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Preview: Toxicological Sciences - current issue

Toxicological Sciences Current Issue





Published: Thu, 25 Jan 2018 00:00:00 GMT

Last Build Date: Thu, 25 Jan 2018 09:50:07 GMT

 






From the Editor's Desk, Editor's Highlights

Thu, 25 Jan 2018 00:00:00 GMT




Green Toxicology—Know Early About and Avoid Toxic Product Liabilities

Mon, 18 Dec 2017 00:00:00 GMT

Abstract
Toxicology uniquely among the life sciences relies largely on methods which are more than 40-years old. Over the last 3 decades with more or less success some additions to and few replacements in this toolbox took place, mainly as alternatives to animal testing. The acceptance of such new approaches faces the needs of formal validation and the conservative attitude toward change in safety assessments. Only recently, there is growing awareness that the same alternative methods, especially in silico and in vitro tools can also much earlier and before validation inform decision-taking in the product life cycle. As similar thoughts developed in the context of Green Chemistry, the term of Green Toxicology was coined to describe this change in approach. Here, the current developments in the alternative field, especially computational and more organo-typic cell cultures are reviewed, as they lend themselves to front-loaded chemical safety assessments. The initiatives of the Center for Alternatives to Animal Testing Green Toxicology Collaboration are presented. They aim first of all for forming a community to promote this concept and then for a cultural change in companies with the necessary training of chemists, product stewards and later regulators.



Editor’s Highlight: Variation in Methylmercury Metabolism and Elimination Status in Humans Following Fish Consumption

Tue, 14 Nov 2017 00:00:00 GMT

Abstract
Evaluating the potential for methylmercury (MeHg) toxicity relies on accurately predicting the mercury (Hg) body burden that results from eating fish. Hg body burden is directly determined by the slow elimination kinetics of MeHg in the human body (kel = 0.014 days−1 or t1/2 =50 days). Existing studies on MeHg half-life in humans demonstrate a wide range values (t1/2 = 30 to >150 days) and has lead to uncertainty in the derivation of a regulatory standard for acceptable daily oral intake. The causes of variation in MeHg toxicokinetics in humans remain little explored. Here we characterize variation in human MeHg metabolism and elimination rate (kel) in 37 adult volunteers who consumed 3 fish meals. We determined MeHg elimination rates via longitudinal Hg analysis in single hairs using laser ablation inductively coupled plasma mass spectrometry. We also measured MeHg metabolism (biotransformation) via speciation of fecal Hg. We find an average kel = 0.0157 days−1 (t1/2 = 44 days) amongst a more than 2-fold variation in kel across the cohort (0.0248–0.0112 days−1; t1/2 = 28–62 days). Although MeHg biotransformation varied widely between individuals, it showed a positive association with elimination rates across the cohort. A more than 2-fold change in kel over a period of 2 years was seen in some individuals. In 2 individuals, who received antibiotic for unrelated health issues, elimination rate was seen to slow significantly. Associations of kel with age, body mass index, gender, and fish eating habits were not observed. We establish that a measure of methylmercury metabolism and eliminaiton status (MerMES) can reduce uncertainty in determining an individual’s MeHg toxicokinetics subsequent to eating fish.



Scaling-Up Ionic Liquid-Based Technologies: How Much Do We Care About Their Toxicity? Prima Facie Information on 1-Ethyl-3-Methylimidazolium Acetate

