of thumb or other substance selection criteria are employed. The cross-validation and external validation experiments confirmed excellent recognitive and predictive capabilities of the resulting models and recommend their future use in evaluating the potential of most organic molecules to be toxic to Tetrahymena.

Animals↗
PubMed2000

Structure-toxicity relationships for aliphatic compounds encompassing a variety of mechanisms of toxic action to Vibrio fischeri.

QSARs based upon the logarithm of the octanol-water partition coefficient, log P, and energy of the lowest unoccupied molecular orbital, ELUMO were developed to model the toxicity of aliphatic compounds to the marine bacterium Vibrio fischeri. Statistically robust, hydrophobic-dependent QSARs were found for chloroalcohols and haloacetonitriles. Modelling of the toxicity of the haloesters and the diones required the use of terms to describe both hydrophobicity and electrophilicity. The differences in intercepts, slopes, and fit of these models suggest different electrophilic mechanisms occur between classes, as well as within the diones and haloesters. In order to model globally the toxicity of aliphatic compounds to V. fischeri, all the data determined in this study were combined with those determined previously for alkanones, alkanals, and alkenals. A highly predictive two-parameter QSAR [pT15 = 0.760(log P) - 0.625(ELUMO) - 0.466; n = 63, s = 0.462, r2 = 0.846, F = 171, Pr > F = 0.0001] was developed for the combined data that models across classes and is independent of mechanisms of action. The toxicity of these compounds to V. fischeri compares well to the toxicity (50% population growth inhibition) to the ciliate Tetrahymena pyriformis (r2 = 0.850).

Bacterial Toxins↗
PubMed1999

Validation of genetically engineered bioluminescent surfactant resistant bacteria as toxicity assessment tools.

Bacteria are useful organisms for measuring acute and chronic toxicity. The most popular toxicity tests utilize the inhibition of bioluminescence as an indication of toxicity. An extensive toxicity database on pure chemical compounds has been created using the bioluminescent microorganism, Vibrio fischeri. However, the use of the Microtox assay in applications for environmental samples is not always successful, due to the test organism. Because the genes for bioluminescence have been cloned from V. fischeri, environmentally relevant test strains can be readily constructed. In this study, surfactant-resistant bioluminescent bacterial strains were constructed by transferring a broad host range plasmid containing the bioluminescent genes under the regulation of a constitutive promoter into strains from several bacterial genera. Two test strains, Stenotrophomonas 3664 and Alcaligenes eutrophus 2050, were approximately 400 times more resistant to the nonionic surfactant polyoxyethylene 10 lauryl ether than V. fischeri and are useful for toxicity reduction evaluations of remediation processes which use surfactants for solubilization of hydrophobic pollutants. The use of these strains as alternative test organisms in the Microtox assay was evaluated using nonpolar narcosis as the baseline toxicity mechanisms. The two test strains and V. fischeri indicated linear fits of EC50 values with the octanol/water partition (Kow) for five nonpolar narcotic compounds in acute assays (r2>0.9) with a slope of approximately 1. For all three strains, the y-intercept values were approximately the same, indicating that sensitivity did not vary. These results indicate that the nonpolar narcosis baseline toxicity mechanism may be useful as a general tool to validate the functioning of genetically engineered bioluminescent microorganisms.

Alcaligenes↗
PubMed1999

Bioavailability, biodegradation, and acclimation of Tetrahymena pyriformis to 1-octanol.

Previous work has indicated that the ubiquitous freshwater ciliate Tetrahymena pyriformis acclimates to the presence of hydrophobic chemicals acting by nonpolar narcosis. Four explanations have been identified to explain this apparent acclimation: (1) genetic adaptation occurs resulting in a resistant population, (2) T. pyriformis quickly biodegrades hydrophobic chemicals resulting in a perceived acclimation response, (3) hydrophobic chemicals are not bioavailable, and (4) T. pyriformis contain an endogenous biochemical adaptation system which can quickly cause cellular changes resulting in acclimation. Results of biodegradation experiments indicated that the total extractable 1-octanol did not change over the duration of the experiments. Bioavailability experiments were performed using the solid-phase microextraction technique. Although there is a decrease in freely available concentrations of 1-octanol over a 2.5 log unit range of Tetrahymena population density, the freely available concentration is constant for the population densities used for population growth experiments. Genetic change is highly unlikely since acclimation occurs in less than the time required for one population division. It is hypothesized that the acclimation response seen in Tetrahymena results from partitioning of the chemical into the membrane followed by active changes in the membrane structure to restore homeostasis.

1-Octanol↗
PubMed1999

Structure-toxicity relationships for benzenes evaluated with Tetrahymena pyriformis.

