Toxicological Sciences Research Articles

A web-based tool for designing experimental studies to detect hormesis and estimate the threshold dose.

Hormesis has been widely observed and debated in a variety of context in biomedicine and toxicological sciences. Detecting its presence can be an important problem with wide ranging implications. However, there is little work on constructing an efficient experiment to detect its existence or estimate the threshold dose. We use optimal design theory to develop a variety of locally optimal designs to detect hormesis, estimate the threshold dose and the zero-equivalent point (ZEP) for commonly used models in toxicology and risk assessment. To facilitate use of more efficient designs to detect hormesis, estimate threshold dose and estimate the ZEP in practice, we implement computer algorithms and create a user-friendly web site to help the biomedical researcher generate different types of optimal designs. The online tool facilitates the user to evaluate robustness properties of a selected design to various model assumptions and compare designs before implementation.

Digital chemical test impresses

Toxicologists this week unveiled a chemical safety screening tool that could greatly reduce the need for six common animal tests. Those tests account for nearly 60% of the estimated 3 million to 4 million animals used annually in risk testing worldwide. The computerized tool—built on a massive database of molecular structures and existing safety data—appears to match, and sometimes improve on, the results of animal tests for properties such as skin sensitization and eye irritation, the researchers report in today9s issue of Toxicological Sciences. But it also has limitations; for instance, the method can9t reliably evaluate a chemical9s risk of causing cancer. And it9s not clear how open regulatory agencies will be to adopting a nonanimal approach, although both European and U.S. regulators say they are open to the idea. Still, the big data approach is encouraging to those seeking to reduce and replace animal testing.

Microextraction techniques in antibiotic monitoring in body fluids: Recent trends and future

ABSTRACTThe analysis of drugs in biomedical discipline targets a broad range of aims such as therapeutic drug monitoring, pharmacokinetic study to investigate the drug bioavailability, bioequivalence tests to evaluate the effect of formulation parameters, toxicology, and forensic science. Because of the low levels of typical antibiotics in plasma, blood, urine, exhalation samples, and other biological fluids as well as complex matrix of biological media, adequate sample preparation methods should be implemented for quantification of antibiotics. In this review, developments in well-established microextraction techniques for the clinical analysis of biological samples will be reviewed and discussed. This article presents an overview of microextraction methods for biological samples, focusing especially on antibiotics.

The effect of Porphyromonas gingivalis Lipopolysaccharide (LPS) on Rat Brain Microglia Classical and Alternative Activation in vitro: MMP‐9 generation

BackgroundThe putative association between periodontal disease (PD), a chronic inflammatory disease affecting 64% of adults 65 years and older, and neuroinflammation, a condition which involves microglia, a cell of the brain innate immune system, remains relatively unexplored. We recently reported that lipopolysaccharide (LPS) of Porphyromonas gingivalis (Pg), a pathogenic bacteria implicated in periodontitis activates both classical (M1‐type) and alternative (M2‐type) activation of neonatal rat microglia (BMG) and concomitant release of superoxide anion, thromboxane B2, cytokines, and chemokines (Toxicological Sciences Supplement, 150 (1), Abstract # 2974, 2017). We hypothesized that classical activated microglia might also release the pro‐inflammatory matrix metalloproteinase‐9 (MMP‐9).MethodsP. gingivalis LPS (Pg LPS) was purchased from InvivoGen (San Diego, CA). E. coli LPS (Ec LPS) 026:B6 (from Difco Lab, Detroit, MI) was used as a positive control. BMG were isolated from neonatal rats, and treated in vitro with either Pg LPS or Ec LPS, in a concentration‐dependent manner, for 18 hours at 35.9°C. BMG were identified by confocal microscopy using the surface marker CD11b/c. Matrix metalloproteinase‐9 was determined with a rat total MMP‐9 DuoSet ELISA kit (R&D Systems).ResultsStatistically significant and concentration‐dependent release of pro‐inflammatory MMP‐9 was observed at > than 1ng/mL Ec LPS and 105 ng/mL Pg LPS.ConclusionsOur results provide support for our working hypothesis, because Pg LPS stimulated BMGs to release pro‐inflammatory MMP‐9 in a time‐ and concentration‐dependent manner. Thus, our current observations extend our studies on the effect of Pg LPS on rat brain microglia activation and contribute to further characterize both periodontitis, and the role of BMG in neuroinflammation and potential neurodegeneration.Support or Funding InformationSupport by College of Dental Medicine, Midwestern University is gratefully acknowledged.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

