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Carcinogenicity testing in experimental animals is typically done under conditions that maximize the potential for detecting an effect. The scientific ideal is to evaluate a chemical’s carcinogenic potential from human data. While controlled exposure studies for carcinogenesis are not ethical, information can sometimes be obtained from epidemiology studies, particularly occupational studies involving high exposures to a limited number of chemicals. Carcinogenicity studies are the longest and most expensive of the extensive battery of toxicology studies required for the registration of pharmaceutical products in the United States, and in other major countries. Carcinogenicity bioassays have two primary objectives, though the second is now more important and (as our understanding of carcinogenesis has increased) is increasingly crowding out the first. The first objective is to detect possible carcinogens. The second objective for a bioassay is to provide a range of dose–response information (with tumor incidence being the response) so that a risk assessment may be performed.

Animal models are commonly used to investigate the developmental basis of human birth defects. Such models may be used for safety assessment studies designed to reveal xenobiotic-related alterations in juvenile animals, or to investigate gene function or generate models of human disease, as with transgenics. Therefore, the evaluation of rodent embryos and placentas can be used to provide insight into various postnatal abnormalities such as structural or cellular abnormalities and early death. Depending on the defect, pups may be born dead, survive for only a short period of time, survive but with poor growth, or survive and be clinically normal. Mice are generally used to generate genetic alterations that can help in identifying genes involved in embryogenesis. Rats are more commonly used for toxicology studies. This article aims to share information on the importance of, and strategies for, mouse embryo, placenta, and metrial gland evaluations. Information on early postnatal development is also provided as well as select examples of developmental information on organ systems needed for postnatal evaluations. A list of additional studies that can aid in the evaluation of prenatal and postnatal phenotypes is also provided.

Regulatory toxicology seeks to ensure that exposures to chemicals encountered in the environment, in the workplace, or in products pose no significant hazards and produce no harm to humans or other organisms, i.e., that chemicals are used safely. The most practical and direct means of ensuring that hazards and harms are avoided is to identify the doses and conditions under which chemical toxicity does not occur so that chemical concentrations and exposures can be appropriately limited. Modern advancements in pharmacology and toxicology have revealed that the rates and mechanisms by which organisms absorb, distribute, metabolize and eliminate chemicals—i.e., the field of kinetics—often determine the doses and conditions under which hazard, and harm, are absent, i.e., the safe dose range. Since kinetics, like chemical hazard and toxicity, are extensive properties that depend on the amount of the chemical encountered, it is possible to identify the maximum dose under which organisms can efficiently metabolize and eliminate the chemicals to which they are exposed, a dose that has been referred to as the kinetic maximum dose, or KMD. This review explains the rationale that compels regulatory toxicology to embrace the advancements made possible by kinetics, why understanding the kinetic relationship between the blood level produced and the administered dose of a chemical is essential for identifying the safe dose range, and why dose-setting in regulatory toxicology studies should be informed by estimates of the KMD rather than rely on the flawed concept of maximum-tolerated toxic dose, or MTD.

Chlorinated cyanurates are added to swimming pools as disinfectants. In the presence of water, these materials hydrolyze to yield cyanurate and hypochlorous acid. To evaluate the safety of exposure to these materials, a comprehensive testing program was undertaken. This review summarizes the results of acute and subchronic tests on chlorinated isocyanurates. Findings from acute, subchronic, reproduction, metabolism, mutagenicity, and chronic/carcinogenicity tests on cyanurate are also summarized. Results from these tests indicate that chlorinated isocyanurates are safe for use in swimming pools.

