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T W Schultz

Publications and source records attributed to T W Schultz.

At least 19 recordsLinked to original sources
PubMed2006

Identification of reactive toxicants: structure-activity relationships for amides.

A diverse series of amides were evaluated for aquatic toxicity (IGC(50)) assessed in the Tetrahymena pyriformis population growth impairment assay and for reactivity (EC(50)) with the model soft nucleophile thiol in the form of the cysteine residue of the tripeptide glutathione. All alkylamides along with some halo-substituted amides are well predicted by the simple hydrophobicity (log K (ow))-electrophilicity (E (lumo)) response-surface model [log(IGC(-1) (50)) = 0.45(log K (ow)) - 0.342(E (lumo)) - 1.11]. However, 2-halo amides with the halogen at the end of the molecule and alpha,beta-unsaturated primary amides are among those derivatives identified as being more toxic than predicted by the model. Amides, which exhibit excess toxicity, were capable of forming covalent bonds through an S(N)2 displacement or a Michael addition. Moreover, only those amides exhibiting excess toxicity were reactive with thiol, suggesting that the reactivity with model nucleophiles such as the thiol group may provide a means of accurately defining reactive toxicants.

Amides↗
PubMed2006

A conceptual framework for predicting the toxicity of reactive chemicals: modeling soft electrophilicity.

Although the literature is replete with QSAR models developed for many toxic effects caused by reversible chemical interactions, the development of QSARs for the toxic effects of reactive chemicals lacks a consistent approach. While limitations exit, an appropriate starting-point for modeling reactive toxicity is the applicability of the general rules of organic chemical reactions and the association of these reactions to cellular targets of importance in toxicology. The identification of plausible "molecular initiating events" based on covalent reactions with nucleophiles in proteins and DNA provides the unifying concept for a framework for reactive toxicity. This paper outlines the proposed framework for reactive toxicity. Empirical measures of the chemical reactivity of xenobiotics with a model nucleophile (thiol) are used to simulate the relative rates at which a reactive chemical is likely to bind irreversibly to cellular targets. These measures of intrinsic reactivity serve as correlates to a variety of toxic effects; what's more they appear to be more appropriate endpoints for QSAR modeling than the toxicity endpoints themselves.

Amino Acids↗
PubMed2006

Structure-activity relationships for flow cytometric data of smaller polycyclic aromatic hydrocarbons.

Using flow cytometry, select polycyclic aromatic hydrocarbons (PAHs) were evaluated for induction of apoptosis in human monocytic THP-1 cells. Based on structure, the PAHs were divided into linear and bay-region-containing compounds. Except for fluorene, the linear PAHs failed to induce apoptosis; all of the bay-region-containing PAHs induce apoptosis. The relationship that a bay-region is required to induce apoptosis is supported by results for benzo[a]pyrene (positive) and 2-methylanthracene (negative). The data for bay-region containing, four-ringed PAH compounds reveal that possessing a linear-region of more than two rings diminishes the ability of a PAH to induce apoptosis. Owing to the steric interactions of the hydrogen atoms of the methyl group and those on the ring carbons, 1-methylanthracene does not have a true bay-region. However, the methyl group substituted in the 1-position does confer a bay-like conformation, which may explain its activity in contrast to its parent derivative anthracene and its 2-postion homologue.

Anthracenes↗
PubMed2005

Non-enzymatic glutathione reactivity and in vitro toxicity: a non-animal approach to skin sensitization.

The development of non-animal methods to predict the potential of chemicals to cause skin sensitization is of great importance. On the basis of many published studies into the underlying chemical mechanisms skin sensitization, the immunological priming which leads to the disease allergic contact dermatitis, is recognized as a reactive chemistry endpoint. Consequently, the combination of chemical assays with in vitro techniques may provide a useful surrogate to animal testing for skin sensitization. This study attempts to investigate the relationship between skin sensitization assessed in the local lymph node assay (LLNA) initially and a thiol reactivity index based on glutathione (GSH), pEC(50) thiol (EC(50) being defined as the concentration of the test substance which gives 50% depletion of free thiol under standard conditions) in combination with a measure of cytotoxicity (pIGC(50)) to Tetrahymena pyriformis (TETRATOX). The pEC(50) thiol values and the pIGC(50) values were determined for twenty-four compounds for which LLNA test data were available. Thiol reactivity was found to discriminate sensitizers from non-sensitizers according to the rule: pEC(50) thiol>-0.55 indicates that the compound will be a skin sensitizer. However, because of metabolic activation a pEC(50) thiol<-0.55 does not necessarily mean that the compound will be a non-sensitizer. Excess toxicity to T. pyriformis (i.e. the extent of toxic potency over that expected by non-polar narcosis) was determined in order to assess biological reactivity. The best discrimination based on excess toxicity in the TETRATOX assay was given by the "rule": excess toxicity>0.50 indicates that the compound will be a skin sensitizer. These approaches become more powerful when combined. When taken together, the thiol and TETRATOX assays predict the sensitization potential of 23 of the 24 compounds correctly. alpha-Hexylcinnamic aldehyde is incorrectly predicted to be a non-sensitizer, whereas LLNA results suggest it may be a weak sensitizer, this inaccuracy being rationalized in terms of its high hydrophobicity. Due to the selectivity of electro(nucleo)philic reactions some sensitizing compounds will not be identified using a single nucleophile such as thiol.

