Article

Discrepancies in the acute versus chronic toxicity of compounds with a designated narcotic mechanism

University of Antwerp, Department of Biology, Laboratory for Ecophysiology, Biochemistry and Toxicology, Groenenborgerlaan 171, 2020 Antwerp, Belgium.
Chemosphere (Impact Factor: 3.5). 01/2012; 87(7):742-9. DOI: 10.1016/j.chemosphere.2011.12.069
Source: PubMed

ABSTRACT In this study, it was illustrated that even for certain simple organic compounds with a designated mode of action (MOA) (i.e. narcotic toxicity) unexpected differences in acute and chronic toxicity can be observed. In a first part of the study, species sensitivity distributions (SSDs) based on either acute or chronic toxicity data of three narcotic test compounds (methanol, ethanol and 2-propanol) were constructed. The results of the acute SSDs were as expected for narcotic compounds: rather similar sensitivity and small differences in toxicity were observed among different species. On the contrary, the chronic SSDs of methanol and ethanol indicated larger interspecies variation in sensitivity. Furthermore, the chronic toxicity trend (ethanol>methanol>2-propanol) was unexpectedly different from the acute toxicity trend (2-propanol>ethanol>methanol) and acute versus chronic extrapolation could not be successfully described for methanol and ethanol using an ACR of 10 (as suggested for narcotic compounds). In contrast to the interspecies approach in the first part of this study, the second part of the study was focused on the assessment of acute and chronic toxicity of the three test compounds in Daphnia magna, which was identified as one of the most sensitive organisms to methanol and ethanol. Here, the differences in acute and chronic toxicity trend were in accordance to the results of the SSDs. The enhancement of membrane penetration due to the small molecular size of methanol and ethanol, in combination with the higher toxicity of their respective biotransformation products were suggested as potential causes of the increased chronic toxicity. Furthermore, it was stressed that larger awareness of these irregularities in acute to chronic extrapolations of narcotic compounds is required and should receive additional attention in further environmental risk assessment procedure.

0 Followers
 · 
84 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Vertebrate testing under the European Union's regulation on Registration, Evaluation, Authorisation and Restriction of Chemical substances (REACH) is discouraged, and the use of alternative nontesting approaches such as quantitative structure–activity relationships (QSARs) is encouraged. However, robust QSARs predicting chronic ecotoxicity of organic compounds to fish are not available. The Ecological Structure Activity Relationships (ECOSAR) Class Program is a computerized predictive system that estimates the acute and chronic toxicity of organic compounds for several chemical classes based on their log octanol–water partition coefficient (KOW). For those chemical classes for which chronic training data sets are lacking, acute to chronic ratios are used to predict chronic toxicity to aquatic organisms. Although ECOSAR reaches a high score against the Organisation for Economic Co-operation and Development (OECD) principles for QSAR validation, the chronic QSARs in ECOSAR are not fully compliant with OECD criteria in the framework of REACH or CLP (classification, labeling, and packaging) regulation. The objective of the present study was to develop a chronic ecotoxicity QSAR for fish for compounds acting via nonpolar and polar narcosis. These QSARs were built using a database of quality screened toxicity values, considering only chronic exposure durations and relevant end points. After statistical multivariate diagnostic analysis, literature-based, mechanistically relevant descriptors were selected to develop a multivariate regression model. Finally, these QSARs were tested for their acceptance for regulatory purposes and were found to be compliant with the OECD principles for the validation of a QSAR. Environ Toxicol Chem 2013;32:2217–2225. © 2013 SETAC
    Environmental Toxicology and Chemistry 10/2013; 32(10). DOI:10.1002/etc.2301 · 2.83 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: It is a tricky but fundamental problem in risk assessment to predict the combined toxicity of several chemicals by methods other than by experiment, especially for binary mixtures, in order to save time and experimental costs. Though several models have been developed, making a choice among them is difficult owing to the variation in mode of inhibition (MOI). To choose a reference model appropriately, we propose an in silico procedure which employs molecular simulation techniques to identify MOI, and which highlights the binding pattern of a small molecule to a biomacromolecule. Specifically, the method is verified by experimental study and shows that 15 binary mixtures of three pesticides, baygon, metacrate, and velpar, inhibit firefly luciferase bioluminescence. The results reveal that the pesticides share the same binding site at the bottom of the luciferin pocket, and combined toxicities could be predicted by the concentration addition model, which enables us to identify the MOI using molecular simulation techniques. In addition, there is a linear relationship between the binding free energy of the mixture (ΔGmix) calculated from the ΔGs of the components and the median effective concentrations (EC50) of the mixture.
    RSC Advances 07/2014; 4(61). DOI:10.1039/C4RA02698E · 3.71 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND Thymol offers an attractive alternative to synthetic chemicals to keep Varroa under control. However, thymol accumulates in bee products and is suspected of having adverse effects on colonies and especially on larvae. In this study, we investigated the effects of acute and chronic exposure to thymol on larvae reared in vitro with contaminated food and compared results to the theoretical larval exposure based on the amount of pollen and honey consumed by larvae during their development. RESULTSThe laboratory assays reveal that, first, the 48 h-LD50 of thymol introduced into larval food is 0.044 mg larva−1. Second, the 6 day-LC50 is 700 mg kg−1 food. A significant decrease of larval survival and mass occurred from 500 mg thymol kg−1 food (P < 0.0001). Finally, vitellogenin expression, which reached a maximum at the fifth instar larvae, is delayed for individuals exposed to 50 mg thymol kg−1 food (P < 0.0006). That is 10 times higher than the theoretical level of exposure. CONCLUSION Based on the level of thymol residue found in honey and pollen, these results suggest that the contamination of food by thymol represents no notable risk for the early-developing larvae. © 2013 Society of Chemical Industry
    Pest Management Science 01/2014; 70(1). DOI:10.1002/ps.3539 · 2.74 Impact Factor