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G D Veith

Publications and source records attributed to G D Veith.

At least 19 recordsLinked to original sources
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↗
PubMed1996

A QSAR evaluation of Ah receptor binding of halogenated aromatic xenobiotics.

Because of their widespread occurrence and substantial biological activity, halogenated aromatic hydrocarbons such as polychlorinated biphenyls (PCBs), polychlorinated dibenzofurans (PCDFs), and polychlorinated dibenzo-p-dioxins (PCDDs) comprise one of the more important classes of contaminants in the environment. Some chemicals in this class cause adverse biological effects after binding to an intracellular cytosolic protein called the aryl hydrocarbon receptor (AhR). Toxic responses such as thymic atrophy, weight loss, immunotoxicity, and acute lethality, as well as induction of cytochrome P4501A1, have been correlated with the relative affinity of PCBs, PCDFs, and PCDDs for the AhR. Therefore, an important step in predicting the effects of these chemicals is the estimation of their binding to the receptor. To date, however, the use of quantitative structure activity relationship (QSAR) models to estimate binding affinity across multiple chemical classes has shown only modest success possibly due, in part, to a focus on minimum energy chemical structures as the active molecules. In this study, we evaluated the use of structural conformations other than those of minimum energy for the purpose of developing a model for AhR binding affinity that encompasses more of the halogenated aromatic chemicals known to interact with the receptor. Resultant QSAR models were robust, showing good utility across multiple classes of halogenated aromatic compounds.

Benzofurans↗
PubMed1994

The electronic factor in QSAR: MO-parameters, competing interactions, reactivity and toxicity.

Reactive chemicals pose unique problems in the development of SAR and QSAR in environmental chemistry and toxicology. Models of the stereoelectronic interactions of reactive toxicants with biological systems require formulation of parameters that quantify the electronic structure of the chemicals. A review of early approaches to modeling reactivity is presented in this work, with emphasis on the generalized polyelectronic perturbation theory. Applications of GPPT are demonstrated with QSARs for predicting toxicity of soft electrophiles and proelectrophiles using superdelocalizability and the charges on frontier orbitals. Prediction of toxicity for hard electrophiles such as organophosphates require atomic charges and bond orders in the QSAR. Special considerations for the orthogonality of factors and for the classification of reactive chemicals are reviewed.

Analysis of Variance↗
PubMed1993

Relationships between descriptors for hydrophobicity and soft electrophilicity in predicting toxicity.

The toxicity of chemicals is orthogonal with individual molecular descriptors used to quantify hydrophobicity and soft electrophilicity when considering large data sets. Estimating the toxicity of reactive chemicals requires descriptors of both passive transport and the stereoelectronic interaction, which are largely independent processes. QSARs using either log P or an electronic parameter alone are only significant for sets of chemicals that represent special, albeit some important, cases in QSAR. Chemicals were clustered according to their reactivity as soft electrophiles by defining isoelectrophilic windows along the toxicity response surface. Within these narrow windows of reactivity, the variation of toxicity was explained by the variation of log P. We observed that the dependence of toxicity on log P in different isoelectrophilic windows decreased as reactivity increased. The data are consistent with toxicity models where competing nucleophilic interaction sites are distributed along the transport route of the chemicals.

Animals↗
PubMed1990

Rules for distinguishing toxicants that cause type I and type II narcosis syndromes.

Narcosis is a nonspecific reversible state of arrested activity of protoplasmic structures caused by a wide variety of organic chemicals. The vast majority of industrial organic chemicals can be characterized by a baseline structure-toxicity relationship as developed for diverse aquatic organisms, using only the n-octanol/water partition coefficient as a descriptor. There are, however, many apparent narcotic chemicals that are more toxic than baseline narcosis predicts. Some of these chemicals have been distinguished as polar narcotics. Joint toxic theory and isobole diagrams were used to show that chemicals strictly additive with phenol were generally more toxic than predicted by narcosis I models and characterized by a different mode of action called narcosis II syndrome. This type of toxicity is exemplified by certain amides, amines, phenols, and nitrogen heterocycles. Evidence is provided that suggests that narcosis II syndrome may result from the presence of a strong hydrogen bonding group on the molecule, and narcosis I syndrome results from hydrophobic bonding of the chemical to enzymes and/or membranes. This shift in toxic action is apparently indistinguishable for narcotic chemicals with log P greater than about 2.7. General rules for selecting the appropriate models are proposed.

Animals↗
PubMed1989

The toxicity of acetylenic alcohols to the fathead minnow, Pimephales promelas: narcosis and proelectrophile activation.

1. The 96-h LC50 values for 16 acetylenic alcohols in the fathead minnow (Pimephales promelas) were determined using continuous-flow diluters. The measured LC50 values for seven tertiary propargylic alcohols agreed closely with the QSAR predictions based upon data for other organic non-electrolytes acting by a narcosis mechanism. 2. Four primary and four secondary propargylic alcohols were 7 to 4600 times more toxic than the respective narcotic toxicity estimated by QSAR. Metabolic activation to electrophilic alpha,beta-unsaturated propargylic aldehydes or ketones is proposed to account for the increased toxicity. 3. 3-Butyn-1-ol and 4-pentyn-2-ol, primary and secondary homopropargylic alcohols, were 320 and 160, respectively, times more toxic than predicted. In this case an activation step involving biotransformation to an allenic electrophile intermediate was proposed.

Animals↗
PubMed1981

Polychlorinated biphenyls and other organic chemical residues in fish from major United States watersheds near the Great Lakes, 1978.