Allergens↗
PubMed2005

Structure-activity relationships for reactivity of carbonyl-containing compounds with glutathione.

For toxicological-based structure-activity relationships to advance, will require a better understanding of molecular reactivity. A rapid and inexpensive spectrophotometric assay for determining the reactive to glutathione (GSH) was developed and used to determine GSH reactivity (reactGSH) data for 21 aliphatic derivatives of esters, ketones and aldehydes. From these data, a series of structure-activity relationships were evaluated. The structure feature associated with reactGSH was an acetylenic or olefinic moiety conjugated to a carbonyl group (i.e. polarized alpha,beta-unsaturation). This structure conveys the capacity to undergo a covalent interaction with the thiol group of cysteine (i.e. Michael- addition). Quantitatively reactGSH of the alpha,beta-unsaturated carbonyl compounds is reliant upon the specific molecular structure with several tendencies observed. Specifically, it was noted that for alpha,beta-unsaturated carbonyl compounds: (1) the acetylenic-substituted derivatives were more reactive than the corresponding olefinic-substituted ones; (2) terminal vinyl-substituted derivatives was more reactive than the internal vinylene-substituted ones; (3) methyl substitution on the vinyl carbon atoms diminishes reactivity and methyl-substitution on the carbon atom farthest from the carbonyl group causes a larger reduction; (4) derivatives with carbon-carbon double bond on the end of the molecule (i.e. vinyl ketone) were more reactive than one with the carbon-oxygen bond at the end of the molecule (i.e. aldehyde) and (5) the ester with an additional unsaturated vinyl groups were more reactive than the derivative having an unsaturated ethyl group.

Acrolein↗
PubMed2004

Trends in structure-toxicity relationships for carbonyl-containing alpha,beta-unsaturated compounds.

Using toxicity data for 30 aliphatic polarized alpha,beta-unsaturated derivatives of esters, aldehydes, and ketones, a series of six structure-toxicity relationships were evaluated. The structure feature of all assessed compounds, an acetylenic or olefinic moiety conjugated to a carbonyl group, is inherently electrophilic and conveys the capacity to exhibit enhanced toxicity. However, the toxic potency of alpha,beta-unsaturated carbonyl compounds is dependent on the specific molecular structure with several trends being observed. Specific observations include: (1) between homologues, the acetylenic-substituted derivative was more toxic than the corresponding olefinic-substituted one, respectively; (2) between olefinic-homologues, terminal vinyl-substituted derivative was more toxic than the internal vinylene-substituted one; (3) within alpha,beta-unsaturated ketones, methyl substitution on the vinyl carbon atoms reduces toxicity with methyl-substitution on the carbon atom farthest from the carbonyl group exhibiting the greater inhibition; (4) between alpha,beta-unsaturated carbonyl compounds with the carbon-carbon double bond on the end of the molecule (vinyl ketones) and those with carbon-oxygen double bonds on the end of the molecule (aldehydes), the ketones are more toxic than the aldehydes; (5) between homologues of alpha,beta-unsaturated esters, those with additional unsaturated moieties (allyl, propargyl, or vinyl groups) were more toxic than homologues having relevant unsaturated moieties (propyl or ethyl groups); (6) between alpha,beta-unsaturated carbonyl compounds with different shaped alkyl-groups (i.e. different degrees of branching), homologues with straight-chain hydrocarbon moieties were more toxic than those with branched groups.

Aldehydes↗
PubMed2003

Selection of data sets for QSARs: analyses of Tetrahymena toxicity from aromatic compounds.

The aim of this investigation was to develop a strategy for the formulation of a valid ecotoxicological-based QSAR while, at the same time, minimizing the required number of toxicological data points. Two chemical selection approaches-distance-based optimality and K Nearest Neighbor (KNN), were used to examine the impact of the number of compounds used in the training and testing phases of QSAR development (i.e. diversity and representivity, respectively) on the predictivity (i.e. external validation) of the QSAR. Regression-based QSARs for the ectotoxic potency for population growth impairment of aromatic compounds (benzenes) to the aquatic ciliate Tetrahymena pyriformis were developed based on descriptors for chemical hydrophobicity and electrophilicity. A ratio of one compound in the training set to three in the test set was applied. The results indicate that from a known chemical universe, in this case 385 derivatives, robust QSARs of equal quality may be developed from a small number of diverse compounds, validated by a representative test set. As a conservative recommendation it is suggested that there should be a minimum of 10 observations for each variable in a QSAR.

Animals↗
PubMed2003

Partial least squares modelling of the acute toxicity of aliphatic compounds to Tetrahymena pyriformis.