A history of the development of the Latin American mutagenesis society: ALAMCTA

The Asociación Latinoamericana de Mutagénesis, Carcinogénesis y Teratogénesis Ambiental (ALAMCTA) is the organizational structure encompassing the five national environmental mutagenesis societies of Latin America. It was founded in 1980 and has held 10 congresses and had 10 presidents, representing members from throughout Latin America. This brief review describes the founding of ALAMCTA and the key events associated with it, including the initiation in 1993 of the influential Alexander Hollaender Courses in Mexico City, and the hosting of the 11th International Conference on Environmental Mutagens (ICEM) in 2013 in Foz do Iguaçu, Brazil. The ALAMCTA has proven to be a central organizing structure for scientists throughout the Latin America, aiming to meet, collaborate, exchange ideas, and promote the science of genetic toxicology and environmental mutagenesis. It has served to integrate scientists from diverse cultures and two language groups on a vast continent to know each other and to work towards common goals of improving public health, supporting basic research, and identifying and trying to solve environmental problems. Given its long history of 37 years and solid foundation due to the dedicated efforts of so many scientists from throughout the region, ALAMCTA is poised to play a critical role in Latin American science long into the future.

The dose response principle from philosophy to modern toxicology: The impact of ancient philosophy and medicine in modern toxicology science.

Since ancient times the concept of dose response, from a toxicological perspective, has been a matter of concern. Already by the 8th century BC and over the years, many enlightened people have attempted to interpret this phenomenon, observing and coming across its results and practical implementation through exposure to chemical substances, either from natural or synthetic sources. Nowadays, the environmental exposure of human populations to chemicals in terms of quantity and quality might differ. Nevertheless, dose response still remains an issue joining hands with scientific and technological progress. The aim of the present review is not only to briefly recount the history of the dose response concept, from ancient time theories to novel approaches, but also to draw the outline of challenges and requirements toxicology science needs to fulfill.

Take a Retrospective Glance at My Studies: A Close Involvement in Toxicological Sciences

Take a Retrospective Glance at My Studies: A Close Involvement in Toxicological Sciences

Bisphenol A (BPA) hazard assessment protocol

Bisphenol A (BPA) hazard assessment protocol

Towards optimisation of induced pluripotent cell culture: Extracellular acidification results in growth arrest of iPSC prior to nutrient exhaustion

Human induced pluripotent stem cells (iPSC) have the potential to radically reduce the number of animals used in both toxicological science and disease elucidation. One initial obstacle culturing iPSC is that they require daily medium exchange. This study attempts to clarify why and propose some practical solutions.Two iPSC lineages were fed at different intervals in a full growth area (FGA) or a restricted growth area (RGA). The FGA consisted of a well coated with Matrigel™ and the RGA consisted of a coated coverslip placed in a well. Glucose, lactate, extracellular pH and cell cycle phases were quantified.Without daily feeding, FGA cultured iPSC had significantly reduced growth rates by day 2 and began to die by day 3. In contrast, RGA cultured cells grew to confluence over 3days. Surprisingly, glucose was not exhausted under any condition. However, extracellular pH reached 6.8 after 72h in FGA cultures. Artificially reducing medium pH to 6.8 also inhibited glycolysis and initiated an increase in G0/G1 phase of the cell cycle, while adding an additional 10mM bicarbonate to the medium increased glycolysis rates.This study demonstrates that iPSC are highly sensitive to extracellular acidification, a likely limiting factor in maintenance of proliferative and pluripotent status. Culturing iPSC in RGA prevents rapid extracellular acidification, while still maintaining pluripotency and allowing longer feeding cycles.

Measurement of uncertainty for blood alcohol concentration by headspace gas chromatography

ABSTRACTMeasurement of uncertainty has recently become more relevant to the science of forensic toxicology for a variety of reasons. From accreditation to court testimony, measurement of uncertainty is being requested to accompany case results. The Toxicology Bureau of the New Mexico Department of Health has conducted a study to estimate a reasonable uncertainty for the mass concentration of ethanol, methanol, acetone, and isopropanol (g/100 mL) determined through dual capillary column headspace gas chromatography. In this measurement of uncertainty for BAC, alcohol encompasses ethanol, methanol, acetone, and isopropanol, and all four analytes are included in the final expanded uncertainty. One expanded uncertainty value incorporates all four analytes, simplifies the calculation, and streamlines the reporting process of the estimation of error. Three major groups were used in the estimation of the blood alcohol concentration expanded uncertainty: GC calibration adjustment slope, GC analytical, and certified reference material. The proportional standard uncertainties for these sources were combined using root-sum-squares to yield a combined standard uncertainty of uc = ±2.39% for the blood alcohol concentration method. The combined standard uncertainty was expanded to a confidence level of 95% with a coverage factor of 2. The final expanded uncertainty for the blood alcohol concentration method was U = ±4.8%.

