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Pyrethroids, which are derived from natural insecticides found in chrysanthemum flowers, are widely utilized in various sectors, including agriculture, forestry, horticulture, and personal insect protection. Due to their widespread use, concerns have arisen regarding their potential estrogenic effects on female reproductive health. This review aims to address data gaps and inconsistencies in previous studies by defining molecular initiating events and key events within the adverse outcome pathway associated with pyrethroid-induced estrogenic effects. To achieve this, we propose utilizing Integrated Approaches to Testing and Assessment (IATA), which incorporate in vitro assays and in vivo assessments to comprehensively investigate the estrogenic effects of pyrethroids. An initial search was conducted in the PubMed database to identify relevant articles. Subsequently, the findings were classified according to the IATA strategy. This review provides an overview of the current understanding of pyrethroids and their estrogenic effects, identifies data gaps, and highlights the use of IATA in existing studies on the estrogenic effects of various pyrethroids. It emphasizes the urgent need for comprehensive research on the estrogenic effects of pyrethroids and highlights the importance of standardized testing methods like IATA to accurately assess their impact on human and environmental health. By promoting the use of Integrated Testing Strategies (ITSs) and addressing data gaps, researchers and regulators can enhance the accuracy of assessments, ensuring better protection of human and environmental health from the potential estrogenic effects of pyrethroid exposure.

Bisphenol A (BPA) exposure has been widely linked to endocrine-disrupting effects. Recently, many substitutes for BPA have been developed as safe structural analogs. However, they have still been reported to have similar adverse effects. The current study evaluated the effects of bisphenol A and eight structural analogs on the transcription of estrogen receptor alpha (ERα). The effects of binary and ternary mixtures prepared from different combinations of BPA analogs were also evaluated for transcription activity. The measured data of the mixtures were compared to the predicted data obtained by the full logistic model, and the model deviation ratio (MDR) was calculated to determine whether the effects were synergistic, antagonistic, or additive. Overall, the results suggest that the effect of bisphenol compound are additive in binary and ternary mixtures.

Abstract Background Titanium dioxide (TiO2) nanoparticles are among the most manufactured nanomaterials in the industry, and are used in food products, toothpastes, cosmetics and paints. Pregnant women as well as their conceptuses may be exposed to TiO2 nanoparticles; however, the potential effects of these nanoparticles during pregnancy are controversial, and their internal distribution has not been investigated. Therefore, in this study, we investigated the potential effects of oral exposure to TiO2 nanoparticles and their distribution during pregnancy. TiO2 nanoparticles were orally administered to pregnant Sprague-Dawley rats (12 females per group) from gestation days (GDs) 6 to 19 at dosage levels of 0, 100, 300 and 1000 mg/kg/day, and then cesarean sections were conducted on GD 20. Results In the maternal and embryo-fetal examinations, there were no marked toxicities in terms of general clinical signs, body weight, food consumption, organ weights, macroscopic findings, cesarean section parameters and fetal morphological examinations. In the distribution analysis, titanium contents were increased in the maternal liver, maternal brain and placenta after exposure to high doses of TiO2 nanoparticles. Conclusion Oral exposure to TiO2 during pregnancy increased the titanium concentrations in the maternal liver, maternal brain and placenta, but these levels did not induce marked toxicities in maternal animals or affect embryo-fetal development. These results could be used to evaluate the human risk assessment of TiO2 nanoparticle oral exposure during pregnancy, and additional comprehensive toxicity studies are deemed necessary considering the possibility of complex exposure scenarios and the various sizes of TiO2 nanoparticles.

Benzalkonium chloride is a cationic surfactant widely used as a disinfectant, preservative, and sanitizer in many public places as well as domestically. The purpose of this study is to compare the acute toxicity of lethal doses (LDx) and the target organs after intratracheal instillation and oral ingestion by mice, which is a preliminary test prior to the repeated dose toxicity test. When Balb/c mice were treated with a single dose of benzalkonium chloride via oral administration, LD50 was 241.7 mg/kg. However, it was comparatively decreased to 8.5 mg/kg following intratracheal treatment, which suggests that lung may be the main target of toxicity. Although the histopathology showed inflammatory responses in the lung after intratracheal instillation, it still did not confirm that the inflammatory responses were the key factors inducing death in the treated animal. Acute and fatal mechanisms such as bronchoconstriction or neurotoxicity associated with benzalkonium chloride exposure should be further investigated.

