Because fetuses are considered the most sensitive to di(2-ethylhexyl) phthalate (DEHP) exposure, the effects of maternal exposures during pregnancy on infant and child health were reviewed from recently reported studies. The major modes of exposure to this chemical are food and indoor air; hence, it remains important to decrease the risk of exposure from contaminated foods. Although DEHP metabolic profiles were not different between pregnant and non-pregnant women, metabolic rates appeared lower in late pregnancy. Maternal serum triglyceride, fatty acids, estradiol, and progesterone levels are normally higher in late pregnancy than in non-pregnancy and early pregnancy, whereas free triiodothyronine and thyroxin levels are low during late pregnancy. Previous epidemiological studies of the effects of maternal exposure to DEHP on the mother, infant, and child show that DEHP disrupts maternal lipid levels and influences infant and child endocrine hormone levels, infant birth parameters, child neurobehavioral development, maturation, and asthma. Because these studies are limited to children less than 10 or 13 years old, further longitudinal follow-up studies are warranted to determine the influences of prenatal DEHP exposures on lifestyle diseases. Additionally, animal studies are needed to reinforce associations between maternal exposure to DEHP and health effects in the subsequent generation, and to elucidate the corresponding mechanisms. The risk of exposure to DEHP during childhood is another important consideration because associations with thyroid function, puberty, and neurobehavioral development have also been observed.

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Herein we analyzed food monitoring data regarding the Fukushima accident. The Japanese government ordered local governments to implement food monitoring after the Fukushima nuclear accident. This protective action for food safety contributed to the reduction of internal radiation exposure derived from the Fukushima accident. According to the food monitoring data collected from March 2011 to March 2015, more than 70% of the samples were beef. One hundred fifty four samples from a total of 776,310 beef samples that were above provisional regulation values or new standard limits were restricted from market distribution. Most of the beef samples were below the detection limits by regulation of consumption of contaminated rice straw. Two hundred forty one from a total of 251,510 beef samples were above the detection limit during fiscal year 2014. The mean committed effective dose due to annual beef consumption was estimated to be 1 µSv. The 99.9 percentile committed effective dose was 20 µSv. Thus, internal exposure due to beef consumption is limited. However, local governments continue regular monitoring for beef in response to social concerns. It should be noted that continuous staff effort and high costs are required to maintain this food surveillance program. A formal evaluation may help to assist in the development of a more effective and efficient food monitoring system.

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Methoxyacetate (MAA), formed by the metabolisms of ethylene glycol monomethyl ether (2-methoxyethanol), di-(2-methoxyethyl) phthalate and 1,6-dimethoxyhexane, is known to be a teratogenic and testicular toxicant in experimental animals. MAA is known to inhibit histone deacetylase and is associated with lactate-carrying monocarboxylate transporter expressed in Sertoli and fetal cells. In cells of rapid division, nucleosomal histone exchanges occur through the methyl and acetyl modifications and rates of nucleic acid syntheses are elevated with consumption of cellular energy. These phenomena are considered to associate with MAA-mediated teratogenicity and phase-selective spermatocyte disorders, and also suggest a mutual adverse-outcome pathway in which MAA-mediated histone deacetylase inhibition is involved through p21 activation as the early events. In addition, a possible functional relationship of one-carbon transferring folate/S-adenosyl methionine cycle with testicular metabolisms of sarcosine and creatine is envisioned. Thus, the mechanisms underlying the MAA toxicities will be discussed in relation to the current understanding of the involvement of the epigenetic phenomena and cell-specific metabolisms.

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The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of butyl benzyl phthalate (BBP) (CAS No.85-68-7) for the revision of the standards and criteria for apparatuses, containers and packages. Major adverse effects of BBP observed are those on body weight, pancreas, liver, kidney, and also on reproduction and development of offspring. FSCJ judged that BBP has no genotoxicity relevant to human health based on the results of genotoxicity studies, and thus judged it to be able to set tolerable daily intake (TDI) on this chemical. Dose-response relationship for human exposure to BBP was unable to obtain from the epidemiological studies, due to the lack of consistency among the results. FSCJ thus concluded it appropriate to specify TDI based on the results of studies in experimental animals rather than the epidemiological data. Similar to the case of bis (2-ethylhexyl) phthalate (DEHP) and dibutyl phthalate (DBP), toxicities toward the offsprings are the most sensitive and critical endpoints for TDI specification. FSCJ concluded it appropriate to establish an overall no-observed-adverse-effect level (NOAEL) of 20 mg/kg bw/day from three available studies on two-generation reproductive toxicity, which were adequately designed. In conclusion, FSCJ specified the TDI of 0.2 mg/kg bw, applying an uncertainty factor of 100 (10 for species difference, 10 for individual difference) to the NOAEL of 20 mg/kg bw/day.

