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In response to various legislative mandates, the US Environmental Protection Agency (USEPA) formed its Endocrine Disruptor Screening Program (EDSP), which in turn, formed the basis of a tiered testing strategy to determine the potential of pesticides, commercial chemicals, and environmental contaminants to disrupt the endocrine system. The first tier of tests is intended to detect the potential for endocrine disruption mediated through estrogen, androgen, or thyroid pathways, whereas the second tier is intended to further characterize the effects on these pathways and to establish a dose-response relationship for adverse effects. One of these tier 2 tests, the Medaka Extended One Generation Reproduction Test (MEOGRT), was developed by the USEPA for the EDSP and, in collaboration with the Japanese Ministry of the Environment, for the Guidelines for the Testing of Chemicals of the Organisation for Economic Co-operation and Development (OECD). The MEOGRT protocol was iteratively modified based on knowledge gained after the successful completion of 9 tests with variations in test protocols. The present study describes both the final MEOGRT protocol that has been published by the USEPA and the OECD, and the iterations that provided valuable insights into nuances of the protocol. The various tests include exposure to 17β-estradiol, 4-t-octylphenol, o,p'- dichlorodiphenyltrichloroethane, 4-chloro-3-methylphenol, tamoxifen, 17β-trenbolone, vinclozolin, and prochloraz. Environ Toxicol Chem 2017;36:3387-3403. Published 2017 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.

A variety of methods and algorithms are available for estimating parameters in the class of a generalized linear model in the presence of missing values. However, there is little information on how this already built model can be used for prediction in new observations with missing data in the covariates. Dropping the observations with missing values is a widespread practice with serious statistical and non-statistical implications. One solution is to fit separate regression models, or submodels, to each pattern of missing covariates. In practice, for any iterative regression method, this approach is computationally intensive. We propose a simple methodology to predict outcomes for individuals with incomplete information based on the estimated coefficients and covariance from the already built model. This method does not require revisiting the original data set used to build the original model and works by generating a first-order approximation of any submodel coefficient estimates. This is achieved by using the SWEEP operator on an augmented covariance matrix obtained from the original model. We refer to this approach as the one-step sweep (OSS) method. The methodology is demonstrated using data from the Department of Veterans Affairs Continuous Improvement in Cardiac Surgery Program (CICSP). These data contain 30 day mortality, the outcome of interest, and risk information for over 14000 patients who underwent coronary artery bypass grafting (CABG) surgery over a four-yearperiod. Using complete data from the first 3.5 years of this study period, a logistic regression model was built. This model was then used to predict mortality for patients undergoing CABG in the most recent 6-months. In order to evaluate the performance of the OSS method we randomly generated observations with missing covariates in the 6-month prediction database. We use this simulation to demonstrate that the computationally efficient OSS substantially reduces the error in risk-adjusted mortality created when cases with incomplete information are eliminated. Lastly, we derive the relationship between the OSS method and data imputation. Copyright © 2002 John Wiley & Sons, Ltd.

A method using reversed phase high performance liquid chromatography/electrospray ionization-mass spectrometry (RP-LC/ESI-MS) has been developed to confirm the identity of dansylated derivatives of cysteine (C) and glutathione (GSH), and their respective dimers, cystine (CSSC) and glutathione disulfide (GSSG). Cysteine, GSH, CSSC and GSSG are present at low concentrations in rainbow trout (Oncorhynchus mykiss) liver cells. Initially, hepatic cells were sampled from a suspension culture and disrupted upon addition of 10% perchloric acid. The reduced thiols present in the cell extracts were acetylated to prevent dimerization and then the C and GSH species were derivatized with dansyl chloride for fluorescence detection. An LC system using a weak anion exchange column (AE) with fluorescence detection (FLD) was used for sensitive routine analysis; however, it produced peaks of unknown origin in addition to the expected analytes. Analytes were then separated on a C18 RP-LC system using a water/acetonitrile gradient with 0.2% formic acid, and detected using LC/ESI-MS at 3.5 KV which produced an intense ion with a minimum limit of detection of less than 0.5 pmole injected (>10:1 signal-to-noise (S/N). Subsequently, fractions of effluent from the AE-LC/FLD system were analyzed by LC/ESI-MS to confirm the presence of the target analytes in routine cell extracts. Monodansylated GSSG was identified as a product that could possibly affect the quantification of GSH and GSSG. Copyright © 2000 John Wiley & Sons, Ltd.

