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Biomedical subjects

John D Walker

Publications and source records attributed to John D Walker.

16 recordsLinked to original sources
PubMed2003

Use of QSARs in international decision-making frameworks to predict ecologic effects and environmental fate of chemical substances.

This article is a review of the use, by regulatory agencies and authorities, of quantitative structure-activity relationships (QSARs) to predict ecologic effects and environmental fate of chemicals. For many years, the U.S. Environmental Protection Agency has been the most prominent regulatory agency using QSARs to predict the ecologic effects and environmental fate of chemicals. However, as increasing numbers of standard QSAR methods are developed and validated to predict ecologic effects and environmental fate of chemicals, it is anticipated that more regulatory agencies and authorities will find them to be acceptable alternatives to chemical testing.

Decision Making, Organizational↗
PubMed2003

Use of QSARs in international decision-making frameworks to predict health effects of chemical substances.

This article is a review of the use of quantitative (and qualitative) structure-activity relationships (QSARs and SARs) by regulatory agencies and authorities to predict acute toxicity, mutagenicity, carcinogenicity, and other health effects. A number of SAR and QSAR applications, by regulatory agencies and authorities, are reviewed. These include the use of simple QSAR analyses, as well as the use of multivariate QSARs, and a number of different expert system approaches.

Animals↗
PubMed2003

An overview of the use of quantitative structure-activity relationships for ranking and prioritizing large chemical inventories for environmental risk assessments.

Ecological risk assessments for chemical stressors are used to establish linkages between likely exposure concentrations and adverse effects to ecological receptors. At times, it is useful to conduct screening risk assessments to assist in prioritizing or ranking chemicals on the basis of potential hazard and exposure assessment parameters. Ranking of large chemical inventories can provide evidence for focusing research and/or cleanup efforts on specific chemicals of concern. Because of financial and time constraints, data gaps exist, and the risk assessor is left with decisions on which models to use to estimate the parameter of concern. In this review, several methods are presented for using quantitative structure-activity relationships (QSARs) in conducting hazard screening or screening-level risk assessments. The ranking methods described include those related to current regulatory issues associated with chemical inventories from Canada, Europe, and the United States and an example of a screening-level risk assessment conducted on chemicals associated with a watershed in the midwest region of the United States.

Databases, Factual↗
PubMed2003

Overview of data and conceptual approaches for derivation of quantitative structure-activity relationships for ecotoxicological effects of organic chemicals.

The use of quantitative structure-activity relationships (QSARs) in assessing potential toxic effects of organic chemicals on aquatic organisms continues to evolve as computational efficiency and toxicological understanding advance. With the ever-increasing production of new chemicals, and the need to optimize resources to assess thousands of existing chemicals in commerce, regulatory agencies have turned to QSARs as essential tools to help prioritize tiered risk assessments when empirical data are not available to evaluate toxicological effects. Progress in designing scientifically credible QSARs is intimately associated with the development of empirically derived databases of well-defined and quantified toxicity endpoints, which are based on a strategic evaluation of diverse sets of chemical structures, modes of toxic action, and species. This review provides a brief overview of four databases created for the purpose of developing QSARs for estimating toxicity of chemicals to aquatic organisms. The evolution of QSARs based initially on general chemical classification schemes, to models founded on modes of toxic action that range from nonspecific partitioning into hydrophobic cellular membranes to receptor-mediated mechanisms is summarized. Finally, an overview of expert systems that integrate chemical-specific mode of action classification and associated QSAR selection for estimating potential toxicological effects of organic chemicals is presented.

Animals↗
PubMed2003

Quantitative structure-activity relationships for predicting potential ecological hazard of organic chemicals for use in regulatory risk assessments.

The use of quantitative structure-activity relationships (QSARs) for deriving the predicted no-effect concentration of discrete organic chemicals for the purposes of conducting a regulatory risk assessment in Europe and the United States is described. In the United States, under the Toxic Substances Control Act (TSCA), the TSCA Interagency Testing Committee and the U.S. Environmental Protection Agency (U.S. EPA) use SARs to estimate the hazards of existing and new chemicals. Within the Existing Substances Regulation in Europe, QSARs may be used for data evaluation, test strategy indications, and the identification and filling of data gaps. To illustrate where and when QSARs may be useful and when their use is more problematic, an example, methyl tertiary-butyl ether (MTBE), is given and the predicted and experimental data are compared. Improvements needed for new QSARs and tools for developing and using QSARs are discussed.