The aim of this study was to evaluate a multivariate statistical model, utilising Partial Least Squares (PLS) analysis, for the prediction of the acute toxicity of aliphatic chemicals to the ciliate Tetrahymena pyriformis. A model was developed that was capable of making a prediction regardless the mechanism of toxic action. The toxicity of 476 compounds, possessing different mechanisms of toxic action was considered. A set of 74 descriptors, including the octanol-water partition coefficient, molecular-orbital descriptors, geometrical, topological and connectivity indices, was generated. A three-component, eight-descriptor PLS model was developed. It was validated by a Y-permutation test and by simulation of external prediction for complementary subsets. A comparison with existing class or mechanism-based models, derived on the same data set, was made.

Animals↗
PubMed2002

Population growth kinetics and bulk membrane lipid alterations in Tetrahymena pyriformis: exposure to pentachlorophenol.

This study describes effects of exposure of the freshwater ciliate Tetrahymena pyriformis to the "classic" weak acid respiratory uncoupler pentachlorophenol (PCP) on the population growth kinetics and membrane lipid profiles. The assessment of growth kinetics of naive populations exposed to PCP, at concentrations eliciting < 50% growth inhibition, showed generation times of exposed cultures similar to generation times of controls but preceded by a short lag phase (< 2 h). Assessment of exposed cultures exhibiting > 50% growth inhibition revealed generation times that increased with increasing concentrations of toxicant. In addition, the relative percentages of selected fatty acid methyl esters (FAMEs) in both pellicle and mitochondrial membranes were examined. Upon exposure to PCP the relative percentages of FAMEs 12:0, 14:0, 16:0, 16:1, and 18:0 did not change. However, with exposure to PCP a decrease was observed for FAMEs 15:0 and 17:0. Conversely, with PCP exposure there was an increase in FAME 18:1. A comparison of these results with those elicited upon exposure to the model narcotic 1-octanol reveals marked differences in both growth kinetics and fatty acid shifts.

1-Octanol↗
PubMed2002

Probabilistic neural network modeling of the toxicity of chemicals to Tetrahymena pyriformis with molecular fragment descriptors.

We present the results of an investigation into the use of a probabilistic neural network (PNN) based methodology to model the 48-60-h ICG50 (inhibitory concentration for population growth) sublethal toxicity to the ciliate Tetrahymena pyriformis. The information fed into the neural network 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 involved. The model was trained on a 1,000 substances data set and validated using an 84 substances external test set. The associated analysis of errors confirms the excellent recognitive and predictive capabilities of the model.

Animals↗
PubMed2002

The effect of precision of molecular orbital descriptors on toxicity modeling of selected pyridines.

The response-surface approach to QSARs attempts to model toxic potency of diverse groups of chemicals while avoiding problems associated with the identification of the mechanism of toxic action or specific chemical class often associated with other approaches. However, while hydrophobicity-dependent, simple regression QSARs derived for congeneric series of organic compounds typically have coefficients of determination greater than 0.90, more heterogeneous multiple regression QSARs exhibit typically 10-15% more unexplained variability. One difference between these approaches is the use of a quantum chemical (QC) descriptor, particularly molecular orbital (MO) energy values such as the energy of the lowest unoccupied molecular orbital (E(LUMO)). The reduced statistical fit exhibited by QSAR models, which include these QC-MO descriptors, could be a result of the variability inherent in the calculation of these descriptors. The present investigation with a structurally and mechanistically diverse set of pyridines revealed that variability is associated with the calculation of the MO descriptor E(LUMO) both between selected Hamiltonians and selected software packages. However, this variability in no way affects the statistical significance of QSARs for toxicity using these values. Specifically, the E(LUMO) values calculated with the PM3 and AM1 Hamiltonians in the two software packages were highly related. There was no relationship between molecular complexity or chemical reactivity and increased differences in individual ELUMO values as described by the standard errors of the mean. Although nine appeared to be the number of calculations, which best minimizes the standard error in energy values relative to computational costs; this minimization did not alter the statistics of the QSARs derived with single vs. mean E(LUMO) values. While the energy of the highest occupied molecular orbital (E(HOMO)) values were not used in the modeling of toxicity, a comparison of these values revealed greater variability between the Hamiltonians and software packages than observed for ELUMO values. Examination of the magnitudes of standard error of the E(HOMO) values in connection to structural features or reactivity likewise revealed no trends.

Forecasting↗
PubMed2001

Observations on the preferential biodegradation of selected components of polyaromatic hydrocarbon mixtures.

The capacity of the naphthalene degrading enzyme (NAH) system of Pseudomonas fluorescens 5R and a number of other NAH system bacterial isolates to degrade mixtures of polyaromatic hydrocarbons (PAHs) and heterocyclic compounds were examined. It was found that all the examined organisms displayed similar patterns of preferential compound degradation when presented with the same mixture. Using strains that possess portions of the NAH system, this preferential degradation was localized to the activity of naphthalene dioxygenase. Comparisons of the first-order rates of compound degradation with the structures of the mixture components indicated that increased deviation from the base structure of naphthalene led to slower disappearance. Structural features that were found to decrease the rate of compound degradation include an increase in the number of methyl substituents and an increase in the size of a substituent.

Biodegradation, Environmental↗