Temperate Versus Arctic: Unraveling the Effects of Temperature on Oil Toxicity in Gammarids.

Shipping activities are increasing with sea ice receding in the Arctic, leading to higher risks of accidents and oil spills. Because Arctic toxicity data are limited, oil spill risk assessments for the Arctic are challenging to conduct. In the present study, we tested if acute oil toxicity metrics obtained at temperate conditions reflect those at Arctic conditions. The effects of temperature (4 °C, 12 °C, and 20 °C) on the median lethal concentration (LC50) and the critical body residue (CBR) of the temperate invertebrate Gammarus locusta exposed to water accommodated fractions of a fuel oil were determined. Both toxicity metrics decreased with increasing temperature. In addition, data for the temperate G. locusta were compared to data obtained for Arctic Gammarus species at 4 °C. The LC50 for the Arctic Gammarus sp. was a factor of 3 higher than that for the temperate G. locusta at 4 °C, but its CBR was similar, although both the exposure time and concentration were extended to reach lethality. Probably, this was a result of the larger size and higher weight and total lipid content of Arctic gammarids compared to the temperate gammarids. Taken together, the present data support the use of temperate acute oil toxicity data as a basis for assessing risks in the Arctic region, provided that the effects of temperature on oil fate and functional traits (e.g., body size and lipid content) of test species are considered. As such, using the CBR as a toxicity metric is beneficial because it is independent of functional traits, despite its temperature dependency. To the best of our knowledge, the present study is the first to report CBRs for oil. Environ Toxicol Chem 2024;43:1627-1637. © 2024 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

On Interactions of Sulfamerazine with Cyclodextrins from Coupled Diffusometry and Toxicity Tests.

This scientific study employs the Taylor dispersion technique for diffusion measurements to investigate the interaction between sulfamerazine (NaSMR) and macromolecular cyclodextrins (ß-CD and HP-ß-CD). The results reveal that the presence of ß-CD influences the diffusion of the solution component, NaSMR, indicating a counterflow of this drug due to solute interaction. However, diffusion data indicate no inclusion of NaSMR within the sterically hindered HP-ß-CD cavity. Additionally, toxicity tests were conducted, including pollen germination (Actinidia deliciosa) and growth curve assays in BY-2 cells. The pollen germination tests demonstrate a reduction in sulfamerazine toxicity, suggesting potential applications for this antimicrobial agent with diminished adverse effects. This comprehensive investigation contributes to a deeper understanding of sulfamerazine-cyclodextrin interactions and their implications for pharmaceutical and biological systems.

Reversible and monitorable nephrotoxicity in rats by the novel potent transcriptional enhanced associate domain (TEAD) inhibitor, K-975.

The Hippo pathway plays an important role in the growth, development, and regeneration of cells and organs. Transcriptional enhanced associate domain (TEAD), a transcription activator of the Hippo pathway, forms the complex with a transcriptional coactivator yes-associated protein (YAP) or a transcriptional coactivator PDZ-binding motif (TAZ). Their excessive activations are involved in carcinogenesis such as malignant pleural mesothelioma (MPM), and thus inhibition of the TEAD complex is expected to have potent anticancer activity against MPM. On the other hand, YAP or TAZ conditional knockout mice have been reported to show abnormal findings in various tissues, including the kidney, liver, and lung. In the present study, we evaluated the systemic toxicity of K-975, a novel TEAD inhibitor, in rats. When K-975 was administered orally to rats for 1 week, proteinuria suggestive of nephrotoxicity was observed. Electron microscopy revealed that K-975 at 300 mg/kg induced glomerular podocyte foot process effacement. After a 2-week recovery period, proteinuria with foot process effacement was recovered completely. Urinalysis and urinary biomarker evaluation suggested that the urinary albumin index (urinary albumin/urinary creatinine) was the most sensitive marker for detecting K-975-induced nephrotoxicity. After 3 cycles of 1-week administration followed by 2-week recovery periods, nephrotoxicity was reversible; however, incomplete reversibility was observed in rats with severe proteinuria. In conclusion, this study revealed that in rats, oral K-975 treatment induced severe proteinuria by podocyte foot process effacement, which was reversible and monitorable by the urinary albumin index, suggesting important information for developing K-975 as an anticancer drug.