Over the last few decades, the world has witnessed multiple viral pandemics, the current severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) pandemic being the worst and most devastating one, claiming millions of lives worldwide. Physicians, scientists, and engineers worldwide have joined hands in dealing with the current situation at an impressive speed and efficiency. One of the major reasons for the delay in response is our limited understanding of the mechanism of action and individual effects of the virus on different tissues and organs. Advances in 3D bioprinting have opened up a whole new area to explore and utilize the technology in fabricating models of these tissues and organs, recapitulating in vivo environment. These biomimetic models can not only be utilized in learning the infection pathways and drug toxicology studies but also minimize the need for animal models and shorten the time span for human clinical trials. The current review aims to integrate the existing developments in bioprinting techniques, and their implementation to develop tissue models, which has implications for SARS-CoV-2 infection. Future translation of these models has also been discussed with respect to the pandemic.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder with genetic and environmental contributors to etiology. Many metals have the potential to be neurotoxic, and their exposures are widespread. The field of metals exposure and ASD research is emerging, and in this review article, we assess the current state of the literature, with emphasis on the previous 2 years. Epidemiology studies are discussed with respect to exposure timing, exposure matrix, and outcome assessment. Toxicology studies are described for exposure dosing and timing, as well as behavioral and molecular outcomes. Further epidemiological and toxicological investigations can identify the timing and importance of metals as ASD risk factors and uncover biological mechanisms for risk mitigation and therapeutic strategies.

The review summarizes the recent data on the toxic effect that engineered metal nanoparticles (NPs) and their oxides (Ag, Au, Cu, CuO, zero-valent iron, TiO2, and ZnO) exert on marine organisms of various taxonomic groups. Toxicity is considered with due regard of the size effects and physicochemical properties of NPs. Available data indicate that metallic NPs may adversely affect algae, bacteria, mollusks, worms, arthropods, echinoderms, chordates, etc. Toxic effects vary from reproductive disorders to death. Only scarce data are available on the NP effect on marine vertebrates (e.g., marine fish). The factors that affect the NP toxicity in an aqueous environment include the physicochemical properties of NPs, species specificities of the test organism, and parameters of the aqueous environment (in particular, salinity, temperature and pH). Exact relationships between the factors and NP toxicity are still poorly understood. In particular, there is no consensus on how salinity affects the NP toxicity in an aqueous environment. Putative mechanisms of NP toxicity include oxidative stress, impaired cell membrane integrity, inflammatory processes with consequent cell dysfunction, DNA damage, and genetic mutations. NPs easily persist within organisms and consequently have a high potential to accumulate in marine food chains. Lack of standardized techniques to detect metallic and metal oxide NPs and weak or absent relevant legislation complicate toxicology studies in marine ecosystems. The above circumstances make it necessary to further evaluate the safety of metallic NPs for marine organisms and especially vertebrates, to study the distant effects associated with NP transition and accumulation in marine food chains, and to unify the respective research protocols. The exact role of environmental factors in modulating NP toxicity and the mechanisms of NP toxicity are also important issues to address in future studies.

Nonclinical development strategies for gene therapies are unique from other modalities. The European Federation of Pharmaceutical Industries and Associates (EFPIA) Gene Therapy Working Group surveyed EFPIA member and nonmember pharmaceutical and biotechnology companies about their current practices for designing and implementing nonclinical toxicology studies to support the development of viral vector-delivered in vivo gene therapies. Compiled responses from 17 companies indicated that these studies had some variability in species selection, study-design elements, biodistribution, immunogenicity or genomic insertion assessments, safety pharmacology, and regulatory interactions. Although there was some consistency in general practice, there were examples of extreme case-by-case differences. The responses and variability are discussed herein. Key development challenges were also identified. Results from this survey emphasize the importance for harmonization of regulatory guidelines for the development of gene-therapy products, while still allowing for case-by-case flexibility in nonclinical toxicology studies. However, the appropriate timing for a harmonized guidance, particularly with a platform that continues to rapidly evolve, remains in question., Graphical Abstract, The European Federation of Pharmaceutical Industries and Associates Gene Therapy Working Group conducted a survey on current practices associated with nonclinical toxicity studies conducted to support the development of in vivo viral vector-delivered gene therapies. Responses provide insight on studies conducted, endpoints evaluated, and challenges faced by biopharmaceutical/biotechnology companies.