Thu, 02 Nov 2017 00:00:00 GMT

Abstract
The potential of the ionic liquid (IL) 1-ethyl-3-methylimidazolium acetate ([C2mim][OAc]) to dissolve a variety of biopolymers such as cellulose and chitin, makes it an attractive candidate for scaled-up industrial utilization. In fact, the first steps towards its use at industrial scale have been taken. This increases the urgency to fill the knowledge gaps in its toxicity and environmental impact in order to predict and control its environmental fate. In this mini-review, we discuss the available literature surrounding this key IL. The literature (through the analysis of toxicity of the anion and the cation separately) suggests that [C2mim][OAc] is a relatively safe choice for industrial applications. However, because the IL should be considered as a compound, with unique properties arising from the interactions between the ions, comprehensive toxicity information for this particular IL is still required. To decide, prima facie, if this IL is toxic or not, evaluation of its influence on human health and ecotoxicity is needed prior to its large scale utilization. We chose in this mini-review to focus on toxicity surrounding this IL and evaluate what is known and what is not. Here with all the information in hand, we hope that the urgent need for [C2mim][OAc] toxicological assessment before it can be used in numerous technologies is highlighted. In the near future, we expect that the assessment of toxicity and environmental fate and impact can be integrated directly into any research into the industrial utilization of this IL and any others contemplated for industrial application.



Editor’s Highlight: An Impaired Immune Tolerance Animal Model Distinguishes the Potential of Troglitazone/Pioglitazone and Tolcapone/Entacapone to Cause IDILI

Tue, 24 Oct 2017 00:00:00 GMT

Abstract
We have developed an animal model of amodiaquine-induced liver injury that has characteristics very similar to idiosyncratic drug-induced liver injury (IDILI) in humans by impairing immune tolerance using a PD1−/− mouse and cotreatment with anti-CTLA-4. In order to test the usefulness of this model as a general model for human IDILI risk, pairs of drugs with similar structures were tested, one of which is associated with a relatively high risk of IDILI and the other not. One such pair is troglitazone and pioglitazone; troglitazone has caused fatal cases of IDILI while pioglitazone is quite safe. Another pair is tolcapone and entacapone; tolcapone can cause serious IDILI; in contrast, although entacapone has been reported to cause liver injury, it is relatively safe. PD1−/− mice treated with anti-CTLA-4 and troglitazone or tolcapone displayed liver injury as determined by ALT levels and histology, while pioglitazone and entacapone showed less signs of liver injury. One possible mechanism by which drugs could induce an immune response leading to IDILI is by causing the release of danger-associated molecular pattern molecules that activate inflammasomes. We found that the supernatants from incubations of troglitazone, tolcapone, or entacapone with hepatocytes were also able to activate inflammasomes in macrophages, while the supernatant from pioglitazone incubations did not. These results are consistent with an immune mechanism for troglitazone- and tolcapone-induced IDILI and add to the evidence that this may be a general model for IDILI.



From the Cover: Harmane-Induced Selective Dopaminergic Neurotoxicity in Caenorhabditis elegans

Mon, 23 Oct 2017 00:00:00 GMT

Abstract
Parkinson’s disease (PD) is a debilitating neurodegenerative disease. Although numerous exposures have been linked to PD etiology, causative factors for most cases remain largely unknown. Emerging data on the neurotoxicity of heterocyclic amines suggest that this class of compounds should be examined for relevance to PD. Here, using Caenorhabditis elegans as a model system, we tested whether harmane exposure produced selective toxicity to dopamine neurons that is potentially relevant to PD. Harmane is a known tremorigenic β-carboline (a type of heterocyclic amine) found in cooked meat, roasted coffee beans, and tobacco. Thus, this compound represents a potentially important exposure. In the nematode model, we observed dopaminergic neurons to be selectively vulnerable, showing significant loss in terms of structure and function at lower doses than other neuronal populations. In examining mechanisms of toxicity, we observed significant harmane-induced decreases in mitochondrial viability and increased reactive oxygen species levels. Blocking transport through the dopamine transporter (DAT) was not neuroprotective, suggesting that harmane is unlikely to enter the cell through DAT. However, a mitochondrial complex I activator did partially ameliorate neurodegeneration. Further, mitochondrial complex I activator treatment reduced harmane-induced dopamine depletion, measured by the 1-nonanol assay. In summary, we have shown that harmane exposure in C. elegans produces selective dopaminergic neurotoxicity that may bear relevance to PD, and that neurotoxicity may be mediated through mitochondrial mechanisms.



