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The developmental and reproductive toxicity associated with exposure to phthalates has motivated a search for alternatives. However, there is limited knowledge regarding the adverse effects of some of these chemicals. We used high-content imaging to compare the effects of mono (2-ethylhexyl) phthalate (MEHP) with six alternative plasticizers: di-2-ethylhexyl terephthalate (DEHTP); diisononyl-phthalate (DINP); diisononylcyclohexane-1,2-dicarboxylate (DINCH); 2-ethylhexyl adipate (DEHA); 2,2,4-trimethyl 1,3-pentanediol diisobutyrate (TXIB) and di-isodecyl-adipate (DIDA). A male germ spermatogonial cell line (C18–4), a Sertoli cell line (TM4) and two steroidogenic cell lines (MA-10 Leydig and KGN granulosa) were exposed for 48 h to each chemical (0.001–100 µM). Cell images were analyzed to assess cytotoxicity and effects on phenotypic endpoints. Only MEHP (100 µM) was cytotoxic and only in C18–4 cells. However, several plasticizers had distinct phenotypic effects in all four cell lines. DINP increased Calcein intensity in C18–4 cells, whereas DIDA induced oxidative stress. In TM4 cells, MEHP, and DINCH affected lipid droplet numbers, while DEHTP and DINCH increased oxidative stress. In MA-10 cells, MEHP increased lipid droplet areas and oxidative stress; DINP decreased the number of lysosomes, while DINP, DEHA, and DIDA altered mitochondrial activity. In KGN cells, MEHP, DINP and DINCH increased the number of lipid droplets, whereas DINP decreased the number of lysosomes, increased oxidative stress and affected mitochondria. The Toxicological Priority Index (ToxPi) provided a visual illustration of the cell line specificity of the effects on phenotypic parameters. The lowest administered equivalent doses were observed for MEHP. We propose that this approach may assist in screening alternative plasticizers. Summary Sentence WhileMEHP was the only chemical displaying cytotoxicity, alternative plasticizers caused cell type-specific phenotypic changes in somatic and germ cell lines. Graphical Abstract

The endocrine disruptive effects of bisphenol A (BPA) and brominated flame retardants (BDE-47) have led to restrictions on their use and increased the pressure to identify safe replacements for these chemicals. Although there is evidence that some of these alternatives may be toxic to spermatogonial and Leydig cells, little is known about the toxicity of emerging replacements on Sertoli cells. We used high-content imaging to compare the effects of legacy chemicals, BPA and BDE-47, to their corresponding replacements. TM4 Sertoli cells were exposed for 48 h to each chemical (0.001–100 µM) followed by cytotoxicity and phenotypic endpoint assessment. The benchmark concentration potency ranking for bisphenols based on cytotoxicity was BPTMC > bisphenol M > BPAF>BPF > BPS > BPA. Human administered equivalent dose (AED) determination ranked BPS as the most potent alternative replacement. The benchmark concentration potency ranking of BDE-47 and organophosphate esters based on cytotoxicity was TDtBPP>BDMPP>TBOEP>TDCPP>TMPP>TPHP>BDE47>IPPP=BPDP=TCPP. Additionally, TM4 cell exposure to BDE-47 increased Calcein intensity (57.9 µM) and affected lysosomes (21.6 µM), while exposure to TPHP and TMPP resulted in cellular oxidative stress changes at benchmark concentration values as low as 0.01 and 0.4 µM, respectively. Overall bioactivity considerations of the chemicals on TM4 via ToxPi analyses and AED modeling further validated emerging replacements as highly potent chemicals in comparison to BPA and BDE-47. These findings demonstrate that many bisphenol and flame retardant replacements are more potent in Sertoli cells than the legacy chemical they are replacing and that phenotypic parameter assessment is an effective tool in chemical toxicity assessment. Summary Sentence In TM4 Sertoli cells, many of the chemicals that are emerging as replacements for BPA and brominated flame retardants show greater toxicity than the chemicals that they are replacing.

