Drug-induced liver injury (DILI) is one of the major concerns during drug development. Wide acceptance of the 3 R principles and the innovation of in-vitro techniques have introduced various novel model options, among which the three-dimensional (3D) cell spheroid cultures have shown a promising prospect in DILI prediction. The present study developed a 3D quadruple cell co-culture liver spheroid model for DILI prediction via self-assembly. Induction by phorbol 12-myristate 13-acetate at the concentration of 15.42 ng/mL for 48 hours with a following 24-hour rest period was used for THP-1 cell differentiation, resulting in credible macrophagic phenotypes. HepG2 cells, PUMC-HUVEC-T1 cells, THP-1-originated macrophages, and human hepatic stellate cells were selected as the components, which exhibited adaptability in the designated spheroid culture conditions. Following establishment, the characterization demonstrated the competence of the model in long-term stability reflected by the maintenance of morphology, viability, cellular integration, and cell-cell junctions for at least six days, as well as the reliable liver-specific functions including superior albumin and urea secretion, improved drug metabolic enzyme expression and CYP3A4 activity, and the expression of MRP2, BSEP, and P-GP accompanied by the bile acid efflux transport function. In the comparative testing using 22 DILI-positive and 5 DILI-negative compounds among the novel 3D co-culture model, 3D HepG2 spheroids, and 2D HepG2 monolayers, the 3D culture method significantly enhanced the model sensitivity to compound cytotoxicity compared to the 2D form. The novel co-culture liver spheroid model exhibited higher overall predictive power with margin of safety as the classifying tool. In addition, the non-parenchymal cell components could amplify the toxicity of isoniazid in the 3D model, suggesting their potential mediating role in immune-mediated toxicity. The proof-of-concept experiments demonstrated the capability of the model in replicating drug-induced lipid dysregulation, bile acid efflux inhibition, and α-SMA upregulation, which are the key features of liver steatosis and phospholipidosis, cholestasis, and fibrosis, respectively. Overall, the novel 3D quadruple cell co-culture spheroid model is a reliable and readily available option for DILI prediction.

We present a fixed-dose combination injectable (FDCI) solution for cattle formulated for a single subcutaneous administration at a dose rate of 1 ml/25 kg of body weight to deliver a dose of 0.2 mg/kg of doramectin and 6.0 mg/kg of levamisole hydrochloride (5.1 mg/kg base equivalent). This drug product is marketed in the United States under the tradename Valcor® and in Australia and New Zealand under the tradename Dectomax V®. Both levamisole and doramectin have histories of safe and effective use in ruminants, with safety margins of 3X and 25X, respectively. Three studies were conducted to demonstrate the safety of the new FDCI: margin of safety (Study 1), and reproductive safety in sexually nulliparous beef heifers (Studies 2 and 3). In Study 1, 3-month-old sexually intact male and female calves were given either saline (control) or 1X, 2X, or 3X FDCI on Days 0, 14, and 28. General health, clinical, and neurological observations were made throughout the study, and clinical and pathology evaluations were made at study end. Studies 2 and 3 demonstrated the reproductive safety of the FDCI on sexually nulliparous beef heifers using estrus synchronization and timed artificial insemination. Treatments of either saline (control) or 3X FDCI were administered to coincide with either folliculogenesis, implantation, organogenesis, early gestation, or late gestation. Reproductive safety was demonstrated by evaluating rates of conception, calving, abortion, and stillbirth, dystocia scores, and calf health. In all studies, the FDCI at 1X, 2X, or 3X dosages was well tolerated. In the margin of safety study, 3X calves showed increased incidence of salivation for up to 8 h post-dosing compared to other groups. Injection sites were palpable post-dosing in all three FDCI groups but resolved by Day 28 in all but one animal each in 2X and 3X. In the reproductive safety studies, the FDCI had no effect on conception, pregnancy, fetal development, or postnatal viability. Injection site swelling was increased in frequency and duration compared to controls. The studies demonstrate the safety of the new FDCI in cattle from 3 months of age and in reproducing heifers during all reproductive stages from folliculogenesis through gestation and up to a month post-partum.

Nitrite and nitrate are well-known food additives used in cured meats and linked to different food safety concerns. However, no study about the possible effect of cooking treatment on the residual level of these compounds before consumption is available. In this work, 60 samples of meat products were analyzed in order to evaluate the variation in residual nitrite and nitrate level after baking, grilling and boiling. The analyses by ion chromatography demonstrated that meat cooking leads to a decrease in nitrite and an increase in nitrate residual levels in the final products. Meat boiling caused an overall decrease in two additives\' concentration, while baking and particularly grilling caused an increase in nitrate and, in some cases, nitrite as well. Some regulatory aspects were also considered, such as the possibility of revising the legal limit of nitrate from the actual 150 mg kg-1 to a more cautious 100 mg kg-1. Indeed, several meat samples (bacon and swine fresh sausage) resulted in a higher nitrate concentration than the legal limit after cooking by grilling (eleven samples) or baking (five samples). Finally, the Margin of Safety evaluation demonstrated a good level of food safety, all values being higher than the protective threshold of 100.