In the field of aquatic toxicology, quantitative structure-activity relationships (QSARs) have developed as scientifically credible models for predicting the toxicity of chemicals when little or no empirical data are available. In recent years, there has been an evolution of QSAR development and application from that of a chemical-class perspective to one that is more consistent with assumptions regarding modes of toxic action. The objective of this research was to develop procedures that relate modes of acute toxic action in the fathead minnow (Pimephales promelas) to chemical structures and properties. An empirically derived database for diverse chemical structures of acute toxicity and corresponding modes of toxic action was developed through joint toxic action studies, the establishment of toxicodynamic profiles, and behavioral and dose-response interpretation of 96-h LC50 tests. Using the results from these efforts, as well as principles in the toxicological literature, approximately 600 chemicals were classified as narcotics (three distinct groups), oxidative phosphorylation uncouplers, respiratory inhibitors, electrophiles/proelectrophiles, acetylcholinesterase inhibitors, or central nervous system seizure agents. Using this data set, a computer-based expert system has been established whereby chemical structures are associated with likely modes of toxic action and, when available, corresponding QSARs.

Predictive models in medical research have gained popularity among physicians as an important tool in medical decision making. Eight methodological strategies for creating predictive models are compared in a large, complex data base consisting of preoperative risk and operative outcome data on 12,712 patients undergoing coronary artery bypass grafting and entered into the Department of Veterans Affairs Cardiac Surgery Risk Assessment Program between April 1987 and March 1990. The models under consideration were developed to predict operative death (any death within 30 days following the surgical procedure or later if the result of a perioperative complication). The two strategies with the best predictive power among the eight examined were stepwise logistic regression alone and data reduction by cluster analysis combined with clinical judgement followed by a logistic regression model. The additive model based on unadjusted relative risks, the model based on Bayes' Theorem, and the logistic model using all candidate variables were good alternatives. Whether or not we imputed values did not have a significant impact on the predictive power of the models.

Solubility values for eight phthalate esters investigated ranged from 0.020 to 121 mg/L. Acute toxicity tests were conducted with fathead minnows (Pimephales promelas) and all eight phthalate esters. Acute and chronic tests were conducted with rainbow trout (Oncorhynchus mykiss) and Japanese medaka (Oryzias latipes) using di-2-ethylhexylphthalate. In addition, the chronic toxicity of the three di-n-butylphthalates and a mixture of these three phthalates was examined using daphnids (Daphnia magna). Fathead minnow 96-h LC50 values for di-n-butyl-ortho-phthalate, di-n-butyl-tere-phthalate, di-n-butyl-iso-phthalate and α, w-butylene di[o-(4-hydroxybutoxycarbonyl)-benzoate] were 1.1, 0.61, 0.90 and 121 mg/L, respectively. Di-n-octyl-ortho-phthalate, di-n-octyl-iso-phthalate and di-n-octyl-tere-phthalate were not acutely toxic to fathead minnows at concentrations that exceeded the water solubility estimates for each phthalate. Di-2-ethylhexyl-phthalate was not acutely toxic to any tested species at the highest tested concentrations. No significant adverse effects were observed on hatchability, survival or growth of rainbow trout exposed to a mean di-2-ethylhexylphthalate concentration of 0.502 mg/L (the highest concentration tested) in a 90-d embryo-larval test. However, exposure to a mean di-2-ethylhexylphthalate concentration of 0.554 mg/L significantly reduced the growth of Japanese medaka during a 168-d larval test. Significant adverse effects on reproduction occurred in 21-d chronic tests with D. magna at concentrations of 1.91, 0.20 and 0.64 mg/L for di-n-butyl-ortho-phthalate, di-n-butyl-iso-phthalate and di-n-butyl-tere-phthalate, respectively. A daphnid mixture test with these three phthalates showed complete additivity, which suggests a similar mode of toxic action.

