Hepatic macrophages play an important role in homeostasis. The functional abnormalities of hepatic macrophages primarily or secondarily influence chemically induced hepatotoxicity. However, the evaluation system based on their functions has not yet been established. Recently, a new concept (M1-/M2-macrophage polarization) was proposed; M1-macropahges are induced by INF-γ, and show high phagocytosis/tissue damage, whereas M2-macropahges are induced by IL-4 and play roles in reparative fibrosis by releasing IL-10 and TGF-β1. In hepatogenesis, CD68-expressing M1-macrophages predominantly exist in embryos; in neonates, in contrast, CD163-/CD204-expressing M2-macrophages appear along the sinusoids and mature as Kupffer cells. Activated Kupffer cells by liposome decrease AST and ALT values, whereas AST and ALT values are increased under Kupffer cells depleted with clodronate treatment. Since Kupffer cells may be involved in clearance of liver enzymes, macrophage condition should be taken into consideration when hepatotoxicity is analyzed. In TAA-induced acute hepatic lesions, INF-γ, TNF-α and IL-6 for M1-factors and IL-4 for M2-factors are already increased before histopathological change; the appearance of CD68-expressing M1-macrophages and CD163-expressing M2-macrophages follows in injured centrilobular lesions, and TGF-β1 and IL-10 are increased for reparative fibrosis. CD68-expressing M1-macrophages co-express MHC class II and Iba-1, whereas CD163-expressing M2-macrophages also express CD204 and Galectin-3. Under macrophage depletion by clodoronate, TAA-treated rat livers show prolonged coagulation necrosis of hepatocytes, and then develop dystrophic calcification without reparative fibrosis. The depletion of hepatic macrophages influences hepatic lesion development. Collectively, a histopathological analysis method for hepatotoxicity according to M1-/M2-macrophage polarization would lead to the refinement of hazard characterization of chemicals in food and feed.
The Food Safety Commission of Japan (FSCJ) conducted a risk assessment on acrylamide (AA) (CAS No. 79-06-1) in foods generated through heating, as a self-tasking risk assessment. In rodent toxicity studies, major adverse effects were observed on neurotoxicity and male reproductive toxicity. Statistically significant increases in incidences were observed in the carcinogenicity studies in Harderian gland, mammary gland, lung and forestomach in mice, and in mammary gland, thyroid and testis in rats. Positive results were also obtained from in vitro and in vivo genotoxicity studies of AA and glycidamide (GA). Therefore, FSCJ recognized AA as a genotoxic carcinogen. Judging from the dietary AA intake among Japanese people, the non-neoplastic risk is extremely low because of sufficient margins of exposure (MOEs). The neoplastic risk, however, could not be excluded due to the insufficient MOEs, although no clear evidence on human health effect have been provided from the epidemiological studies. It is important to note that no consistent relationships between AA exposure and cancer incidences have been observed even in the studies focusing on the highly exposed populations in occupational settings. FSCJ thus concluded that continual efforts are necessary to reduce dietary AA intakes in accordance with the principle of ALARA (as low as reasonably achievable) from the viewpoint of public health.
The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of tolfenamic acid (CAS No. 13170–19-5), an anti-inflammatory drug, based on the submitted documents including original research papers1,2,3), together with reference to the reports from the European Medical Agency (EMEA) and the Australian government. No genotoxicity relevant to human health were suggested by the results from the various genotoxicity studies on tolfenamic acid. Therefore, an acceptable daily intake (ADI) is possible to be established for the toxicity. Major adverse effects of tolfenamic acid were observed on GI tract (erosions and ulcers). No carcinogenicity was observed in repeated dose toxicity studies in mice and rats. The lowest no-observed-adverse-effect level (NOAEL) was 1 mg/kg bw/day, based on the necrosis of GI mucosal epithelium in a one-month subacute toxicity study in rabbits, the adverse effect observed at the lowest dose among the toxicity studies. FSCJ thus specified the ADI of 0.01 mg/kg bw/day for tolfenamic acid by applying a safety factor of 100 to the NOAEL of 1 mg/kg bw/day in the one-month subacute toxicity study in rabbits.
The Food Safety Commission of Japan (FSCJ) conducted a safety assessment of MON 87411 line, a maize tolerant to glyphosate and resistant to Coleoptera, based on the documents submitted by the applicant. The documents, evaluated based on the “Standards for the Safety Assessment of Genetically Modified Foods (Seed plants)” (Decision of the Commission dated 29 January 2004), included the safety of the inserted genes, toxicity and allergenicity of the protein produced from the inserted genes, post-insertion analyses of the nucleotide sequences, stability of the inserted genes in the successive generations, influence on metabolic pathways in the plants, comparative characterization of nutrients and toxic ingredients in plants. Consequently, no emergences of safety concerns were recognized based on the comparison between this line and the conventional counterpart. The dsRNA originated from DvSnf7 fragment is unlikely to pose unintended adverse effect to human. In conclusion, no concern relevant to human health is raised on the maize MON 87411 line, tolerant to glyphosate and resistant to Coleoptera.
The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of glyphosate (CAS No. 1071-83-6), an amino acid herbicide, based on results from various studies. Major adverse effects of glyphosate were observed on reduced gain of body weight, GI tract (diarrhea, increased cecum weight, bowel dilatation, thickening of intestinal mucosa), and liver (increased alkaline phosphatase (ALP), hepatocellular hypertrophy). Glyphosate had no neurotoxicity, carcinogenicity, reproductive toxicity, teratogenicity, and genotoxicity. As the whole, the lowest value among no-observed-adverse-effect levels (NOAELs) was 100 mg/kg bw/day obtained in the 90-days and one-year toxicity studies in dogs, and in the developmental toxicity studies of rabbits. FSCJ thus established an acceptable daily intake (ADI) for glyphosate at 1 mg/kg bw/day, applying a safety factor of 100 to the NOAEL. The lowest NOAEL for adverse effects elicited by a single oral administration of glyphosate was 1,000 mg/kg bw observed in an acute toxicity studies in rats and mice. It is thus unnecessary to specify an acute reference dose (ARfD), due to the exceeding of the cut off level (500 mg/kg bw).