Uses and limitations of quantitative structure-activity relationships (QSARs) to categorize substances on the Canadian domestic substance list as persistent and/or bioaccumulative,and inherently toxic to non-human organisms

Under sections 73 and 74 of the revised Canadian Environmental Protection Act (CEPA 1999), Environment Canada and Health Canada must "categorize" and "screen" about 23,000 substances on the Domestic Substances List (DSL) for persistence (P), bioaccumulation (B), and inherently toxic (iT) properties. Since experimental data for P, B and iT are only available for a few DSL substances, a workshop was held to address issues associated with the use of Quantitative Structure-Activity Relationships (QSARs) to categorize these substances. This paper describes the results of an 11-12 November 1999 International Workshop sponsored by Environment Canada to discuss potential uses and limitations of QSARs to categorize DSL substances as either persistent or bioaccumulative and iT to non-human organisms and to recommend future research needed to develop methods for predicting the P, B and iT of difficult-to-model substances.     

Global Government applications of analogues,SAR s and QSAR s to predict aquatic toxicity,chemical or physical properties,environmental fate parameters and health effects of organic chemicals

Faced with the need to predict physical and chemical properties, environmental fate, ecological effects and health effects of organic chemicals in the absence of experimental data, several Government organizations have been applying analogues, Structure Activity Relationships (SARs) and Quantitative Structure Activity Relationships (QSARs) to develop those predictions. To establish some benchmarks for monitoring future increases in applications of analogues, SARs and QSARs by global Government organizations, this paper describes the current applications of analogues, SARs and QSARs by Australian, Canadian, Danish, European, German, Japanese, Netherlands, and United States Government organizations to predict physical and chemical properties, environmental fate, ecological effects and health effects of organic chemicals.     

QSARs for identifying and prioritizing substances with persistence and bioconcentration potential

From the 8511 chemicals with 1998 production volumes reported to the U.S. Environmental Protection Agency (U.S. EPA), the TSCA Interagency Testing Committee's (ITC's) Degradation Effects Bioconcentration Information Testing Strategies (DEBITS) was used to identify 56 chemicals. The DEBITS Quantitative Structure-Activity Relationships (QSARs) and the U.S. EPA's PBT profiler QSARs were used to predict the persistence and bioconcentration factors of these 56 chemicals. Partial order ranking was used to prioritise the chemicals based on persistence and bioconcentration potential.     

Evaluation of the Use of QSARS for Priority Setting and Risk Assessment

Abstract

Impending changes in EEC legislation have accelerated the need to define the principles and practical considerations of the use of QSARs in priority setting and risk assessment. It is important to delineate the limitations of this approach and to review whether and how this information should be used in the risk assessment. The value and limitations of QSARs for use in priority setting and risk assessment will not be discussed in detail since the European Chemical Industry Ecology and Toxicology Centre (ECETOC) has only recently established a Task Force to tackle this issue. The terms of reference of the Task Force are: (1) compare the predictions obtained with QSARs to measured data using ECETOC databases and other sources of data and comment on the validity and applicability of such QSARs; (2) identify and review software packages which are available for accessing and using appropriate QSARs; (3) identify those aspects of environmental distribution, fate and effects where the further development of QSARs is desirable and feasible; and (4) provide a scientific basis for ECETOC's contribution to the activities of the European Chemicals Bureau (ECB) in this area. In this short paper, only an initial and personal evaluation is made of when and where to use QSARs in the priority setting and risk assessment process within the regulatory framework. Some critical remarks and suggestions are provided to guide future developments and integration of QSARs in the risk assessment process.     

U.S. EPA Regulatory Perspectives on the Use of QSAR for New and Existing Chemical Evaluations

Abstract

As testing is not required, ecotoxicity or fate data are available for ≈ 5% of the approximately 2,300 new chemicals/year (26,000 + total) submitted to the US-EPA. The EPA's Office of Pollution Prevention and Toxics (OPPT) regulatory program was forced to develop and rely upon QSARs to estimate the ecotoxicity and fate of most of the new chemicals evaluated for hazard and risk assessment. QSAR methods routinely result in ecotoxicity estimations of acute and chronic toxicity to fish, aquatic invertebrates, and algae, and in fate estimations of physical/chemical properties, degradation, and bioconcentration. The EPA's Toxic Substances Control Act (TSCA) Inventory of existing chemicals currently lists over 72,000 chemicals. Most existing chemicals also appear to have little or no ecotoxicity or fate data available and the OPPT new chemical QSAR methods now provide predictions and cross-checks of test data for the regulation of existing chemicals. Examples include the Toxics Release Inventory (TRI), the Design for the Environment (DfE), and the OECD/SIDS/HPV Programs. QSAR screening of the TSCA Inventory has prioritized thousands of existing chemicals for possible regulatory testing of: 1) persistent bioaccumulative chemicals, and 2) the high ecotoxicity of specific discrete organic chemicals.     

