59 research outputs found
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
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)
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