Animals↗
PubMed2003

Quantitative structure-activity relationships for human health effects: commonalities with other endpoints.

This article describes the use of quantitative structure-activity relationships (QSARs) to predict toxicity endpoints for ecologically relevant and human-surrogate species. The interrelationships between the endpoints, and the possibilities of exploring the commonalities of chemical action from one species to another as well as from one endpoint to another, are evaluated. A number of toxic endpoints are discussed including mutagenicity and carcinogenicity; developmental toxicity (teratogenicity); acute toxicity; skin sensitization; skin, eye, and sensory irritation; and the modeling of membrane permeability. A number of electrophilic molecular substructures have been identified that are common to a number of toxicities. It is postulated that if such a substructure is observed in a molecule, it may exhibit a range of toxicities. Further, there appear to be relationships between the toxicity to ecologically relevant and human-surrogate species, which may allow for appreciation and possible extrapolation in both directions. Overall, however, QSARs are limited by the paucity of available toxicological data and information.

Animals↗
PubMed2003

Quantitative structure-activity relationship models for prediction of estrogen receptor binding affinity of structurally diverse chemicals.

The demonstrated ability of a variety of structurally diverse chemicals to bind to the estrogen receptor has raised the concern that chemicals in the environment may be causing adverse effects through interference with nuclear receptor pathways. Many structure-activity relationship models have been developed to predict chemical binding to the estrogen receptor as an indication of potential estrogenicity. Models based on either two-dimensional or three-dimensional molecular descriptions that have been used to predict potential for binding to the estrogen receptor are the subject of the current review. The utility of such approaches to predict binding potential of diverse chemical structures in large chemical inventories, with potential application in a tiered risk assessment scheme, is discussed.

Animals↗
PubMed2003

Quantitative structure-activity relationships for predicting skin and respiratory sensitization.

Quantitative structure-activity relationships (QSARs) for predicting skin and respiratory sensitization are reviewed. Overall, progress has been hampered by the sparseness of good quality experimental data, a fact that makes it difficult, at this time, to recommend one or two QSARs for predicting skin and respiratory sensitization. Creation of appropriate data sets for uninvestigated classes of chemicals by experimentation should facilitate the development of more robust QSARs for predicting skin and respiratory sensitization. Such QSARs will be valuable in the evaluation of identifiable toxic hazards where dose responses are relevant, as is the case for skin and respiratory sensitization.

Administration, Cutaneous↗
PubMed2003

Quantitative structure-activity relationships for predicting skin and eye irritation.

Recent quantitative structure-activity relationships (QSARs) for the prediction of skin and eye irritation were reviewed. The QSARs in these areas are hindered by the lack of quality in vivo data and by a lack of understanding of the mechanisms of action. Creation of appropriate data sets for experimentation would facilitate the development of robust QSARs for predicting skin and eye irritation.

Animals↗
PubMed2003

Quantitative structure-activity relationships for predicting percutaneous absorption rates.

Quantitative structure-activity relationships (QSARs) for predicting percutaneous absorption rates were reviewed. Overall progress has been hampered by the sparseness of good quality experimental data. A number of researchers have used the same data set to develop QSARs for predicting percutaneous absorption rates, a fact that makes it difficult, at this time, to recommend one or two QSARs for predicting percutaneous absorption rates. Identification of chemicals within domains of large chemical universes that should be tested to improve QSARs and the subsequent development of experimental percutaneous absorption rates for those chemicals will facilitate the development of more robust QSARs for predicting percutaneous absorption rates.

Absorption↗
PubMed2003

Quantitative structure-activity relationships for predicting mutagenicity and carcinogenicity.

Quantitative structure-activity relationships (QSARs) for predicting mutagenicity and carcinogenicity were reviewed. The QSARs for predicting mutagenicity and carcinogenicity have been mostly limited to specific classes of chemicals (e.g., aromatic amines and heteroaromatic nitro chemicals). The motivation to develop QSARs for predicting mutagenicity and carcinogenicity to screen inventories of chemicals has produced four major commercially available computerized systems that are able to predict these endpoints: Deductive estimation of risk from existing knowledge (DEREK) toxicity prediction by komputer assisted technology (TOPKAT), computer automated structure evaluation (CASE), and multiple computer automated structure evaluation (Multicase). A brief overview of these and some other expert systems for predicting mutagenicity and carcinogenicity is provided. The other expert systems for predicting mutagenicity and carcinogenicity include automatic data analysis using pattern recognition techniques (ADAPT), QSAR Expert System (QSAR-ES), OncoLogic computer optimized molecular parametric analysis of chemical toxicity system (COMPACT), and common reactivity pattern (COREPA).