Evaluation of Critical Body Residue QSARS for Predicting Organic Chemical Toxicity to Aquatic Organisms

Abstract

The critical body residue (CBR) is the concentration of chemical bioaccumulated in an aquatic organism that corresponds to a defined measure of toxicity (e.g., mortality). The CBR can provide an alternative measure of toxicity to traditional waterborne concentration measurements (e.g., concentration in water causing 50% mortality). The CBR has been suggested as a better estimator of dose than the external water concentration and has been postulated to be constant for chemicals with the same mode of action. CBR QSARs have both theoretical and experimental support, developed primarily from studies on the acute toxicity of narcotic chemicals to small fish. CBR QSARs are less well developed for the aquatic toxicity of non-narcotic chemicals. CBRs vary substantially with the mode of action and toxicity endpoint, and may be affected by genetic, hormonal or environmental variation. CBR QSARs may not be applicable to very hydrophobic chemicals, chemicals with specific modes of action, or those with toxicity controlled by kinetic processes such as biotransformation. CBRs models have not been developed or evaluated for sediment and dietary exposure routes. Application of CBR QSARs to contaminated site assessments will require further research and development.     

An interlaboratory study to improve the quality of chemical and biological measurements in waste water

 Analyses of waste water are routinely performed to monitor the level of contamination. To verify the quality of such determinations the National Institute of Chemistry, with the support of the Ministry of Environment and Spatial Planning and the Slovenian Accreditation Agency, organizes interlaboratory comparisons. Over the last 3 years, five interlaboratory trials named "MPP-Waste Water" were organized. Each round attracted around 50 participants, mostly from Slovenia and some from abroad, which enabled the testing of SIST ISO methods or alternative methods. We prepared samples for determination of harmful substances that are important for the characterization of waste water; physico-chemical parameters (pH), global parameters – chemical oxygen demand (COD), biochemical oxygen demand (BOD₅), metals (mercury, cadmium, copper, nickel, lead and chromium (VI)), nutrients (ammonia and total phosphorus), anions (chloride, nitrite, nitrate, sulphate) and toxicity to Daphnia magna. For the analysis of each parameter we prepared two samples at two different concentration levels. The materials used in the proficiency testing were carefully prepared and their homogeneity and stability were verified. The purpose of this scheme was to enable participants to check their day-to-day analytical performance. The results should enable the participants to improve the quality of their analyses.

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Received: 24 October 2002 Accepted: 2 January 2003

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Acknowledgments We would like to thank the Ministry of Environment and Spatial Planning and the Ministry for Education, Science and Sport for providing financial support. We would like to thank members of the Technical Committee: Mrs. Marjana Kovacˇicˇ, Dr. Katja Otrin-Debevc, Prof. Dr. Marjan Veber and Mrs. Boža Gregorc for their valuable support. Special thanks are due to Dr. Adrian Van der Veen who helped us in running the first PT.

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Presented at CERMM-3, Central European Reference Materials and Measurements Conference: The function of reference materials in the measurement process, May 30–June 1, 2002, Rogaška Slatina, Slovenia

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Correspondence to M. Cotman     

The Book Corner

Abstract

CHROMATOGRAPHIC ANALYSIS OF PHARMACEUTICALS, John A. Adamovics, Editor, Volume 49, Chromatographic Science Series, Marcel Dekker, Inc., New York, 1990. Price – 16125.00 (USA and Canada), $150.00 (all other countries).

PACKINGS AND STATIONARY PHASES IN CHROMATOGRAPHIC TECHNIQUES, Klaus K. Unger, Editor, Volume 47, Chromatographic Licience Series, Marcel1 Dekker, Inc., New York. Price – $150.00 (USA and Canada), $180.00 (all other countries).

DOWNSTREAM PROCESSING AND BIOSEPARATION. RECOVERY AND PURIFICATION OF BIOLOGICAL PRODUCTS, J.-F. P. Hammel, J. B. Hunter, S. K. Slkdar, eds, ACS Symposlum Serles No. 419, AmerIcan Chemlcal Soclety, Washlngton, 1990. Price, US$69.95, 311 pp.     