Hair dye products include a range of chemicals, depending on the type and color. A common primary intermediate compound used to achieve the permanent effect of hair dye is para-phenylenediamine (PPD). 4-aminobiphenyl (4-ABP) has reportedly been found as a trace contaminant (presumably from the para-phenylenediamine [PPD] ingredient) in consumer permanent hair dye. While several regulatory agencies have designated 4-ABP as a human bladder carcinogen based on evidence in humans and experimental animals, only the Office of Environmental Health Hazard Assessment (OEHHA) have established a cancer risk value for 4-ABP of 0.03 μg/day based on liver tumors developed in mice. A hypothetical dermal risk assessment was performed to estimate the bladder cancer risk associated with exposure to 4-ABP from personal use of permanent hair dye potentially containing incidental 4-ABP. Previously published laboratory analyses characterizing 4-ABP concentrations in consumer hair dyes indicate the concentrations can range from below the limit of detection to 8120 ppb. Precautionary estimates of human scalp surface area, maximum skin adherence, hair dye retention factor, and percent dermal absorption were used to estimate the daily systemic exposure doses (SEDs) from dermal application of hair dye. The estimated SEDs ranged from 0.05 to 3000 pg/day. A margin of safety (MOS) was calculated as the ratio of the NSRL to the SED and ranged from 10 to 570,000. The results of this study suggest that there is no indication of increased risk of bladder cancer in humans from exposure to 4-ABP in consumer hair dye, especially as it is extremely unlikely that a consumer would use permanent hair dye on a daily basis (as this assessment models).

Quaternary ammonium compounds (QACs) are widely used in consumer products because of their unique antibacterial properties, and dishwashing detergents are a major source of exposure through oral, inhalation, and dermal routes. The three classes of QACs, including benzalkonium chloride (BAC), n-alkyldimethylethylbenzylammonium chloride (ADEBAC), and di-n-alkyldimethylammonium chloride (DDAC), in spray and non-spray types of dishwashing detergents were quantified by high-performance liquid chromatography-mass spectrometry. A tiered risk assessment approach was also considered. In the Tier 1 assessment, the mean and worst-case exposure were estimated to screen for rough exposure and risk levels. In the Tier 2 assessment, mean and upper-tail exposure levels were calculated based on the exposure parameters of Korean consumers using Monte Carlo simulation. QACs had a low frequency of detection of up to 20% in dishwashing detergents, and the contents of detected QACs varied depending on the individual samples. Based on the results of the Tier 1 assessment, BACs and DDACs posed potential health risks via inhalation and dermal routes. Tier 2 assessment suggested that the current level of oral and dermal exposure of Korean consumers to QACs in dishwashing detergents is unlikely to pose a health risk, even for upper-tail exposure groups. However, the present results suggest that spray-type DDACs may pose a health risk in the upper-tail inhalation exposure group, and further investigation is required to clarify this risk.

Aluminum is an element found in nature and in cosmetic products. It can interfere with the metabolism of other cations, thus inducing gastrointestinal disorder. In cosmetics, aluminum is used in antiperspirants, lipsticks, and toothpastes. The aim of this work is to investigate aluminum bioavailability after accidental oral ingestion derived from the use of a toothpaste containing a greater amount of aluminum hydroxide than advised by the Scientific Committee on Consumer Safety (SCCS). To simulate in vitro toothpaste accidental ingestion, the INFOGEST model was employed, and the amount of aluminum was measured through the ICP-AES analysis. Tissue barrier integrity was analyzed by measuring transepithelial electric resistance, and the tissue architecture was checked through light microscopy. The margin of safety was also calculated. Overall, our results indicate that the acute exposure to aluminum accidentally ingested from toothpastes is safe for the final user, even in amounts higher than SCCS indications.

