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The intestinal barrier is complex and consists of multiple layers, and it provides a physical and functional barrier to the transport of luminal contents to systemic circulation. While the epithelial cell layer and the outer/inner mucin layer constitute the physical barrier and are often referred to as the intestinal barrier, intestinal alkaline phosphatase (IAP) produced by epithelial cells and antibacterial proteins secreted by Panneth cells represent the functional barrier. While antibacterial proteins play an important role in the host defense against gut microbes, IAP detoxifies bacterial endotoxin lipopolysaccharide (LPS) by catalyzing the dephosphorylation of the active/toxic Lipid A moiety, preventing local inflammation as well as the translocation of active LPS into systemic circulation. The causal relationship between circulating LPS levels and the development of multiple diseases underscores the importance of detailed examination of changes in the “layers” of the intestinal barrier associated with disease development and how this dysfunction can be attenuated by targeted interventions. To develop targeted therapies for improving intestinal barrier function, it is imperative to have a deeper understanding of the intestinal barrier itself, the mechanisms underlying the development of diseases due to barrier dysfunction (eg, high circulating LPS levels), the assessment of intestinal barrier function under diseased conditions, and of how individual layers of the intestinal barrier can be beneficially modulated to potentially attenuate the development of associated diseases. This review summarizes the current knowledge of the composition of the intestinal barrier and its assessment and modulation for the development of potential therapies for barrier dysfunction-associated diseases.

The concept of foetal viability has evolved significantly and has been influenced by advancements in neonatal care and legal frameworks. This review explores the complexities of defining foetal viability in India’s contemporary medical landscape, particularly in light of the recent extension of the Medical Termination of Pregnancy (MTP) Act to 24 weeks. The article examines the confusion surrounding the classification of extreme preterm births, Medical Termination of Pregnancy (MTP) Act, and prenatal documentation during sonography. It addresses the challenges in distinguishing between preterm birth and abortion and proposes solutions to standardize definitions and practices.

N,N-Dimethylacetamide (DMAC), which is widely used as an industrial solvent, can be absorbed via the respiratory tract and skin of humans exposed to it. Hepatotoxicity is a main health risk of DMAC exposure in humans, and the relevant cases and epidemiological studies are reviewed herein. No hepatotoxicity was identified in workers exposed to ~3 ppm DMAC, and among workers exposed to >9 ppm DMAC the DMAC exposure was not observed to contribute significantly to liver damage. However, a case of liver damage was identified in which the calculated 8-hour weighted average was 12.8 mg/m3 (3.6 ppm). The skin absorption notation for DMAC is indicated based on human volunteer studies. The evidence regarding DMAC’s potential carcinogenicity in humans is not sufficient, and our literature search identified no report of DMAC as a reproductive toxicant in humans. Further case reports and epidemiological studies are necessary to determine the acceptable DMAC exposure limit for workers and thus protect them from DMAC’s toxicity.

Our aim was to report integrative evidence for the health risk assessment of ortho-toluidine (OT) in bladder cancer in a mini-review of the recent studies of humans, experimental animals, and OT skin permeability. Bladder cancer cases were identified in workers in Japan who were occupationally exposed in 2014-2017 to aromatic amines, primarily to the human carcinogen OT. A key epidemiological study of 98 aromatic amine-exposed workers in Japan showed a clear OT exposure-response relationship with a standardized incidence ratio. A rat model experimental study also indicated that OT and acetoaceto-o-toluidine are potent bladder carcinogens. Multiple mechanisms of OT-related bladder cancer have been proposed: metabolic activation to reactive metabolites that bind DNA and proteins, mutagenicity, oxidative DNA damage, chromosomal damage, and cytotoxicity by OT. Recent comprehensive analyses of DNA adducts in rats identified a number of common oxidative DNA adducts, including 8-OHdG, in the rat urothelium and indicated that oxidative stress may play a crucial role in the development of urinary cancer caused by OT. The skin permeability of 6 aromatic amines (o-toluidine, aniline, p-toluidine, o-anisidine, 2,4-dimethylaniline, and o-chloroaniline) was examined with the use of a 3-dimensional (3D) reconstructed human skin model; ~70%-80% of the 6 aromatic amines had permeated through the 3D skin within 8 hours. Genotoxic potency testing in a human urothelial cell line using γ-H2AX, a marker of DNA damage, suggested that OT exhibited strong γ-H2AX generation. Prolonged dermal exposure to OT along with other genotoxic aromatic amines over many years may contribute to the development of bladder cancer.