Molecular Lipophilicity Calculations of Chemically Heterogeneous Chemicals and Drugs on the Basis of Structural Similarity and Physicochemical Parameters

Abstract

QSARs based on molecular polarizability (α) and H-bond acceptor factors (∑C_a) as independent variables provided good predictability of octanol/water partition coefficients (P) for chemicals and drugs. However, for some molecules containing few functional groups, the calculated values deviated significantly from those observed. This approach gave good results when applied to a set of 138 chemicals and drugs previously studied by Mannhold and Dross who compared other methods to calculate log P values.

At the same time, three variations on a molecular similarity approach were pursued. In this study, a large training set with experimentally determined octanol/water partition coefficients (P) was searched for structures closely related to the compound-of-interest. The most successful of these variations took the mean log P value of few most closely related compounds after each was adjusted for differences between their and the compound-of-interest's polarizabilities (α) and H-bond acceptor capacities (∑C_a).     

Phosphorylated Allylchlorides: A Source of new Structures and Transformations

Abstract

General methods have been elaborated for the synthesis of O (or S)-phosphorylated vinylcholines, including the corresponding betaines of mono-, bis- and polymer structures, 5-membered heterocycles with P, O, S, N atoms in the cycle and exo- CHX= (X=H, C1) bond. The key substances, O-phos- phorylated allylchlorides, were obtained either by the well known Perkov reaction or according to scheme (I), worked out by us. The scheme is based on the reactions of 3- or 4-coordinated phosphorus with substituted ketones in the presence of triethylamine (B:).     

One-dimensional Chain Crown Ether Complexes. Synthesis and Crystal Structure of Benzo-18-Crown 6 Complexes with Na 2 [M(SCN) 4 ] (M = Pd, Pt)

Two benzo-18-crown-6 (B18-C-6) complexes: [Na(B18-C-6)]₂[Pd(SCN)₄](H₂O)({bf 1}) and [Na(B18-C-6)]₂[Pt(SCN)₄]...0.5C₂H₄C1₂ (2)have been synthesized and characterized by elemental analysis, IR spectrum and X-raydiffraction analysis. The crystal of complex 1 belongs to monoclinic, space group P2₁/n with cell dimensions, a = 1.0481(3), b = 1.2864 (3), c = 1.7003 (4) nm, = 93.626(4)°, V = 2.2879 (9) nm³, Z = 2, D_calcd = 1.491 g/cm³, F(000) = 1060, R₁ = 0.0562, wR₂ = 0.1412 and 2 is triclinic, spacegroup P1 with cell dimensions, a = 0.9581(3), b = 1.2173 (3), = 2.1198 (6) nm, = 79.522(4), = 77.911(4), = 78.617(4)°, V = 2.3442(11) nm³ Z = 2, D_calcd = 1.626 g/cm³, F(000) = 1154, R₁ = 0.0515, wR₂ = 0.0612.Two complexes show one-dimensional chain of [Na(B18-C-6)]⁺ complex cations and [M(SCN)₄]^2- (M = Pd, Pt) complex anion bridged by Na–O–Na interactions of H₂O molecule or Na-O bond of B18-C-6 between adjacent [Na(B18-C-6)]⁺ units respectively.     

Symbiosis between Microorganisms from Kombucha and Kefir: Potential Significance to the Enhancement of Kombucha Function

Gluconacetobacter sp. A4 (G. sp. A4), which had strong ability to produce d-saccharic acid 1, 4 lactone (DSL), was the key functional bacteria isolated from the kombucha preserved. This paper investigated the interaction between G. sp. A4 and ten different strains of lactic acid bacteria (LAB) obtained from kefir. The result suggested that the LAB promoted DSL production of G. sp. A4 to different extents, ranging from 4.86% to 86.70%. Symbiosis between G. sp. A4 and LAB was studied. LAB’s metabolites, xylitol, and acetic acid, were utilized by G. sp. A4, and it promoted the growth of G. sp. A4 and yield of DSL. Therefore, in developing starter cultures for kombucha fermentation process, a mixed flora of LAB and G. sp. A4 would be the optimal combination.     

Modelling of the Biological Activity for a Set of Ceramic Fibre Materials: A QSAR Study

Abstract

The objective was to develop quantitative structure-activity relationships (QSARs) for a set of nine ceramic raw materials. The samples were characterized by a chemical analysis (both X-ray fluorescence and neutron activation analysis) and the morphology was determined by electron microscopy in combination with automated image analysis. Further, the fibre samples were subjected to two biological activity assays, measuring cytotoxicity and hydroxyl radical production. To investigate the produced data structures, principal component analysis (PCA) and partial least squares (PLS) were applied together with rigorous validation techniques. Significant QSARs were found for both biological activity assays. The morphology of the fibres plays an important role for the cytotoxicity and their trace element background is related to the hydroxyl radical production.     

