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Fenpropathrin is an insecticide that is widely used in agriculture. It remains unknown whether fenpropathrin exposure increases the risk of Parkinson's disease. We found that fenpropathrin increased oxidative stress both in vitro and in vivo. Additionally, fenpropathrin increased production of ROS, NOS2, and HO-1, and decreased SOD and GSH in astrocytes. We further found that fenpropathrin-mediated oxidative stress might inhibit autophagic flow, including decreased expression of LC3A/B and enhanced expression of SQSTM1 via down-regulation of CDK-5, an upstream marker of autophagy. In mice, autophagy was slightly different from that found in astrocytes, as reflected in the increased expressions of LC3A/B and SQSTM1. Our findings elucidate the toxicological phenomena and pathogenic mechanisms of fenpropathrin and may provide guidance for improved pesticide control and environmental protection.

The title of the 2016 Society of Toxicologic Pathology (STP) Symposium was the “Basis and Relevance of Variation in Toxicologic Responses.” Many factors may contribute to variation in toxicologic responses and can confound results, complicate interpretation of data, interfere with reproducibility, and make extrapolation to humans problematic. This brief overview summarizes speaker presentations from each session which describes important factors that may impact the interpretation of nonclinical discovery and developmental toxicity studies. In addition, summaries of the Continuing Education (CE) courses and other educational events that occurred during the Symposium are highlighted.

The identification of adverse health effects has a central role in the development and risk/safety assessment of chemical entities and pharmaceuticals. There is currently a need for better alignment regarding how nonclinical adversity is determined and characterized. The European Society of Toxicologic Pathology (ESTP) therefore coordinated a workshop to review available definitions of adversity, weigh determining and qualifying factors of adversity based on case examples, and recommend a practical approach to define and characterize adversity in toxicology reports, to serve as a valuable prerequisite for future organ- or lesion-specific workshops planned by the ESTP.

Introduction: Numerous studies employing various animal models have found that perinatal stress, encountered in utero during sensitive developmental stages or shortly after birth, disrupts both sexual differentiation and sexual behavior in offspring. The biochemical, cellular, genetic and epigenetic events which are involved in the organismal response to perinatal stress are currently under investigation. Methods, Results and Discussion: In this review, the reader is introduced to perinatal stressors as a toxicological phenomenon, and several recently characterized epigenetic responses to said stressors are discussed.

Quantification of nucleic acids has become a common procedure in many toxicology laboratories. Among the technologies that accomplish this is the fluorogenic 5 ′-nuclease assay, commonly known as TaqMan. Three TaqMan applications for genetic and molecular toxicology are presented in this article: quantification of gene expression, detection of genetic polymorphisms, and quantification of chromosomal DNA deletions. Of these, quantification of gene expression is the most widely used, and established TaqMan as a benchmark technology for nucleic acid quantification. Two additional applications, polymorphism detection and quantification of DNA deletions, demonstrate the flexibility and quantitative strengths that make TaqMan so powerful, including high precision, excellent sensitivity, and broad linear dynamic range. These and similar applications improve our ability to investigate genetic and molecular dimensions of toxicological phenomena, and have promoted the widespread use of TaqMan in toxicology departments in the pharmaceutical industry. In addition to presenting these applications, the authors discuss some of the challenges of integrating TaqMan and other new technologies into the drug development process.

The increased acceptance of the use of structure–activity relationship (SAR) approaches to toxicity modelling has necessitated an evaluation of the limitations of the methodology. In this study, the limit of the capacity of the MULTICASE SAR program to model complex biological and toxicological phenomena was assessed. It was estimated that, provided the data set consists of at least 300 chemicals, divided equally between active and inactive compounds, the program is capable of handling phenomena that are even more “complex” than those modelled up to now (for example, allergic contact dermatitis, Salmonella mutagenicity, biodegradability, inhibition of tubulin polymerisation). However, within the data sets currently used to generate SAR models, there are limits to the complexity that can be handled. This may be the situation with regard to the modelling of systemic toxicity (for example, the LD50).

Obviously, insight into the mechanistic basis of toxicological can be concluded that the two phenomena are related mechanistically to one action is needed to assess the risks posed by chemicals. One another. (Similarly, if the observed prevalence is significantly lower than the of the approaches to the elucidation of this problem is to expected one, this suggests that the two phenomena are antagonistic to one evaluate the congruence between the induction of different another, e.g. they could compete for a specific receptor.) toxicological phenomena. Thus, if a group of chemicals induces In implementing such an approach, it quickly becomes obvious that there is a dearth of experimental data on the same chemicals across a variety of a significantly higher than expected incidence of both chromo- toxicological end points. Hence, the significance of the observed joint somal aberrations and developmental anomalies, then one prevalences cannot be ascertained. The current approach was devised to might conclude that the two phenomena are related, possibly overcome this shortcoming. It is based upon the availability of characterized

The CASE/MULTICASE structure-activity relationship (SAR) system was used to assess a new procedure to investigate the mechanistic relatedness of various toxicological endpoints. The method consisted of predicting the activity of 10,000 randomly selected chemicals using validated and characterized SAR models from a variety of biological and toxicological endpoints. The prevalence of chemicals predicted to possess the ability to induce two or more toxicological effects simultaneously should provide a measure of the mechanistic relatedness of these phenomena. Eight toxicological endpoints were predicted and the results were compared to predictions based on an eye irritation SAR model. Allergic contact dermatitis demonstrated a 29.6% greater than expected overlap between expected and observed results (p0.001). Similar results were seen for respiratory hypersensitivity (33.1%), sensory irritation (28.9%), cell toxicity (25.9%), and Ah receptor binding (19.8%). A lesser degree of overlap was seen between eye irritation and Salmonella mutagenicity (11.5%) and the inhibition of gap junction intercellular communication (6.7%). Moreover, a negative overlap, suggesting possibly an antagonistic phenomena, was observed between eye irritation and alpha 2 mu-induced nephropathy. These results indicate that this method can provide a useful tool to investigate mechanistic relatedness between diverse toxicological endpoints.

The availability of validated and characterized SAR models of toxicological phenomena provides a method to apply SAR technology to a variety of environmental, public health and industrial situations. These include (i) the prioritization of environmental pollutants for control and/or regulation, (ii) the design of multi-action optimized therapeutics from which the potential for unwanted side-effects have been engineered out, (iii) the development of SAR-based computer-driven screening procedure to identify candidate therapeutics based upon combinatorial chemistry or compilations of molecular structures, (iv) the generation of toxicological profiles to be used in the selection of benign chemicals in the early stages of product development.

In vitro toxicology generally refers to the study of toxicological phenomena in non-whole-animal models. This broader connotation includes studies utilizing isolated organs, tissue slices, explants cultures, and isolated primary cells, as well as cell lines and subcellular fractions (e.g., microsomes). These model systems have made major contributions to toxicological sciences, particularly in our understanding of the mechanisms of toxicity, xenobiotic metabolism, and species differences in expressions of toxicity. This unit reviews the use of in vitro models and their value in toxicology testing. Curr. Protoc. Toxicol. 34:20.1.1-20.1.6. © 2007 by John Wiley & Sons, Inc. Keywords: alternative methodologies; in vitro assays