From the Cover: 2.45-GHz Microwave Radiation Impairs Hippocampal Learning and Spatial Memory: Involvement of Local Stress Mechanism-Induced Suppression of iGluR/ERK/CREB Signaling

Mon, 23 Oct 2017 00:00:00 GMT

Abstract
Microwave (MW) radiation induced oxidative stress reduces dendritic arborization, spine density and number of hippocampal pyramidal neurons and hence, impair learning and spatial memory through p53-dependent/independent apoptosis of hippocampal neuronal and nonneuronal cells. However, the mechanisms responsible for MW radiation induced impairment in memory formation remains still unknown. This study elucidates the effect of short (15 days) and long-term (30 and 60 days) low level 2.45 GHz MW radiation-induced local stress on the hippocampal spatial memory formation pathway in adult male mice. Twelve-weeks old mice were exposed to 2.45 GHz MW radiation (continuous-wave with overall average Power density of 0.0248 mW/cm2 and overall average whole body SAR value of 0.0146 W/Kg) @ 2 h/d for 15, 30, and 60 days. Learning and spatial memory was assessed by 8-arm radial maze. We have investigated the alterations in serum corticosterone level and the expression of glucocorticoid receptor, corticotropin-releasing hormone (CRH), inducible nitric oxide synthase (i-NOS), iGluRs, PSD-95-neuronal NOS (n-NOS) system, protein kinase A, protein kinase Cε-ERK1/2-pERK1/2 in all the hippocampal subregions, viz. CA1, CA2, CA3, and DG through immunohistochemistry/immunofluorescence and alterations in the expression of hippocampal glucocorticoid receptor, CRH-receptor 1 (CRH-R1), cAMP-response element-binding (CREB), and phosphorylated-CREB (p-CREB) through western blot analysis. We observed that 2.45 GHz MW irradiated mice showed slow learning and significantly increased number of working and reference memory errors in radial maze task. Further, 2.45 GHz MW radiation exposure increases serum corticosterone level and the expression of CRH, CRH-R1, and i-NOS, while the expression of iGluRs, n-NOS, PSD-95, protein kinase Cε, protein kinase A, ERK-p-ERK, CREB, and p-CREB decreases in above mentioned hippocampal subregions in a duration dependent manner. Our findings led us to conclude that 2.45 GHz MW radiation exposure induced local stress suppresses signaling mechanism(s) of hippocampal memory formation.



Sexually Dimorphic Impact of Chromium Accumulation on Human Placental Oxidative Stress and Apoptosis

Mon, 23 Oct 2017 00:00:00 GMT

Abstract
Environmental contamination with hexavalent chromium (CrVI) is a growing problem both in the United States and developing countries. Hexavalent chromium is widely used in numerous industries. Environmental exposure to CrVI adversely affects pregnancy outcomes and subsequent health of 2 generations, resulting in higher pregnancy loss, spontaneous abortion and low birth rate. Pregnant women exposed to CrVI through occupational settings experience increased risk of spontaneous abortion, stillbirth, preterm birth, and neonatal death. Children of the CrVI exposed women experience respiratory problems, perinatal jaundice, and increased birth defects. Because placental dysfunction may have a role in such adverse pregnancy outcome, we tested the hypothesis that environmental Cr exposure in pregnant women results in Cr accumulation in the human placenta, which could increase placental oxidative stress by disrupting antioxidant machinery and inducing apoptosis. Studies using frozen, deidentified human term placenta samples indicated that: (1) Cr accumulates in human term placenta tissues and (2) increase in Cr accumulation is positively correlated with oxidative stress and apoptotic markers, and altered antioxidants levels. Interestingly, there was a sexual dimorphism in the correlation between Cr accumulation and oxidative stress, and expression of apoptotic and antioxidant markers. Mechanistic in vitro studies using human trophoblast cells BeWo confirmed the detrimental effects of Cr in altering antioxidant genes. For the first time, this study provides evidence in support of a positive correlation between Cr accumulation in the human placenta and accelerated oxidative stress, with a gender bias toward the male sex.



