Discriminating toxicant classes by mode of action: 3. Substructure indicators§

Decision support for selecting suitable QSARs for predictive purposes is suggested by a stepwise procedure: The first tier pre-filters the compounds based on substructure indicators for baseline versus excess toxicity. This step, if sufficiently conservative, discriminates chemicals, whose toxicity can be reliably estimated from their log?K _OW from those, that require further classification by biological and chemical domain. A test set of 115 chemicals from 9 different MOA classes was used to compare the discriminatory power of several classification schemes based on substructure indicators. Performance, evaluated by contingency table statistics, is varied and no single scheme provides sufficient applicability and reliability for pre-filtering chemical inventories. Major improvements are feasible with combined use of three classification schemes: assignments of baseline toxicants are protective, recognition of excess toxicants is acceptable and applicability range increases favourably.     

Effects of Chemical Reactivity on the Toxicity of Phosphorus Fluoridates

Abstract

Semiempirical quantum calculations were performed on a series of organophosphorus fluoridates to determine the relative reactivity for hydrolysis. This value was determined by subtracting the energy of the metastable intermediate from the energy of the stable molecule. Plotting this relative reactivity for each compound vs. its toxicity resulted in a parabolic curve with nerve agents and other similarly toxic compounds in the center. The more reactive phosphinates and less reactive phosphates were at the edges of the graph in the region of lower toxicity. The results indicate that for compounds meeting minimal structural requirements, chemical reactivity is the principal determinant of cholinesterase inhibition.     

Exploration of Pb2+ Selective Behavior of Calix[6]arene Ester Derivative

The selective behavior of calix[n]arene ester derivatives in two-phase extraction systems using polarographic technique has been investigated. Calix[4]arene tetraester derivative shows remarkable Na⁺ over Pb²⁺ selectivity; whereas calix[6]arene hexaester derivative shows Pb²⁺ over Na⁺ selectivity. The interference of some selected cations (Na⁺, K⁺, Cu²⁺ and Mg²⁺) were also examined and no significant effect on the selectivity behavior as well as extraction ability of these ionophores was found except Na⁺. The study reveals for the first time that the calix[6]arene hexaester derivative is highly Pb²⁺ selective ionophore and can be employed in the field of sensor as well as separation science and technology. The work also highlights the usefulness of polarographic technique in trace metal determination.     

PASS: identification of probable targets and mechanisms of toxicity†

Toxicity of chemical compound is a complex phenomenon that may be caused by its interaction with different targets in the organism. Two distinct types of toxicity can be broadly specified: the first one is caused by the strong compound's interaction with a single target (e.g. AChE inhibition); while the second one is caused by the moderate compound's interaction with many various targets. Computer program PASS predicts about 2500 kinds of biological activities based on the structural formula of chemical compounds. Prediction is based on the robust analysis of structure-activity relationships for about 60,000 biologically active compounds. Mean accuracy exceeds 90% in leave-one-out cross-validation. In addition to some kinds of adverse effects and specific toxicity (e.g. carcinogenicity, mutagenicity, etc.), PASS predicts ～2000 kinds of biological activities at the molecular level, that providing an estimated profile of compound's action in biological space. Such profiles can be used to recognize the most probable targets, interaction with which might be a reason of compound's toxicity. Applications of PASS predictions for analysis of probable targets and mechanisms of toxicity are discussed.     

Repeatability analysis of the Tetrahymena pyriformis population growth impairment assay

Assessments necessary to ensure the safety of both humans and the environment are challenged by the sheer number of chemicals in use today. Chemical legislation, such as REACH, aims to use alternative methods to reduce the reliance on in vivo animal testing. Consequently, databases such as the TETRATOX database, containing data from the Tetrahymena pyriformis population growth impairment assay, have been used extensively to develop computational models which aid in priority setting and initial hazard assessments. To use any toxicological data, an assessment of quality is required. One important aspect of quality is the repeatability of the assay. This study considered TETRATOX assay data for 85 structurally and mechanistically diverse compounds. The repeatability of replicate determinations was assessed and factors relating to repeatability are discussed. Despite the majority of compounds demonstrating excellent repeatability, it was found that the mechanism of action is likely to be a modulating factor, with compounds acting via electrophilic mechanisms being more likely to exhibit reduced repeatability than those acting via narcotic mechanisms. It is evident from this study that the TETRATOX assay is a robust and highly repeatable assay, suitable for use in toxicological modelling studies and priority setting.     

Invariant Joint Transform CorrelatorⅠ: Mapping Filter

l.IntroductionAVanderLugtcomp1exlnatchingspatialcorreIator[1jandajointtransformcorrela-tor[z~ejaret``omaJorkindsofcorrelators,however,theyaresensitivetoscalingandro-tationvariance.Thisdisadvantageisaseverelimitationforthemtobeusedinpracticalapplications-Invariantprocessingwiththeclassicalopticalcorre1atorwithproPertiesotherthanPOsitiondemandsthatthepropertyisrepresentedasashift.WithaIog-POlarmafrping[="j,thesizeandorientationw'il1beexpressedasshiftparameters,orratherrotationascyc1icshift.…     

Comparison of the acute toxicity of tributyltin and copper to veliger larvae of Nassarius reticulatus (L.)

The ban on the use of tributyltin (TBT) is promoting an increasing use of copper as an active biocide in antifouling paints, with consequent rising levels of this metal in the environment. This study assesses the acute toxicity of copper and tributyltin to the larvae of the mollusc gastropod Nassarius reticulatus. Recently hatched veligers were exposed to nominal TBT‐Sn concentrations of 0.9, 1.4, 1.9, 2.8, 3.8, 4.7 and 5.6 µg l^?1 and nominal copper concentrations of 9.4, 23.4, 46.9, 70.3, 93.8, 117.2, 140.6 and 164.1 µg l^?1 for up to 96 h, under static conditions (17 ± 1 °C and 33 ± 1 psu). The percentage of larval mortality was determined for each organometal/metal concentration and exposure time (1, 24, 48, 72 and 96 h). Both TBT and copper had a highly significant effect on larvae survival (p < 0.001) for all times of exposure, except for the first hour in the particular case of TBT. The lowest observed effect concentration for TBT‐Sn decreased over time from 3.8 µg l^?1 at 24 h to 1.9 µg l^?1 at 96 h, whereas for copper it remained constant over time (46.9 µg l^?1). The median lethal concentration (LC₅₀) for TBT‐Sn decreased from 4.87 µg l^?1 at 24 h to 1.78 µg l^?1 at 96 h, and the LC₅₀ for copper decreased from 83.08 µg l^?1 at 24 h to 58.84 µg l^?1 at 96 h. TBT is far more toxic to N. reticulatus larvae than copper. However, owing to the higher copper environmental concentrations, the risk factors of the two biocides may approach each other. This stresses the need to find adequate substitutes for organotin biocides in future antifouling paints. Copyright © 2005 John Wiley & Sons, Ltd.