How not to develop a quantitative structure-activity or structure-property relationship (QSAR/QSPR).

Although thousands of quantitative structure-activity and structure-property relationships (QSARs/QSPRs) have been published, as well as numerous papers on the correct procedures for QSAR/QSPR analysis, many analyses are still carried out incorrectly, or in a less than satisfactory manner. We have identified 21 types of error that continue to be perpetrated in the QSAR/QSPR literature, and each of these is discussed, with examples (including some of our own). Where appropriate, we make recommendations for avoiding errors and for improving and enhancing QSAR/QSPR analyses.

Evolution of the international workshops on quantitative structure-activity relationships (QSARs) in environmental toxicology.

This presentation will review the evolution of the workshops from a scientific and personal perspective. From their modest beginning in 1983, the workshops have developed into larger international meetings, regularly held every two years. Their initial focus on the aquatic sphere soon expanded to include properties and effects on atmospheric and terrestrial species, including man. Concurrent with this broadening of their scientific scope, the workshops have become an important forum for the early dissemination of all aspects of qualitative and quantitative structure-activity research in ecotoxicology and human health effects. Over the last few decades, the field of quantitative structure/activity relationships (QSARs) has quickly emerged as a major scientific method in understanding the properties and effects of chemicals on the environment and human health. From substances that only affect cell membranes to those that bind strongly to a specific enzyme, QSARs provides insight into the biological effects and chemical and physical properties of substances. QSARs are useful for delineating the quantitative changes in biological effects resulting from minor but systematic variations of the structure of a compound with a specific mode of action. In addition, more holistic approaches are being devised that result in our ability to predict the effects of structurally unrelated compounds with (potentially) different modes of action. Research in QSAR environmental toxicology has led to many improvements in the manufacturing, use, and disposal of chemicals. Furthermore, it has led to national policies and international agreements, from use restrictions or outright bans of compounds, such as polychlorinated biphenyls (PCBs), mirex, and highly chlorinated pesticides (e.g. DDT, dieldrin) for the protection of avian predators, to alternatives for ozone-depleting compounds, to better waste treatment systems, to more powerful and specific acting drugs. Most of the recent advances in drug development could not have been achieved without the use of QSARs in one form or another. The pace of such developments is rapid and QSARs are the keystone to that progress. These workshops have contributed to this progress and will continue to do so in the future.

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.

Linear regression and computational neural network prediction of tetrahymena acute toxicity for aromatic compounds from molecular structure.

A quantitative structure toxicity relationship (QSTR) has been derived for a diverse set of 448 industrially important aromatic solvents. Toxicity was expressed as the 50% growth impairment concentration (ICG(50)) for the ciliated protozoa Tetrahymena and spans the range -1.46 to 3.36 log units. Molecular descriptors that encode topological, geometrical, electronic, and hybrid geometrical-electronic structural features were calculated for each compound. Subsets of molecular descriptors were selected via a simulated annealing technique and a genetic algorithm. From this reduced pool of descriptors, multiple linear regression models and nonlinear models using computational neural networks (CNNs) were derived and then used to predict the ICG(50) values for an external set of representative compounds. An average of 10 nonlinear CNN models with 11-5-1 architecture was found to best describe the system with root-mean-square errors of 0.28, 0.29, and 0.34 log units for the training, cross validation, and prediction sets, respectively.

Modeling acute toxicity of chemicals to Daphnia magna: a probabilistic neural network approach.

A methodology based on probabilistic neural networks (PNNs) is applied to model the acute toxicity (48-h LC50) of a set of 700 highly diverse chemicals to Daphnia magna. First, cross-validation experiments confirming the potential use of the PNN as modeling tool for the problem at hand were performed. Next, various approaches to construct-improved models are presented. The resulting four models are then validated using an external test set of 76 additional compounds. Input to the PNNs is derived solely from simple molecular descriptors and structural fragments and excludes bulk property parameters, such as the water solubility or the octanol/water partition coefficient.

Modeling the toxicity of chemicals to Tetrahymena pyriformis using molecular fragment descriptors and probabilistic neural networks.

The results of an investigation into the use of a probabilistic neural network (PNN)-based methodology to model the 48-h ICG50 (inhibitory concentration for population growth) sublethal toxicity of 825 chemicals to the ciliate Tetrahymena pyriformis are presented. The information fed into the neural networks 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 employed. The cross-validation and external validation experiments confirmed excellent recognitive and predictive capabilities of the resulting models and recommend their future use in evaluating the potential of most organic molecules to be toxic to Tetrahymena.

