Identification and Description of the Uncertainty, Variability, Bias and Influence in Quantitative Structure-Activity Relationships (QSARs) for Toxicity Prediction

Improving regulatory confidence in, and acceptance of, a prediction of toxicity from a quantitative structure-activity relationship (QSAR) requires assessment of its uncertainty and determination of whether the uncertainty is acceptable. Thus, it is crucial to identify potential uncertainties fundamental to QSAR predictions. Based on expert review, sources of uncertainties, variabilities and biases, as well as areas of influence in QSARs for toxicity prediction were established. These were grouped into three thematic areas: uncertainties, variabilities, potential biases and influences associated with 1) the creation of the QSAR, 2) the description of the QSAR, and 3) the application of the QSAR, also showing barriers for their use. Each thematic area was divided into a total of 13 main areas of concern with 49 assessment criteria covering all aspects of QSAR development, documentation and use. Two case studies were undertaken on different types of QSARs that demonstrated the applicability of the assessment criteria to identify potential weaknesses in the use of a QSAR for a specific purpose such that they may be addressed and mitigation strategies can be proposed, as well as enabling an informed decision on the adequacy of the model in the considered context

Revisions to the derivation of the Australian and New Zealand guidelines for toxicants in fresh and marine waters

The Australian and New Zealand Guidelines for Fresh and Marine Water Quality are a key document in the Australian National Water Quality Management Strategy. These guidelines released in 2000 are currently being reviewed and updated. The revision is being co-ordinated by the Australian Department of Sustainability, Environment, Water, Population and Communities, while technical matters are dealt with by a series of Working Groups. The revision will be evolutionary in nature reflecting the latest scientific developments and a range of stakeholder desires. Key changes will be: increasing the types and sources of data that can be used; working collaboratively with industry to permit the use of commercial-in-confidence data; increasing the minimum data requirements; including a measure of the uncertainty of the trigger value; improving the software used to calculate trigger values; increasing the rigour of site-specific trigger values; improving the method for assessing the reliability of the trigger values; and providing guidance of measures of toxicity and toxicological endpoints that may, in the near future, be appropriate for trigger value derivation. These changes will markedly improve the number and quality of the trigger values that can be derived and will increase end-users’ ability to understand and implement the guidelines in a scientifically rigorous manner

Systematic review and meta-analysis of early life exposure to di(2-ethylhexyl) phthalate and obesity related outcomes in rodents

Background: It has been suggested that the plasticizer di(2-ethylhexyl) phthalate (DEHP) exerts obesogenic effects after pre- or perinatal exposure. Objective: A systematic review with meta-analyses was conducted of early life exposure to DEHP, or its biologically active metabolite mono(2-ethylhexyl) phthalate (MEHP), on the obesity related outcome measures body weight, fat (pad) weight, triglycerides, free fatty acids and leptin in experimental rodent studies. Methods: The applied methodology was pre-specified in a rigorous protocol. Relevant articles were identified using PubMed and EMBASE and meta-analyses were performed using mean differences (MD) and random effects model when at least five studies could be included per outcome measure. Risk of bias and the quality of evidence was assessed using established methodologies. Results: Overall, 31 studies could be included and meta-analyses could be performed for body weight and fat weight. Early life exposure to DEHP was significantly associated with increased fat weight (MD ¼ 0.02; 95% CI: 0.00, 0.03), while a non-significant association was estimated for body weight (MD ¼ 0.14; 95% CI: 0.32, 0.04). There was substantial heterogeneity across studies and the information was insufficient to assess the risk of bias for most studies. No meta-analyses could be conducted for other outcome measures, because too few studies were available. Conclusions: The results of this systematic review indicate that early life exposure to DEHP is potentially associated with increased adiposity in rodents. More data is needed to strengthen the evidence base.This project received funding from the European Community's Seventh Framework Programme [FP7/2007e2013] under grant agreement OBELIX n 227391 and the Netherlands Organization for Scientific Research (NWO-VIDI 864.09.005)