Editor’s Highlight: Effects of Intraperitoneal Injection of SnS2 Flowers on Mouse Testicle

Mon, 23 Oct 2017 00:00:00 GMT

Abstract
SnS2 nanoflowers (SnS2 NFs) have been widely used in photoelectric and catalytic applications. However, its explosure and reproductive toxicity is unknown. The aim of this study was to investigate the effect of exposure to 3 different sized-SnS2 flowers (dose: 38 mg/kg; size: 50, 80, and 200 nm) in testes of mice for 4 weeks by intraperitoneal injection. Though the body weight of mice treated or not with SnS2 NFs was not different, and SnS2 NFs were distributed to the organs including liver, kidney, spleen, heart, brain, and testis, more distribution SnS2 NFs (50 and 80 nm) were found in testicle tissues compared with SnS2 flowers (200 nm) in those tissues. The results of sperm count and survival analysis, histopathological evaluation, and qRT-PCR detection showed that there was moderate reproductive toxicity induced by the small-sized SnS2 NFs in testicle tissues. Furthermore, elevated malondialdehyde level and decreased superoxide dismutase activity were also observed in the SnS2 NFs (dose: 38 mg/kg; size: 50 and 80 nm) treated groups. Likewise, the qRT-PCR data indicated that SnS2 NFs can induce apoptosis and inflammation responses. Although the pro-inflammation marker of TNF-α, IL-1β, iNOS, and COX-2 at the mRNA levels were higher expression in 50 and 80 nm groups than that in control and 200 nm group, no statistical significance existed between 50 and 80 nm groups. Accordingly, the repeated-dose toxicity of SnS2 NFs in testicle tissues was also observed in a dose-dependent manner by intraperitoneal injection of SnS2 NFs (size: 50 nm; 0.38, 3.8, and 38 mg/kg) for 4 weeks, when determined by sperm count, survival rate, and qRT-PCR analysis. In addition, transmission electron microscopy showed that the ultrastructural abnormalities formed by the small-sized SnS2 NFs in testes were more severe than those formed by the large-sized SnS2 in testes. Taken together, these findings implied that the SnS2 NFs activated inflammation responses that signified apoptosis in murine testes. This study provided useful information for risk analysis and regulation of SnS2 NFs by administration agencies.



Transient Changes in Hepatic Physiology That Alter Bilirubin and Bile Acid Transport May Explain Elevations in Liver Chemistries Observed in Clinical Trials of GGF2 (Cimaglermin Alfa)

Mon, 23 Oct 2017 00:00:00 GMT

Abstract
GGF2 is a recombinant human neuregulin-1β in development for chronic heart failure. Phase 1 clinical trials of GGF2 were put on hold when transient elevations in serum aminotransferases and total bilirubin were observed in 2 of 43 subjects who received single doses of GGF2 at 1.5 or 0.378 mg/kg. However, aminotransferase elevations were modest and not typical of liver injury sufficient to result in elevated serum bilirubin. Cynomolgus monkeys administered a single 15 mg/kg dose of GGF2 had similar transient elevations in serum aminotransferases and bilirubin as well as transient elevations in serum bile acids. However, no hepatocellular necrosis was observed in liver biopsies obtained during peak elevations. When sandwich-cultured human hepatocytes were treated with GGF2 for up to 72 h at concentrations approximately 0.8-fold average plasma Cmax for the 0.378 mg/kg dose, no cytotoxicity was observed. Gene expression profiling identified approximately 50% reductions in mRNAs coding for bilirubin transporters and bile acid conjugating enzymes, as well as changes in expression of additional genes mimicking the interleukin-6-mediated acute phase response. Similar gene expression changes were observed in GGF2-treated HepG2 cells and primary monkey hepatocytes. Additional studies conducted in sandwich-cultured human hepatocytes revealed a transient and GGF2 concentration-dependent decrease in hepatocyte bile acid content and biliary clearance of taurocholate without affecting biliary taurocholate efflux. Taken together, these data suggest that GGF2 does not cause significant hepatocellular death, but transiently modifies hepatic handling of bilirubin and bile acids, effects that may account for the elevations in serum bilirubin observed in the clinical trial subjects.