Objectives: Many chemicals have been used for industrial purposes, and some of them are carcinogenic to humans. However, the molecular mechanisms of their carcinogenetic effects have not been well understood. Reactive oxygen species are generated from industrial chemicals and contribute to carcinogenesis. Particles and fibers are accumulated in respiratory systems by inhalation exposure and cause chronic inflammation. Under inflammatory conditions, reactive nitrogen species are generated from inflammatory and epithelial cells. These species cause oxidative and nitrative DNA damage, leading to carcinogenesis. We carried out experiments on DNA damage induced by various industrial chemicals and investigated their molecular mechanisms.Methods: We examined oxidative DNA damage induced by industrial chemicals using DNA fragments derived from human cancer-relevant genes by polyacrylamide gel electrophoresis. Using immunohistochemistry and immunocytochemistry we also examined the formation of 8-nitroguanine (8-nitroG), a DNA lesion formed under inflammatory conditions, in lung tissues and cultured cells exposed to industrial chemicals.Results: Benzene and o-toluidine metabolites caused oxidative damage to DNA fragments in the presence of Cu(II). H2O2 and Cu(I) were generated during oxidation of these chemicals and involved in DNA damage. 8-NitroG formation was observed in lung tissues of asbestos-exposed mice and humans. Carbon nanomaterials and indium compounds induced 8-nitroG formation in human lung epithelial cells via the release of damage-associated molecular patterns from exposed cells.Conclusions: Various industrial chemicals are considered to induce carcinogenesis by causing oxidative and nitrative DNA damage. These findings provide an insight into risk assessment of industrial chemicals and prevention of carcinogenesis in workplaces.

Before 2000, very little attention had been paid to the health effects of indium, a rare metal, because there was very little information in the literature on its toxicity. A fatal case of indium-tin oxide (ITO) inhalation occurred in 2001, followed by concerns regarding occupational exposure to indium compounds and their health effects. Epidemiological studies and case reports have established a causal relationship between the inhalation of insoluble indium compounds, mainly ITO, and the development of lung damage. This review focuses on the results of animal studies of ITO and other insoluble indium compounds. Available data indicate that insoluble indium compounds such as ITO, indium arsenide (InAs), indium phosphide (InP), and copper indium gallium diselenide (CIGS) solar cell materials are toxic to the lungs of animals. In addition to lung damage, ITO nanoparticles have been found to cause kidney damage, whereas InAs, InP, and ITO cause testicular damage. Furthermore, there is compelling evidence for the carcinogenic potential of InP in long-term inhalation studies using rats and mice, which was evident in rats exposed to ITO. Based on the results of these animal experiments, the International Agency for Research on Cancer evaluated InP as probably carcinogenic to humans (Group 2A) and ITO as possibly carcinogenic to humans (Group 2 B). Based on the results of animal studies, it should be noted that occupational exposure of humans to insoluble indium compounds not only may cause lung damage, but also lung carcinogenesis and kidney or testicular damage in the future. Greater attention should be directed towards human occupational exposure to insoluble indium compounds.

In 2012, a social issue arose concerning a high incidence of cholangiocarcinoma (bile duct cancer) among printing workers. The cause was prolonged exposure to high concentrations of 1,2-dichloropropane that was included in the ink cleaning agent. Until then, it was not known that this substance could cause cancer in humans. The author was involved in this incident from the beginning. This article describes the course from the start of the investigation to the recognition of cholangiocarcinoma as an occupational disease. Furthermore, the article presents the pathological characteristics of occupational cholangiocarcinoma, as well as epidemiological analysis results.

