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T W Schultz

Publications and source records attributed to T W Schultz.

At least 73 records · Page 4Linked to original sources
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

A novel QSAR approach for estimating toxicity of phenols.

Toxicity values (log IGC50(-1)) for 60 phenols tested in the 2-d static population growth inhibition assay with the ciliate Tetrahymena pyriformis were tabulated. Each chemical was selected so the series formed uniform coverage of the hydrophobicity/ionization surface. A high quality hydrophobicity-dependent (log Kow) structure-toxicity relationship (log IGC50(-1) = 0.741 (log Kow)-1.433; n = 17; r2 = 0.970; s = 0.134; F = 486.55; Pr > F = 0.0001) was developed for phenols with pKa values > 9.8. Similarly, separate hydrophobicity-dependent relationships were developed for phenols with pKa values of 4.0, 5.1, 6.3, 7.5, and 8.7. Comparisons of intercepts and slopes, respectively, revealed phenols with pKa values of 6.3 to be the most toxic and the least influenced by hydrophobicity. These relationships were reversed for the more acidic and basic phenols. Plots of toxicity versus pKa for nitro-substituted phenols and phenols with log Kow values of either 1.75 or 2.50 further demonstrated bilinearity between toxicity and ionization. In an effort to more accurately model the relationship between toxicity and ionization, the absolute value function [6.3-pKa] was used to model ionization affects for derivatives with pKa values between 0 and 9.8. For derivatives with pKa value > 9.8, a value of 3.50 was used to quantitate ionization effects. The use of log Kow in conjunction with this modified pKa (delta pKa) resulted in the structure-toxicity relationship (log IGC(50)-1 = 0.567 (log Kow)-0.226 (delta pKa)-0.079; n = 54; r2 = 0.926; s = 0.215; F = 321.06; Pr > F = 0.0001). Derivatives with a nitro group in the 4-position typically did not model well with the above equation.

Animals↗
PubMed1995

Quantitative structure-toxicity relationships and volume fraction analyses for selected esters.

The acute toxicity of aliphatic and aromatic mono and diesters in two eucaryotic organisms was compared. The test systems were the static 2-d Tetrahymena pyriformis 50% population growth impairment (IGC50(-1)) assay, and the flow-through 4-d Pimephales promelas 50% mortality (LC50(-1)) assay. In ciliates, esters act via the nonpolar narcosis mechanism of toxic action. This was indicated by: the high quality 1-octanol/water partition coefficient (log Kow) dependent quantitative structure-activity relationship (QSAR), log IGC50(-1) = 0.79 (log Kow) - 1.93, n = 15, r2 = 0.945, s = 0.22, f = 222.37 Pr > f = 0.001); volume fraction (Vf) (0.8e-02); and "a" coefficient (0.3) which are not different from other nonpolar narcotics. In vivo hydrolysis in Tetrahymena appears to be insignificant. However, in fish, presumably because of more active esterases, in vivo hydrolysis is significant and leads to greater toxicity of esters than observed for nonpolar narcotics. Moreover, it leads to a unique high quality QSAR, log LC50(-1) = 0.64 (log Kow) - 0.64, n = 14, r2 = 0.945, s = 0.22, f = 207.08, Pr > f = 0.0001). Due to in vivo hydrolysis, a nonreducing concentration gradient is formed between water and fish. Therefore, the fish take up more toxicant as compared to a situation that leads to thermodynamic equilibrium. Additional information about the mechanism of ester toxicity in fish was gained by applying corrections for hydrolysis in volume fraction analyses. The corrected Vf (0.6e-02) is very close to the one found for nonpolar narcotics (0.7e-02).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

The effects of benomyl and its breakdown products carbendazim and butyl isocyanate on the structure and function of tracheal ciliated cells.

