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Introduction Lidocaine is a common local anesthetic used during minor procedures performed on pediatric patients. A rare but toxic and life-threatening side effect of lidocaine is methemoglobinemia. It should be considered in children who are hypoxic after exposure to an oxidizing agent. Methods We developed this simulation case for pediatric emergency medicine (PEM) fellows, but it can be adapted for interprofessional simulation. The case involved a 1-month-old male with hypoxia and resulting central cyanosis after exposure to lidocaine. The team performed an initial evaluation and intervention, collected a history, and developed a differential diagnosis for hypoxia and central cyanosis in an infant. Methemoglobinemia was confirmed by CO-oximetry. Preparatory materials, a debriefing guide, and scenario evaluation forms assisted with facilitation. Results Fifty-six participants (including 18 PEM fellows) completed this simulation across four institutions. Participants rated the scenario on a 5-point Likert scale (1 = strongly disagree, 5 = strongly agree), finding it to be relevant to their work (median = 5) and realistic (median = 5). After participation in the simulation, learners felt confident in their ability to recognize methemoglobinemia (median = 4) and implement a plan to stabilize an infant with hypoxia (median = 4). Discussion This simulation represents a resource for learners in the pediatric emergency department. It teaches the recognition and management of an infant with lidocaine toxicity and resultant methemoglobinemia. It uses experiential learning to teach and reinforce a systematic approach to the evaluation and management of a critically ill infant with acquired methemoglobinemia.

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.

Wahrend der Schwangerschaft befinden sich nahezu alle fetalen Organsysteme in einem vulnerablen Entwicklungszustand. Umwelteinflusse in diesem Zeitraum konnen daher zu dauerhaften morphologischen und funktionellen Storungen der Organe fuhren, die eine Krankheitsdisposition im spateren Leben verursachen. Wahrend hierfur im englischsprachigen Raum der Begriff der „developmental origins of health and disease“ (entwicklungsbedingter Ursprunge von Gesundheit und Erkrankung, DoHaD) gepragt wurde, wird im deutschsprachigen Raum vorwiegend die Bezeichnung „fetale oder perinatale Programmierung“ verwendet. Traditionell wurden viele Umwelteinflusse v. a. unter teratologischen Gesichtspunkten untersucht, d. h., der Fehlbildungsaspekt stand im Vordergrund. Viele Auswirkungen einer intrauterinen Exposition ausern sich jedoch nicht unbedingt in Form offensichtlicher Fehlbildungen zum Zeitpunkt der Geburt, sondern verursachen zunachst eher subklinische Veranderungen. Der vorliegende Beitrag gibt eine Ubersicht uber die moglichen Auswirkungen haufiger und relevanter schadlicher Umwelteinflusse in der Schwangerschaft auf die fetoplazentare Einheit sowie auf die spatere Disposition des Kindes fur neurologische, pneumologische und renale Erkrankungen. Im Einzelnen werden Daten vorgestellt, die Studien den Bereichen Substanzabusus (Alkohol, Tabak, Medikamente, illegale Drogen), Toxikologie/Strahlung sowie akuter und chronischer Stressbelastung entstammen.

The glycation of proteins is non-physiological post-translational incorporation of carbohydrates onto the free amines or guanidines of proteins and some lipids. Although the existence of glycated proteins has been known for forty years, a full understanding of their pathogenic nature has been slow in accruing. In recent years, however, glycation has gained widespread acceptance as a contributing factor in numerous metabolic, autoimmune, and neurological disorders, tying together several confounding aspects of disease etiology. From diabetes, arthritis, and lupus, to multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer’s, and Parkinson’s diseases, an emerging glycation/inflammation paradigm now offers significant new insight into a physiologically important toxicological phenomenon. It exposes novel drug targets and treatment options, and may even lay foundations for long-awaited breakthroughs. : This ‘current frontier’ article briefly profiles current knowledge regarding the underlying causes of glycation, the structural biology implications of such modifications, and their pathological consequences. Although several emerging therapeutic strategies for addressing glycation pathologies are introduced, the primary purpose of this mini-review is to raise awareness of the challenges and opportunities inherent in this emerging new medicinal target area.

The assessment of acute toxicity is one of the most important stages to ensure the safety of chemicals with potential applications in pharmaceutical sciences, biomedical research, or any other industrial branch. A huge and indiscriminate number of toxicity assays have been carried out on laboratory animals. In this sense, computational approaches involving models based on quantitative-structure activity/toxicity relationships (QSAR/QSTR) can help to rationalize time and financial costs. Here, we discuss the most significant advances in the last 6 years focused on the use of QSAR/QSTR models to predict acute toxicity of drugs/chemicals in laboratory animals, employing large and heterogeneous datasets. The advantages and drawbacks of the different QSAR/QSTR models are analyzed. As a contribution to the field, we introduce the first multitasking (mtk) QSTR model for simultaneous prediction of acute toxicity of compounds by considering different routes of administration, diverse breeds of laboratory animals, and the reliability of the experimental conditions. The mtk-QSTR model was based on artificial neural networks (ANN), allowing the classification of compounds as toxic or non-toxic. This model correctly classified more than 94% of the 1646 cases present in the whole dataset, and its applicability was demonstrated by performing predictions of different chemicals such as drugs, dietary supplements, and molecules which could serve as nanocarriers for drug delivery. The predictions given by the mtk-QSTR model are in very good agreement with the experimental results.