Disinfectants including polyhexamethylene guanidine phosphate (PHMG) and mixtures of chloromethylisothiazolinone/ methylisothiazolinone (CMIT/MIT) have been widely used in Korea to prevent microbial growth in the humidifier water, which triggered an outbreak of serious respiratory diseases. In addition to the respiratory syndrome, disease-related symptoms including liver toxicity, asthma, and skin allergies were also found after extensive survey of people exposed to the humidifier disinfectants (HDs). In this study, eye irritation tests were performed based on the Organization for economic co-operation and development (OECD) test guidelines 492 using EpiOcularTM which is a tissue model of reconstructed human cornea-like epithelium. As results, the raw materials of PHMG (26% as active ingredient) and CMIT/MIT (1.5% as active ingredient) were classified under UN globally harmonized system of classification and labeling of chemical (GHS) category 1 or category 2. However, aqueous dilutions of raw materials such as market products of HDs that contain 0.13% of PHMG and 0.03% of CMIT/MIT or further dilutions of the market products for humidifier that contain 0.0013% of PHMG and 0.0003% of CMIT/MIT were classified under any category, which suggested absence of eye irritation at the test concentration.

An analysis of patients and fatalities due to exposure to polyhexamethylene guanidine (PHMG) shows that PHMG causes mainly lung diseases such as pulmonary fibrosis. However, no research on the other organs has been conducted on this matter yet. So, an in-depth discussion on toxicological techniques is needed to determine whether or not PHMG is toxic to organs other than just the lungs. For the test of target organ toxicity by PHMG exposure, a toxicokinetic study must first be conducted. However, measurement method for PHMG injected into the body has not yet been established because it is not easy to analyze polymer PHMG, so related base studies on analytical technique for PHMG including radio-labeling chemistry must come first. Moreover, research on exposure-biomarker and effect-biomarker must also be conducted, primarily related to clinical application. Several limitations seem to be expected to apply the biomarker study to the patient because much time has passed after exposure to the humidifier disinfectant. It is why a more comprehensive toxicological researches must be introduced to the causality for the victims.

Objectives The widely promising applications of graphene nanomaterials raise considerable concerns regarding their environmental and human health risk assessment. The aim of the current study was to evaluate the toxicity profiling of graphene family nananomaterials (GFNs) in alternative in vitro and in vivo toxicity testing models. Methods The GFNs used in this study are graphene nanoplatelets ([GNPs]–pristine, carboxylate [COOH] and amide [NH2]) and graphene oxides (single layer [SLGO] and few layers [FLGO]). The human bronchial epithelial cells (Beas2B cells) as in vitro system and the nematode Caenorhabditis elegans as in vivo system were used to profile the toxicity response of GFNs. Cytotoxicity assays, colony formation assay for cellular toxicity and reproduction potentiality in C. elegans were used as end points to evaluate the GFNs’ toxicity. Results In general, GNPs exhibited higher toxicity than GOs in Beas2B cells, and among the GNPs the order of toxicity was pristine>NH2>COOH. Although the order of toxicity of the GNPs was maintained in C. elegans reproductive toxicity, but GOs were found to be more toxic in the worms than GNPs. In both systems, SLGO exhibited profoundly greater dose dependency than FLGO. The possible reason of their differential toxicity lay in their distinctive physicochemical characteristics and agglomeration behavior in the exposure media. Conclusions The present study revealed that the toxicity of GFNs is dependent on the graphene nanomaterial’s physical forms, surface functionalizations, number of layers, dose, time of exposure and obviously, on the alternative model systems used for toxicity assessment.

Objectives Effects of nanoparticles including zinc oxide nanoparticles, titanium oxide nanoparticles, and their mixtures on skin corrosion and irritation were investigated by using in vitro 3D human skin models (KeraSkinTM) and the results were compared to those of an in vivo animal test. Methods Skin models were incubated with nanoparticles for a definite time period and cell viability was measured by the 3-(4, 5-dimethylthiazol-2-yl)-2.5-diphenyltetrazolium bromide method. Skin corrosion and irritation were identified by the decreased viability based on the pre-determined threshold. Results Cell viability after exposure to nanomaterial was not decreased to the pre-determined threshold level, which was 15% after 60 minutes exposure in corrosion test and 50% after 45 minutes exposure in the irritation test. IL-1α release and histopathological findings support the results of cell viability test. In vivo test using rabbits also showed non-corrosive and non-irritant results. Conclusions The findings provide the evidence that zinc oxide nanoparticles, titanium oxide nanoparticles and their mixture are ‘non corrosive’ and ‘non-irritant’ to the human skin by a globally harmonized classification system. In vivo test using animals can be replaced by an alternative in vitro test.

