Norovirus gastroenteritis remains a leading cause of morbidity and is still a major public health problem worldwide. The virus usually causes mild and self-limiting gastroenteritis symptoms in all age groups, mainly through the fecal-oral transmission route. However, the virus is highly contagious, relatively stable in the environment, and has long virus-shedding duration. These characteristics result in frequent outbreaks and make the control of the outbreaks difficult. In addition, the diversity of norovirus genetic characteristics and the emergence of new variants every one or two years may make the virus to escape the immunity. Moreover, the human immune response to norovirus infection still remains unclear and recurrent infection is possible. The diagnosis of norovirus infection is mainly based on reverse transcription polymerase chain reaction (RT-PCR), Loop-mediated isothermal amplification (LAMP), and immunochromatography (IC). There are no specific anti-norovirus drugs and treatment focuses mainly on supportive care, especially preventing and treating dehydration. Development of a norovirus vaccine has many difficulties and limitations, but some progress and some vaccine candidates have passed a phase II clinical trial. To prevent norovirus infection, hygiene is still the key point. Moreover, laws, regulations, and official guidelines are issued to help to manage norovirus infection and outbreak. This review provides an overview of norovirus infection and further discusses key characteristics of the virus, along with pathogenesis, clinical manifestation, diagnosis, treatment, prevention and control of the virus infection. We also view the virus through the lens of foodborne illnesses, and cover the current situation of the disease in Japan and research progress made so far.
The Food Safety Commission of Japan (FSCJ) conducted assessments on human health risks associated with the Bovine Spongiform Encephalopathy (BSE) agent, in response to requests from the Ministry of Health, Labour and Welfare of Japan (MHLW). FSCJ conducted risk assessments under the assumption that the present feed control measures are maintained in Japan, the US, Canada, France and the Netherlands. The assessments were also based on the current BSE status and infection risks in cattle in these countries, and interspecies barrier of BSE transmission between cattle and humans. Consequently, FSCJ concludes that in these countries, variant Creutzfeldt-Jakob disease (vCJD) is highly unlikely to develop in association with consumption of BSE prions through meat and offal (excluding the tonsils and distal ileum) from cattle at or under 30 months of age. Conclusions on the domestic and border measures are as follows: 1) Domestic measures: Negligible influences to human health are predicted from the changes in the age limit for BSE testing of cattle in Japan from the current 20 months to 30 months; changes in definition on age of specified risk materials (SRMs: skull excluding tonsils, spinal cord and vertebral column) from “all ages” to “over 30 months of age” in Japan have negligible influences to human health: 2) Border measures: Negligible influences to human health are predicted from the changes in the age restriction from the current 20 months to 30 months on cattle meat and offal imported from the US and Canada; negligible influences to human health are predicted between the current ban and implementation of the age restriction of 30 month on import of cattle meat and offal from France and the Netherlands; changes in definition on age of SRMs (skull excluding tonsils, spinal cord and vertebral column) from “all ages” (equivalent to “import ban” for France and the Netherland) have negligible influences to human health.
The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of malathion (CAS No. 121–75-5), an organophosphorus pesticide, based on summary reports made by applicants and documents from JMPR, the governments of the US, EU and others. A major adverse effect of malathion observed is inhibition of ChE activity in the brain and red blood cells. None of the reproductive toxicity, teratogenicity, developmental neurotoxicity or genotoxicity relevant to human health was observed. No carcinogenicity was observed in rats. In an 18-month carcinogenicity study in mice, an increased incidence of hepatocellular adenomas was observed. However, a genotoxic mechanism was not likely to be involved in the tumor development, therefore it is reasonable to establish a threshold in the assessment. FSCJ specified the acceptable daily intake (ADI) for malathion at 0.29 mg/kg bw/day, applying a safety factor of 100 to the no-observed-adverse-effect level (NOAEL) of 29 mg/kg bw/day obtained in the two-year chronic toxicity study and two-year combined chronic toxicity/carcinogenicity study in rats. Since the lowest NOAEL after a single oral dose was 15 mg/kg bw observed in the randomized double-blind study in humans, FSCJ specified the acute reference dose (ARfD) of 1.5 mg/kg bw applying a safety factor of 10 (1 for a clinical single oral dosing study in humans and 10 for individual difference) to the NOAEL.
The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of propiconazole (CAS No. 60207–90-1), one of triazole-type fungicides, based on results from various studies. Major adverse effects of propiconazole observed are on hepatocellular hypertrophy, vacuolation and necrosis in the liver of rats and mice, and on congested duodenal mucosa and others in the gastrointestinal tract of dogs. Neither reproductive toxicity nor genotoxicity was observed. Although increases in the incidence of hepatocellular adenomas and carcinomas in male rats were observed in carcinogenicity tests, a genotoxic mechanism is unlikely to participate in the tumor development. It was thus considered possible to establish a threshold dose. Developmental toxicity tests in rats and rabbits showed cleft palate in the fetuses at the dose with maternal toxicity. Based on the results from various studies, FSCJ specified the residue definition for this dietary risk assessment in agricultural and livestock products to be propiconazole (parent compound only). The lowest no-observed-adverse-effect level (NOAEL) obtained in all studies referred was 1.9 mg/kg bw/day obtained in a one-year chronic toxicity study in dogs. FSCJ specified an acceptable daily intake (ADI) of 0.019 mg/kg bw/day by applying a safety factor of 100 to the NOAEL.