Pregnancy diagnosis and embryo counting are important end points in reproductive, developmental biology and toxicology studies. The purpose of the present study was to assess the feasibility and efficacy of magnetic resonance imaging (MRI) for early pregnancy diagnosis and embryo counting in the laboratory rat. Female Wistar rats were subjected to whole-body MRI scanning using a 1.5T MRI scanner, employing a isotropic T2-weighted 3D short-tau inversion recovery sequence from day 8 to day 12 post coitum (pc) or without prior mating, under general anaesthesia for pregnancy diagnosis and embryo counting. MRI examination was followed by laparotomy and visual inspection of the uterus to verify MRI findings. By day 8 pc, uterine bulges, characteristic of pregnancy, were depicted as oval-shaped structures of high intensity signal. By day 10 pc, embryonic vesicles were detected at the medial side of the uterine bulges. Pregnancy was diagnosed with 0% false-negative diagnosis and 100% accuracy by day 11 pc, while embryos were counted with 100% accuracy by day 12 pc. In conclusion, MRI proved to be a feasible and reliable non-invasive imaging method of early pregnancy diagnosis and embryo counting in the laboratory rat.

The incidence and range of spontaneous microscopic lesions were determined in the eyes of male and female control Sprague-Dawley and Han Wistar rats. Data were collected retrospectively from 1411, 817, 970, 658, and 3999 rats from control groups of 4-, 13-, 26-, 52-, and 104-week studies, respectively, carried out between 1997 and 2019. Microscopic lesions of the eye were rare in 4- and 13-week studies, uncommon in 26- and 52-week studies, and were of relatively higher incidence in 104-week studies. Neoplastic lesions were sporadic and were only observed in 104-week studies. In Sprague-Dawley rats, the most common lesions (>1% in 104-week studies) were retinal degeneration, retinal rosettes/folds, and lenticular degeneration. The Han Wistar rats presented a range of ocular lesions similar to the Sprague-Dawley rats. However, retinal degeneration occurred with an earlier onset and at higher incidences, ranging from >5% in 26-week studies up to 45.72% in 104-week studies. In both strains, females exhibited higher incidences and severities of retinal degeneration. It is hoped that reference to the incidences reported here will facilitate the differentiation of spontaneous lesions from test article–induced lesions in toxicology studies in these strains of rat.

Flame retardants are widely used in electronic equipment, construction materials, and furniture to prevent fires from starting and to slow progression. Environmental monitoring studies show their presence in house dust, biomonitoring studies occasionally detect the chemicals in biological samples, and animal toxicology studies show high-dose effects. Yet laboratory studies and real-world fire statistics confirm that flame retardants have benefits that need to be weighed against possible risks to human health. Tetrabromobisphenol A (TBBPA), is used to make brominated epoxy printed wiring boards, and to a lesser extent, flame retarded acrylonitrile butadiene styrene (ABS) plastic is often used to make electronic casings. Evaluating available toxicology data and using conservative exposure assumptions, the risks of using TBBPA in these applications is exceedingly low. Given the benefits of TBBPA and flame retardants, it is essential that carefully conducted, chemical- and use-specific risk assessment be used to inform regulatory action which could possibly undermine public fire protection.

Since the discovery of graphene, research on two-dimensional (2D) quantum materials has generated a plethora of novel materials with the potential to significantly change our lives. Owing to their unique quantum, electronic, and excitonic properties, biosensing and bio-imaging are two specific areas where these quantum materials have started to make a large impact. This article provides a holistic overview into the properties, synthesis methods, biological applications, and toxicology studies of commonly studied quantum materials. Recent research into the biological applications of graphene and transition metal dichalcogenides is highlighted and their unique electronic properties are explored. Though tremendous research is generated in discovering new 2D materials, toxicology studies in the area are lacking. Historically, toxicology studies have lagged significantly behind new material discovery often with dire consequences. The product development cycle of polymeric materials is a testament to the negative consequences of having a reactionary approach to toxicology. With 2D materials set to become a widespread part of everyday life in the near future, we comment on the need for a proactive approach to examining and understanding their toxicology.