The effects of the fungicide benomyl and its breakdown products, carbendazim and butyl isocyanate, were examined on canine tracheal epithelial tissue in primary culture. Changes in ciliary frequencies were monitored with an optical spectrum analysis system. Serial dilutions of the test compounds were prepared in 100% corn oil and applied to the cell cultures for intervals up to 6 hours and frequencies measured at intervals of 15 minutes to 1 hour. Benomyl and butyl isocyanate caused concentration-dependent decreases in ciliary beat frequency. Benomyl at 300 micrograms/ml (3 mM) caused ciliostasis within 75 minutes of exposure. Butyl isocyanate at a molar concentration three times lower than benomyl (1 mM) caused a similar response, although within 30 minutes. The IBC50 for benomyl was 0.75 mM, while for butyl isocyanate it was 0.52 mM. Carbendazim caused a moderate decrease in frequency over a 6 hour exposure period. Benomyl caused moderate to severe swelling of the mitochondria of ciliated epithelial cells with other cell organelles appearing normal. Butyl isocyanate did not cause any noticeable effect on cell ultrastructure and the apparently low rate of penetration of carbendazim into cells made it impossible to obtain an effect which justified ultrastructural analysis. It appears, at least for benomyl and butyl isocyanate, that while the physiological effect of these two compounds (inhibition of ciliary beat) is the same, the sites of action in the cell may be different.

Animals↗
PubMed1995

Quantitative structure-activity study of the toxicity of benzonitriles to the ciliate Tetrahymena pyriformis.

The toxicities of 34 benzonitriles to Tetrahymena pyriformis have been measured. Structure-activity relationships indicate that for these compounds different mechanisms of toxic action are taking place dependent on the nature of the substituent. Benzonitrile itself, some halogenated and the toluene derivatives model as non-polar narcotics; more polar substituents model well as polar narcotics; whilst the nitro and aldehyde substituted benzonitriles, and compounds that may be metabolised to benzoquinone are shown to exhibit considerable excess toxicity and, thus, the probability is that they are acting by a specific mechanism of action. After the removal of two outliers, QSAR analysis reveals a significant three parameter equation, and confirms the importance of hydrophobicity and descriptors of reactivity for the comprehension and the prediction of the toxicity of the benzonitriles.

Animals↗
PubMed1995

Structure-toxicity relationships for alkanones and alkenones.

The relative toxicity (log IGC-1(50)) of 54 selected alkanones, both aliphatic and aromatic, as well as, alkenones and alkynones was evaluated in the static Tetrahymena pyriformis population growth assay. Excess toxicity, an indicator of bioreactivity, was associated only with the alpha-beta unsaturated alkenones and alkynones. Moreover, the alkynones were found to be more toxic than corresponding alkenones. A high quality 1-octanol/water partition coefficient (log Kow) dependent structure-toxicity relationship, log IGC-1(50) = 0.86 (log Kow) - 2.27; r2 = 0.955, was developed for alkanones. This QSAR represented the nonpolar narcosis mechanism of toxic action. Toxicity of alkenones was predicted by the highest-occupied-molecular-orbital energy (HOMO), log IGC-1(50) = -3.474 (HOMO) -35.357; r2 = 0.897, and the difference between HOMO and the lowest-unoccupied-molecular-orbital energy (LUMO), log IGC-1(50) = -3.559 (HOMO-LUMO gap) - 36.106; r2 = 0.903. The alpha-beta unsaturated ketones are considered soft electrophiles. Moreover, the toxicity of the aliphatic alkanones and alkenones was predicted by log Kow and LUMO, log IGC-1(50) = 0.69 (log Kow) - 2.55 (LUMO) + 0.05; r2 = 0.852.

Animals↗
PubMed1995

Quantitative structure-activity relationships for estimating the no-observable-effects concentration in fathead minnows (Pimephales promelas).

Quantitative structure-activity relationships, based on hydrophobicity measured as the 1-octanol/water partition coefficient (Kow), have been developed for predicting the acute no-observable-effects concentration (NOEC) for fathead minnows (Pimephales promelas), using a mechanism/mode of action approach. Models were developed for nonpolar narcotics, amine narcotics, polar narcotics, ester narcotics, and respiratory uncouplers. A set of bioreactive chemicals were evaluated, but models based on hydrophobicity alone are inadequate for these chemicals. Additionally, a strong correlation was observed between the acute NOEC and acute lethality measured as the 50% lethal concentration (LC50) for 407 chemicals, regardless of the mechanism/mode of action. This relationship is modeled by the equation log NOEC-1 = 1.007 (log LC50) + 0.246; n = 407, r2 = 0.989, s = 0.142, f = 38095.6, and Pr > f = 0.0001. Examination of the relationship between the acute NOEC and the subchronic NOEC for four mechanisms/modes of action implies that the acute to subchronic ratio is not independent of mechanism of action. The resulting ratios were 6.42 (+/- 3.01) for nonpolar narcosis, 80.00 (+/- 17.78) for polar narcosis, 10.05 (+/- 4.59) for respiratory uncoupling, and 3.94 (+/- 1.72) for bioreactivity.