Comparative acute toxicity values for Ceriodaphnia dubia, Scapholeberis sp. and Pimephales promelas exposed to copper were used to calculate water effect ratios (e.g., site water LC50 value/reference water LC50 value), which reflect the difference in the biological availability and/or toxicity of copper between water from the Naugatuck River, Connecticut and Lake Superior reference water. These ratios were used to modify U.S. Environmental Protection Agency (EPA) ambient aquatic life criteria for copper to site- and station-specific criteria, using the indicator procedure of the U.S. EPA guidelines for deriving site-specific water quality criteria. A water effect ratio of 1.0 was established using unpolluted upstream water, resulting in a site-specific criterion maximum concentration (CMC) and criterion continuous concentration (CCC) of 8.7 and 6.2 μg/L copper, respectively. Mean water effect ratios of 3.9 to 7.0, reflective of reduced biological availability and/or toxicity of copper, were determined for four successive downstream stations where the water contained copper and other industrial and domestic wastes. The resulting station-specific CMCs and CCCs ranged from 32 to 57 and 22 to 39 μg/L copper, respectively. These copper criteria were compared with effluent-contributed ambient copper concentrations and ecological survey data from each downstream station to ascertain impact on aquatic life. It was concluded that the national and site-specific criteria derived for copper would be protective of the river's aquatic life because a relatively healthy aquatic community existed where these criteria were exceeded slightly. Whether or not the station-specific criteria were protective could not be determined because these criteria were not exceeded at stations with healthy communities; however, where they were exceeded, impaired aquatic communities were evident. Generally, C. dubia survival and young production data from receiving water tests and copper addition tests, conducted just prior to the acute toxicity tests, were also indicative of reduced copper biological availability and/or toxicity in the Naugatuck River at downstream stations.

Complications were surveyed prospectively in 2,029 catheterizations performed on 1,483 patients from the 13 centers participating in the VA Cooperative Study on Valvular Heart Disease. Complications were reported in 6.9% of 1,559 preoperative procedures of which 2.6% were major and 0.2% fatal. Clinical predictors of complications were hypertension and the precatheterization diagnosis of aortic stenosis. Nevertheless, patients with aortic stenosis successfully tolerated left ventriculography, which was routinely performed regardless of the magnitude of gradient. Procedural predictors of complication were brachial arteriotomy (vascular occlusion) and transseptal catheterization (tamponade). Among the 470 postoperative catheterizations performed solely for research purposes, there were six complications, of which five were bleeding events in patients taking warfarin. Transseptal catheterization was safer in postoperative patients with no cases of tamponade in 125 procedures.

Unsaturated tuff beneath Yucca Mountain, Nevada, is being evaluated by the U.S. Department of Energy as a host rock for a potential repository for high-level radioactive waste. As part of the Nevada Nuclear Waste Storage Investigations Project of the U.S. Department of Energy, the U.S. Geological Survey has been conducting hydrologic, geologic and geophysical investigations at Yucca Mountain and the surrounding region to provide data for evaluation of the potential suitability of the site. Hydrologic investigations of the unsaturated zone at this site began in 1982. A 17.5-inch- (44.5-centimeter) diameter borehole (USW UZ-1) was drilled by the reverse-air vacuum-drilling technique to a depth of 1269 feet (387 meters). This borehole was instrumented at 33 depth levels. At 15 of the levels, three well screens were embedded in coarse-sand columns. The sand columns were isolated from each other by thin layers of bentonite, columns of silica flour, and isolation plugs consisting of expansive cement. Thermocouple psychrometers and pressure transducers were installed within the screens and connected to the data-acquisition system at the land surface through thermocouple and logging cables. Two of the screens at each level were equipped with access tubes to allow collection of pore-gas samples. In addition to these instruments, 18 heat-dissipation probes were installed within the columns of silica flour, some of which also had thermocouple psychrometers. After more than two years of monitoring, the majority of the instruments were still functioning and producing reasonable data. A slow recovery from the disturbed state to natural conditions was detected during the first 90 days of monitoring; this recovery was probably a result of the large diameter of the borehole. Preliminary results indicated that suction pressures for the welded units ranged from −2 to −15 bars (−0.2 to −1.5 mega pascals). Some agreement existed between data from psychrometers and from heat-dissipation probes, except where silica flour was not in equilibrium with the formation. Water fluxes estimated in the matrix of the repository host-rock unit range from 4 × 10−3 to 2 × 10−2 inches per year (0.1 to 0.5 millimeter per year) using matric-potential distribution, and from −1 × 10−3 to −2 × 10−3 inches per year (−0.025 to −0.05 millimeter per year) using geothermal gradient. Responses to short-term barometric fluctuations were detected to a maximum depth of about 300 feet (91 meters) in the borehole. Below this depth, only long-term barometric fluctuations were detectable. Equivalent effective hydraulic conductivity, estimated from air permeability, ranged from 0.6 to 2 feet per day (0.2 to 0.6 meters per day).

A new, simple system for cooling and maintaining prefilled syringes of injectate in a dry, sterile environment for thermodilution cardiac output using a thermoelectric cold plate is described. Rates and uniformity of cooling were studied. Uniform cooling is achieved in about 60 minutes if refrigerated injectate is used.