An open-sourced statistical application for identifying complex toxicological interactions of environmental pollutants.

The rising number of chemicals that humans are exposed to on a daily basis, as well as advances in biomonitoring and detection technologies have highlighted the diversity of individual exposure profiles (complex body burdens). To address this, the toxicological sciences have begun to shift away from examining toxic agents or stressors individually to focusing on more complex models with multiple agents or stressors present. Literature on interactions between chemicals is fairly limited in comparison with dose-response studies on individual toxicants, which is largely due to experimental and statistical challenges. Experimental designs capable of identifying these complex interactions are often avoided or not evaluated to their fullest potential because of the difficulty associated with appropriate analysis as well as logistical factors. To assist with statistical analysis of these types of experiments, an online, open-sourced statistical application was created for investigators to use to analyze and interpret potential toxicant interactions in laboratory experimental data using a full-factorial three-way analysis of variance (ANOVA). This model utilizes backward selection on interaction terms to model main effects and interactions.

Evolution of toxicological science: the need for change

Evolution requires change but the field of toxicology has not kept pace. The top ten problems urging change are: 1) disparity of testing requirements and risk acceptance for different products and geographical areas; 2) throughput and testing costs versus testing needs; 3) limited predictivity for humans; 4) precautionary approaches from drug development adapted to other areas; 5) animal use; 6) traditional tests unsuitable for new products; 7) lack of coverage for new hazards; 8) failure to address mixtures of toxicants; 9) lack of coverage for individual susceptibilities and vulnerable subpopulations; 10) poor basic research and publication standards. The intransigence at the root of these problems is discussed with reference to current international toxicological policies and methods. For each, the limitations are reviewed with reference to key literature. While current approaches are still needed, there is room for substantial change. To meet the challenges of the 21st century, revolution rather than evolution is required.

Use of a Constrained Mixture Design to Optimize a Procedure for Closed Vessel Microwave-Assisted Digestion of Vegetal Leaves

Background: Reliable analytical methods for metals determination in tea is a demand of the nutritional and toxicological sciences. In this work, a constrained mixture design has been applied to develop an efficient closed-vessel microwave-assisted digestion procedure for Ca, Cu, Fe, K, Mg, Mn, Na, Sr and Zn determination in vegetal leaves used for tea preparation. Keywords: Constrained mixture design, final acidity, ICP OES, metal, microwave-assisted digestion, residual carbon, vegetal leaves.

Global environmental health: an interview with Sally Perreault Darney

Abstract Pollution-induced health problems are of concern across the world. In China, the recent and rapid surge of economic development has been associated with public health problems as well as environmental degradation. We recently spoke with Sally Perreault Darney, Ph.D., the Editor-in-Chief of Environmental Health Perspectives (EHP), the foremost journal about environmental health. Published by the National Institute of Environmental Health Sciences (NIEHS), a part of the US National Institutes of Health, this fully open-access journal publishes peer-reviewed research and commentary, as well news and opinion across the many disciplines that contribute to the field of environmental health, including toxicology, epidemiology, risk assessment and exposure science. We wanted to learn her perspectives on the role that research plays in defining and solving environmental health problems in today's world. Dr. Darney holds a Ph.D. in Biomedical Science and enjoyed a productive research career in the US Environmental Protection Agency (EPA)'s Office of Research and Development, before joining NIEHS in 2015.

Annual report of the Emerging Risks Exchange Network 2015

Annual report of the Emerging Risks Exchange Network 2015

Completing the Link between Exposure Science and Toxicology for Improved Environmental Health Decision Making: The Aggregate Exposure Pathway Framework.

