Structural AlertsA New Classification Model to Discriminate Excess Toxicity from Narcotic Effect Levels of Organic Compounds in the Acute Daphnid Assay

Abstract

Quantitative and qualitative structure-activity relationships (QSARs) have a great potential to support the risk assessment of chemicals, provided there are tools available that allow evaluation of the suitability of QSARs for the compounds of interest. In this context, a pragmatic approach is to discriminate excess toxicity from narcotic effect levels, because the latter can be estimated from QSARs and thus have a low priority for experimental testing. To develop a respective scheme for the acute daphnid toxicity as one of the primary ecotoxicological endpoints, 1067 acute toxicity data entries for 380 chemicals involving the daphnid species Daphnia magna were taken from the on-line literature, and quality checks such as water solubility were employed to eliminate apparently odd data entries. For 36 known narcotics with LC50 values referring to D. magna, a reference baseline QSAR is derived. Compounds with LC50 values above a certain threshold defined relative to their predicted baseline toxicity are classified as exerting excess toxicity. Three simple discrimination schemes are presented that enable the identification of excess toxicity from structural alerts based on the presence or absence of certain heteroatoms and their chemical functionality. Moreover, a two-step classification approach is introduced that enables a prioritization of organic compounds with respect to their need for experimental testing. The discussion includes reaction mechanisms that may explain the association of structural alerts with excess toxicity, a comparison with predictions derived from mode of action-based classification schemes, and a statistical analysis of the discrimination performance in terms of detailed contingency table statistics.

Prediction of Toxicity, Sensory Responses and Biological Responses with the Abraham Model

“…Often, individual authors have reported the numerical value as a median immobilization effective concentration at the time of measurement, and in a later paper, the same authors referred to the same measured value as the median lethal molar concentration, and vice versa. Von der Ohe et al (2005) made similar observations regarding the published toxicity data for water fleas in their statement ".... some studies use mortality (LC 50 ) and immobilization (EC 50 , effective concentration 50%) as identical endpoints in the context of daphnid toxicity". Von der Ohe et al made no attempt to distinguish between the two.…”

Predicting skin sensitization potential of organic compounds based on toxicity enhancement to Tetrahymena pyriformis, fathead minnow, and Daphnia magna

“…Basic toxicity (defined as minimal toxicity correlated with hydrophobicity) of the 65 compounds to the three aquatic organisms were calculated through log K ow regression models (van Leeuwen et al 1992;von der Ohe et al 2005;Ellison et al 2008). The baseline toxicity models for each organism are summarized in Table 2; hydrophobicity, log K ow , was obtained using EPI Suite 4.1 software.…”

“…Toxicity enhancement (T e ), previously termed excess toxicity, is widely used to determine whether a compound can elicit reactive toxicity through a comparison with its baseline toxicity (von der Ohe et al 2005;Schramm et al 2011). T e ¼ 10 has been proposed as a threshold to discriminate reactive from non-reactive compounds.…”

Developing Methods to Predict Chemical Fate and Effect Endpoints for Use Within REACH

“…Therefore it seems that in the first phase of REACH more pragmatic approaches based on the occurrence of fragments, like in AS-TER or as proposed by von der Ohe et at. [58], will be used with the known limitations described above.…”