Public health nursing data. Building the knowledge base for high-risk prenatal clients.

PURPOSE: To examine and compare referral reason, clinical pathway variance, and intensity of need for care for high-risk prenatal clients of public health nurses. DESIGN: A prospective, descriptive design was used for this pilot study. METHODS: Reasons for referral to the high-risk prenatal home visitation program, variances from a prenatal clinical pathway, and intensity of need for care scores obtained using the Community Health Intensity Rating Scale (CHIRS) were collected at 28 weeks and 38 weeks of gestation from the clinical records of 20 high-risk prenatal clients (age range 16-43 years) visited by five expert public health nurses in one midplains public health nursing department. RESULTS: Findings indicated that the three sources of clinical data provided congruent but not identical data, with each contributing elements needed to specify public health nurses interventions for high-risk prenatal clients. CLINICAL IMPLICATIONS: Collaborative clinical research studies such as this one are useful in advancing evidenced-based practice in clinical agencies. The congruence between the clinical path variance and the intensity of need for care scores reaffirms the importance of the domain of health behavior intervention as a major aspect of public health nurses practice.

Patterns of health resource utilization, costs, and intensity of need for primary care clients receiving public health nursing case management.

Case management has been promoted as a managed care strategy that improves quality of care and contains costs. Health resource utilization patterns and associated costs were examined for a generalized primary care population receiving a public health nursing model of case management intervention during a 30-week period. Subjects were referred by providers practicing in an academic health science center and included two client subsamples: chronically ill adults and younger families requiring health maintenance. Health resource utilization patterns and associated costs were examined in relation to intensity of need for care levels as determined by the Community Health Intensity Rating Scale. Results of this pilot study suggest that during public health nursing case management intervention, health resource utilization patterns changed from the preintervention period. Total health resource utilization costs were correlated with care needs related to health management behavior of the chronically ill.

Using probabilistic neural networks to model the toxicity of chemicals to the fathead minnow (Pimephales promelas): a study based on 865 compounds.

We investigate the use of probabilistic neural networks (PNN) to model the acute toxicity (96-hr LC50) to the fathead minnow (Pimephales promelas) based on a 865 chemicals data set. In contrast to most other toxicological models, the octanol/water partition coefficient is not used as input parameter. The information fed into the neural network is solely based on simple molecular descriptors as can be derived from the chemicals' structures and indicates the potential of this approach as general methodology for the estimation of toxicological effects of chemicals.

Prediction of fathead minnow acute toxicity of organic compounds from molecular structure.

Interest in the prediction of toxicity without the use of experimental data is growing, and quantitative structure-activity relationship (QSAR) methods are valuable for such predictions. A QSAR study of acute aqueous toxicity of 375 diverse organic compounds has been developed using only calculated structural features as independent variables. Toxicity is expressed as -log(LD(50)) with the units -log(millimoles per liter) and ranges from -3 to 6. Multiple linear regression and computational neural networks (CNNs) are utilized for model building. The best model is a nonlinear CNN model based on eight calculated molecular structure descriptors. The root-mean-square log(LD(50)) errors for the training, cross-validation, and prediction sets of this CNN model are 0.71, 0.77, and 0.74 -log(mmol/L), respectively. These results are compared to a previous study with the same data set which included many more descriptors and used experimental data in the descriptor pool.

Correlations of Vibrio fischeri bacteria test data with bioassay data for other organisms.

Linear relationships of the median lethal concentrations of several hundreds of chemicals for a variety of organisms with Vibrio fischeri median effective concentrations are investigated. Significant correlations can be developed for many aquatic species including the fishes fathead minnow, bluegill, catfish, goldfish, goldorfe, guppy, killifish, rainbow trout, sheepshead minnow, and zebrafish; the water flea Daphnia sp.; such crustaceans as Artemia sp. and Crangon sp.; the ciliate Tetrahymena pyriformis; and algae, such as Chlorella sp. These interspecies relationships can be used to estimate order-of-magnitude type toxic effects of many substances for these aquatic organisms. Highly significant relationships can be obtained when selecting compounds on a chemical basis, such as alcohols, ketones, aromatics, etc., which allow the calculation of the compounds' toxicities to the corresponding aquatic species with increased accuracy and confidence. Analogous correlations with mammalian (rat and mouse) oral, intraperitoneal, and intravenous median lethal dose (LD50) data are much weaker than those for most aquatic species. However, there are significant differences between these three routes of administration and the intravenous LD50 data show the best relationship with the Vibrio data.