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.

The potential of a drug to cause certain organ toxicities is somehow implicitly contained in its full pharmacological profile, provided the drug reaches and accumulates at the various organs where the different interacting proteins in its profile, both targets and off-targets, are expressed. Under this assumption, a computational approach was implemented to obtain a projected anatomical profile of a drug from its in vitro pharmacological profile linked to protein expression data across 47 organs. It was observed that the anatomical profiles obtained when using only the known primary targets of the drugs reflected roughly the intended organ targets. However, when both known and predicted secondary pharmacology was considered, the projected anatomical profiles of the drugs were able to clearly highlight potential organ off-targets. Accordingly, when applied to sets of drugs known to cause cardiotoxicity and hepatotoxicity, the approach is able to identify heart and liver, respectively, as the organs where the proteins in the pharmacological profile of the corresponding drugs are specifically expressed. When applied to a set of drugs linked to a risk of Torsades de Pointes, heart is again the organ clearly standing out from the rest and a potential protein profile hazard is proposed. The approach can be used as a proxy indicator of potential in vivo organ toxicities.

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.

Research in toxicology generates vast quantities of data which reside on the Web and are subsequently appropriated and utilized to support further research. This data includes a broad spectrum of information about chemical, biological and radiological agents which can affect health, the nature of the effects, treatment, regulatory measures, and more. Information is structured in a variety of formats, including traditional databases, portals, prediction models, and decision making support tools. Online resources are created and housed by a variety of institutions, including libraries and government agencies. This paper focuses on three such institutions and the tools they offer to the public: the National Library of Medicine (NLM) and its Toxicology and Environmental Health Information Program, the United States Environmental Protection Agency (EPA), and the Organisation for Economic Co-operation and Development (OECD). Reference is also made to other relevant organizations.

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).

Currently available substructure-based structure-activity relationship (SAR) methodologies, if expertly used, can be employed to predict the toxicological potential of therapeutic agents. Moreover, with robust SAR models of toxicological phenomena, it is feasible to understand the basis of these toxicities and to ascertain their relevance to possible human health risks. At present, SAR approaches to the evaluation of toxicity must be used in conjunction with human expert knowledge. The currently available technology can be used to design molecules of reduced toxicity which retain their therapeutic effectiveness. Keywords: SAR; structure-activity; toxicity; modeling; mechanism

This paper examines the epistemological warrant for a toxicological phenomenon known as chemical hormesis. First, it argues that conceptual confusion contributes significantly to current disagreements about the status of chemical hormesis as a biological hypothesis. Second, it analyzes seven distinct concepts of chemical hormesis, arguing that none are completely satisfactory. Finally, it suggests three ramifications of this analysis for ongoing debates about the epistemological status of chemical hormesis. This serves as a case study supporting the value of philosophical methodologies such as conceptual clarification for addressing contemporary scientific disputes, including policy-related scientific disputes that may be heavily influencedby social and political factors.

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.

As more and more nanomaterials with novel physicochemical properties or new functions are created and used in different research fields and industrial sectors, the scientific and public concerns about their toxic effects on human health and the environment are also growing quickly. In the past decade, the study of the toxicological properties of nanomaterials/nanoparticles has formed a new research field: nanotoxicology. However, most of the data published relate to toxicological phenomena and there is less understanding of the underlying mechanism for nanomaterial-induced toxicity. Nanomaterial-induced reactive oxygen species (ROS) play a key role in cellular and tissue toxicity. Herein, we classify the pathways for intracellular ROS production by nanomaterials into 1)the direct generation of ROS through nanomaterial-catalyzed free-radical reactions in cells, and 2)the indirect generation of ROS through disturbing the inherent biochemical equilibria in cells. We also discuss the chemical mechanisms associated with above pathways of intracellular ROS generation, from the viewpoint of the high reactivity of atoms on the nanosurface. We hope to aid in the understanding of the chemical origin of nanotoxicity to provide new insights for chemical and material scientists for the rational design and creation of safer and greener nanomaterials.

Recently, free radical involving active oygen speceies and nitric oxide are widely investigated because of their role in physiological, pathological and toxicological phenomena. Electron spin resonance (ESR) spectrometer is used for detecting free radicals. More recently, in vivo ESR has been developed to analyse free radical reactions in living animals. In the present paper, ESR measurement of bioradicals is reviewed, including its principle, application of spin trapping technique, in vivo ESR system, and non-invasive analysis of free radical reaction in mice.

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

Structure-activity relationship (SAR) modeling of toxicological phenomena is optimal when the ratio of toxicants to non-toxicants included in the model is unity. Frequently, however, the experimental data available are enriched with toxicants, this appears to be especially true for genotoxicity data sets. It is demonstrated herein, using a Salmonella mutagenicity data set, that when there is a paucity of non-toxicants, the learning set may be augmented with physiological chemicals on the assumption that they are non-genotoxic.