Editor’s Highlight: Ethylene Glycol Teratogenicity: A Role for Embryonic Acidosis?

Mon, 23 Oct 2017 00:00:00 GMT

Abstract
Ethylene glycol (EG) is a developmental toxicant in pregnant rats and mice. A suggested mechanism for this toxicity is that the EG metabolite, glycolic acid (GA), causes acidosis which may affect the embryonic heart rate (HR). This inhibition would cause periods of embryonic bradycardia and arrhythmia resulting in increased embryonic death and malformation in surviving embryos. This hypothesis was investigated using gestational day (GD) 11 and 13 rat embryos in vitro. Increasing concentrations of GA or lactic acid in the incubation medium caused a decrease in external pH (pHe) and a concentration-dependent decrease in embryonic HR. Increased concentrations of GA or lactic acid with pHe corrected to normal levels did not affect HR. Severely decreased pHe, caused by reduced NaHCO3 in the incubation medium, had little effect on the HR of GD 13 embryos but substantially reduced the HR of GD 11 embryos. These results suggest that increased monocarboxylate concentration (glycolate or lactate) needs to be in combination with increased H+ concentration (low pHe) to influence the embryonic HR. These results implicate the monocarboxylate transporter reported to be present in the early postnatal rat heart, the chick embryonic heart throughout development, and the chorioallantoic placenta. The results showed some evidence that the adverse effect of GA and reduced pHe on the embryonic HR increased with duration of exposure and hence lends support to the suggested mechanism of embryotoxicity for EG.



Uncoupling Effect of F16 Is Responsible for Its Mitochondrial Toxicity and Anticancer Activity

Mon, 23 Oct 2017 00:00:00 GMT

Abstract
As a novel delocalized lipophilic cation, F16 selectively accumulates in mitochondria of carcinoma cells and shows a broad spectrum of antiproliferative action towards cancer cell lines. In order to reveal the mode of action and molecular mechanism of F16 inducing cytotoxicity, we investigated the effects of F16 on cancer cells and isolated mitochondria relative to its precursor compound (E)-3-(2-(pyridine-4yl)vinyl)-1 H-indole (PVI), which has a similar structure without positive charge. It was found that PVI did not accumulate in mitochondria, and exhibited lower cytotoxicity compared to F16. However, when they were directly incubated with mitochondria, both F16 and PVI were observed to induce damage to mitochondrial structure and function. Moreover, it was found that F16 as well as PVI acted as uncouplers on mitochondria, and further rescue experiments revealed that the addition of adenosine 5′-triphosphate was the most effective way to recover the cell viability decreased by F16. Thus it was concluded that the decreased intracellular adenosine 5′-triphosphate availability induced by the uncoupling effect of F16 was a major factor in F16-mediated cytotoxicity. Futhermore, the results indicated that the uncoupling effect of F16 is attributed to its chemical stucture in common with PVI but independent of its positive charge. The study may shed light on understanding the underlying mechanism of action for F16, and providing suggestions for the design of new mitochondria-targeted antitumor molecules.