Nonclinical toxicology studies are conducted to characterize the potential toxicities and establish a safe starting dose for new drugs in clinical studies, but the question remains as to how predictable/translatable the nonclinical safety findings are to humans. In many cases, there is good concordance between nonclinical species and patients. However, there are cases for which there is a lack of predictivity or translatability that led to early termination of clinical studies due to unanticipated toxicities or early termination of programs before making it to the clinic due to unacceptable nonclinical toxicities assumed to be translatable. A few case examples of safety findings that are translatable versus safety findings that are not translatable and why they are not translateable were presented as a symposium at the 38th Annual Meeting of the American College of Toxicology in Palm Springs, California, and are discussed in this article.

A report is made on the 2-day, 20th annual conference held by the Association for Comparative Clinical Pathology (ACCP). This included two workshops that were given by veterans of the toxicologic clinical pathology community including on haematotoxicity and on the interpretation of clinical pathology data of pre-clinical toxicology studies in support of pharmaceuticals in development. Also, included was a series of scientific and technology presentations on the latest developments in toxicologic and veterinary clinical pathology. Key developments presented on were the invention of a rapid and simple diagnostic test for lymphoma, the Atellica- automated chemistry analyser for laboratory animals, and development of an advanced flow cytometric technique for bone marrow. Distinguished invited speakers gave lectures on treatment of acute myeloid leukaemia and on comparison of surgical and medical treatments for diabetic nephropathy. Technology vendors described in 5-minute presentations their latest products. And poster presenters also gave 5-minute presentations describing their work. The report is illustrated by photographs taken during the conference, capturing the presenters of talks and featuring new student presenters. This is followed by abstracts of most of the scientific presentations that were given. A few abstracts that had been submitted the previous year are also included, as there had been no report on this ACCP meeting of 2018. There were lighter moments, including a wine reception, conversations at the conference centre pub, a great conference dinner featuring the best of English cuisine, and trips to the conference center spa and recreation facilities.

Insecticides are valuable and widely used tools for the control of pest insects. Despite the use of synthetic insecticides for >50 years, we continue to have a limited understanding of the genes that influence the key steps of the poisoning process. Major barriers for improving our understanding of insecticide toxicity have included a narrow range of tools and/or a large number of candidate genes that could be involved in the poisoning process. Herein, we discuss the numerous tools and resources available in Drosophila melanogaster that could be brought to bear to improve our understanding of the processes determining insecticide toxicity. These include unbiased approaches such as forward genetic screens, population genetic methods and candidate gene approaches. Examples are provided to showcase how D. melanogaster has been successfully used for insecticide toxicology studies in the past, and ideas for future studies using this valuable insect are discussed.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a well-known environmental poison that exist in the environment for many years. However, its effect on the male reproductive system has not been clearly stated. We conducted a meta-analysis of the effect of TCDD on the male reproductive system of rodents about TCDD. Results showed that that TCDD exposure reduced the testis weight (weighted mean difference [WMD]: −0.035, 95% confidence interval [CI]: −0.046 to −0.025), sperm count (WMD: −35, 95% CI: −42.980 to −27.019), and blood testosterone concentration (WMD: −0.171, 95% CI: −0.269 to −0.073). According to our research results, TCDD can cause damage to the male reproductive system of rodents through direct or indirect exposure. In order to further explore the potential hazards of TCDD to humans, more human-related research needs to be carried out.

This symposium synopsis summarizes key points discussed related to clinical pathology data interpretation for reproduction and juvenile toxicology studies. In pregnant and growing animals, several changes in clinical pathology parameters linked to growth/maturation of organ and physiological functions can occur, and understanding these changes is important to enable accurate interpretation of clinical pathology data. A brief overview of the general approach to clinical pathology data analysis according to contemporary practices is provided, followed by a discussion focused specifically on reproductive and juvenile clinical pathology. In this context, the approach to recognize and differentiate changes that may be related to pregnancy and growth as opposed to those that may be related to test article effects is highlighted.