Animals↗
PubMed1994

Toxicological assessment of biotransformation products of pentachlorophenol: Tetrahymena population growth impairment.

Pentachlorophenol (PCP) is a widespread contaminate of soils and ground water throughout North America. Earlier studies have indicated that microbial biodegradation leads to the formation of intermediate metabolites which are more toxic than the parent compound. Microbial degradation is by three general pathways: dechlorination, methylation, and oxidation. The relative toxicity of PCP and 25 of its identified intermediates of microbial transformation was evaluated in the static Tetrahymena pyriformis population growth assay. Dechlorination of chlorophenols resulted in a decrease in toxicity because of a decrease in both hydrophobicity and reactivity. Moreover, dechlorination of chloroanisoles resulted in a decrease in toxicity due to a decrease in hydrophobicity. Since there was a decrease in reactivity, methylation of chlorophenols resulted in a decrease in toxicity. Oxidation of chlorophenols resulted in enhanced toxicity owing to increased reactivity and concomitant decreased hydrophobicity.

Animals↗
PubMed1994

Mechanism-based comparisons of acute toxicities elicited by industrial organic chemicals in procaryotic and eucaryotic systems.

Comparisons of toxicities elicited by nonpolar and polar narcotics, weak acid uncouplers of oxidative phosphorylation, and bioreactive chemicals between the eucaryotic systems Pimephales promelas and Tetrahymena pyriformis and the procaryotic systems Escherichia coli and Photobacterium phosphoreum were performed. Each chemical had been a priori assigned a mechanism/mode of action based on the results from previous studies with eucaryotic systems. Hydrophobicity-dependent QSARs for nonpolar narcosis for both the E. coli and the P. phosphoreum endpoints was developed. However, due to the lack of a significant relationship between P. phosphoreum toxicity and log Kow, such a QSAR for polar narcosis was developed only for the E. coli endpoint. Except for 4-nitroaniline (the only chemical in the examined group that required activation to become the Michael receptor), all chemicals containing reactive substructures revealed excess toxicity over polar narcosis QSAR for E. coli endpoints. Moreover, chloroacidic acid and ethyl chloroacetate in this system also appear to be bioreactive. The only mechanism that seemed to not exist in the procaryotic system was uncoupling of oxidative phosphorylation. Chemicals from this group, except 2,4-dinitroaniline, did not exhibit excess toxicity over polar narcosis QSAR. This was thought to be explained by the lack of mitochondria in procaryotes, the target site of uncoupling agents in eucaryotes. In addition, evaluation of toxicities of halogen-substituted short-chain carboxylic alcohols indicated that their mechanisms vary, depending upon the type of substitution and the system.

Alcohols↗
PubMed1993

Quantitative relationships of structure-activity and volume fraction for selected nonpolar and polar narcotic chemicals.

The relative toxicity of selected industrial organic chemicals was secured from the literature for the static 48-h Tetrahymena pyriformis 50% population growth impairment and the flow-through 96-h Pimephales promelas 50% mortality endpoints. Chemicals were selected to represent the nonpolar narcosis (aliphatic alcohols and aliphatic ketones) and polar narcosis (anilines and phenols) mechanisms of toxic action. molar volume (MV) and 1-octanol/water partition coefficient (log Kow) data were generated for each chemical. High-quality, log Kow dependent quantitative structure-activity relationships were observed for each chemical class and mechanism of action for both endpoints. The volume fraction (Vf) for each chemical in the target phase was determined from the toxicant concentration in the water (toxicity data), the MV, and the target/water partition coefficient (Ktw) with Ktw considered equal to Kow (1-a). Analyses of target sites, by way of "a" revealed that "a" was constant for a mechanism of action regardless of chemical class, but distinct for a given test system. Mean Vt was constant for each mechanism of action regardless of chemical class or test system. These results suggest, at least for reversible physical mechanisms, that volume fraction analyses are significant in determining the mechanism of toxic action of a chemical.

