Biomedical subjects

M T Cronin

Publications and source records attributed to M T Cronin.

At least 19 recordsLinked to original sources

PubMed2001

The use of pH measurements to predict the potential of chemicals to cause acute dermal and ocular toxicity.

Regulatory guidelines for the assessment of acute dermal and ocular toxicity refer to the need to take the pH values of chemicals into consideration, since the acidic and basic properties of chemicals are known to play a role in the generation of acute dermal and ocular lesions. However, not all test guidelines provide an objective interpreting pH measurements in terms of acute skin or eye toxicity. The aim of this study was to develop classification models based on pH data for predicting the potential of chemicals to cause skin corrosion, skin irritation and eye irritation. The possible application of these models in the context of tiered testing strategies is discussed.

Chemical Phenomena↗

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

Prediction models for eye irritation potential based on endpoints of the HETCAM and neutral red uptake tests.

The aim of this study was to explore the possibility of distinguishing between eye irritants (I; EU risk phrases R36 and R41) and nonirritants (NI), by using in vitro endpoints of the hen's egg test on the chorioallantoic membrane (the HETCAM test) and the neutral red uptake (NRU) test. Prediction models were derived by applying binary logistic regression to the in vitro data for these endpoints, which were taken from the report of a German validation study on the use of the HETCAM and 3T3 NRU tests as alternatives to the Draize eye irritation test. Whereas the validation study led to the conclusion that the combined use of the two tests enables a satisfactory discrimination between severe (R41) and nonsevere (NI, R36) eye irritants, the results of the present study indicate that the two in vitro tests can also be used to discriminate between nonirritants (NI) and irritants (R36 and R41).

3T3 Cells↗

PubMed2001

Microfluidic arrays in genetic analysis.

The goal of genetic analysis is to discover genetic markers that are informative for providing high confidence, positive predictive value in managing phenotypic outcomes. Primary consensus sequence data, genetic polymorphism databases and associated phenotype data are rapidly making genetic analysis more useful. Therefore, genetic analysis applications are gradually becoming more mainstream. The diversity and complexity of genetic analysis currently requires an array of analytical techniques, instrument platforms and software to support all the steps from data acquisition to interpretation. As supporting research technologies mature, they are incorporating increasing levels of automation, system integration and miniaturization. Microfluidic arrays are positioned to play a key role in routine genetic analysis, particularly as they begin to appear in more fully integrated analytical platforms.

Animals↗

PubMed2001

Utilization of new technologies in drug trials and discovery.

It has become widely accepted that individual genetic variation is a prime determinant in both disease susceptibility and toxic response to therapeutic agents and xenobiotics. Emerging genetic sequence data and phenotype association studies are expected to enable disease risk prediction and guide subsequent therapeutic approaches in individual cases. However, making a good match between an individual genetic profile, disease risk prediction, and appropriate therapeutic intervention will require genotyping many polymorphic sites in large numbers of genes or single nucleotide polymorphism sites throughout the genome. Additionally, each polymorphism will have to be associated with a phenotype. Presumably, a composite phenotype may be predicted by integrating anticipated contributions from each polymorphism contributing to the complex genotype. Methods for executing such large-scale genotyping studies are rapidly evolving and becoming available. DNA microarray technology applied in hybridization-based genotyping assays is particularly well suited to respond to the accelerating pace of polymorphism discovery and the associated demand for highly parallel genotyping capability.

Base Sequence↗

PubMed1999

Investigation of the mechanism of flux across human skin in vitro by quantitative structure-permeability relationships.

Permeability coefficients for 114 compounds across excised human skin in vitro were taken from Kirchner et al. Forty-seven descriptors were calculated encompassing the relevant physicochemical parameters of the compounds. Quantitative structure-permeability relationships (QSPRs) were developed using least-squares regression analysis. A two-parameter QSPR, describing the permeability coefficients (Kp) across excised skin, was obtained: log Kp=0.772 log P -0.0103 Mr - 2.33 where log P is the logarithm of the octanol-water partition coefficient and Mr is molecular mass. This equation indicates that percutaneous absorption is mediated by the hydrophobicity and the molecular size of the penetrant. Comparison with a QSPR based on penetration across a synthetic (polydimethylsiloxane) membrane suggests that the mechanisms of drug flux across polydimethylsiloxane membranes and excised human skin are significantly different.

Chemical Phenomena↗

PubMed1998

QSAR study of the toxicity of benzoic acids to Vibrio fischeri, Daphnia magna and carp.