The widely promising applications of graphene nanomaterials raise considerable concerns regarding their environmental and human health risk assessment. The aim of the current study was to evaluate the toxicity profiling of graphene family nananomaterials (GFNs) in alternative in vitro and in vivo toxicity testing models. Methods The GFNs used in this study are graphene nanoplatelets ([GNPs]-pristine, carboxylate [COOH] and amide [NH2]) and graphene oxides (single layer [SLGO] and few layers [FLGO]). The human bronchial epithelial cells (Beas2B cells) as in vitro system and the nematode Caenorhabditis elegans as in vivo system were used to profile the toxicity response of GFNs. Cytotoxicity assays, colony formation assay for cellular toxicity and reproduction potentiality in C. elegans were used as end points to evaluate the GFNs' toxicity. Results In general, GNPs exhibited higher toxicity than GOs in Beas2B cells, and among the GNPs the order of toxicity was pristine>NH2>COOH. Although the order of toxicity of the GNPs was maintained in C. elegans reproductive toxicity, but GOs were found to be more toxic in the worms than GNPs. In both systems, SLGO exhibited profoundly greater dose dependency than FLGO. The possible reason of their differential toxicity lay in their distinctive physicochemical characteristics and agglomeration behavior in the exposure media. Conclusions The present study revealed that the toxicity of GFNs is dependent on the graphene nanomaterial's physical forms, surface functionalizations, number of layers, dose, time of exposure and obviously, on the alternative model systems used for toxicity assessment. [ABSTRACT FROM AUTHOR]

Purpose: Toxicity caused by acetaminophen and its toxic mechanisms in the liver have been widely studied, including effects involving metabolism and oxidative stress. However, its adverse effects on heart have not been sufficiently investigated. This study evaluated the cardiac influence and molecular events occurring within the myocardium in rats treated with a dose of acetaminophen large enough to induce conventional liver damage. Materials and Methods: Male rats were orally administered a single dose of acetaminophen at 1,000 mg/kg-body weight, and subsequently examined for conventional toxicological parameters and for gene expression alterations to both the heart and liver 24 hours after administration. Results: Following treatment, serum biochemical parameters including aspartate aminotransferase and alanine aminotransferase were elevated. Histopathological alterations of necrosis were observed in the liver, but not in the heart. However, alterations in gene expression were observed in both the liver and heart 24 hours after dosing. Transcriptional profiling revealed that acetaminophen changed the expression of genes implicated in oxidative stress, inflammatory processes, and apoptosis in the heart as well as in the liver . The numbers of up-regulated and down-regulated genes in the heart were 271 and 81, respectively, based on a two-fold criterion. Conclusion: The induced expression of genes implicated in oxidative stress and inflammatory processes in the myocardium reflects molecular levels of injury caused by acetaminophen (APAP), which could not be identified by conventional histopathology. [ABSTRACT FROM AUTHOR]

Silver particles are used in various consumer products due to their positive effects, which include sterilization and antibacterial properties. However, it has been reported that silver nanoparticles (AgNPs) have strongly acute toxic effects on various cells. Therefore, the cytotoxicity of AgNPs was investigated, using Escherichia coli as a model organism, from the standpoint of three key metrics (ionic ratio, size, and agglomeration) that are the most relevant physicochemical properties. The findings indicated that cytotoxicity is depressed by the agglomeration of AgNPs. The order of toxic sensitivity was as follows: total Ag concentration > ionic ratio > size, the order of which was inversely related to the extent of agglomeration. Environ. Toxicol. Chem. 2010;29:2154-2160. © 2010 SETAC [ABSTRACT FROM AUTHOR]