The novel properties and functions of nanomaterials have naturally alerted toxicologists to the fact that such materials may also have novel effects on the human body and other living organisms. In particular, materials with high stability or biopersistency have been shown to have a tendency to accumulate in the body, leading to chronic toxicity including carcinogenicity. However, in the early stages of toxicity research, the information is often limited to the effects of short-term exposure studies, and findings on chronic effects are very much delayed. In this context, it was exceptional that studies on multi-walled carbon nanotubes (MWCNTs) have started with the verification of their potential to induce mesothelioma. This toxicological endpoint was expected on the basis of existing knowledge of asbestos and asbestos-like fiber particles. This movement has led to the achievement of the original mission of “modern toxicology,” which is “to achieve a win-win situation where both industrial promotion and safety assurance are ensured by communicating and sharing toxicity information to developers and consumers at a stage before mass production and consumption begins, that is, before massive exposure of the general public begins.”Inaccurate toxicity assessments of asbestos in the 1980s and 1990s allowed its spread to our living environment, which is difficult to decontaminate, and the damage continues to this day. However, the case described here could be an example of realizing the proposition that “nanomaterials, the flagship of high technology, must not repeat the same mistakes.”

Bromopropane was introduced commercially as an alternative to ozone-depleting and global-warming solvents. The identification of 1-bromopropane neurotoxicity in animal experiments was followed by reports of human cases of 1-bromopropane toxicity. In humans, the most common clinical features of 1-bromopropane neurotoxicity are decreased sensation, weakness in extremities, and walking difficulties. Moreover, decreased cognition, abnormal findings on brain magnetic resonance imaging, urinary incontinence, and numbness in the perineal area have also been described in workers exposed to 1-bromopropane. Murine histological studies showed that exposure to 1-bromopropane reduced the density of brain noradrenergic axons. Furthermore, proteome studies demonstrated 1-bromopropane-induced changes in the expression of proteins in the hippocampus of rats, similar to the changes seen in mice exposed to acrylamide, suggesting a common mechanism of electrophile-induced neurotoxicity. In addition to its neurotoxicity, 1-bromopropane also induces male reproductive toxicity in rats, although the targeted areas in the reproductive system differ from those affected by 2-bromopropane. However, exposure to high levels of 1-bromopropane was reported to induce spermatogenic cell degeneration, similar to that caused by 2-bromopropane, suggesting common mechanism(s) underlying 1- and 2-bromopropane-induced male reproductive toxicity. Plural approaches, including human, animal, and mechanistic studies, are useful for identification of 1-bromopropane neurotoxicity. The International Agency for Research on Cancer summarized that 1-bromopropane as well as 2-bromopropane share several key characteristics of carcinogens. Plural approaches can establish evidence-based preventive medicine by modification of the conventional evidence-based medicine (EBM), which has been developed for therapeutic medicine and is represented by the EBM pyramid.

Objectives: The natural fibrous mineral, asbestos, has been useful in industry for many centuries. In the 1960s, epidemiology recognized the association between asbestos exposure and mesothelioma, and in 1987 the International Agency for Research on Cancer designated all kinds of asbestos as Group 1 carcinogens. However, various scientific enigmas remained regarding the molecular mechanisms of asbestos-induced mesothelial carcinogenesis. This review article was undertaken to reveal and summarize recent discoveries to resolve those enigmas.Methods: We collected recent important findings from our own laboratory and others to explain why mesothelial cells are the target for asbestos-induced carcinogenesis and what are the key molecular mechanisms.Results: The long incubation period of 30-40 years for mesothelial carcinogenesis after asbestos exposure allows the asbestos fibers to go through the pulmonary parenchyma from the central to peripheral portions and ultimately reach the parietal mesothelium by piercing visceral pleura. Asbestos fibers have affinity for hemoglobin and histones, thus accumulating iron on the surface while traveling through the lung. Mesothelial cells are phagocytic cells, engulfing iron-coated asbestos fibers. Accordingly, homozygous deletion of the p16INK4a tumor suppressor gene, a signature of excess iron-induced carcinogenesis, is acquired through oxidative DNA damage. Recently, exosome-dependent iron transfer from asbestos-fed macrophages to mesothelial cells was reported. Similar molecular mechanisms are observed with multiwalled carbon nanotubes of ~50-nm diameter.Conclusions: Physical dimensions, biopersistence, and affinity to iron/histones are essential for fibrous material to be carcinogenic to mesothelial cells. Therefore, local iron reduction may be a strategy to prevent mesothelial carcinogenesis.