Animals↗
PubMed2003

Quantitative structure-activity relationships for predicting metabolism and modeling cytochrome p450 enzyme activities.

Quantitative structure-activity relationships (QSARs) for predicting phase I and phase II metabolism and for modeling cytochrome P450 enzyme activities are described and reviewed. Papers dealing with three-dimensional techniques such as comparative molecular field analysis and pharmacophore modeling are included. This review focuses on those cytochrome P450 isoenzymes that are expressed in human hepatocytes and that are commonly responsible for the majority of drug and xenobiotic metabolism. Substrate-type selectivity information for those isoenzymes is included. The importance of lipophilicity correlations in xenobiotic metabolism predictions are outlined. A brief inclusion of available material on the prediction phase II conjugation biotransformations such as glucuronidation, sulfation, glycination, and glutathionation are included. Historical information is briefly discussed, but more detailed reviews are provided for papers published since 1997.

Animals↗
PubMed2003

Guidelines for developing and using quantitative structure-activity relationships.

Numerous quantitative structure-activity relationships (QSARs) have been developed to predict properties, fate, and effects of mostly discrete organic chemicals. As the demand for different types of regulatory testing increases and the cost of experimental testing escalates, there is a need to evaluate the use of QSARs and provide some guidance to avoid their misuse, especially as QSARs are being considered for regulatory purposes. This paper provides some guidelines that will promote the proper development and use of QSARs. While this paper uses examples of QSARs to predict toxicity, the proposed guidelines are applicable to QSARs used to predict physical or chemical properties, environmental fate, ecological effects and health effects.

Animals↗
PubMed2003

Quantitative cationic-activity relationships for predicting toxicity of metals.

Developing and validating quantitative cationic-activity relationships or (Q)CARs to predict the toxicity metals is challenging because of issues associated with metal speciation, complexation and interactions within biological systems and the media used to study these interactions. However, a number of simplifying assumptions can be used to develop and validate (Q)CARs to predict the toxicity of metals: The ionic form is the most active form of a metal; the bioactivity of a dissolved metal is correlated with its free ion concentration or activity; most metals exist in biological systems as cations, and differences in metal toxicity result from differences in metal ion binding to biological molecules (ligand-binding). In summary, it appears that certain useful correlations can be made between several physical and chemical properties of ions (mostly cations) and toxicity of metals. This review provides a historical perspective of studies that have reported correlations between physical and chemical properties of cations and toxicity to mammalian and nonmammalian species using in vitro and in vivo assays. To prepare this review, approximately 100 contributions dating from 1839 to 2003 were evaluated and the relationships between about 20 physical and chemical properties of cations and their potential to produce toxic effects were examined.

Animals↗
PubMed2002

Prediction of estrogen receptor binding for 58,000 chemicals using an integrated system of a tree-based model with structural alerts.

A number of environmental chemicals, by mimicking natural hormones, can disrupt endocrine function in experimental animals, wildlife, and humans. These chemicals, called "endocrine-disrupting chemicals" (EDCs), are such a scientific and public concern that screening and testing 58,000 chemicals for EDC activities is now statutorily mandated. Computational chemistry tools are important to biologists because they identify chemicals most important for in vitro and in vivo studies. Here we used a computational approach with integration of two rejection filters, a tree-based model, and three structural alerts to predict and prioritize estrogen receptor (ER) ligands. The models were developed using data for 232 structurally diverse chemicals (training set) with a 10(6) range of relative binding affinities (RBAs); we then validated the models by predicting ER RBAs for 463 chemicals that had ER activity data (testing set). The integrated model gave a lower false negative rate than any single component for both training and testing sets. When the integrated model was applied to approximately 58,000 potential EDCs, 80% (approximately 46,000 chemicals) were predicted to have negligible potential (log RBA < -4.5, with log RBA = 2.0 for estradiol) to bind ER. The ability to process large numbers of chemicals to predict inactivity for ER binding and to categorically prioritize the remainder provides one biologic measure to prioritize chemicals for entry into more expensive assays (most chemicals have no biologic data of any kind). The general approach for predicting ER binding reported here may be applied to other receptors and/or reversible binding mechanisms involved in endocrine disruption.

Animals↗