Environmental estrogens have been implicated as etiological agents for breast cancer. This study 15 aimed at identifying mechanistic information regarding the estrogenicity and carcinogenicity of environmental estrogens through structure-activity relationship(SAR) and quantitative SAR (QSAR) modeling. To facilitate this investigation, the computer-based expert-system MULTICASE is used in addition to other molecular modeling techniques. Learning sets have been derived from bioassays designed to detect estrogenic chemicals. These databases include an in vitro estrogen competitive binding assay, an in vitro NCF-7 cell proliferation assay and a whole animal uterine weight increase assay (currently being derived). The SAIL and QSAR models derived from these databases are considered in conjuction with preexisting SAIL and QSAR models for rodent carcinogenicity as well as for other toxicological phenomena to identify features that are common to estrogenicity and carcinogenicity.

In Colombia (South America) during recent decades the administration of scopolamine, extracted from plants belonging to the Datura or Brugmansia genus, has become an important neurologic and toxicologic phenomenon. These extracts have been popularly known as "Burundanga." Chemical characteristics and clinical features of scopolamine intoxication are described. Anterograde amnesia and submissive behavior found in patients intoxicated with scopolamine are analyzed. Burundanga intoxication is related to other toxic phenomena found in different countries and similitudes with transient global amnesia are emphasized.

Recent advances in fields of insect physiology and insect toxicology have emphasized the desirability of sound bases for the expression of the physiological and toxicological phenomena discovered. In the higher animals the metabolic rate as determined by the respiratory quotient and the calorific output is commonly expressed with relation to body surface. The respiration of insects has been studied by many workers (Lee, 1929), several of whom have measured the oxygen intake and the carbon dioxide output. McGovran (1931) has dctermined the quantity of air passing through the tracheal system of the grasshopper per gram of body weight. Bodine (1921), in addition, has expressed the carbon dioxide output of certain Orthoptera not only on the basis of body weight but also as a function of the weight to the two-thirds power, the latter being a very rough approximation of the body surface. He found a much better agreement of the data when it was compared to the two-thirds power of the weight rather than to the weight alone, and has stated that the surface law probably holds for insects as well as for higher animals. Many workers in entomology would no doubt express their results with relation to body surface for the purpose of comparison with similar results available for higher animals, if the surface area of insects could be readily obtained.

Many environmental applications of biotechnology involve deliberate release of organisms into the environment, where they must survive and multiply to perform their functions. Examples of such applications include degradation of toxic chemicals and in-situ leaching of ores. It is natural, when developing a scheme for assessing environmental risks of these microorganisms, to take as a point of departure existing schemes for assessing environmental risks of toxic contaminants. The components of such risk assessments, characterized by the National Academy of Sciences [1] as “hazard identification,” “dose-response assessment,” “exposure assessment,” and “risk characterization”, derive from a systematic examination of the physical, chemical, and toxicological phenomena underlying the risk: the emission rate of the toxicant, its dispersion in air and water, the chemical transformations occurring during transport, and the relationship between the dose to the exposed organism (usually man) and the toxicological effect.

In this discussion I will not attempt to summarize all of the papers presented during this symposium because it would be impossible to recount all of the new observations that were presented as well as to evaluate the current status of the several areas that were reviewed. It would seem more appropriate to place these new achievements into perspective within the constantly flowing stream of toxicological knowledge that has been handed down to us from our pharmacological and toxicological predecessors. The work that each of us does, after all, is a link in a chain connecting us in our attempts to gain insights into toxicological phenomena which occur in the cells of man and animals.

It is an honor to attend this Symposium organized to pay respects to the late Professor Piet De Somer. The range of the subject matter under discussion is testimony to the breadth of Prof. P. De Somer’s scientific interests just as the Rega Institute is an Embodiment of his recognition that scientific progress requires the commitment of tangible resources. Clearly Prof. De Somer was a scientist who recognized the need to explore practical means to foster a productive relationship between scientific progress and its practical applications.

One of the main criteria which determine the possibility of the use of a particular type of ice-melter reagents (IMR) is the degree of their safety for the environment and human health, which is reflected in the establishment of safe doses and concentrations. In this regard, the current area of research is to improve the ecological and epidemiological principles of risk assessment of modern types of anti-icing agents. Currently available data concerning monitoring soil studies and the snow held in various cities of Russia, show that there is a process of accumulation of the main components of IMR - sodium and chlorine ions in the areas related to the roadway. The article is designated a problem of existing methodological approaches to the assessment of the phytotoxic impact in the investigation of anti-icing agents in the laboratory. There was executed the comparative characteristics of the results of the preliminary pilot studies on the phytotoxic properties of IMR under using different substrates for germination of seeds - soil and filter paper. The data obtained are characterized by differences in the degree of phytotoxic action of the same species depending upon ice-melter reagents methodical setting circuit laboratory experiment. As a result, there was shown the imperfection of the existing method of rapid analysis in relation to ice-melter materials (IMM).