Evidence has been accumulating that environmental chemicals contained in foods can cause neurodevelopmental disabilities. However, regular developmental neurotoxicity (DNT) studies require large numbers of animals for detection of subtle dose-response changes, and it is urgent concern to establish a rapid and efficient evaluation system of DNT. Evidence from our recent studies points to the notion that adult neurogenesis in the hippocampus may represent vulnerable endpoint to cause DNT. Adult neurogenesis is the postnatal process of continued production of new neurons through the adult stage in the brain. Monitoring of granule cell lineage in the subgranular zone (SGZ) and γ-aminobutyric acid (GABA)-ergic interneurons in the dentate hilus is effective for detection of target cell populations of DNT as manifested by disruption of neurogenesis. Especially, reelin-expressing GABAergic interneurons are a useful marker to detect disruption of the migration and correct positioning of developing neurons following impairment of neurogenesis. Because axon terminal toxicants target granule cell lineage population growing dendritic processes, there may be common target mechanisms between the DNT and adult-type neurotoxicity affecting mature nervous system. Adult neurogenesis may also be a suitable endpoint for detection of DNT in a scheme of standard regular 28-day toxicity study. In other words, adult-type neurotoxicity could be detected by measuring the cellular responses in adult neurogenesis. Moreover, it should be stressed that there may be epigenome toxicity mechanisms to affect the process of hippocampal neurogenesis involving both neuronal stem cells and interneuron subpopulations, with continued disruption through the adult stage. These findings suggest that hippocampal neurogenesis is considered to be a critical target of environmental neurotoxicants contained in foods.
A novel type of encephalopathy associated with the ingestion of Sugihiratake mushroom (Pleurocybella porrigens) occurred in patients with chronic renal failure treated on hemodialysis in fall, 2004 in Japan. To clarify the mechanism of encephalopathy onset, we, for the first time, purified the cyanogen glycoside fraction (CG) from Sugihiratake mushroom using reversed phase high-performance liquid chromatography and hydrophilic interaction chromatography. Furthermore, we investigated single dose toxicity of the CG in an adenine-induced rat model of chronic renal damage (CRD). Pathological examination of kidneys indicates the development of CRD. Oral administration of the CG induces the accumulation of thiocyanate in the hemolyzed blood and brain in CRD rats, although no morphological changes were found in the brain. No further enhancement of kidney damage is observed after the oral administration of the CG in CRD rats. This is the first experimental report to suggest that acute encephalopathy, induced by Sugihiratake mushroom intake in the patients with chronic renal failure, is associated with intoxication of cyanide and thiocyanate, presumably produced metabolically produced after the ingestion of Sugihiratake mushroom.
The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of mandestrobin (CAS No. 173662–97-0), a strobilurin fungicide, based on results from various studies. Major adverse effects of mandestrobin observed are hepatocellular hypertrophy and increased liver weights, and hypertrophy of thyroid follicular cells. Mandestrobin did not show any neurotoxicity, carcinogenicity, reproductive toxicity, teratogenicity or genotoxicity. Based on the above results, only mandestrobin (parent compound) was identified as the residue definition for dietary risk assessment in agricultural products. Though FSCJ could not specify a no-observed-adverse-effect level (NOAEL) in female parent rats in a two-generation reproductive toxicity study, the NOAEL of 26.7 mg/kg bw/day was obtained in female rats in a combined two-year chronic toxicity/carcinogenicity study which was conducted for a longer period with the lower dose. FSCJ thus considered the NOAEL in female rats to be 26.7 mg/kg bw/day. The lowest NOAEL in the toxicological studies was 19.2 mg/kg bw/day in a one-year chronic toxicity study in dogs. Applying a safety factor of 100 to the NOAEL, FSCJ specified an acceptable daily intake (ADI) to be 0.19 mg/kg bw/day. The lowest NOAEL for potential adverse effects of a single oral administration of mandestrobin was 1,000 mg/kg bw obtained in an acute neurotoxicity study in rats. FSCJ considered it unnecessary to specify an acute reference dose (ARfD), since the NOAEL was above the cut-off level (500 mg/kg bw).