1-Octanol↗
PubMed1993

Thrombopoietin from human embryonic kidney cells stimulates an increase in megakaryocyte size of sublethally irradiated mice.

Previous work showed that treatment of irradiated mice with a thrombocytopoiesis-stimulating factor (TSF or thrombopoietin) decreased the degree and duration of thrombocytopenia in the period after irradiation. In an attempt to elucidate the radio-protective effects of TSF, femoral megakaryocyte sizes and numbers were measured in mice treated with 3.0 Gy of 137Cs gamma rays and TSF. For controls, other irradiated mice were given human serum albumin (HSA), the carrier protein for TSF, rabbit anti-mouse platelet serum (RAMPS), or normal rabbit serum (NRS); megakaryocyte sizes and numbers were studied on Days 7-14. The results showed that irradiated, TSF-treated mice had significantly larger megakaryocytes on all days assessed compared to HSA-treated control mice. Likewise, RAMPS-treated mice had significantly larger megakaryocytes 14 days after irradiation compared to NRS-treated mice. Megakaryocyte numbers were significantly depressed in TSF-treated mice on Days 7-10 and 14 and on Day 10 in RAMPS-treated mice, compared to their respective controls. Therefore, irradiated mice treated with TSF yielded results similar to RAMPS-treated mice. Megakaryocyte sizes and numbers were also determined for mice treated with 40,000 U/mouse of interleukin-6 (IL-6), 227 U/mouse of granulocyte-macrophage colony-stimulating factor (GM-CSF), or a combination of both cytokines; bovine serum albumin (BSA) was used as a control for these cytokine treatments. Unlike TSF treatment, GM-CSF significantly increased megakaryocyte numbers on both Days 10 and 14; the combination of both growth factors also increased megakaryocyte numbers on Day 14 compared to BSA-treated control mice. However, megakaryocyte size was decreased in GM-CSF-treated mice and in mice treated with both growth factors on Day 10. High levels of IL-6 failed to affect megakaryocyte size or number significantly on any day evaluated. The data of the present report, showing that TSF significantly increases megakaryocyte sizes and platelet counts of sublethally irradiated mice, indicate that thrombopoietin will be useful in treating patients undergoing bone marrow transplantation and/or patients with platelet production problems.

Animals↗
PubMed1992

Adapting to the changing hospital-physician relationship.

The future health care environment will make it difficult--if not impossible--for hospitals and physicians to function independently. Trends in health care are going to force hospitals and physicians to reexamine and restructure their traditional relationships. This restructuring will have to be accomplished in the midst of competitive pressures from a variety of sources and with interference from various governmental and regulatory agencies. The success--if not the survival--of hospitals and their medical staffs depends upon a mutually beneficial relationship between hospitals and physicians.

Hospital Administration↗
PubMed1992

QSARs for monosubstituted phenols and the polar narcosis mechanism of toxicity.

Eighty 2-, 3-, and 4-position monosubstituted phenols representing various substituents were evaluated for relative toxicity, log IGC50(-1), with a short-term static protocol in the Tetrahymena population growth inhibition bioassay. Quantitative structure-activity relationships (QSAR) were examined using the 1-octanol/water partition coefficient (log K(ow)) and ionization constant (pKa) as independent variables. Four derivatives did not elicit the measured response at saturation. Five derivatives revealed altered high-performance liquid chromatography spectra with time. None of these derivatives were included in QSAR development. In addition, the carboxyl and nitroso derivatives were detected as statistical outliers. The model log IGC50(-1) = 0.6655 (log K(ow)) - 0.1464 (pKa) + 0.2206, n = 67, r2 = 0.909, s = 0.212, was found to be an excellent predictor of activity of phenols which elicit their toxic response by the polar narcosis mode of action. For the most part the tested derivatives showed little abiotic loss over the duration of the bioassay.

Animals↗