Background Flaws in the science supporting pesticide risk assessment and regulation stand in the way of progress in mitigating the human health impacts of pesticides. Critical problems include the scope of regulatory testing protocols, the near-total focus on pure active ingredients rather than formulated products, lack of publicly accessible information on co-formulants, excessive reliance on industry-supported studies coupled with reticence to incorporate published results in the risk assessment process, and failure to take advantage of new scientific opportunities and advances, e.g. biomonitoring and “omics” technologies. Recommended Actions Problems in pesticide risk assessment are identified and linked to study design, data, and methodological shortcomings. Steps and strategies are presented that have potential to deepen scientific knowledge of pesticide toxicity, exposures, and risks. We propose four solutions: (1) End near-sole reliance in regulatory decision-making on industry-supported studies by supporting and relying more heavily on independent science, especially for core toxicology studies. The cost of conducting core toxicology studies at labs not affiliated with or funded directly by pesticide registrants should be covered via fees paid by manufacturers to public agencies. (2) Regulators should place more weight on mechanistic data and low-dose studies within the range of contemporary exposures. (3) Regulators, public health agencies, and funders should increase the share of exposure-assessment resources that produce direct measures of concentrations in bodily fluids and tissues. Human biomonitoring is vital in order to quickly identify rising exposures among vulnerable populations including applicators, pregnant women, and children. (4) Scientific tools across disciplines can accelerate progress in risk assessments if integrated more effectively. New genetic and metabolomic markers of adverse health impacts and heritable epigenetic impacts are emerging and should be included more routinely in risk assessment to effectively prevent disease. Conclusions Preventing adverse public health outcomes triggered or made worse by exposure to pesticides will require changes in policy and risk assessment procedures, more science free of industry influence, and innovative strategies that blend traditional methods with new tools and mechanistic insights.

Minipigs are commonly utilized in dermal toxicology studies, necessitating documentation of background findings, including neoplastic lesions. We describe a case of a Yucatan minipig with a squamous cell carcinoma at the mucocutaneous junction of the lip. The neoplasm appeared grossly as a slightly raised area of skin with ulceration. Histologically, there were nests and trabeculae of neoplastic squamous epithelial cells undergoing keratinization. Multifocally, rafts of these cells were within lymphatic vessels. Squamous cell carcinoma has not previously been reported in Yucatan or other laboratory minipigs, however, has been reported uncommonly in nonlaboratory pot-bellied pigs. Although squamous cell carcinoma has been associated with ultraviolet exposure or papillomavirus in various species, this was unable to be confirmed in this case.

In vitro cell culture practices are valuable techniques to understand the mechanisms behind vital in vivo biological processes. In vitro cells have helped us to attain a deeper understanding of functions and mechanisms conserved in the course of evolution. Toxicology studies are inevitable in drug discovery, pesticide development, and many other fields that directly interact with human beings. The proper involvement and regulatory steps that have been taken by animal ethical societies in different parts of the world resulted in the reduced in vivo use of mammals in toxicological studies. Nevertheless, experimental animals are being killed where no replacement is available. The use of mammals could be reduced by using the in vitro systems. Nowadays, invertebrate cell lines are also play important role in toxicology testing. This review analyzes the cause and consequence of insect in vitro models in toxicology studies.

Both landfill leachate and sewage sludge are complex mixtures of many potentially toxic substances in unknown and unpredictable amounts and concentrations. Both types of matrices can pose a risk to human health and the functioning of ecosystems if released into the environment. Therefore, constant monitoring of the toxicity of these mixtures is necessary. However, traditional methods of analysis of sewage sludge/landfill leachate are mainly based on physicochemical studies that do not fully reflect the effects of these mixtures on living organisms. For this purpose, research based on biological models, including mammalian, mainly human, cells is recommended and increasingly implemented. A variety of cytotoxicity tests, based on various metabolic transformations in living cells, are a very useful tool in landfill leachate/sewage sludge toxicology studies. This paper reviews the methods used in the study of the cytotoxicity of environmental matrices and the cell lines used in these studies as biological models.