The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of mosapride citrate (CAS No. 112885–42-4), a gastrointestinal agent, based on documents including a written application for marketing approval of a new veterinary medicinal product. Although hepatocellular and thyroid follicular cell tumors were induced in carcinogenicity studies in rats and mice, no genotoxicities were suggested in all the studies of mosapride citrate. The involvement of genotoxic mechanism is thus unlikely. Therefore, an acceptable daily intake (ADI) for mosapride citrate is able to be specified. In a 26-week subacute toxicity study using both sexes of rats, the no-observed-adverse-effect level (NOAEL) and the lowest-observed-adverse-effect level (LOAEL) values were obtained, respectively, to be 2 mg/kg bw/day and 10 mg/kg bw/day for the female, and to be 10 mg/kg bw/day and 50 mg/kg bw/day for the male. However, hepatocellular swelling observed in the female in the 26-week subacute toxicity study was also observed in the 104-week carcinogenicity study in the male given 10 mg/kg bw/day (lowest dose) and in the female given 30 mg/kg bw/day. Liver altered foci were observed in the female given 10 mg/kg bw/day (LOAEL), and the NOAEL value for the female was 3 mg/kg bw/day. Lowest values for all the hepatic lesion was 10 mg/kg bw/day for the female on both the 26-week and 104-week studies. A clear sex-related difference was observed in the plasma levels of mosapride in rats, in which the higher levels were observed in the female. The result, together with the data on the 26-week study, suggests that the NOAEL value in the male rats is unlikely to be lower than 3 mg/kg bw/day. FSCJ judged it appropriate to adopt this value as the NOAEL for the ADI of mosapride citrate, based on the following reasons: 1) The clear sex-related difference was observed in the plasma levels of mosapride in rats, in which the higher levels were observed in the female; and 2) The common ratio of the dose was smaller in the 104-week carcinogenicity study than that in the 26-week subacute toxicity study. Consequently, FSCJ established an ADI of 0.03 mg/kg bw/day, applying a safety factor of 100 (10 for species difference, 10 for individual difference) to the NOAEL obtained in the 104-week carcinogenicity study in rats.
The Food Safety Commission of Japan (FSCJ) conducted a risk assessment on antimicrobial-resistant bacteria resulting from the use of enramycin designated as a feed additive in livestock animals. Enramycin is not used in human. Moreover, no reports are available on bacterial cross-resistance between enramycin and other antimicrobials with enramycin-like chemical structures and modes of action. The lack of the cross resistance has also been suggested by differences in precise mechanisms of their actions. Investigations of acquiring antimicrobial-resistance have suggested possible generation of enramycin resistance in Gram-positive bacteria such as enterococcus and Staphylococcus aureus, but enramycin-resistant enterococcus has not been reported. Field investigations on drug susceptibility of Clostridium perfringens derived from chickens have shown low minimum inhibitory concentrations (MICs) of enramycin without significant annual variations. Emergence of food-derived antimicrobial-resistant bacteria hazardous to human health is unlikely based on these results of hazard identification, although a possible selection of enramycin-resistant bacteria due to its use in livestock animals cannot be neglected. Thus, FSCJ concluded that the risk to human health of the food-derived antimicrobial-resistant bacteria selected through the use of enramycin in livestock animals is “Negligible”.
The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of tolprocarb (CAS No. 911499–62-2), a fungicide, based on results from various studies. Major adverse effects of tolprocarb observed are decreased body weight gain, hepatocellular hypertrophy and increased liver weights, and increased organ weights and colloid degeneration of the thyroid. Tolprocarb showed no carcinogenicity, reproductive toxicity, teratogenicity and genotoxicity. Based on the results from various studies, only tolprocarb (parent compound) was identified as the residue definition for dietary risk assessment in agricultural and marine products. The lowest no-observed-adverse-effect level (NOAEL) obtained in all tests was 20.5 mg/kg bw/day in a two-year carcinogenicity study in rats. FSCJ specified an acceptable daily intake (ADI) of 0.2 mg/kg bw/day, applying a safety factor of 100 to the NOAEL. The lowest NOAEL for potential adverse effects of a single oral administration of tolprocarb was 600 mg/kg bw obtained in a general pharmacological study in rats. FSCJ considered it unnecessary to specify an acute reference dose (ARfD), since the NOAEL was above the cut off level (500 mg/kg bw).
The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of sedaxane (CAS No.874967–67-6), a pyrazole carboxamide fungicide, based on results from various studies. Major adverse effects of sedaxane observed are decreased body weight gain, decrease in food intake, and centrilobular hepatocellular hypertrophy. Sedaxane did not show any neurotoxicity, teratogenicity, reproductive toxicity, genotoxicity and immunotoxicity. In a two-year combined chronic toxicity/carcinogenicity study in rats, increased incidence of uterine adenocarcinomas was observed. Increased incidence of hepatocellular tumors was also observed in an 80-week carcinogenicity test in mice. However, a genotoxic mechanism was unlikely to be involved in the tumor induction. It was thus considered possible to establish a threshold in the assessment. Based on the above results, only sedaxane (parent compound) was identified as the residue definition for dietary risk assessment in agricultural products. The lowest no-observed-adverse-effect level (NOAEL) in the toxicological studies was 11 mg/kg bw/day in a combined two-year chronic toxicity/carcinogenicity study in rats. Applying a safety factor of 100 to the NOAEL, FSCJ specified the acceptable daily intake (ADI) of 0.11 mg/kg bw/day. The lowest NOAEL for adverse effects resulted from a single oral administration of sedaxane was 30 mg/kg bw observed in an acute neurotoxicity study in rats. Applying a safety factor of 100 to the NOAEL, FSCJ specified 0.3 mg/kg bw as the acute reference dose (ARfD).