The uses of zebrafish (Danio rerio) as an in vivo model for toxicological studies: A review based on bibliometrics.

An in vivo model is necessary for toxicology. This review analyzed the uses of zebrafish (Danio rerio) in toxicology based on bibliometrics. Totally 56,816 publications about zebrafish from 2002 to 2023 were found in Web of Science Core Collection, with Toxicology as the top 6 among all disciplines. Accordingly, the bibliometric map reveals that "toxicity" has become a hot keyword. It further reveals that the most common exposure types include acute, chronic, and combined exposure. The toxicological effects include behavioral, intestinal, cardiovascular, hepatic, endocrine toxicity, neurotoxicity, immunotoxicity, genotoxicity, and reproductive and transgenerational toxicity. The mechanisms include oxidative stress, inflammation, autophagy, and dysbiosis of gut microbiota. The toxicants commonly evaluated by using zebrafish model include nanomaterials, arsenic, metals, bisphenol, and dioxin. Overall, zebrafish provide a unique and well-accepted model to investigate the toxicological effects and mechanisms. We also discussed the possible ways to address some of the limitations of zebrafish model, such as the combination of human organoids to avoid species differences.

Toxicity test profile for deep eutectic solvents: A detailed review and future prospects.

Deep eutectic solvents (DESs) are preferable in terms of starting materials, storage and synthesis, simplicity, and component material affordability. In several industries ranging from chemical, electrochemical, biological, biotechnology, material science, etc., DES has demonstrated remarkable potential. Despite all these accomplishments, the safety issue with DES must be adequately addressed. Different DES interacts with the cellular membranes differently. It is not possible to classify all DES as easily biodegradable. By expanding the current understanding of the toxicity and biodegradation of DES, interactions between organisms and cellular membranes can be linked. The DES toxicity profile varies according to their concentration, the nature of the individual components, and how they interact with living things. Therefore, the results of this review can serve as a baseline for DES development in the future.

Anti-Candida activity and in vitro toxicity screening of antifungals complexed with ß-cyclodextrin.

The emergence of resistant fungal species and the toxicity of currently available antifungal drugs are relevant issues that require special consideration. Cyclodextrins inclusion complexes could optimize the antimicrobial activity of such drugs and create a controlled release system with few side effects. This study aimed to assess the in vitro toxicity and antifungal effectiveness of nystatin (Nys) and chlorhexidine (Chx) complexed or not with ß-cyclodextrin (ßCD). First, a drug toxicity screening was performed through the Artemia salina bioassay. Then, the minimum inhibitory concentrations (MICs) against Candida albicans were determined with the broth microdilution test. After MICs determination, the cytotoxicity of the drugs was evaluated through the methyl-thiazolyl-tetrazolium (MTT) and neutral red (NR) assays and through cell morphology analysis. The PROBIT analysis was used to determine the median lethal concentration (LC50), and the cell viability values were submitted to one-way analysis of variance(ANOVA)/Tukey (α = 0.05). Overall, the ßCD-complexed antifungals were less toxic against A. salina than their raw forms, suggesting that inclusion complexes can reduce the toxicity of drugs. The MICs obtained were as follows: Nys 0.5 mg/L; Nys:ßCD 4 mg/L; Chx 4 mg/L; and Chx:ßCD 8 mg/L. Chx showed significant cytotoxicity (MTT: 12.9 ± 9.6%; NR: 10.6 ± 12.5%) and promoted important morphological changes. Cells exposed to the other drugs showed viability above 70% with no cellular damage. These results suggest that antifungals complexed with ßCD might be a biocompatible option for the treatment of Candida-related infections.

Effects of two weeks of food restriction on toxicological parameters in cynomolgus monkeys.