Twenty-six composite samples of fish were collected during 1978 from United States watersheds near the Great Lakes and analyzed for polychlorinated biphenyls (PCBs) and related organic chemicals. PCB mixtures resembling Aroclor 1254 were found in all samples, and mixtures resembling Aroclor 1242 (or 1016) were found in 77 percent of the samples. Total PCB concentrations in the whole-fish composite samples ranged from 0.13 to 14.6 ppm; 65 percent of the samples contained more than 2 ppm PCBs. DDT and its metabolites were found in all samples. sigma DDT concentration was 1.66 ppm, and 81 percent of the samples contained less than 1.0 ppm sigma DDT. Chlordane ranged from less than 0.001 to 2.57 ppm in 38 percent of the samples. Hexachlorobenzene was found in 65 percent of the samples, ranging from less than 0.005 to 0.447 ppm. Other chemicals identified by gas chromatography/mass spectrometry included petroleum hydrocarbons and chlorobenzenes, chlorostyrenes, chlorophenols, and chlorinated aliphatic compounds. Fish from the Ashtabula River (Ohio), Rock River (Ohio), and Wabash River (Indiana) contained extremely complex residues of chlorinated and other organic chemicals.

Animals↗
PubMed1980

Identification of hazardous organic chemicals in fish from the Ashtabula River, Ohio, and Wabash River, Indiana.

Composite fish samples from the Wabash River, IN, and the Ashtabula River, OH, were analyzed by conventional pesticide procedures for PCBs, DDTs, chlordane components, and hexachlorobenzene. Additional aliquots of each sample were processed by gel permeation chromatography and were analyzed with gas chromatography--mass spectrometry by using both electron impact and negative chemical ionization modes. These analyses resulted in the identification of a series of chlorinated alkanes, chlorinated alkenes, chlorinated alkylamines containing 2--5 carbons, and polychlorinated styrenes in the Ashtabula River sample, and a series of chlorinated norbornenes, pentachlorobenzyl alcohol, and pentachlorophenol in the Wabash River sample.

Animals↗
PubMed1979

Polychlorinated biphenyls and other organic chemical residues in fish from major watersheds of the United States, 1976.

Composite samples of fish were collected from major United States watersheds in 1976 and analyzed for PCBs and related organic chemicals. PCBs were found in 93 percent of the fish samples; 53 percent of the samples contained more than 5 ppm PCBs, whole fish basis, which is the current tolerance level set by the Food and Drug Administration, U.S. Department of Health, Education and Welfare. Only 14 percent of the samples contained less than the proposed action level of 2 ppm PCBs. PCB concentrations ranged from less than 0.3 ppm to 140 ppm in the composite samples. sigma DDT concentrations ranged from less than 0.05 ppm to 4.53 ppm. Hexachlorobenzene was identified in 19 percent of the samples, and chlordane components were identified in 36 percent of the samples. Chemicals identified by gas chromatography/mass spectrometry but not quantified include chlorinated benzenes, styrenes, anisoles, phenols, anilines, propanes, and butadienes, as well as mixtures of petroleum hydrocarbons.

Animals↗
PubMed1977

Residues of PCB's and DDT in the western Lake Superior ecosystem.

Fish from western Lake Superior (1972-73) contained DDT and PCB residues at concentrations greater than o.1 ppm. The most predominant PCB's were those containing 3 to 6 chlorine atoms per molecule, and GLC data indicated that the mixtures were most like the commercial product Aroclor 1254(2). Other chlorinated contiminants identified by GC/MS analyses and occurring at concentrations less than 0.1 ppm were hexachlorobenzene (C6Cl6), chlordane, nonaclor, and dieldrin. Lindane, which has been previously reported in Lake Superior, was below the detection limit of approximately 0.01 ppm. The relationship between the size of lake trout and the concentration of total DDT in the fish was compared to measurements reported in previous studies. The comparison suggests that DDT residues have declined since 1968. The concentration of PCBs was estimated to be 0.8 ng/L in Lake Superior water and 0.1 ppm in large zooplankton. The apparent bioconcentration factor for PCBs in Lake Superior fish ranged from 10(5) to 10(6). The concentration of total DDT and PCBs in the larger Lake Superior fish exceeded the 5 ppm tolerance level established by the U.S. Food and Drug Administration for these chemicals in fish tbe used for human consumption.

Animals↗
PubMed1976

Isolation and identification of polychlorinated styrenes in Great Lakes fish.

Octachlorostyrene was prepared by two independent synthetic routes, and GC retention time data as well as a mass spectrum of the standard were obtained. A comparison of these data with those observed for a component in fish from Lake Huron, Lake Ontario, and the lower Detroit River indicates that octachlorostyrene is present in fish residues from these sources. In addition, mass spectral data indicated the presence of several hepta and hexachlorostyrene isomers in these fish. Further studies should be concerned with quantification of OCS and evaluation of possible sources of these compounds, such as impurities in products produced by exhaustive chlorination or as by-products in the electrolytic production of chlorine.

Animals↗
PubMed1975

Preparative method for gas chromatographic/mass spectral analysis of trace quantities of pesticides in fish tissue.

A large capacity, low efficiency pesticide cleanup method is combined with a small capacity, high efficiency method for gas chromatographic/mass spectral analysis of fish tissue. Trace chemicals are extracted from the tissue, removed from the bulk of the co-extracted lipids through selective desorption from Micro Cel-E, and isolated from the remaining lipids by gel permeation chromatography. The procedure is capable of cleaning up the extract from several hundred grams of fish, minimizes sample contamination, and permits identification of xenobiotic chemicals present at ng/g concentrations.

Chromatography, Gas↗