Background: Air pollution is known to contribute to respiratory and cardiovascular mortality and morbidity. Oxidative stress has been suggested as one of the main mechanisms for these effects on health. Objective: The aim of this study was to analyze the effects of exposure to particulate matter (PM) with aerodynamic diameters ⩽ 10 μ (PM10) and ⩽ 2.5 μ (PM2.5) and polycyclic aromatic hydrocarbons (PAHs) on urinary malondialdehyde (MDA) levels in schoolchildren. Methods: The study population consisted of 120 schoolchildren. The survey and measurements were conducted in four cities-two in China (Ala Shan and Beijing) and two in Korea (Jeju and Seoul)- between 4 and 9 June 2007. We measured daily ambient levels of PM and their metal components at the selected schools during the study period. We also measured urinary 1-hydroxypyrene (1-OHP) and 2-naphthol, to assess PAH exposure, and MDA, to assess oxidative stress. Measurements were conducted once a day for 5 consecutive days. We constructed a linear mixed model after adjusting for individual variables to estimate the effects of PM and PAH on oxidative stress. Results: We found statistically significant increases in urinary MDA levels with ambient PM concentrations from the current day to the 2 previous days (p < 0.0001). Urinary 1-OHP level also showed a positive association with urinary MDA level, which was statistically significant with or without PM in the model (p < 0.05). Outdoor PM and urinary 1-OHP were synergistically associated with urinary MDA levels. Some metals bound to PM10 (aluminum, iron, strontium, magnesium, silicon, arsenic, barium, zinc, copper, and cadmium) and PM2.5 (magnesium, iron, strontium, arsenic, cadmium, zinc, aluminum, mercury, barium, and copper) also had significant associations with urinary MDA level. Conclusion: Exposure to PM air pollution and PAHs was associated with oxidative stress in schoolchildren. [ABSTRACT FROM AUTHOR]

In this study, ambient TSP, PM10, and PM2.5 in a residential area located in the northern part of Seoul were monitored every other month for 1 year from April 2005 to February 2006. The monthly average levels of TSP, PM10, and PM2.5 had ranges of 71∼158, 40∼106, and 28∼43 μg/m3, respectively. TSP and PM10 showed highest concentration in April; this seems to be due to Asian dust from China and/or Mongolia. However, the fine particle of PM2.5 showed a relatively constant level during the monitoring period. Heavy metals in PM 10 and PM2.5, such as Cr, As, Cd, Mn, Zn and Pb, were also analysed during the same period. The monthly average concentrations of heavy metal in PM2.5 were Cr:1.9∼22.7 ng/m3; As:0.9∼2.5 ng/m3; Cd: 0.6∼7 ng/m3; Mn:6.1∼22.6 ng/m3; Zn: 38.9∼204.8 ng/m3, and Pb: 21.6∼201.1 ng/m3. For the health risk assessment of heavy metals in ambient particles, excess cancer risks were calculated using IRIS unit risk. As a result, the excess cancer risks of chromium, cadmium, and arsenic were shown to be more than one per million based on the annual concentration of heavy metals, and chromium showed the highest excess cancer risk in ambient particles in Seoul. [ABSTRACT FROM AUTHOR]

The sequence of cytochrome P4501A (CYP1A) cDNA of medaka (Oryzias latipes) was determined, and its messenger ribonucleic acid (mRNA) regulation by β-naphthoflavone (βNF) was evaluated. The determined cDNA sequence contained 2,349 base pairs (bp), and the open reading frame contained a total of 1,563 bp encoding 521 predicted amino acids. The induction of CYP1A mRNA in medaka was evaluated using reverse transcription-polymerase chain reaction. The concentration-dependent induction of CYP1A mRNA in the liver was observed after exposure to βNF at nominal concentrations of 20, 100, and 500 µg/ L for 2 d. Time-dependent changes of CYP1A mRNA levels were also observed in the liver, gill, gut, and caudal fin tissues of medaka exposed to 100 µg/L of βNF for 7 d. Our results showed that the degree of CYP1A mRNA induction in the gill, gut, and caudal fin after exposure to βNF was relatively higher than that in the liver, possibly because of low basal levels of CYP1A mRNA in the gill, gut, and caudal fin of nonexposed fish. The induction of medaka CYP1A mRNA was also observed after exposure to an environmental sample, landfill leachate. The CYP1A mRNA inductions in the gill, gut, and caudal fin were also higher than that in the liver as shown in the βNF-treated groups. These results show that CYP1A mRNA determination in the gill, gut, and caudal fin, which are in direct contact with the polluted water, may become a useful method for monitoring CYP1A-inducible chemicals. [ABSTRACT FROM AUTHOR]

Attempts to establish a screening tool for endocrine disruption by assessing the choriogenin hydrogen mRNA expression using medaka, Oryzias latipes. Analysis of the sequence of cDNA and genomic DNA of medaka choriogenin hydrogen (H); Cloning of choriogenin H.