Zebrafish Locomotor Responses Reveal Irritant Effects of Fine Particulate Matter Extracts and a Role for TRPA1

Tue, 17 Oct 2017 00:00:00 GMT

Abstract
Exposure to fine particulate matter (PM) air pollution causes adverse cardiopulmonary outcomes. Yet, the limited capacity to readily identify contributing PM sources and associated PM constituents in any given ambient air shed impedes risk assessment efforts. The health effects of PM have been attributed in part to its capacity to elicit irritant responses. A variety of chemicals trigger irritant behavior responses in zebrafish that can be easily measured. The purposes of this study were to examine the utility of zebrafish locomotor responses in the toxicity assessment of fine PM and its chemical fractions and uncover mechanisms of action. Locomotor responses were recorded in 6-day-old zebrafish exposed for 60 min in the dark at 26 °C to the extractable organic matter of a compressor-generated diesel exhaust PM (C-DEP) and 4 of its fractions (F1–F4) containing varying chemical classes of increasing polarity. The role of the transient receptor potential (TRP) cation channel TRPA1, a chemical sensor in mammals and zebrafish, in locomotor responses to C-DEP, was also examined. Acrolein, an environmental irritant and known activator of TRPA1, and all extracts induced concentration-dependent locomotor responses whose potencies ranked as follows: polar F3 > weakly polar F2 > C-DEP > highly polar F4 > nonpolar F1, indicating that polar and weakly polar fractions that included nitro- and oxy-polyaromatic hydrocarbons (PAHs), drove C-DEP responses. Irritant potencies in fish positively correlated with mutagenic potencies of the same extracts in strains of Salmonella sensitive to nitro- and oxy-PAHs, further implicating these chemical classes in the zebrafish responses to C-DEP. Pharmacologic inhibition of TRPA1 blocked locomotor responses to acrolein and the extracts. Taken together, these data indicate that the zebrafish locomotor assay may help expedite toxicity screening of fine PM sources, identify causal chemical classes, and uncover plausible biological mechanisms.



Sustainable Production of Fine Chemicals and Materials Using Nontoxic Renewable Sources

Mon, 16 Oct 2017 00:00:00 GMT

Abstract
Due to declining hydrocarbon resources and strengthening environmental regulations, significant attention is directed toward sustainable and nontoxic supplies for the development of green technologies in a variety of industries. This account provides an overview on the sources and recent applications of such materials surveying the most common nontoxic and renewable resources that can be obtained from biological sources. Developing a broad array of technologies based on these materials would establish a truly sustainable green chemical industry. The study thematically discusses various compound groups, eg, carbohydrates, proteins, and triglycerides (oils). Since often the monomers or building blocks of these biopolymers are of significant importance and produced in large amounts, the applications of these compounds are also reviewed.



TCDD, FICZ, and Other High Affinity AhR Ligands Dose-Dependently Determine the Fate of CD4+ T Cell Differentiation

Fri, 13 Oct 2017 00:00:00 GMT

Abstract
FICZ and TCDD, two high-affinity AhR ligands, are reported to have opposite effects on T cell differentiation with TCDD inducing regulatory T cells and FICZ inducing Th17 cells. This dichotomy has been attributed to ligand-intrinsic differences in AhR activation, although differences in sensitivity to metabolism complicate the issue. TCDD is resistant to AhR-induced metabolism and produces sustained AhR activation following a single dose in the μg/kg range, whereas FICZ is rapidly metabolized and AhR activation is transient. Nonetheless, prior studies comparing FICZ with TCDD have generally used the same 10–50 μg/kg dose range, and thus the two ligands would not equivalently activate AhR. We hypothesized that high-affinity AhR ligands can promote CD4+ T cell differentiation into both Th17 cells and Tregs, with fate depending on the extent and duration of AhR activation. We compared the immunosuppressive effects of TCDD and FICZ, along with two other rapidly metabolized ligands (ITE and 11-Cl-BBQ) in an acute alloresponse mouse model. The dose and timing of administration of each ligand was optimized for TCDD-equivalent Cyp1a1 induction. When optimized, all of the ligands suppressed the alloresponse in conjunction with the induction of Foxp3 Tr1 cells on day 2 and the expansion of natural Foxp3+ Tregs on day 10. In contrast, a low dose of FICZ induced transient expression of Cyp1a1 and did not induce Tregs or suppress the alloresponse but enhanced IL-17 production. Interestingly, low doses of the other ligands, including TCDD, also increased IL-17 production on day 10. These findings support the conclusion that the dose and the duration of AhR activation by high-affinity AhR ligands are the primary factors driving the fate of T cell differentiation.