Metal derivatives of thiosemicarbazones: crystal structure of [chloro bis(triphenylphosphino) (thiophene-2-carbaldehyde thiosemicarbazone) copper(I)] complex

Reactions of copper(I) halides (X = Cl, Br, I) with thiophene-2-carbaldehyde thiosemicarbazone and triphenylphosphine in 1 : 1 : 2 molar ratio yield tetrahedral mononuclear complexes, [CuX(η¹-S-Httsc)(Ph₃P)₂] (X = Cl, 1; Br, 2; I, 3), characterized by elemental analysis, IR, NMR (¹H, ¹³C, ³¹P), and single crystal X-ray crystallography (1). The unit cell of 1 has two independent distorted tetrahedral molecules (1a and 1b) with different bond parameters. One acetonitrile is entrapped between them. Crystal data: C₈₆H₇₇Cl₂Cu₂N₇P₄S₄ 1: triclinic, P-1, a = 12.8810(9), b = 18.5049(13), c = 18.7430(13) Å, α = 63.7130(10), β = 89.0960(10), γ = 85.5010(10)°, V = 3992.4(5) ų, Z = 2, R _(int) = 0.0314. Bond parameters: 1a, Cu(1A)–Cl(1A), 2.3803(5); Cu(1A)–S(1A), 2.3822(5); Cu(1A)–P(1A), 2.2498(5) Å; P(1A)–Cu(1A)–P(2A), 124.294(19)°; 1b, Cu(1B)–Cl(1B), 2.3975(5); Cu(1B)–S(1B), 2.3756(5); Cu(1B)–P(1B), 2.2777(5) Å; P(1B)–Cu(1B)–P(2B), 127.156(19)°.     

Books Section

Abstract

Colombo, A.G. (1992). Environmental Impact Assessment. Kluwer Academic Publishers, Dordrecht, p. 334 + xii pp., Hardcover, ISBN: 0-7923-1589-8, Dfl180.00; £61.00.

Martin, G. and Laffort, P. (1991). Odeurs et Désodorisation dans l'Environnement. (Odors and Desodorisation in the Environment). TEC & DOC – Lavoisier, Paris. p. 452 + xxiv pp., Hardcover, In French, ISBN: 2-85206-605-X, FF 565.00.

Yalkowsky, S. H. and Banerjee, S. (1992). Aqueous Solubility: Methods of Estimation for Organic Compounds. Marcel Dekker, Inc., New York. p. 264 + vi pp., Hardcover, ISBN: 0-8247-8615-7, US$99.75 (U.S. and Canada) US$114.50 (all other countries).     

Synthesis of Boron–Nitrogen–Phosphorus Compounds from N-Silylphosphoranimines

Two modes of reactivity of N-silylphosphoranimines have been utilized to prepare the title compounds containing either B–N=P or Si–N=P–N–B linkages. First, silicon-nitrogen bond cleavage reactions of the N-silylphosphoranimines, Me₃SiN=PMe(R)OCH₂CF₃ (1: R=Me, 2: R=Ph), with various chloroboranes gave the new N-borylphosphoranimines, Ph(Me₂N)B–N=PMe₂OCH₂CF₃ (2) and [(Me₃Si)₂N](Cl)B–N=PMe₂OCH₂CF₃ (10). In other cases, however, the expected B–N=P products were unstable and cyclic phosphazenes [Me(R)P=N]_3,4 were obtained. Second, deprotonation-substitution reactions of the aminophosphoranimines, Me₃SiN=P(R)Me–N(R)H, were used to prepare a series of novel (borylamino)-phosphoranimines, Me₃SiN=P(R)(Me)–N(R)–B(NMe₂)₂ (18: R=Me, R=t-Bu; 19: R=R=Me; 20: R=Ph, R=t-Bu; 21: R=Ph, R=Me) and Me₃SiN=PMe₂–N(t-Bu)–B(Ph)X (22: X=NMe₂, 23: X=OCH₂CF₃). All of the new boron–nitrogen–phosphorus products were fully characterized by multinuclear NMR (¹H, ¹³C, and ³¹P) spectroscopy and elemental analysis.     

Mass-Spectrometry of Phosporic and Arsenic Heterocycles

Abstract

Some O,P,B (I)-, N,P,B (II), - As,N(III) - heterocycles and 1,3,2-dioxaborinanes(IV) have been studied by a high resolution mass-spectrometry of electron impact.