Although there are at least seven manufacturers producing left-sided double-lumen tubes (DLTs), there have been few reports comparing the segments of these DLTs. In this study, we compared various segments of left-sided DLTs further.
We examined five manufacturers\' left-sided DLTs: Mallinckrodt, Portex, Rüsch, Sheridan, and Daiken-medical. We conducted the following six trials or measurements, and three supplemental trials or measurements: First, we tried to pass various sizes of steel balls down each lumen in order from the smallest (3 mm) to largest (4.5 mm). If the ball passed on the first attempt, we tried just once; otherwise, we made a second attempt. Second, we measured the external diameter of tracheal and bronchial cuff using a profile projector. Third, we measured the length of the cuff and tip of the bronchial segment of the tubes using the profile projector. Fourth, we measured various lengths of the tubes. Fifth, we measured the external diameter of both lumens and the tubules for tracheal and bronchial cuff inflation. Finally, we measured various cross-sectional areas including the tracheal lumen, bronchial lumen, and tubules for cuff inflation. We also conducted three supplemental studies. First, we measured air volume in the cuff when intracuff pressure equaled 2 or 3 kPa. Second, we defined the configuration of the tracheal and bronchial cuffs. Third, we defined the presence or absence of bevels and also measured the angle of the bevels using the profile projector.
We performed nine trials and measurements and found large disparities between each manufacturer\'s tubes.
The large disparities found between the measurements of the five manufacturers\' tubes may be due to different lots or changes in specifications made by each manufacturer. We found tubes exhibiting lower quality, such as deformations, and non-universal and inconsistent sizing, in the comparison of the manufacturers\' tubes. Practitioners should be aware of the features and aspects of these tubes.

Facial cosmetics are the most commonly consumed product, mainly by the women from all over the world irrespective of their age. The facial cosmetics may be contaminated with several toxic elements, which can get absorb on to the facial skin and migrate to the blood vessels. Hence the absorbed toxic elements can cause further adverse effects on the human body. The present study aims to assess the toxic element contents (arsenic, lead, nickel, mercury, and cadmium) in commonly consumed facial cosmetics (face powder, foundation, lightning creams, moisturizer, eye shadow, lipsticks, eyeliner, blush, mascara, sunscreen) and to carry out the risk assessment through different methods. The dermal risk was evaluated as SED, NOAEL, MoS, HQ and ILCR, which is linked with the exposure of selected toxic elements. The total CDDE for all selected elements in facial cosmetic products was found in increasing order as follow: face powder > foundation > lightning creams > moisturizer > eye shadow > lipsticks > eyeliner > blush > mascara > sunscreen. The HQ and HI values for selected elements were found to be < 1 in all facial cosmetics. Whereas the probable MoS of selected toxic elements in all facial cosmetics except eyeliner were found to be 3-4 folds lower than the minimum value of 100 regulated by the WHO.

Safety assessment of UV filters for human health by the Scientific Committee on Consumer Safety (SCCS) is based on the estimation of internal dose following external (skin) application of cosmetic products, and comparison with a toxicological reference value after conversion to internal dose. Data from human biomonitoring (HBM) could be very useful in this regard, because it is based on the measurement of real-life internal exposure of the human population to a chemical. UV filters were included in the priority list of compounds to be addressed under the European Human Biomonitoring Initiative (HBM4EU), and risk assessment of benzophenone-3 (BP-3) was carried out based on HBM data. Using BP-3 as an example, this study investigated the benefits and limitations of the use of external versus internal exposure data to explore the usefulness of HBM to support the risk assessment of cosmetic ingredients. The results show that both approaches did indicate a risk to human health under certain levels of exposure. They also highlight the need for more robust exposure data on BP-3 and other cosmetic ingredients, and a standardized framework for incorporating HBM data in the risk assessment of cosmetic products.

Preservatives are essential additives in dishwashing detergents and wet wipes. Ensuring the safe use of preservatives in products is important for public health, as some preservatives are associated with health issues. In this study, the content of 12 preservatives in 105 dishwashing detergents and 105 wet wipes was determined, where these compounds are commonly found, among consumer products. A realistic exposure estimation was considered by using Korean consumer-specific exposure parameters for adults and babies. A probabilistic risk assessment was conducted by applying the Monte Carlo simulation method. Benzoic acid (41%) and cetylpyridinium chloride (30%) were the most commonly used preservatives in dishwashing detergents and wet wipes, respectively, although their content in different products (benzoic acid: 0.28-19.4 mg/g in dishwashing detergents; cetylpyridinium chloride: 0.003-0.64 mg/g in wet wipes) varied widely. The calculated median and upper-limit margin of safety (MOS) values related to systemic health effects and skin sensitization from exposure to preservatives largely exceeded the target MOS, which confirmed the safety of the products. Exposure to preservatives from wet wipes was several times higher in babies than in adults. Sensitivity analysis revealed that the amount of the product used, frequency of use, and weight fraction of the preservative were the major contributors to the exposure to preservatives from dishwashing detergents and wet wipes.