From the Cover: Identification of Natural Products as Inhibitors of Human Organic Anion Transporters (OAT1 and OAT3) and Their Protective Effect on Mercury-Induced Toxicity

Fri, 13 Oct 2017 00:00:00 GMT

Abstract
Mercury accumulates in kidneys and produces acute kidney injury. Semen cassiae (SC), a widely consumed tea and herbal medicine in Eastern Asia, has been reported to have protective effects on kidneys. In this study, SC extract was shown to almost abolish the histological alterations induced by mercuric chloride in rat kidneys. A total of 22 compounds were isolated from SC, and 1,7,8-methoxyl-2-hydroxyl-3-methyl-anthraquinone was detected in SC for the first time. Among the eight compounds identified in the blood of rats after SC treatment, six were strong inhibitors of human organic anion transporter 1 and 3 (OAT1 and OAT3). Inhibitory studies revealed that OAT1 and OAT3 were inhibited by SC constituents, in both a competitive and noncompetitive manner. Both OAT1- and OAT3-overexpressing cells were susceptible to the cytotoxicity of the cysteine–mercury conjugate, but only OAT1-overexpressing cells could be protected by 200 μM probenecid or 10 μM of the eight inhibitors in SC, suggesting that OAT1 is the major determinant in the cellular uptake of mercury. To facilitate the identification of inhibitors of OAT1 and OAT3, models of OAT1 and OAT3 were constructed using recently determined protein templates. By combining in silico and in vitro methods, inhibitors of OAT1 and OAT3 were predicted and validated from SC constituents. Collectively, the present study suggests that additional inhibitors of OAT1 and OAT3 can be predicted and validated from natural products by combining docking and in vitro screening, and could be a source of pharmaceutical compounds for developing treatments for mercury-induced kidney injury.



From the Cover: Inhibitors of Nicotinamide Phosphoribosyltransferase Cause Retinal Damage in Larval Zebrafish

Mon, 09 Oct 2017 00:00:00 GMT

Abstract
Nicotinamide phosphoribosyltransferase (NAMPT) has been investigated as a target for oncology because it catalyzes a rate-limiting step in cellular energy metabolism to produce nicotinamide adenine dinucleotide. Small molecule inhibitors of NAMPT have been promising drug candidates but preclinical development has been hindered due to associated retinal toxicity. Here we demonstrate that larval zebrafish can predict retinal toxicity associated with this mechanism revealing an attractive alternative method for identifying such toxicities. Zebrafish permit higher throughput testing while using far lower quantities of test article compared with mammalian systems. NAMPT inhibitor-associated toxicity manifested in zebrafish as a loss of response to visual cues compared with auditory cues. Zebrafish retinal damage associated with NAMPT inhibitor treatment was confirmed through histopathology. Ranking 6 NAMPT inhibitors according to their impact on zebrafish vision revealed a positive correlation with their in vitro potencies on human tumor cells. This correlation indicates translatable pharmacodynamics between zebrafish and human NAMPT and is consistent with on-target activity as the cause of retinal toxicity associated with NAMPT inhibition. Together, these data illustrate the utility of zebrafish for identifying compounds that may cause ocular toxicity in mammals, and, likewise, for accelerating development of compounds with improved safety margins.