The toxicities of benzoic acids to Vibrio fischeri, Daphnia magna and carp were measured. The results showed that the toxicity to V. fischeri and Daphnia decreased in the order of bromo > chloro > fluoro approximately equal to aminobenzoic acids. The toxicity of substituted benzoic acids to carp and Daphnia was much lower that to V. fischeri. The results also showed that the toxicity of benzoic acids to Daphnia decreased as the pH increased. It is suggested that ionized and non-ionized forms have different toxic responses. The non-ionized form may play an important role in toxicity because the toxicity of benzoic acids to Daphnia greatly decreases as the pH increases. The toxicity of benzoic acids to Daphnia may operate through non-polar narcosis, based on the regression results between the toxicities and partition coefficients (log P) and apparent partition coefficients (log D). However, toxicity cannot be predicted from non-polar baseline models because the ionized and non-ionized form of benzoic acids have different contributions to toxicity. Compared with the single descriptors, the prediction of toxicity of the benzoic acids was improved remarkably by using log P with pKa and log P with ELUMO. For the toxicity of benzoic acids to V. fischeri, it is suggested that the toxic mechanism may be different from the mechanism in Daphnia and carp. A probable reason is that V. fischeri is a unicellular organism with low lipid content, and hence both ionized and non-ionized forms of benzoic acids can easily cross the cell membrane and contribute to toxicity.

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↗

PubMed1998

Quantitative structure-activity analyses of nitrobenzene toxicity to Tetrahymena pyriformis.

Toxicity data for the 50% growth inhibitory concentration against Tetrahymena pyriformis (log (IGC50-1)) for 42 alkyl- and halogen-substituted nitro- and dinitrobenzenes were obtained experimentally. Log (IGC50-1) along with the hydrophobicity, the logarithm of the 1-octanol/water partition coefficient (log Kow), and the molecular orbital properties, the lowest unoccupied molecular orbital energy (Elumo) and maximum acceptor superdelocalizability (Amax), were used to develop quantitative structure-activity relationships (QSARs). All the nitroaromatic compounds tested had toxicity in excess of baseline, nonpolar narcosis. The nitrobenzenes were thought to elicit their toxic response through multiple (and mixed) mechanisms. No high-quality relationship was observed between toxicity and hydrophobicity, or Elumo, individually. However, a strong relationship ¿log (IGC50-1) = 16.4(Amax) - 4.64; n = 42, r2 = 0.847, s = 0.279, F = 229¿ was obtained. In an effort to improve predictability, two-parameter QSAR, or response surface, analyses were performed. These analyses resulted in the following QSARs: ¿log (IGC50-1) = 0.206(log Kow) - 16.0(Amax) - 5.04; n = 42, r2 = 0.897, s = 0.229, F = 180¿ and ¿log (IGC50-1) = 0.467(log Kow) - 1.60(Elumo) - 2.55; n = 42, r2 = 0.881, s = 0.246, F = 154¿.

Animals↗

PubMed1998

An investigation of the mechanism of flux across polydimethylsiloxane membranes by use of quantitative structure-permeability relationships.

Quantitative structure-permeability relationships (QSPRs) based on readily calculated parameters have been developed to study penetration across a polydimethylsiloxane membrane. Maximum steady-state flux values for 256 compounds through a polydimethylsiloxane membrane were taken from previous studies. Forty-three physicochemical parameters were calculated for each compound and their significance to flux determined. Removal of fourteen outliers enabled derivation of a significant three-parameter QSPR based on the number of hydrogen-bond acceptor and donor groups and sixth-order path molecular connectivity. Models based on parameters important for penetration across human skin (log P and molecular weight) were comparatively poor. This model suggests that the mechanism of flux across a polydimethylsiloxane membrane is based mainly on hydrogen-bonding effects; as such it occurs via a mechanism of action different from that of penetration of the skin in man.

Administration, Cutaneous↗

PubMed1997

Validation of Vibrio fisheri acute toxicity data: mechanism of action-based QSARs for non-polar narcotics and polar narcotic phenols.

Quantitative structure-activity relationships (QSARs) have been utilized to validate toxicity data to Vibrio fisheri (the acute Microtox test) at each of the 5-, 15- and 30-min endpoints. Statistically robust QSARs were found for chemicals acting by a non-polar narcosis mechanism of action (MOA). The baseline, non-polar narcosis QSARs were similar to those found in other aquatic organisms, thus indicating that for this MOA, the acute V. fisheri assay makes a suitable surrogate for higher test species. For the toxicity of phenols, previously modeled in other species with parameters describing membrane transport (i.e. hydrophobicity) and soft electrophilicity or ionization, no significant relationships were obtained. The use of acute V. fisheri toxicity data is not recommended for extrapolation to higher species for these compounds. Despite this recommendation, it was noted, however, that a 'minimal' phenolic toxicity was apparent that was analogous to polar narcosis in other species. This confirmed that a polar narcosis MOA does operate in the acute V. fisheri system analogous to other species. For all the compounds considered, there were highly significant correlations between the toxicities at each endpoint, indicating that data from different time endpoints were effectively interchangeable.

Narcotics↗

PubMed1997

Structural basis for the haemotoxicity of dapsone: the importance of the sulphonyl group.