Animals frequently eat less after a test-article treatment in nonclinical toxicological studies, and it can be difficult to distinguish test article-derived toxicities from secondary changes related to this reduced food intake. Therefore, in this study, we restricted the food intake of cynomolgus monkeys (Cambodian, male, n=2 or 3, 48 ± 3 months old) to 25% of the control for two weeks and evaluated the effects on toxicological parameters (general conditions, body weight, electrocardiography, urinalysis, hematology, blood chemistry, bone marrow analysis, pathological examination). After 2 weeks, the monkeys exhibited decreases in bone marrow erythropoiesis (e.g., decreases in reticulocytes and bone marrow erythrocytes), as well as glycogenesis induction (e.g., increase in aspartate aminotransferase (AST)) and malnutrition (e.g., decrease in triglyceride and systemic adipocytes atrophy). Additionally, histopathological analysis revealed granuloma and inflammatory cell infiltration in coronary fat, which had never been found in previous food restriction studies using other animal species. These findings will enable researchers to more accurately evaluate the toxicological risks of test articles that simultaneously induce food intake reduction.

Acute poisoning by chlorpyrifos differentially impacts survival and cardiorespiratory function in normotensive and hypertensive rats.

Hypertension is the most important and well-known risk factor for cardiovascular disease (CVD). Recently, acute organophosphate (OP) poisoning has also been pointed as a CVD risk factor. Despite this evidence, no studies have contrasted the acute toxicosis and cardiovascular (CV) effects of OP poisoning under conditions of normotension and hypertension. In this work, adult male normotensive Wistar and Spontaneously Hypertensive rats (SHR) were intraperitoneally injected with saline or chlorpyrifos (CPF), an OP compound, monitored for acute toxicosis signs and 24-h survival. After poisoning, blood pressure, heart rate and ventilation were recorded, the Bezold-Jarisch Reflex (BJR), the Chemoreflex (CR) were chemically activated, as well as the cardiac autonomic tone (AUT) was assessed. Erythrocyte and brainstem acetylcholinesterase and plasmatic butyrylcholinesterase (BuChE) activities were measured as well as lipid peroxidation, advanced oxidation protein products (AOPP), nitrite/nitrate levels, expression of catalase, TNFα and angiotensin-I converting enzyme (ACE-1) within the brainstem. CPF induced a much more pronounced acute toxicosis and 33 % lethality in SHR. CPF poisoning impaired ventilation in SHR, the BJR reflex responses in Wistar rats, and the chemoreflex tachypneic response in both strains. CPF inhibited activity of cholinesterases in both strains, increased AOPP and nitrite/nitrate levels and expression of TNFα and ACE-1 in the brainstem of Wistar rats. Interestingly, SHR presented a reduced intrinsic BuChE activity, an important bioscavenger. Our findings show that, CPF at sublethal doses in normotensive rats lead to lethality and much more pronounced acute toxicity signs in the SHR. We also showed that cardiorespiratory reflexes were differentially impacted after CPF poisoning in both strains and that the cardiorespiratory disfunction seems to be associated with interference in cholinergic transmission, oxidative stress and inflammation. These results points to an increased susceptibility to acute toxicosis in hypertension, which may impose a significant risk to vulnerable populations.

Anti-inflammatory, anti-tussive effects and toxicity evaluation of Qingfei Dayuan granules.