In search of meaning: identifying competencies relevant to evaluation of the community health nurse generalist.

The purpose of this study was to identify the competencies that faculty look for in evaluating the performance of baccalaureate community health nursing students. The approach to the research was qualitative and utilized an inductive analysis methodology. Eight faculty members provided data on how they judged the clinical performance of 92 students in a semester-long community health nursing course. Thirty-five competencies emerged from the data which were grouped into two domains of performance evaluation: socialization to the community health nurse role and community health nurse clinical practice.

Regression and cluster analysis of the acute toxicity of 267 chemicals to six species of biota and the octanol/water partition coefficient.

The acute toxicities of 267 compounds to six aquatic and one terrestrial species were investigated with correlation, principal component and cluster analysis techniques for relationships with each other and with the compounds' octanol/water partition coefficient. Selection of the investigated chemicals was based on the availability of at least three of the following measured parameters: acute (24-h to 96-h) lethal concentrations (LC50) to the fish fathead minnow (Pimephales promelas), the fish goldorfe (Leuciscus idus melanotus), the zooplankter Daphnia magna, the ciliate Tetrahymena pyriformis, and the algae Scenedesmus quadricauda; the (30-min) inhibitory concentrations (EC50) to the luminescent marine bacterium Photobacterium phosphoreum (the Microtox test); the acute oral dose (LD50) for the common Norway rat and the octanol/water partition coefficient (log P or log Kow). The results indicate highly significant correlations between the fathead minnow, goldorfe and Daphnia LC50 and the Photobacterium EC50 concentrations. The cluster and principal components analyses did not detect any clearly defined groups of compounds. The toxicities were also highly collinear with the octanol/water partition coefficients for all species except the rat, where two relationships are indicated, with the division at log P = 2.00.

The acute toxicity of pulse-dosed, para-substituted phenols to larval American flagfish (Jordanella floridae): a comparison with toxicity to photoluminescent bacteria and predicted toxicity using log Kow.

The acute toxicity of nine para-substituted phenols was determined using a pulse-exposure testing protocol and 8-day-old larval American flagfish (Jordanella floridae). Relative tolerance was assessed by determining the 2-h pulse exposure concentration causing 20 and 50% mortality (PE LC20 and PE LC50) over the subsequent 94 h. Four bioassays were run for each phenol and yielded the following mean PE LC20 values (mg 1(-1)) in descending order of toxicity: p-aminophenol, 0.06; hydroquinone, 0.13; phenol, 0.70; p-nitrophenol, 0.81; p-cyanophenol, 3.0; p-chlorophenol, 3.3; p-hydroxyacetophenone, 4.2; p-hydroxybenzyl alcohol, 6.4; and p-hydroxybenzoic acid, 170. These toxicities did not correlate significantly with either previously reported toxicity values for the photoluminescent bacteria Photobacterium phosphoreum, or with the log octanol-water partition coefficient. For some of the compounds, however, sensitivities were quite close to previously reported rainbow trout chronic no-observed-effect concentrations based on continuous exposure. Caution is urged with respect to applying "low-level" biota techniques or simple quantitative structure-activity correlations such as Kow when attempting to predict the toxicity of specific chemicals to fish.

Congener-specific analysis of the accumulation of polychlorinated biphenyls (PCBs) by aquatic organisms in the maximum turbidity zone of the St. Lawrence estuary, Québec, Canada.

The polychlorinated biphenyl (PCB) contamination of the biota of the St. Lawrence estuary maximum turbidity zone (MTZ) was investigated. The species analyzed consist of zooplankton (mostly Neomysis americana), larval smelt (Osmerus mordax), juvenile smelt, juvenile tomcod (Microgadus tomcod) and adult smelt, tomcod and capelin (Mallotus villosus). A significant increase in total PCB contamination from zooplankton to all fish developmental stages indicates that the St. Lawrence MTZ is a site of significant PCB contamination. The total PCB contamination of adult smelt and tomcod sampled in the St. Lawrence MTZ was greater than the limit of 0.1 ppm set by the International Joint Commission for the protection of predators. For zooplankton, tomcod and capelin, significant correlations were found between lipid content and PCB contamination. The congener-specific analyses showed that the bioconcentration factor of the individual congeners varied with the species involved and with the molecular structure of the congener. It was found that the chlorine atoms in positions 2, 4 and 5 on at least one phenyl ring of the PCB molecule was a dominant factor causing accumulation of PCBs in aquatic organisms. The pattern of PCB congeners found in beluga (Delphinapterus leucas) whale tissues is similar to the PCB pattern found in the St. Lawrence estuary MTZ biota.