The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of metronidazole (CAS No. 443–48-1), an antiprotozoan agents, based on evaluation documents from Joint FAO/WHO Expert Committee on Food Additives (JECFA) and European Medical Agency (EMEA), and others. Metronidazole showed both positive and negative results on the in vivo and in vitro genotoxicity studies. Metronidazole is reduced in bacteria, and the hydroxylamine produced during the reduction exerts genotoxicity after reacting directly with DNA. Since enzymes that reduce nitro compounds are present also in mammals including humans, the nitro group of metronidazole is possible to be reduced by such enzymes to exert the genotoxicity in humans. Although the reduction of metronidazole in vivo seems less likely to occur in mammals than in bacteria, DNA damage occurred after a single application of the therapeutic dose of metronidazole in humans. The genotoxic potential of metronidazole is not thus excluded in humans. In carcinogenicity studies in mice and rats, metronidazole was demonstrated to be carcinogenic. Epidemiological studies in human have suggested an association between metronidazole and tumor occurrence. International Agency for Research on Cancer (IARC) categolized metronidazole into a group of substances which are possibly carcinogenic to humans (group 2B). FSCJ could not exclude the potential of metronidazole to be a genotoxic carcinogen. Therefore FSCJ concluded that it is not appropriate to specify an acceptable daily intake (ADI) for metronidazole.
The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of flumioxazin (CAS No. 103361–09-7), an N-phenylphthalimide herbicide, based on summary reports submitted by the applicants and documents from the governments of the US and Australia. Major adverse effects of flumioxazin observed are on blood (anemia), and liver (hepatocellular hypertrophy and increased organ weight). None of neurotoxicity, immunotoxicity and carcinogenicity, as well as genotoxicity relevant to human health were observed. In a two-generation reproduction study of flumioxazin in rats, decreased copulation index and birth rate, and decreased viability index on day 4 of the offsprings were observed. In developmental toxicity tests in rats, cardiovascular malformations including ventricular septal defect, and skeletal malformations such as curvature of the scapula were identified in fetuses. Based on the results from various studies, FSCJ specified the residue definition for dietary risk assessment in agricultural and livestock products to be flumioxazin (parent compound only). The lowest no-observed-adverse-effect level (NOAEL) obtained in all studies was 1.8 mg/kg bw/day in a combined two-year chronic toxicity/carcinogenicity study in rats. FSCJ specified an acceptable daily intake (ADI) of 0.018 mg/kg bw/day by applying a safety factor of 100 to the NOAEL.
The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of dibutyl phthalate (DBP) (CAS No.84–74-2) for the revision of the standards and criteria for apparatuses, containers and packages. DBP showed major adverse effects on liver and kidney, and also showed the reproductive and developmental toxicities (mice, rats and rabbits). The reproductive toxicities were observed in both sexes of experimental animals (mice and rats). No consistent results were obtained on human epidemiological studies, although some data suggested the possible association of DBP exposures with toxicological parameters including reproductive/developmental systems No definitive studies on carcinogenicity and chronic toxicity were available with DBP in experimental animals. No clear information is thus available on the carcinogenic effects of DBP in humans to date. FSCJ judged that DBP has no genotoxicity relevant to human health. Therefore, it is appropriate to specify a tolerable daily intake (TDI) based on the results of reproductive-developmental toxicity studies in experimental animals. Among the test values for the no-observed-adverse-effect level (NOAEL) or the lowest-observed-adverse-effect level (LOAEL), the lowest value was the LOAEL of 2.5 mg/kg bw/day in a dietary toxicity study in rats. FSCJ judged it appropriate to apply an uncertainty factor of 500 (10 for species difference, 10 for individual difference, and additional 5 for the use of the LOAEL) to the LOAEL (0.25 mg/kg bw/day) and specified the TDI of 0.005 mg/kg bw/day.
The Food Safety Commission of Japan (FSCJ) conducted a safety assessment of MON87769 line, a soybean producing stearidonic acid, based on the documents submitted by the applicant. The documents evaluated included the safety of the inserted genes, toxicity and allergenicity of the protein produced from the inserted genes, post-insertion analysis of the nucleotide sequences, stability of the inserted genes in the successive generations, influence on metabolic pathways in plants, comparative characterization of nutrients and toxic ingredients in plants. Newly produced adverse effects on humans derived from this line are unlikely based on the comparison between this line and the conventional counterpart. In conclusion, no concern relevant to human health is raised on the stearidonic acid producing soybean MON87769 line.