OBJECTIVE: To study the anti-inflammatory and anti-tussive effects of Qingfei Dayuan granules (, QFDY), and to evaluate the acute and sub-chronic toxicity of QFDY. METHODS: Anti-inflammatory effects were evaluated by murine model of xylene induced ear edema in mice. Ear swelling degree was calculated and tumor necrosis factor-α, interleukin-1ß and interleukin-6 were determined. Anti-tussive evaluations were carried out in the mouse cough model induced by ammonia liquor. Latent period cough and number of cough within 3 min were counted. In acute toxicity study, the rats were randomly divided into test group and solvent control group. Body weighs, food intakes and general clinical signs were monitored. In the sub-chronic toxicity study, QFDY was administered to rats at 0, 4, 8 and 16 g/kg per day for 28 and 30 d of post treatment was conducted. Mortalities, clinical signs, body weight changes, food intakes, ophthalmological examinations, hematological parameters, biochemical indicators, electrolyte indicators, urinalyses and histopathological examinations were monitored. RESULTS: QFDY significantly inhibited the development of ear edema in anti-inflammatory assay and decreased cough frequency caused by ammonia liquor. The results presented a dose-effect relationship. In acute toxicity study, no abnormality exhibited at dose of 24.0 g/kg per day during the 14-d observation period. In the sub-chronic toxicity study, higher reticulocyte count, lymphocyte and lower Cl-, blood urea nitrogen were analyzed compared with the solvent control group. But the differences were considered to be incidental and not clinically toxic. Obvious dose-effect relationship of urine color was observed, and the three test groups at the end of the experiments resulted in significant increase in urobilinogen, bilirubin, ketone body and urine leukocyte. However, all the positive indicators returned to normal in the recovery period. Therefore, no toxicological changes were found during the study period. CONCLUSION: QFDY showed significant anti-inflammatory and anti-tussive effects in mice. The lethal dose (LD50) of per oral QFDY in rats was estimated to be more than 24.0 g/kg per day and the no observed adverse effect level was over 16 g/kg per day, which suggested that QFDY is relatively safe for oral medication at the present dose on rats. Our experimental results provide a reference for the further development and research of QFDY.

Description and validation of an improved method to feed solitary bees (Osmia spp.) known amounts of pesticides.

Pesticide exposure is an important driver of bee declines. Laboratory toxicity tests provide baseline information on the potential effects of pesticides on bees, but current risk assessment schemes rely on one species, the highly social honey bee, Apis mellifera, and there is uncertainty regarding the extent to which this species is a suitable surrogate for other pollinators. For this reason, Osmia cornuta and Osmia bicornis have been proposed as model solitary bee species in the EU risk assessment scheme. The use of solitary bees in risk assessment requires the development of new methodologies adjusted to the biology of these species. For example, oral dosing methods used with honey bees cannot be readily applied to solitary bees due to differences in feeding behaviour and social interactions. In this study, we describe the "petal method", a laboratory feeding method, and validate its use in acute and chronic exposure oral tests with Osmia spp. We conducted five experiments in which we compared the performance of several artificial flowers combining visual and olfactory cues against the petal method, or in which variations of the petal method were confronted. We then use the results of these experiments to optimize the feeding arenas and propose standardized methods for both acute and chronic exposure tests. The petal method provides high levels of feeding success, thus reducing the number of bees needed. It works with a wide variety of petal species and with both female and male Osmia spp., thus ensuring reproducibility across studies. To validate the use of the petal method in ecotoxicology tests, we assess the toxicity of a standard reference insecticide, dimethoate, in O. cornuta adults and determine LD50 values for this species. The petal method should facilitate the inclusion of solitary bees in risk assessment schemes therefore increasing the protection coverage of pesticide regulation.

Environmental exposure and ecological risk of perfluorinated substances (PFASs) in the Shaying River Basin, China.

There have been concerns raised about the environmental effects of perfluoroalkyl substances (PFASs) because of their toxicity, widespread distribution, and persistence. Understanding the occurrences and ecological risk posed by PFASs is essential, especially for the short-chain replacements perfluorobutanoic acid (PFBA) and perfluorobutane sulfonic acid (PFBS), which are now becoming predominant PFASs. The lack of aquatic life criteria (ALC), however, prevents an accurate assessment of the ecological risks of PFBA and PFBS. This study thus investigated the occurrence of 15 PFASs at 29 sampling sites in Shaying River Basin (in China) systematically, conducted the toxicity tests of PFBA and PFBS on eight resident aquatic organisms in China, and derived the predicted non-effect concentration (PNEC) values for PFBA and PFBS for two environmental media in China. The results showed that the total PFASs concentrations (ΣPFASs) ranged from 5.07 to 20.32 ng/L (average of 10.95 ng/L) in surface water, whereas in sediment, ΣPFASs ranged from 6.46 to 20.05 ng/g (dw) (average of 11.51 ng/g). The presence of PFBS was the most prominent PFASs in both water (0.372-8.194 ng/L) and sediment (4.54-15.72 ng/g), demonstrating that short-chain substitution effects can be observed in watersheds. The PNEC values for freshwater and sediment were 6.60 mg/L and 8.30 mg/kg (ww), respectively, for PFBA, and 14.04 mg/L, 37.08 mg/kg (ww), respectively, for PFBS. Ecological risk assessment of two long-chain PFASs, perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), and two short-chain PFASs, PFBA and PFBS, using the hazard quotient method revealed that Shaying River and other major River Basins in China were at risk of PFOS contamination. This study contributes to a better understanding of the presence and risk of PFASs in the Shaying River and first proposes the ALCs for PFBA and PFBS in China, which could provide important reference information for water quality standards.