Export of mirex from Lake Ontario to the St. Lawrence Estuary.

The relative importance of migrating eels and suspended particulate material (biotic and abiotic) as transporters of mirex from Lake Ontario to the St. Lawrence River Estuary is evaluated in the context of a possible adverse impact on the St. Lawrence beluga population. Our estimates suggest that transport of mirex out of Lake Ontario by eels (2270 g annually) is almost twice that due to suspended particulate flux (1370 g annually). Mass balance calculations for mirex in Lake Ontario indicate that transport by migrating eels and particulate matter, combined with coverage of surficial sediments by continuing deposition of new material, could effectively "cleanse" Lake Ontario of mirex inputs in 100 years or less. Using mirex as a prototype to simulate the fate of hydrophobic organic chemicals in Lake Ontario led to a revised sediment budget for this final lake in the Great Lakes-St. Lawrence system. According to this budget, 94% of the suspended particulate material entering Lake Ontario is retained in the depositional basins and, by inference, most hydrophobic organic contaminants and metal forms having a dominant association with the particulate phase, would be expected to behave in a similar fashion.

Correlation of metal ion toxicities to mice.

Recently reported correlations of acute ip LD50 metal ion toxicities to mice by Turner et al. (1983), have been re-investigated using the ion-specific parameters reported by Kaiser (1980) for sublethal metal ion toxicities to Daphnia magna. For the 15 ions with partially or completely filled d-shells, Rh(III), Fe(III), Cr(III), Mn(II), Co(II), Pd(II), Ni(II), Au(III), Zn(II), Pt(II), Ag(I), Cu(II), In(III), Hg(II), and Cd(II), a correlation coefficient of r2 = 0.76 is found. This is a significant improvement over the value of r2 = 0.36 observed for the 14 divalent metal ions by Turner et al. with the softness parameter sigma as the independent variable. This re-investigation proves the applicability of the ionization potential and redox potential derived parameters for the quantitative correlation of metal ion toxicities to both aquatic and terrestrial biota.

An exploratory study of life-change events, social support and pregnancy decisions in adolescents.

This exploratory, descriptive study investigated the relationship of life-change events and family and social support to decision making in pregnant adolescents. The convenience sample consisted of 43 subjects aged 14 to 18 years coming to two midwestern clinics for pregnancy testing. Instruments were the Adolescent Life Change Event Questionnaire and the Demographic and Social Support Questionnaire. Data analysis involved three groups: continue the pregnancy (N = 30); abort (N = 9); and undecided (N = 4). Kruskal-Wallis one-way analysis of variance by ranks was used to test for differences between groups on overall life-change unit (LCU) scores and social support scores. Chi square, Fisher Exact Tests and step method multiple discriminant analysis were used to determine if specific life changes were more associated with particular outcome decisions. While not statistically significant, the overall LCU scores were higher and the social support scores lower for the continue group than for the abortion group. Subjects in the abortion group were younger, more likely to have experienced "getting grounded," and more involved in school and social activities. More subjects in the continue group reported personal and family health problems.

PIP: This exploratoy study investigats the relationship of life-change events and family and social support to decision making in pregnant adolescents. The convenience sample consisted of 43 subjects aged 14 to 18 years coming to 2 midwestern, urban American clinics for pregnancy testing. Instruments were the Adolescent Life Change Event Questionnaire and the Demographic and Social Support Questionnaire. Data analysis involved 3 groups: continue the pregnancy (N=30); abort (N=9); and undecided (N=4). Kurskal-Wallis 1-way analysis of variance by ranks was us%ed to test for differences between groups on overall life-change unit (LUC) scores ans social support scores. Chi-square, Fisher Exact Tests and step method multiple discriminant analysis were used to determine if specific life changes were more associated with particular outcome decisions. While not statistically significant, the overall LCU scores were higher and the social support scores lower for the continue group than for abortion group. Subjects in the abortion group were younger, were more likely to have experienced getting grounded, and more involved in school and social activities. More subjects in the continue group reported personal and family health problems.