The Need for, and the Role of the Toxicological Chemist in the Design of Safer Chemicals

Mon, 18 Sep 2017 00:00:00 GMT

Abstract
During the past several decades, there has been an ever increasing emphasis for designers of new commercial (nonpharmaceutical) chemicals to include considerations of the potential impacts a planned chemical may have on human health and the environment as part of the design of the chemical, and to design chemicals such that they possess the desired use efficacy while minimizing threats to human health and the environment. Achievement of this goal would be facilitated by the availability of individuals specifically and formally trained to design such chemicals. Medicinal chemists are specifically trained to design and develop safe and clinically efficacious pharmaceutical substances. No such formally trained science hybrid exists for the design of safer commercial (nonpharmaceutical) chemicals. This article describes the need for and role of the “toxicological chemist,” an individual who is formally trained in synthetic organic chemistry, biochemistry, physiology, toxicology, environmental science, and in the relationships between structure and commercial use efficacy, structure and toxicity, structure and environmental fate and effects, and global hazard, and trained to integrate this knowledge to design safer commercially efficacious chemicals. Using examples, this article illustrates the role of the toxicological chemist in designing commercially efficacious, safer chemical candidates.



The Impact of Novel Assessment Methodologies in Toxicology on Green Chemistry and Chemical Alternatives

Mon, 18 Sep 2017 00:00:00 GMT

Abstract
The field of experimental toxicology is rapidly advancing by incorporating novel techniques and methods that provide a much more granular view into the mechanisms of potential adverse effects of chemical exposures on human health. The data from various in vitro assays and computational models are useful not only for increasing confidence in hazard and risk decisions, but also are enabling better, faster and cheaper assessment of a greater number of compounds, mixtures, and complex products. This is of special value to the field of green chemistry where design of new materials or alternative uses of existing ones is driven, at least in part, by considerations of safety. This article reviews the state of the science and decision-making in scenarios when little to no data may be available to draw conclusions about which choice in green chemistry is “safer.” It is clear that there is no “one size fits all” solution and multiple data streams need to be weighed in making a decision. Moreover, the overall level of familiarity of the decision-makers and scientists alike with new assessment methodologies, their validity, value and limitations is evolving. Thus, while the “impact” of the new developments in toxicology on the field of green chemistry is great already, it is premature to conclude that the data from new assessment methodologies have been widely accepted yet.



The Molecular Design Research Network

Wed, 30 Aug 2017 00:00:00 GMT

Abstract
Herein, we provide an overview of a research network that is aimed at fostering interdisciplinary collaboration between chemists and toxicologists with the goal of rationally designing safer commercial chemicals. The collaborative is the Molecular Design Research Network (MoDRN) that was created in 2013 with funding from the EPA-National Science Foundation Networks for Sustainable Molecular Design and Synthesis (NSMDS) program. MoDRN is led by 4 universities, Baylor University, University of Washington, The George Washington University, and Yale University. The overarching goal of the network is to enable and empower the design of safer chemicals based on the fourth Principle of Green Chemistry that states, “chemical products should be designed to preserve efficacy of function while minimizing toxicity.”



Identifying Greener and Safer Plasticizers: A 4-Step Approach

Wed, 02 Aug 2017 00:00:00 GMT

Abstract
The health and economic burden of endocrine disrupting chemicals, such as the plasticizer di(2-ethylhexyl) phthalate (DEHP), is prompting industry to develop alternatives. However, the absence of requirements for manufacturers to ensure the safety of these alternatives has led to the generation of replacements that may have similar or worse effects than the original chemicals. Consequently, there is increasing recognition by scientists, regulators and industry that proactive approaches are needed to develop safe chemical substitutes. We propose a 4-step approach for the design, characterization and toxicological testing of responsible alternative chemicals that we illustrate with our ongoing studies on DEHP replacements. Our approach is comprised of: (1) the design and characterization of alternative chemicals based on innovative chemical structures and environmental considerations; (2) large-scale in vitro cell-based high throughput and selective ex vivo studies to preselect the most innocuous alternatives; (3) an acute toxicity in vivo study to rule out overt toxicity of the selected candidates; and (4) an in utero and lactational exposure study comparing the effects of selected candidates to those currently in use, emphasizing commonly described phenotypes after exposure to the latter. Using this 4-step approach, we have identified 2 alternative chemicals displaying good plasticizing properties, better biodegradability, and less leaching than DEHP without any apparent toxicity in vivo. This process has thus far proven useful in the proactive identification of responsible chemical replacements for DEHP.