Preliminary study on the acute effects of hydrogen sulfide on Amphipoda (Lysianassoidea; Pseudorchomene sp. and Anonyx sp.) collected from deep-sea floors in the Sea of Japan.

To study the environmental impact of the assessment technologies for the development of shallow methane hydrate zones in the Sea of Japan, deep-sea amphipods (Pseudorchomene sp. and Anonyx sp.) were collected from a depth of approximately 1000 m and were tested for H2S toxicity. At 0.57 mg L-1 H2S, all specimens of Pseudorchomene sp. were dead after 96 h, whereas all individuals survived at 0.18 mg L-1. Moreover, Anonyx sp. had a survival rate of 17 % after 96 h at 0.24 mg L-1. A similar toxicity test was conducted with the coastal amphipod Merita sp., a detritivore, and all individuals died within 24 h at 0.15 mg L-1. These results suggested that compared with coastal detritivorous amphipods, deep-sea detritivorous amphipods, which also live near biomats with sediment H2S concentrations exceeding 10 mg L-1, showed a higher tolerance to H2S.

Assessment of acute inhalation toxicity of citric acid and sodium hypochlorite in rats.

BACKGROUND: Citric acid (CA) and sodium hypochlorite (NaOCl) have been used to disinfect animals to protect them against avian influenza and foot-and-mouth disease. OBJECTIVES: We performed a good laboratory practice (GLP)-compliant animal toxicity study to assess the acute toxic effects of CA and NaOCl aerosol exposure in Sprague-Dawley rats. METHODS: Groups of five rats per sex were exposed for 4 h to four concentrations of the two chemicals, i.e., 0.00, 0.22, 0.67, and 2.00 mg/L, using a nose-only exposure. After a single exposure to the chemicals, clinical signs, body weight, and mortality was observed during the observation period. On day 15, an autopsy, and then gross findings, and histopathological analysis were performed. RESULTS: After exposure to CA and NaOCl, body weight loss was observed but recovered. Two males died in the CA 2.00 mg/L group and, two males and one female died in the 2.00 mg/L NaOCl group. In the gross findings and histopathological analysis, discoloration of the lungs was observed in the CA exposed group and inflammatory lesions with discoloration of the lungs were observed in the NaOCl exposed group. These results suggest that the lethal concentration 50 (LC50) of CA is 1.73390 mg/L for males and > 1.70 mg/L for females. For NaOCl, the LC50 was 2.22222 mg/L for males and 2.39456 mg/L for females. CONCLUSIONS: The Globally Harmonized System is category 4 for both CA and NaOCl. In this study, the LC50 results were obtained through a GLP-based acute inhalation toxicity assessment. These results provide useful data to reset safety standards for CA and NaOCl use.

Cytotoxic and Genotoxic Effects of Waterpipe on Oral Health Status: Systematic review and meta-analysis.