Pharmaceuticals have been present in our world’s waters since humans began experimenting with medicines; however, product propagation and ready access to pharmaceuticals coupled with burgeoning human population have significantly increased the loading of these compounds into the environment. Pharmaceutically active compounds (PhACs) are considered to produce a biological activity on humans and animals. Drugs manufacturing processes lead to release of toxic organic compounds and their metabolites into the environment. Safety and toxicology studies have used to investigate the side effects of pharmaceuticals on human and animal health. Treatment processes can and do reduce the concentrations of pharmaceuticals in water, however, the degree of efficacy is often a function of chemical structure, cost, and energy. All treatment processes have some degree of side effects, such as generation of residuals or by-products. This paper provides a concise report on removal of PhACs by recent advances oxidation processes (AOPs) where hydroxyl radicals (HO . ) acts as a common oxidant and the improvement of biodegradability to a level amicable for subsequent biological treatment.

Long-lived environmentally persistent free radical (EPFR) exposures have been shown in toxicology studies to lead to respiratory and cardiovascular effects, which were thought to be due to the persistence of EPFR and their ability to produce reactive oxygen species. To characterize EPFR exposure and resulting health impacts, it is necessary to identify and systematize analysis protocols. Both direct measurement and solvent extraction methods have been applied to analyze environmental samples containing EPFR. The use of different protocols and solvents in EPFR analyses makes it difficult to compare results among studies. In this work, we reviewed EPFR studies that involved solvent extraction and carefully reported the details of the extraction methodology and retrieval recovery. EPFR recovery depends on the structure of the radical species and the solvent. For the limited number of studies available for review, the polar solvents had superior recovery in more studies. Radicals appeared to be more oxygen-centered following extraction for fly ash and particulate matter (PM) samples. Different solvent extraction methods to retrieve EPFR may produce molecular products during the extraction, thus potentially changing the sample toxicity. The number of studies reporting detailed methodologies is limited, and data in these studies were not consistently reported. Thus, inference about the solvent and protocol that leads to the highest EPFR extraction efficiency for certain types of radicals is not currently possible. Based on our review, we proposed reporting criteria to be included for future EPFR studies.

Determining adversity of effects in toxicology studies continues to pose a dilemma to practicing toxicologists and pathologists. How this determination is made may follow either a focused or broad approach to assessing the study data. The choice of which approach is best is dependent on a variety of factors. Therefore, we present a philosophical perspective on the determination of adversity across toxicology studies that may be applied in inhalation studies and those conducted by other routes of exposure.

In 2002, Lauren Black had grown frustrated with her job. She had been working at the US Food and Drug Administration as a reviewer for just over a decade. “I saw too many resources wasted,” she says. Drug companies were submitting a surplus of animal studies along with excessive or simply irrelevant data. “I thought it was time to go out and work further upstream.” So she took a job at Charles River Laboratories, a contract research organization (CRO) that drug companies turn to for animal models, toxicology studies, and more. In her 17 years there, Black has helped streamline research and package it into digestible forms for FDA review. And today, she’s taking that thinning to its most extreme form by leading the company’s role in developing N-of-1 therapies—drugs that are custom designed for a single individual’s exceedingly rare genetic mutation. Although Charles River has been involved with only

The interpretation of clinical pathology results from nonclinical safety studies is a fundamental component in hazard identification of new drug candidates. The ever-increasing complexity of nonclinical safety studies and sophistication of modern analytical methods have made the interpretation of clinical pathology information by a highly trained subject matter expert imperative. Certain interpretive techniques are particularly effective in the identification and characterization of clinical pathology effects. The purpose of this manuscript is to provide an overview of contemporary interpretive practices for clinical pathology results and to provide nonbinding recommendations aimed at improving consistency, quality, and overall value of clinical pathology interpretations generated in support of nonclinical toxicology studies.

Clinical pathology reporting practices are diverse among individuals and organizations involved in nonclinical toxicology studies. Clear, informative, and consistent reporting of clinical pathology results increases their value and avoids misinterpretation, resulting in decreased drug development costs. In recent years, certain common practices in clinical pathology reporting have been embraced by industry leaders and more consistently utilized across the pharmaceutical industry. The purpose of this manuscript is to review current clinical pathology reporting practices and to provide nonbinding suggestions to improve consistency, quality, and value of clinical pathology reports generated in support of nonclinical toxicology studies.