Toxicity data for 200 substituted benzenes tested in the two-day Tetrahymena pyriformis population growth impairment assay representing the neutral narcosis, polar narcosis, respiratory uncoupling, and weak and strong electrophilic mechanisms of toxic action were evaluated. A quantitative structure-toxicity model correlating toxic potency [log(IGC(50)(-)(1))] with hydrophobicity quantified by the 1-octanol/water partition coefficient (log K(ow)) and electrophilic reactivity quantified by the molecular orbital parameter, maximum superdelocalizability (S(max)), was developed. This model [log(IGC(50)(-)(1)) = 0.50(log K(ow)) + 9.85(S(max)) - 3.47; n = 197, r(2) = 0.816, s = 0.34, F = 429, Pr > F = 0.0001] allows for the prediction of acute potency without the a priori identification of the mechanism of action. The examination of residuals reveals that neutral narcotics with high volatility (e.g., methyl- and chloro-substituted benzenes) and highly reactive fluoro- and nitro-containing derivatives are fitted poorly. A comparison of observed (obs) and predicted (pred) toxicities on the additional set of derivatives [log(obs IGC(50)(-)(1)) = 1.05[log(pred IGC(50)(-)(1))] + 0.02; n = 20, r(2) = 0.979, s = 0.13, F = 825, Pr > F = 0.0001] validated the model as a good predictor of toxicity regardless of the mechanism of toxic action.

Animals↗
PubMed1999

QSAR analyses of the toxicity of aliphatic carboxylic acids and salts to Tetrahymena pyriformis.

Carboxylic acids have been conspicuously absent from the quantitative structure activity relationship (QSAR) literature. This study investigated the aquatic toxicity (log(IGC50(-1)) of selected mono- and di-carboxylic acids and their sodium, or disodium salts, tested in the Tetrahymena population growth assay. The relationship between log(IGC50(-1)) and hydrophobicity as described by the 1-octanol/water partition coefficient (log Kow) revealed a distinct sub-class. The relationship [log(IGC50(-1)) = 0.27(log Kow) - 0.68; n = 16, r2 = 0.943, s = 0.07, F = 233, Pr > F = 0.0001] was derived for mono-carboxylic acids. The QSAR [log(IGC50(-1)) = 0.19(log Kow) - 0.66; n = 9, r2 = 0.951, s = 0.08, F = 135, Pr > F = 0.0001] was generated for the di-carboxylic acids. Regression analysis of data for the monosodium carboxylic acid salts yielded the model, log(IGC50(-1)) = 0.60 (log Kow) + 0.58; n = 4, r2 = 0.932, s = 0.19, F = 41.2, Pr > F = 0.008. Values for the ionization constant (pKa) and the energy of the lowest unoccupied molecular orbital (ELUMO) do not vary within the sub-class for saturated acids. Moreover, pKa and ELUMO did not describe differences in toxicity between sub-classes of saturated aliphatic carboxylic acids and salts. However, these descriptors did vary for unsaturated acids. Inclusion of unsaturated acids afforded the derivation of a global response-surface for all aliphatic carboxylic acids, log(IGC50(-1)) = 0.25(log Kow) - 0.13(ELUMO) - 0.54; n = 34, r2 = 0.850, s = 0.138, F = 87.9, Pr > F = 0.0001. Outliers to the response-surface included small molecules that provided 2-positions in which the molecule could potentially undergo electrophilic attacked and other more large, hydrophobic molecules.

Animals↗
PubMed1998

Structure-toxicity relationships for three mechanisms of action of toxicity to Vibrio fischeri.

Quantitative structure-activity relationships (QSARs) have been developed with the logarithm of the inverse of 15-min toxicity (pT15) to Vibrio fischeri (the acute Microtox test). Statistically, robust QSARs were found for alkanones acting by the nonreactive, baseline narcosis mechanism of action [pT15 = 0.99 (log Kow)-2.08, n = 6, s = 0.24, r2 = 0.988, F = 405]; aldehydes acting by the Schiff base-forming mechanism of electrophilicity [pT15 = 0.55(log Kow)-0.58, n = 6, s = 0.07, r2 = 0.994, F = 782]; and alkenals acting by the Michael-type acceptor mechanism of electrophilicity [pT15 = 0.52(log Kow) + 0.35, n = 6, s = 0.19, r2 = 0.914, F = 54.5]. Efforts to model toxicity across mechanism of action resulted in the development of a response surface [pT15 = 0.79(log Kow)-1.17 (ELUMO)-0.41, n = 19, s = 0.46, r2 = 0.892, F = 75.3]. In addition, an excellent correlation was found between Tetrahymena pyriformis [log(1/IGC50)] and V. fischeri. [log(1/IGC50) = 0.86(pT15)-0.25, n = 19, s = 0.25, r2 = 0.957, F = 405] toxicity.

Aldehydes↗