This systematic review and meta-analysis aimed to assess the cytotoxic and genotoxic impacts of waterpipe smoking on oral health. The databases MEDLINE, Cochrane Library and Dimensions were searched to find studies evaluating whether waterpipe smokers exhibited any cytotoxic or genotoxic effects on their oral cells compared to non-smokers, with regard to mouth neoplasms. Particularly, changes in DNA methylation and p53 expression were assessed. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were adopted for the systematic review. Review Manager was utilised for statistical analysis with a significance level at P <0.05. To assess the grades of the included articles, a risk of bias analysis was summarised. A forest plot, including some of the included articles included, was created regarding the different grades. A total of 20 studies were included in this review. The results showed that waterpipe smoking has cytotoxic and genotoxic effects on oral cells, with a risk difference of 0.16. Although the published articles are few in number, all confirm the devastating effects of waterpipe smoking related to the carcinogenicity. Waterpipe smoking is harmful to oral health. It causes a series of detrimental cellular and genetic modifications such as acanthosis, epithelial dysplasia and hyperparakeratosis. In addition, waterpipe smoke contains several carcinogenic compounds. As it releases many harmful organic compounds, waterpipe smoking increases the incidence of oral cancer.

Experimental Studies on Zooplankton-Toxic Cyanobacteria Interactions: A Review.

Cyanobacterial blooms have been recognized as a problem in fresh water for about 150 years. Over the past 50 years, experimental studies on the subject have gained importance considering the increasing need to control toxic cyanobacterial blooms. This article presents information on the different lines of research that have been undertaken on zooplankton-cyanobacteria interactions over the past 50 years. These include information on filtering/ingestion rates and phytoplankton preferences of small and large rotifers, cladocerans, and copepods; growth rates of zooplankton on cyanobacterial diets; feeding rates of other freshwater invertebrates on cyanobacteria; role of zooplankton in top-down biomanipulation efforts; effect of cyanotoxins on zooplankton; bioaccumulation of cyanotoxins; and physical and chemical control of cyanobacterial blooms. We also highlight measures that have led to successful lake management and improvement of water quality in selected waterbodies.

Evaluating ecotoxicological assays for comprehensive risk assessment of toxic metals present in industrial wastewaters in the Republic of Korea.

Toxicity tests represent a rapid, user-friendly and cost-effective means to assess the impact of wastewater quality on aquatic ecosystems. There are not many cases where wastewater management standards are set based on various bio-based ecotoxicity values. Here, we tested a novel multitaxon approach to compare standard water quality indices to toxicity metrics obtained from ecotoxicity tests, conducted using aquatic organisms representing several trophic levels (Aliivibrio, Ulva, Daphnia, and Lemna), for 99 industrial wastewater samples from South Korea. For five wastewater samples, the concentrations of Se, Zn, or Ni exceeded the permissible limits (1, 5, and 3 mg L-1, respectively). All the four physiochemical water quality indices tested were positively correlated with Se and Pb concentrations. The toxicity unit (TU) scores indicated a declining sensitivity to pollutants, in the order Lemna (2.87) >Daphnia (2.24) >Aliivibrio (1.78) >Ulva (1.42). Significant correlations were observed between (1) Cd and Ni, and Aliivibrio, (2) Cu and Daphnia, (3) Cd, Cu, Zn, and Cr and Lemna, and (4) Cu, Zn, and Ni and Ulva. Daphnia-Lemna and Lemna-Ulva were found to be good indicators of ecologically harmful Se and Ni contents in wastewater, respectively. We suggest that regulatory thresholds based on these bioassays should be set at TU = 1 for all the species or at TU = 1 for Aliivibrio and Ulva and TU = 2 for Daphnia and Lemna, if the number of companies whose wastewater discharge exceeds the allowable TU levels is <1 % or 5 % of the total number of industries, respectively. Taken together, these findings could help in establishing a rapid, ecologically relevant wastewater quality assessment system that would be useful for developing strategies to protect aquatic ecosystems.

Calibration of an acute toxicity model for the marine crustacean, Artemia franciscana, nauplii to support oil spill effect assessments.

