Comparisons of PNEC derivation logic flows under example regulatory schemes and implications for ecoTTC.

Derivation of Predicted No Effect Concentrations (PNECs) for aquatic systems is the primary deterministic form of hazard extrapolation used in environmental risk assessment. Depending on the data availability, different regulatory jurisdictions apply application factors (AFs) to the most sensitive measured endpoint to derive the PNEC for a chemical. To assess differences in estimated PNEC values, two PNEC determination methodologies were applied to a curated public database using the EnviroTox Platform (www.EnviroToxdatabase.org). PNECs were derived for 3647 compounds using derivation procedures based on example US EPA and a modified European Union chemical registration procedure to allow for comparisons. Ranked probability distributions of PNEC values were developed and 5th percentile values were calculated for the entire dataset and scenarios where full acute or full chronic data sets were available. The lowest PNEC values indicated categorization based on chemical attributes and modes of action would lead to improved extrapolations. Full acute or chronic datasets gave measurably higher 5th percentile PNEC values. Algae were under-represented in available ecotoxicity data but drove PNECs disproportionately. Including algal inhibition studies will be important in understanding chemical hazards. The PNEC derivation logic flows are embedded in the EnviroTox Platform providing transparent and consistent PNEC derivations and PNEC distribution calculations.

Risk factors.

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Statistical properties of thermodynamic quantities for cyclodextrin complex formation.

Literature values of DeltaG degrees (change in Gibbs free energy), DeltaH degrees (change in enthalpy), and TDeltaS degrees (temperature times change in entropy) for 1:1 complex formation by alpha-, beta-, and gamma-cyclodextrins constitute normally distributed populations with the following statistical parameters (all energy quantities in kcal mol(-1); n is the number of data points; mu is the population mean; sigma is the standard deviation): for alpha-cyclodextrin, n = 512, micro(DeltaG) = -2.85, sigma(DeltaG) = 1.23, micro(DeltaH) = -4.77, sigma(DeltaH) = 2.98, micro(TDeltaS) = -1.96, and sigma(TDeltaS) = 2.72; for beta-cyclodextrin, n = 415, micro(DeltaG) = -3.67, sigma(DeltaG) = 1. 37, micro(DeltaH) = -4.24, sigma(DeltaH) = 2.89, micro(DeltaS) = -0. 56, and sigma(TDeltaS) = 2.63; for gamma-cyclodextrin, n = 42, micro(DeltaG) = -3.71, sigma(DeltaG) = 1.19, micro(DeltaH) = -3.10, sigma(DeltaH) = 3.39, micro(TDeltaS) = +0.69, and sigma(TDeltaS) = 3. 29. The temperature is 298.15 K. The mean DeltaG degrees values correspond to binding constants of 123, 490, and 525 M(-1) for alpha-, beta-, and gamma-cyclodextrins, respectively.

Binding of substituted acetic acids to alpha-cyclodextrin in aqueous solution.

Complex binding constants of 23 aliphatic acids with alpha-cyclodextrin in aqueous solution were measured by potentiometry, solubility, or competitive spectrophotometry at 25 degrees C. All systems formed 1:1 acid:cyclodextrin complexes, and some of them also formed 1:2 complexes. The conjugate acids formed stronger complexes than did the conjugate bases (except for glycine). Empirical correlations of complex stabilities are shown with partition coefficients, surface areas, molar refraction, and other descriptors. Complex stability appears to result from the hydrophobic effect, the dispersion interaction, and interaction of the carboxylic acid group with the cyclodextrin.

Supervision and staff training for children's group psychotherapy: general principles and applications with cumulatively traumatized, inner-city children.

Cumulatively traumatized children frequently benefit from theme-centered, trauma-focused psychotherapy groups, which promote recovery from trauma and enhance ego functioning. Unfortunately, even as children's group programs proliferate, therapists are still routinely assigned to supervisors who neither understand nor appreciate the modality. Modality-specific supervision is critical in treating traumatized children in groups, because such children are at significant risk of retraumatization. This article surveys and discusses problematic supervisory practices; advocates modality-specific supervision focusing on peer interaction, multiple transference enactments, and group culture; and describes a process-oriented consultation group that facilitates modality-specific cognitive and affective learning.

Binding of cyclodextrins to alicyclic and aromatic substrates: complex formation of alpha-, beta-, and gamma-cyclodextrins with substituted cyclohexanecarboxylic acids and phenylalkanoic acids.