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The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of metoclopramide (CAS No. 364-62-5) as a veterinary medicinal product used to gastrointestinal motility disorder, based on the documents submitted from the Ministry of Health, Labour and Welfare (MHLW). Various in vivo and in vitro genotoxicity studies suggested no apparent genotoxicity of metoclopramide relevant to human health. No carcinogenicity study nor the detail of chronic toxicity study was available, but metoclopramide is unlikely a genotoxic carcinogen. FSCJ concluded, therefore, that the acceptable daily intake (ADI) for metoclopramide can be specified. The lowest value among no-observed-adverse-effect levels (NOAELs) and lowest-observed-adverse-effect levels (LOAELs) in various toxicological studies was 0.5 mg/kg bw/day in a 6-month subacute toxicity study in dogs (LOAEL), as a toxic indicator of clinical signs including restlessness. FSCJ considered it appropriate to apply an additional safety factor of 10 on the specification of the ADI based on the LOAEL, taking into account of the lack of carcinogenicity tests, reproductive toxicity tests and neurotoxicity tests, and insufficient data of chronic toxicity tests. Accordingly, the specified ADI is 0.0005 mg/kg bw/day for metoclopramide, applying a safety factor of 1,000 (10 for species difference, 10 for individual difference and 10 for the additional factor) to the LOAEL of 0.5 mg/kg bw/day in a 6-month subacute toxicity study in dogs.

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The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of picoxystrobin (CAS No. 117428-22-5), a strobilurin fungicide, based on results from various studies. Major adverse effects of picoxystrobin observed are decreased body weight gain, hepatocellular hypertrophy in mice, as well as mucosal hyperplasia and dilated mucosal gland of the duodenum in mice. No neurotoxicity, reproductive toxicity, teratogenicity, immunotoxicity or genotoxicity relevant to human health were observed. Although increased incidences of interstitial cell adenomas were observed in a two-year chronic toxicity/carcinogenicity study in rats, genotoxic mechanism was unlikely to be involved in the tumor induction, and therefore, FSCJ concluded that it is possible to establish a threshold dose in the assessment. Based on the above results, only picoxystrobin (parent compound) was identified as the residue definition for dietary risk assessment in agricultural products. The lowest no-observed-adverse-effect level (NOAEL) obtained was 4.6 mg/kg bw/day in a one-year chronic toxicity study in dogs. FSCJ specified the acceptable daily intake (ADI) of 0.046 mg/kg bw/day, applying a safety factor of 100 to the NOAEL. In an acute neurotoxicity study in rats, NOAEL was not obtained, but the lowest-observed-adverse-effect level (LOAEL) was 200 mg/kg bw. In developmental toxicity studies, NOAELs obtained for adverse effects possibly caused by a single oral administration of picoxystrobin were 25 mg/kg bw/day in rabbits and 30 mg/kg bw/day in rats. Considering those results comprehensively, FSCJ specified an acute reference dose (ARfD) of 0.2 mg/kg bw based on the LOAEL of 200 mg/kg bw obtained from an acute neurotoxicity study in rats, applying a safety factor of 1,000 (10 for species difference, 10 for individual difference, and 10 for the adopted LOAEL value).

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The Food Safety Commission of Japan (FSCJ) conducted risk assessments of peracetic acid preparation used as an antimicrobial agent and its chemical components, based on results from various studies. These include following food additives: peracetic acid (CAS No. 79-21-0); 1-hydroxyethylidene-1,1-diphosphonic acid (HEDP) (CAS No. 2809-21-4); octanoic acid (CAS No. 124-07-2); acetic acid (CAS No. 64-19-7); and hydrogen peroxide (CAS No. 7722-84-1). In addition to these individual additives, peroctanoic acid was also evaluated, because it is formed in the preparation during processing. FSCJ concluded that use of peracetic acid preparation and its chemical components are of no concern relevant to human health as long as used appropriately as additives.

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