Amongst omics technologies, metabolomics should have particular value in regulatory toxicology as the measurement of the molecular phenotype is the closest to traditional apical endpoints, whilst offering mechanistic insights into the biological perturbations. Despite this, the application of untargeted metabolomics for point-of-departure (POD) derivation via benchmark concentration (BMC) modelling is still a relatively unexplored area. In this study, a high-throughput workflow was applied to derive PODs associated with a chemical exposure by measuring the intracellular metabolome of the HepaRG cell line following treatment with one of four chemicals (aflatoxin B 1 , benzo[a]pyrene, cyclosporin A, or rotenone), each at seven concentrations (aflatoxin B 1 , benzo[a]pyrene, cyclosporin A: from 0.2048 μM to 50 μM; rotenone: from 0.04096 to 10 μM) and five sampling time points (2, 6, 12, 24 and 48 h). The study explored three approaches to derive PODs using benchmark concentration modelling applied to single features in the metabolomics datasets or annotated metabolites or lipids: (1) the 1st rank-ordered unannotated feature, (2) the 1st rank-ordered putatively annotated feature (using a recently developed HepaRG-specific library of polar metabolites and lipids), and (3) 25th rank-ordered feature, demonstrating that for three out of four chemical datasets all of these approaches led to relatively consistent BMC values, varying less than tenfold across the methods. In addition, using the 1st rank-ordered unannotated feature it was possible to investigate temporal trends in the datasets, which were shown to be chemical specific. Furthermore, a possible integration of metabolomics-driven POD derivation with the liver steatosis adverse outcome pathway (AOP) was demonstrated. The study highlights that advances in technologies enable application of in vitro metabolomics at scale; however, greater confidence in metabolite identification is required to ensure PODs are mechanistically anchored.

Per- and polyfluoroalkyl substances (PFAS) are found in many consumer and industrial products. While some PFAS, notably perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), are developmentally toxic in mammals, the vast majority of PFAS have not been evaluated for developmental toxicity potential. A concentration–response study of 182 unique PFAS chemicals using the zebrafish medium-throughput, developmental vertebrate toxicity assay was conducted to investigate chemical structural identifiers for toxicity. Embryos were exposed to each PFAS compound (≤100 μM) beginning on the day of fertilization. At 6 days post-fertilization (dpf), two independent observers graded developmental landmarks for each larva (e.g., mortality, hatching, swim bladder inflation, edema, abnormal spine/tail, or craniofacial structure). Thirty percent of the PFAS were developmentally toxic, but there was no enrichment of any OECD structural category. PFOS was developmentally toxic (benchmark concentration [BMC] = 7.48 μM); however, other chemicals were more potent: perfluorooctanesulfonamide (PFOSA), N-methylperfluorooctane sulfonamide (N-MeFOSA), ((perfluorooctyl)ethyl)phosphonic acid, perfluoro-3,6,9-trioxatridecanoic acid, and perfluorohexane sulfonamide. The developmental toxicity profile for these more potent PFAS is largely unexplored in mammals and other species. Based on these zebrafish developmental toxicity results, additional screening may be warranted to understand the toxicity profile of these chemicals in other species.

Identifying reliable negative control compounds is essential for determining the sensitivity and specificity of screening assays. However, well-characterized negative controls for developmental neurotoxicity behavioral assays in larval zebrafish (Danio rerio) are lacking. This study evaluated nine chemicals with no reported evidence of mammalian developmental neurotoxicity, and a positive control (fluoxetine) for developmental and neurodevelopmental (i.e., behavioral) toxicity in zebrafish. Embryos were exposed to each chemical (≤100 µM) during development, 0–5 days post-fertilization (dpf), then assessed as larvae (6 dpf) using a locomotor behavior light–dark transition test. Behavior was analyzed using two methods: (1) the traditional method, comparing the average total distance moved, and (2) a 13-endpoint approach analyzing 13 aspects of the locomotor profile. Results showed that ibuprofen, omeprazole, and fluoxetine induced developmental toxicity (teratogenesis), with fluoxetine also causing behavioral neurotoxicity. Behavioral effects of developmental exposure to selegiline hydrochloride depended on the analysis method. Exposure to the other six chemicals (D-mannitol, glycerol, L-ascorbic acid, metformin hydrochloride, saccharin, and sodium benzoate), as well as ibuprofen or omeprazole, did not produce behavioral effects using either analysis method. Identifying negative control chemicals is essential for evaluating behavioral alterations precipitated by unknown substances and will assist with screening new chemicals for neurodevelopmental toxicity.