Complex binding constants of the three native cyclodextrins with seven cyclohexane derivatives (all possessing the carboxylic acid group) and with the series C6H5(CH2)nCOOH (n = 0 to 4) were measured in aqueous solution at 25 degrees C by potentiometry and the solubility method. These results, combined with literature data, indicate that alpha- and gamma-cyclodextrins bind with comparable strength to both the cyclohexyl and phenyl moieties, with beta-cyclodextrin binding significantly more strongly. These acid series are compared with several series CH3(CH2)nX, where X is CH3, COOH, COO-, OH, SO3-, etc., and it is concluded that the X group (for X other than methyl) contributes appreciably to complex stability, perhaps by means of an extracavity interaction. The COOH group provides a further augmentation of complex stability. NMR CIS and ROESY results indicate the presence of isomeric complexes in both the cyclohexyl and phenylalkanoic series, and clearly demonstrate the existence of intracavity inclusion. An NOE study of the alpha-cyclodextrin: cyclohexanecarboxylate system provides evidence for inclusion combined with interaction outside (that is, at the rim of) the cavity.

Memory, language, and praxis in Alzheimer's disease: norms for outpatient clinical trial populations.

The cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog) is designed specifically to assess memory, language, and praxis dysfunctions characteristic of Alzheimer's disease (AD). In this report, we use data from 1,648 AD participants in two identical 26-week multicenter drug trials to derive clinical trial population-based norms for ADAS-Cog subtest scores. All 11 ADAS-Cog item scores were sensitive to differences in dementia severity judged either by baseline Mini-Mental State Exam (MMSE) scores or by Global Deterioration Scale (GDS) stage of dementia. Using ADAS-Cog subtest scores alone, 85 percent of GDS 4 subjects and 69 percent of GDS 5 subjects could be classified correctly. In a stepwise discriminant analysis, orientation was the item with the greatest discriminatory power between subjects with GDS 4 and GDS 5 stages of dementia. ADAS-Cog subtest scores also varied by age, gender, educational level, and concurrent use of anti-inflammatory drugs or estrogen (in women). Such normative data may facilitate the selection of appropriate outcome measures to investigate differential treatment effects on specific cognitive domains or in specific AD subpopulations.

Prediction of binding constants of alpha-cyclodextrin complexes.

Proceeding from a phenomenological theory of pairwise interactions (solvent-solvent, solvent-solute, and solute-solute), the binding constant K11 (in M-1) for 1:1 complex formation by alpha-cyclodextrin at a substrate binding site, at 25 degrees C in water, is given by log K11 = -1.74 - [Z] + 0.032(-delta A), where [Z] incorporates solvent-solute (solvation) and solute-solute interactions and delta A is the decrease in nonpolar surface area (in A2 molecule-1) on the substrate that is exposed to solvent when the binding site enters the cyclodextrin cavity. delta A is estimated from the structure of the binding site. Three levels of approximation are described for estimating [Z]. At the third (highest) level, the procedure when applied to 569 complex systems generated predicted values of log K11 that agreed within 0.30 unit of the experimental values in 58% of cases, and that agreed within 1.00 unit in 95% of cases.

Solvent effects on chemical processes. 11. Solvent effects on the kinetics of decarboxylative dechlorination of N-chloro amino acids in binary aqueous-organic solvents.

The phenomenological theory of solvent effects is extended to chemical reaction rates and is tested against experimental data on the decarboxylative dechlorination of N-chloroalanine and N-chloroleucine at 25 degrees C in binary aqueous-organic solvent mixtures. The organic cosolvents studied were methanol, ethanol, l-propanol, 2-propanol, ethylene glycol, propylene glycol, acetonitrile, and dioxane. Reaction rates increased in all cosolvent systems. The kinetic solvent effects could be quantitatively described by the theory, and the parameters of the theory (solvation exchange constants K1 and K2 and cavity surface area parameter delta g++) were found to possess magnitudes reasonable for the physical significance assigned to them. In particular, the delta g++ value is consistent with a recent measurement of the volume of activation delta V++ of the reaction.

Solvent effects on chemical processes. 10. Solubility of alpha-cyclodextrin in binary aqueous-organic solvents: relationship to solid phase composition.

The equilibrium solubility at 25 degrees C of alpha-cyclodextrin was measured in several binary aqueous-organic solvent mixtures, the organic cosolvents being methanol, 2-propanol, ethylene glycol, and acetone. Solubility maxima were observed as the solvent composition was varied from pure water to pure cosolvent. The maximum in methanol systems was hardly detectable, but it was very pronounced in 2-propanol and acetone, and two maxima were seen in the ethylene glycol system. Karl Fischer analysis of the solid phase isolated from 2-propanol/water equilibrium systems showed that alpha-cyclodextrin hexahydrate is the stable form in water, whereas a solid phase containing three water molecules per molecule of alpha-cyclodextrin is the stable form in the presence of 2-propanol. The appearance of a solubility maximum in this system, and by extension presumably in the other cosolvent systems, is attributed to the existence of more than one stable solid phase of alpha-cyclodextrin.