The prominent position that propofol occupies as an anaesthetic and sedative agent is very gratifying. It is a personal honour that my involvement for many years in the discovery, development, and introduction of propofol has been recognised with my selection to receive the prestigious 2018 Lasker-DeBakey Clinical Medical Research Award. It has been a privilege for me to work with so many highly skilled and enthusiastic anaesthetists, and I welcome the opportunity to present some personal reflections on my time as a veterinary anaesthetist, as a research biologist in the Anaesthetics Project Team at ICI Pharmaceuticals Division (which later became Zeneca, then merged with Astra to form AstraZeneca), and as a Clinical Scientist within the Medical Department. There I became involved in the design and management of clinical trials of propofol and the clinical validation and introduction of the first commercial target controlled infusion system. With four different formulations, three repetitions of the pharmacology and toxicology studies, and two clinical trial programmes, it was a long haul between discovery of the anaesthetic properties of 2,6-diisopropylphenol in 1973 and first commercial use of propofol in a soybean oil emulsion in 1986. Throughout this process, credit is due to the clinical anaesthetists and researchers who have defined and extended the place of propofol in clinical practice.

Fusarium graminearum and related species produce regulated mycotoxins that contaminate important food commodities resulting in serious agricultural and animal productivity losses. F. graminearum DAOMC 242077 was isolated from soft wheat in Eastern Canada and an investigation of this strains secondary metabolites confirmed it produced the recently discovered type-A trichothecene 7α-hydroxy, 15-deacetylcalonectrin (3ANX; 1). In an effort to prepare large amounts of its deacetylated product 7α-hydroxy, 3, 15-dideacetylcalonectrin (NX; 2), F. graminearum DAOMC 242077 was grown using conditions favoring the biosynthesis of trichothecenes to enable large amounts of 3ANX (1) to be purified. The structure of 3ANX (1) was confirmed by interpretation of spectroscopic data, physical properties and LC-HRMS. A simple hydrolysis scheme was developed to convert 3ANX (1), to NX (2). The objective of this study was to generate and chemically characterize 3ANX (1) and NX (2) reference materials for the scientific community for toxicology studies, analytical method development and exposure assessments.

[Image: see text] Herein, we report the discovery of a novel potent, selective, CNS penetrant, and orally bioavailable mGlu(4) PAM, VU0652957 (VU2957, Valiglurax). VU2957 possessed attractive in vitro and in vivo pharmacological and DMPK properties across species. To advance toward the clinic, a spray-dried dispersion (SDD) formulation of VU2957 was developed to support IND-enabling toxicology studies. Based on its overall profile, VU2957 was evaluated as a preclinical development candidate for the treatment of Parkinson’s disease.

Microphysiological systems (MPS) are making advances to provide more standardized and predictive physiologically relevant responses to test articles in living tissues and organ systems. The excitement surrounding the potential of MPS to better predict human responses to medicines and improving clinical translation is overshadowed by their relatively slow adoption by the pharmaceutical industry and regulators. Collaboration between multiorganizational consortia and regulators is necessary to build an understanding of the strengths and limitations of MPS models and closing the current gaps. Here, we review some of the advances in MPS research, focusing on liver, intestine, vascular system, kidney and lung and present examples highlighting the context of use for these systems. For MPS to gain a foothold in drug development, they must have added value over existing approaches. Ideally, the application of MPS will augment in vivo studies and reduce the use of animals via tiered screening with less reliance on exploratory toxicology studies to screen compounds. Because MPS support multiple cell types (e.g. primary or stem-cell derived cells) and organ systems, identifying when MPS are more appropriate than simple 2D in vitro models for understanding physiological responses to test articles is necessary. Once identified, MPS models require qualification for that specific context of use and must be reproducible to allow future validation. Ultimately, the challenges of balancing complexity with reproducibility will inform the promise of advancing the MPS field and are critical for realization of the goal to reduce, refine and replace (3Rs) the use of animals in nonclinical research.