Metal oxide nanomaterials (MONMs) are among the most highly utilized classes of nanomaterials worldwide, though their potential to induce DNA damage in living organisms is known. High-throughput in vitro assays have the potential to greatly expedite analysis and understanding of MONM induced toxicity while minimizing the overall use of animals. In this study, the high-throughput CometChip assay was used to assess the in vitro genotoxic potential of pristine copper oxide (CuO), zinc oxide (ZnO), and titanium dioxide (TiO2) MONMs and microparticles (MPs), as well as five coated/surface-modified TiO2 NPs and zinc (II) chloride (ZnCl2) and copper (II) chloride (CuCl2) after 2–4 h of exposure. The CuO NPs, ZnO NPs and MPs, and ZnCl2 exposures induced dose- and time-dependent increases in DNA damage at both timepoints. TiO2 NPs surface coated with silica or silica–alumina and one pristine TiO2 NP of rutile crystal structure also induced subtle dose-dependent DNA damage. Concentration modelling at both post-exposure timepoints highlighted the contribution of the dissolved species to the response of ZnO, and the role of the nanoparticle fraction for CuO mediated genotoxicity, showing the differential impact that particle and dissolved fractions can have on genotoxicity induced by MONMs. The results imply that solubility alone may be insufficient to explain the biological behaviour of MONMs.

Multiple studies have demonstrated the presence of microorganisms commonly associated with surgical site infections (SSIs), in the air within the operating theatre (OT). In some countries such Italy, the limit of microbial concentration in the air for OT with turbulent airflows is 35 CFU/m3 for an empty OT and 180 CFU/m3 during activity. This study aims to hypothesize new benchmarks for the airborne microbial load in turbulent airflow operating theatres in operational and at rest conditions using the percentile distribution of data through a 17-year environmental monitoring campaign in various Italian hospitals that implemented a continuous quality improvement policy. The quartile distribution analysis has shown how in operational and at rest conditions, 75% of the values were below 110 CFU/m3 and 18 CFU/m3, respectively, which can be considered a new benchmark for the monitored OTs. During the initial stages of the monitoring campaign, 28.14% of the concentration values in operational conditions and 29.29% of the values in at rest conditions did not conform to the Italian guidelines’ reference values. In contrast, during the last 5 years, all values in both conditions conformed to the reference values and 98.94% of these values were below the new benchmarks. Continuous improvement has allowed contamination to be reduced to levels well below the current reference values.

Pacific salmon influence temperate terrestrial and freshwater ecosystems through the dispersal of marine-derived nutrients and ecosystem engineering of stream beds when spawning. They also support large fisheries, particularly along the west coast of North America. We provide a comprehensive synthesis of relationships between the densities of Pacific salmon and terrestrial and aquatic ecosystems, summarize the direction, shape, and magnitude of these relationships, and identify possible ecosystem-based management indicators and benchmarks. We found 31 studies that provided 172 relationships between salmon density (or salmon abundance) and species abundance, species diversity, food provisioning, individual growth, concentration of marine-derived isotopes, nutrient enhancement, phenology, and several other ecological responses. The most common published relationship was between salmon density and marine-derived isotopes (40%), whereas very few relationships quantified ecosystem-level responses (5%). Only 13% of all relationships tended to reach an asymptote (i.e., a saturating response) as salmon densities increased. The number of salmon killed by bears and the change in biomass of different stream invertebrate taxa between spawning and nonspawning seasons were relationships that usually reached saturation. Approximately 46% of all relationships were best described with linear or curved nonasymptotic models, indicating a lack of saturation. In contrast, 41% of data sets showed no relationship with salmon density or abundance, including many of the relationships with stream invertebrate and biofilm biomass density, marine-derived isotope concentrations, or vegetation density. Bears required the highest densities of salmon to reach their maximum observed food consumption (i.e., 9.2 kg/m² to reach the 90% threshold of the relationship’s asymptote), followed by freshwater fish abundance (90% threshold = 7.3 kg/m² of salmon). Although the effects of salmon density on ecosystems are highly varied, it appears that several of these relationships, such as bear food consumption, could be used to develop indicators and benchmarks for ecosystem-based fisheries management.