Oil spill risk and impact assessments rely on time-dependent toxicity models to predict the hazard of the constituents that comprise crude oils and petroleum substances. Dissolved aromatic compounds (ACs) are recognized as a primary driver of aquatic toxicity in surface spill exposure scenarios. However, limited time-dependent toxicity data are available for different classes of ACs to calibrate such models. This study examined the acute toxicity of 14 ACs and 3 binary AC mixtures on Artemia franciscana nauplii at 25 °C. Toxicity tests for 3 ACs were also conducted at 15 °C to evaluate the role of temperature on toxicity. The ACs investigated represented parent and alkylated homocyclic and nitrogen-, sulfur- and oxygen-containing heterocyclic structures with octanol-water partition coefficients (log Kow) ranging from 3.2 to 6.6. Passive dosing was used to expose and maintain concentrations in toxicity tests which were confirmed using fluorometry, and independently validated for 6 ACs using GC-MS analysis. Mortality was assessed at 6, 24, and 48 h to characterize the time course of toxicity. No mortality was observed for the most hydrophobic AC tested, 7,12-dimethylbenz[a]anthracene, due to apparent water solubility constraints. Empirical log LC50 s for the remaining ACs were fit to a linear regression with log Kow to derive a critical target lipid body burden (CTLBB) based on the target lipid model. The calculated 48 h CTLBB of 47.1 ± 8.1 µmol/g octanol indicates that Artemia nauplii exhibited comparable sensitivity to other crustaceans. A steep concentration-response was found across all compounds as evidenced by a narrow range (1.0-3.1) in the observed LC50 /LC10 ratio. Differences in toxicokinetics were noted, and no impacts of temperature-dependence of AC toxicity were found. Toxicity data obtained for individual ACs yielded acceptable predictions of observed binary AC mixture toxicity. Results from this study advance toxicity models used in oil spill assessments.

Animal use and opportunities for reduction in carcinogenicity studies supporting approved new drug applications in the U.S., 2015-2019.

A minimum of 65,341 rats and mice were used in 109 carcinogenicity studies conducted for new drug applications approved by the U.S. Food and Drug Administration from 2015 through 2019. By analyzing how these animals were used, we compared the potential for reducing animal use of implementing existing international guidelines and recommendations. The greatest reduction, 18.7%, would result from evaluating exposure by microsampling blood in main studies to replace toxicokinetics satellites, which used three-fold more mice than rats. A similar reduction, 17.3%, would result from replacing 33 long-term studies in mice with short-term studies in transgenic mice. Based on histopathology findings in chronic studies, 15 long-term studies in rats could have been waived, using 8410 fewer rats. Simply using single, rather than dual, negative control groups would result in a 7.8% reduction, and eliminating positive control groups would use 640 fewer transgenic mice. Combined, an estimated 46% reduction would be achieved, using approximately 29,876 fewer animals. The publication of an addendum to the main carcinogenicity testing guideline promises to decrease the number of long-term studies conducted in rats and mice and presents opportunity to promote full harmonization and implementation of related recommendations that would further dramatically reduce animal use.

The Preliminary Assessment of New Biomaterials Necessitates a Comparison of Direct and Indirect Cytotoxicity Methodological Approaches.

BACKGROUND: Cytotoxicity testing is a primary method to establish the safety of biomaterials, e.g., biocomposites. Biomaterials involve a wide range of medical materials, which are usually solid materials and are used in bone regeneration, cardiology, or dermatology. Current advancements in science and technology provide several standard cytotoxicity testing methods that are sufficiently sensitive to detect various levels of cellular toxicity, i.e., from low to high. The aim was to compare the direct and indirect methodology described in the ISO guidelines UNE-EN ISO 10993-5:2009 Part 5. METHODS: Cell proliferation was measured using WST-1 assay, and cytotoxicity was measured using LDH test kit. RESULTS: The results indicate that the molecular surface of biomaterials have impact on the cytotoxicity and proliferation profile. Based on these results, we confirm that the indirect method does not provide a clear picture of the cell condition after the exposure to the surface, and moreover, cannot provide complete results about the effects of the material. CONCLUSIONS: Comparison of both methods shows that it is pivotal to investigate biomaterials at the very early stages using both indirect and direct methods to access the influence of the released toxins and surface of the material on the cell condition.