Driven by major scientific advances in analytical methods, biomonitoring, computation, and a newly articulated vision for a greater impact in public health, the field of exposure science is undergoing a rapid transition from a field of observation to a field of prediction. Deployment of an organizational and predictive framework for exposure science analogous to the "systems approaches" used in the biological sciences is a necessary step in this evolution. Here we propose the aggregate exposure pathway (AEP) concept as the natural and complementary companion in the exposure sciences to the adverse outcome pathway (AOP) concept in the toxicological sciences. Aggregate exposure pathways offer an intuitive framework to organize exposure data within individual units of prediction common to the field, setting the stage for exposure forecasting. Looking farther ahead, we envision direct linkages between aggregate exposure pathways and adverse outcome pathways, completing the source to outcome continuum for more meaningful integration of exposure assessment and hazard identification. Together, the two frameworks form and inform a decision-making framework with the flexibility for risk-based, hazard-based, or exposure-based decision making.

Banned: A History of Pesticides and the Science of Toxicology. By Frederick Rowe Davis . New Haven : Yale University Press , 2014 . 288 pp. Illustrations, tables, notes, and index. Cloth $40.00.

<i> Banned: A History of Pesticides and the Science of Toxicology. </i> By Frederick Rowe Davis . New Haven : Yale University Press , 2014 . 288 pp. Illustrations, tables, notes, and index. Cloth $40.00.

The principle of safety evaluation in medicinal drug - how can toxicology contribute to drug discovery and development as a multidisciplinary science?

Pharmaceutical (drug) safety assessment covers a diverse science-field in the drug discovery and development including the post-approval and post-marketing phases in order to evaluate safety and risk management. The principle in toxicological science is to be placed on both of pure and applied sciences that are derived from past/present scientific knowledge and coming new science and technology. In general, adverse drug reactions are presented as "biological responses to foreign substances." This is the basic concept of thinking about the manifestation of adverse drug reactions. Whether or not toxic expressions are extensions of the pharmacological effect, adverse drug reactions as seen from molecular targets are captured in the category of "on-target" or "off-target", and are normally expressed as a biological defense reaction. Accordingly, reactions induced by pharmaceuticals can be broadly said to be defensive reactions. Recent molecular biological conception is in line with the new, remarkable scientific and technological developments in the medical and pharmaceutical areas, and the viewpoints in the field of toxicology have shown that they are approaching toward the same direction as well. This paper refers to the basic concept of pharmaceutical toxicology, the differences for safety assessment in each stage of drug discovery and development, regulatory submission, and the concept of scientific considerations for risk assessment and management from the viewpoint of "how can multidisciplinary toxicology contribute to innovative drug discovery and development?" And also realistic translational research from preclinical to clinical application is required to have a significant risk management in post market by utilizing whole scientific data derived from basic and applied scientific research works. In addition, the significance for employing the systems toxicology based on AOP (Adverse Outcome Pathway) analysis is introduced, and coming challenges on precision medicine are to be addressed for the new aspect of efficacy and safety evaluation.

History of Japanese Society of Toxicology.

Founded in 1981, the Japanese Society of Toxicology (JSOT) has grown into an organization of nearly 3,000 members working together to advance the nation's scientific knowledge and understanding of toxicology through the implementation of planning that ensures a systematic and efficient expenditure of energies and resources, and is closely aligned with a strategy for accomplishing the Society's long-range plans. To promote public education in toxicology, the Society organizes public lectures during each year's annual meeting. Other activities include hosting scientific conferences, promoting continuing education, and facilitating international collaboration. Internally, the JSOT operates five standing committees: General Affairs, Educational, Editorial, Finance, and Science and Publicity to handle its necessary relationships. To bestow official recognition, the Society established its Toxicologist Certification Program in 1997, and has certified 536 members as Diplomat Toxicologists (DJSOT) as of May 1, 2016. Furthermore, on the same date, 43 JSOT members were certified as Emeritus Diplomats of the JSOT (EDJSOT). The Society has launched two official journals, the "Journal of Toxicological Sciences (JTS)" in 1981 and "Fundamental Toxicological Sciences (Fundam. Toxicol. Sci.)" in 2014. As for participation in the international organizations, the JSOT (then known as the Toxicological Research Group) joined the International Union of Toxicology as a charter member in 1980, and became a founding member of the Asian Society of Toxicology at its inauguration in 1994. Into the future, the JSOT will continue working diligently to advance knowledge and understanding of toxicology and secure its place among the interdisciplinary fields of science, humane studies, and ethics.

File 120: The Database of DNA profiles from the National Institute of Toxicology and Forensic Sciences of people affected by the subtraction of newborns

File 120: The Database of DNA profiles from the National Institute of Toxicology and Forensic Sciences of people affected by the subtraction of newborns