The structural basis of dapsone (4,4'-diaminodiphenyl sulphone) haemotoxicity has been determined by investigation of the in vitro bioactivation of a series of 4-substituted arylamines. In the presence of rat liver microsomes, dapsone (100 microM) was the most potent former of methaemoglobin in human erythrocytes (44.8 +/- 6.7%). Substitution of the sulphone group with sulphur (11.6 +/- 1.4% methaemoglobin), oxygen (4.5 +/- 1.1%), nitrogen (0.0 +/- 3.2%), carbon (13.6 +/- 0.8%) or a keto group (34.0 +/- 6.1%) resulted in a decrease in methaemoglobin formation. Only one compound, 4,4'-diaminodiphenylamine, generated significant (P < 0.001) amounts of methaemoglobin (25.6 +/- 2.5%) in the absence of NADPH. To assess further the role of the 4-substituent in methaemoglobinaemia, the toxicity of a series of 4-substituted aniline derivatives was also studied. Of the anilines studied, 4-nitroaniline caused the most methaemoglobin (36.5 +/- 8.0%), whilst aniline caused the least (0.3 +/- 0.5%). Overall, there was a significant correlation (r2 = 0.83) between the haemotoxicity and the Hammett constant, sigma(p), suggesting that it is the electron-withdrawing properties of the substituent that influence the methaemoglobin formation. In the presence of microsomes prepared from two human livers, dapsone was the most haemotoxic bis arylamine, whereas 4-iodoaniline was the most potent methaemoglobin former (60.6 and 73.6%) and aniline the least potent (1.1 and 2.4%). As a whole, these results indicate that the sulphonyl group, which is essential for the pharmacological activity of dapsone, is also largely responsible for the haemotoxicity seen with this drug.

Animals↗

PubMed1996

Cystic fibrosis mutation detection by hybridization to light-generated DNA probe arrays.

We have combined photochemistry and photolithography with solid-phase DNA synthesis chemistry to form a new technology that makes high density oligonucleotide probe array synthesis possible. Hybridization to these two-dimensional arrays containing hundreds or thousands of oligonucleotide probes provides a powerful DNA sequence analysis tool. Two types of light-generated DNA probe arrays have been used to test for a variety of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. One array, made up of 428 probes, was designed to scan through the length of CFTR exon 11 and identify differences from the wild type reference sequence. The second type of array contained 1480 probes chosen to detect known deletions, insertions, or base substitution mutations. The validity of the probe arrays was established by hybridizing them with fluorescently labeled control oligonucleotide targets. Characterized mutant CFTR genomic DNA samples were then used to further test probe array hybridization specificity. Finally, ten unknown patient samples were genotyped using the CFTR probe array assay. The genotype assignments were identical to those obtained by PCR product restriction fragment analysis. Our results show that light-generated DNA probe arrays are highly effective in analyzing complex mutation and polymorphism patterns in a relatively large gene such as CFTR.

Base Sequence↗

PubMed1996

Structure-toxicity relationships for phenols to Tetrahymena pyriformis.

Quantitative structure-activity relationships are developed for the toxicity of 166 varied phenol derivatives to the ciliate Tetrahymena pyriformis. A variety of physico-chemical descriptors were calculated but no significant relationship could be obtained for all 166 compounds. When certain chemical groups were omitted from the correlation however, notably the carboxyl-, amino-, nitro, nitroso and acetamide- substituted phenols, an excellent correlation was obtained between toxicity and two parameters. These two parameters (log P and energy of the lowest unoccupied molecular orbital) are explained mechanistically in that they model transport and electrophilicity. The resultant QSAR gave accurate prediction of the toxicity of alkyl, halogenated, alkoxy and aldehyde substituted phenols.

Aldehydes↗

PubMed1996

The use of cluster significance analysis to identify asymmetric QSAR data sets in toxicology. An example with eye irritation data.

Cluster significance analysis is a tool that allows the identification of "embedded clusters' in QSAR datasets. It is successfully applied to an eye irritation data set to show that these data are indeed asymmetric. The method identifies five parameters that form an embedded cluster of eye irritants amongst non irritants, although full separation is not achieved. This method has considerable potential to identify potential non-linearity in toxicology data sets and for parameter reduction. It is shown also that this can be obtained relatively quickly with an analysis performed on 100,000 subsets containing the same information as an analysis on 1,000,000 subsets.

Cluster Analysis↗

PubMed1995

Quantitative structure-activity relationships as a tool to assess the comparative toxicity of organic chemicals.

Quantitative structure-activity relationships of toxicity are discussed as a means of assessing the value of the Microtox test which uses the light-emitting bacterium Vibrio fisheri (Photobacterium phosphoreum) as a replacement for toxicity testing in higher species. The Microtox test is found to be a good surrogate for testing in fish, for compounds acting by the narcosis mechanism. However, for reactive chemicals the Microtox test significantly underestimates the potential hazard. It should not therefore be used in isolation for such chemicals, but rather as part of a battery of tests.

Animals↗