Population characteristics of cyclodextrin complex stabilities in aqueous solution.

Binding constants (K11) of 1:1 complexes of alpha-cyclodextrin, beta-cyclodextrin, and gamma-cyclodextrin with many substrates (guests) were collected from published sources and subjected to statistical analysis. All systems refer to 25 +/- 5 degrees C and aqueous solution. The frequency distributions of log K11 are satisfactorily described by normal distributions with the following parameters (n = number of complexes, mu = population mean, sigma = population standard deviation): alpha-cyclodextrin, n = 663, mu = 2.11, sigma = 0.90; beta-cyclodextrin, n = 721, mu = 2.69, sigma = 0.89; gamma-cyclodextrin, n = 166, mu = 2.55, sigma = 0.93. Stabilities of pairs of cyclodextrin complexes with a common substrate are not precisely correlated, but they do not appear to be wholly independent quantities. The stabilities of alpha-cyclodextrin complexes are consistent with a recent interpretation of solvent effects on alpha-cyclodextrin complex stabilities.

Postmyocardial infarction patients: experience from the SAVE trial.

Improving patient survival is the ultimate goal after acute myocardial infarction. Although thrombolytics, aspirin, and beta-blockers have greatly decreased mortality, structural changes such as ventricular dilatation evolving within the myocardium during and after acute myocardial infarction indicate a poor prognosis. The Survival and Ventricular Enlargement trial demonstrated that when administered 3 to 16 days after acute myocardial infarction in selected patients, captopril, the angiotensin-converting enzyme inhibitor, reduces ventricular dilatation, prevents the development of congestive heart failure, and reduces morbidity and mortality. This paper reviews results of that trial and presents guidelines for effective captopril dosage after acute myocardial infarction.

Nasal versus oral midazolam for sedation of anxious children undergoing laceration repair.

STUDY OBJECTIVE: To compare the efficacy and safety of a single dose of midazolam, as an oral solution of 0.5 mg/kg, or nasal drops of 0.25 mg/kg, in children undergoing emergency department laceration repair. DESIGN: Double-blind, double-placebo, randomized trial. Children underwent standard wound care when judged to demonstrate a reduction in anxiety following study medication. PARTICIPANTS: Fifty-eight patients between 1 and 10 years of age with uncomplicated lacerations judged to be anxious by emergency physicians. RESULTS: An anxiety score and vital signs were recorded at routine intervals. Groups were comparable with respect to age, laceration characteristics, initial vital signs, and anxiety scores. Both groups demonstrated reductions (mean +/- SD) in anxiety scores over time (P < .05; maximum at 10 minutes; 1.2 +/- 0.9 mm for nasal and 0.8 +/- 1.3 for oral), with no significant differences between groups (repeat-measures ANOVA). Median observer-rated effectiveness using a visual analog scale (maximum effectiveness, 10 mm) was not significantly different between groups: nasal, 7.6 mm and oral, 6.9 (Mann-Whitney U test: minimum detectable difference, 0.7, with alpha = 0.05 and beta = 0.2). Complications were judged to be minor only, and were more frequent in the nasal group (5 of 28, 4 with nasal burning) versus 1 of 26 in the oral group. Time from midazolam to ED discharge was not significantly different between groups: nasal, 54 +/- 15 minutes and oral, 57 +/- 16 minutes. CONCLUSION: A single dose of oral or nasal midazolam results in reduced anxiety and few complications in selected children undergoing laceration repair in the ED. The oral route was associated with fewer administration problems.

Solvent effects on chemical processes. 8. Demethylation kinetics of aspartame in binary aqueous-organic solvents.

The kinetics of demethylation of aspartame were studied in binary aqueous-organic solvent mixtures at 25 degrees C under two solution conditions, namely 1.0 M HCl (pH 0.28 in water) and carbonate buffer (pH 10.1 in water). Under these conditions solvent effects on the acid dissociation constants of aspartame do not complicate the interpretation of the kinetics. The organic cosolvents were acetone, acetonitrile, dimethyl sulfoxide, dioxane, tetrahydrofuran, and methanol. The observed kinetic solvent effects were modest in magnitude, not exceeding a factor of 3 in rate constant, relative to the fully aqueous solution. The rate changes included both increases and decreases, and in some solvent mixtures extrema were observed. It is concluded that at least two contributory factors, identified as an electrostatic (dielectric constant) effect and a solvation effect, must be operating to produce the observed kinetic solvent effects.