Background Although biocides at low concentrations have been used to control pests, they can be more harmful than industrial chemicals as humans are directly and frequently exposed to such biocides. Benzalkonium chloride (BAC or BKC) is a non-toxic substance used to control pests. Recently, BAC has been increasingly used as a component in humidifier disinfectants in Korea, raising a serious health concern. Moreover, it poses significant health hazards to workers handling the chemical because of direct exposure. In the present study, we aimed to evaluate the respiratory toxicity of BAC due to its inhalation at exposure concentrations of 0.8 (T1 group), 4 (T2 group) and 20 (T3 group) mg/m 3 . Results In our previous study on the acute inhalational toxicity of BAC, bleeding from the nasal cavity was observed in all the rats after exposure to 50 mg/m 3 BAC. Therefore, in this study, 20 mg/m 3 was set as the highest exposure concentration, followed by 4 and 0.8 mg/m 3 as the medium and low concentrations for 6 h/day and 14 days, respectively. After exposure, recovery periods of 2 and 4 weeks were provided. Additionally, alveolar lavage fluid was analyzed in males of the BAC-exposed groups at the end of exposure and 2 weeks after exposure to evaluate oxidative damage. In the T3 group exposed to BAC, deep breathing, hoarseness, and nasal discharge were observed along with a decline in feed intake and body weight, and nasal discharge was also observed in the T1 and T2 groups. ROS/RNS, IL-1β, IL-6, and MIP-2 levels decreased in a concentration-dependent manner in the bronchoalveolar lavage fluid. Histopathological examination showed cellular changes in the nasal cavity and the lungs of the TI, T2, and T3 groups. Conclusions As a result, it was confirmed that the target organs in the respiratory system were the nasal cavity and the lungs. The adverse effects were evaluated as reversible responses to oxidative damage. Furthermore, the no observed adverse effect level was found to be less than 0.8 mg/m 3 and the lowest benchmark dose was 0.0031 mg/m 3 . Accordingly, the derived no-effect level of BAC was calculated as 0.000062 mg/m 3 .

The fundamental characteristic of a semi-permeable porous material is that the solvent is allowed to pass through it but the solute is not. Due to this characteristic, a solute concentration gradient can drive chemical osmosis flow in the solution-saturated semi-permeable porous material. Although analytical solutions have been derived for one-dimensional chemical osmosis induced flow and solute concentration variation problems, computational simulations of two-dimensional chemical osmosis induced flow and solute concentration variation problems remain lacking to date. To fill this gap, a new mathematical model is first established, in this paper, for describing two-dimensional chemical osmosis induced flow and solute concentration variation problems in solution-saturated semi-permeable porous materials. Then a computational simulation procedure, which contains the finite difference and finite element methods, is proposed to solve the partial differential equations involved in the established mathematical model. For the purpose of verifying the proposed computational simulation procedure, the analytical solution of a benchmark problem has been derived mathematically. The related computational simulation results have demonstrated that: (1) the proposed computational simulation procedure is correct and accurate for solving chemical osmosis induced flow and solute concentration variation problems; and (2) the applied boundary conditions have significant effects on the computational simulation results of two-dimensional chemical osmosis induced flow and solute concentration variation problems in the solution-saturated semi-permeable porous material.