Mutsuko Hirata-Koizumi

National Institute of Health Sciences, Japan, Edo, Tōkyō, Japan

Are you Mutsuko Hirata-Koizumi?

Claim your profile

Publications (58)101.7 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Hydroquinone (HQ) is used in skin bleaching agents, hair dyes, and finger nail treatments. Many skin-lightening cosmetics that contain HQ are currently marketed in Japan. Concerns have been expressed regarding health risks to the general population because the carcinogenicity of HQ was previously suggested in animal studies. HQ induced hepatocellular adenomas and forestomach hyperplasias in mice and renal tubular cell adenomas in male rats. In the present study, the lacZ transgenic mutation assay was conducted according to OECD test guideline 488 to determine whether mutagenic mechanisms were involved in HQ-induced carcinogenesis. Male Muta™ mice were repeatedly administered HQ orally at dosages of 0, 25, 50, 100, or 200 mg/kg bw/day for 28 days. Body weight gain was decreased in all treatment groups. No significant differences were observed in mutant frequencies in the liver, stomach, lung, or kidney between HQ-treated mice and the concurrent negative controls, whereas the significant induction of mutations was noted in the positive control, N-ethyl-N-nitrosourea. These results suggest that a mutagenic mechanism is not responsible for HQ-induced carcinogenesis.
    Mutation Research/Genetic Toxicology and Environmental Mutagenesis 10/2014; 775-776. DOI:10.1016/j.mrgentox.2014.10.009 · 2.48 Impact Factor
  • Source
    Toxicology Letters 09/2014; 229. DOI:10.1016/j.toxlet.2014.06.786 · 3.36 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Historical control data on rodent developmental toxicity studies, performed between 1994 and 2010, were obtained from 19 laboratories in Japan, including 10 pharmaceutical and chemical companies and 9 contract research organizations. Rats, mice, and hamsters were used for developmental toxicity studies. Data included maternal reproductive findings at terminal cesarean sections and fetal findings including the spontaneous incidences of external, visceral, and skeletal anomalies. No noticeable differences were observed in maternal reproductive data between laboratories. Inter-laboratory variations in the incidences of fetuses with anomalies appeared to be due to differences in the selection of observation parameters, observation criteria, classification of the findings, and terminology of fetal alterations. Historical control data are useful for the appropriate interpretation of experimental results and evaluation of the effects of chemical on reproductive and developmental toxicities.
    Congenital Anomalies 01/2014; 54(3). DOI:10.1111/cga.12050 · 0.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Male and female rats were given perfluorooctadecanoic acid (PFOdA) by gavage at 40, 200 or 1,000 mg/kg/day, and each female was mated with a male in the same dose group after 14-day administration. Males were dosed for 42 days and females were dosed throughout the gestation period until day 5 of lactation. One female given 1,000 mg/kg/day was euthanized on day 18 of gestation due to a moribund condition; however, no other treatment-related clinical signs of toxicity were observed. Body weights fell at 1,000 mg/kg/day from day 28 through the administration period in males and throughout gestation and lactation in females. Red blood cell count, hemoglobin level and hematocrit were decreased at 200 and 1,000 mg/kg/day in males and activated partial thromboplastin time was prolonged at 1,000 mg/kg/ day in females. Histopathological examination revealed hepatic changes, such as centrilobular hypertrophy and necrosis, in males given 200 and 1,000 mg/kg/day and in females given 1,000 mg/kg/day. Pancreatic zymogen granule was decreased in both sexes at 1,000 mg/kg/day. As for reproductive and developmental toxicity, there were decreases in the number of corpora lutea, implantation, total number of pups born and the number of live pups on postnatal days 0 and 4 at 1,000 mg/kg/day. At this dose, birth weights of pups were decreased and postnatal body weight gain was inhibited. Based on these findings, the NOAEL of PFOdA was considered to be 40 mg/kg/day for repeated dose toxicity and 200 mg/kg/day for reproductive/developmental toxicity.
    The Journal of Toxicological Sciences 01/2014; 37(1):63-79. DOI:10.1002/tox.21996 · 1.38 Impact Factor
  • Toxicology Letters 08/2013; 221:S206. DOI:10.1016/j.toxlet.2013.05.486 · 3.36 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A 28-day repeated dose toxicity test and reproduction/developmental toxicity test for N,N'-diphenyl-p-phenylenediamine (DPPD) were conducted in [Crl:CD(SD)] SPF rats. Male and female rats were dosed with DPPD by gavage for 28days at 0, 100, 300, or 1000mg/kg bw/day or for a total of 42-46days at 0, 8, 50, or 300mg/kg bw/day. No significant adverse effects were observed in the repeated dose toxicity study up to 1000mg/kg bw/day in both sexes. In the reproduction/developmental toxicity study, two females showed piloerection, hypothermia, and pale skin; one died and the other showed dystocia on day 23 of pregnancy at 300mg/kg bw/day. Another female delivered only three live pups at 300mg/kg bw/day. A significantly prolonged gestation period was observed at 50 and 300mg/kg bw/day. The NOAELs of repeated dose toxicity and reproduction/developmental toxicity were considered to be 1000 and 8mg/kg bw/day, respectively.
    Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 02/2013; 56. DOI:10.1016/j.fct.2013.02.029 · 2.61 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Crl:CD(SD)rats were given 3-cyanopyridine by gavage at 0, 5, 30 or 180 mg/kg/day. Males were dosed for 42 days beginning 14 days before mating, and females for 40-53 days beginning 14 days before mating to day 3 of lactation, including throughout the mating and gestation periods. General toxicity, mainly liver damage, was observed in males at >= 30 mg/kg/day and in females at >= 5 mg/kg/day. Sertoli cell vacuolation was observed at 180 mg/kg/day, and spermatocyte damages were observed at >= 30 mg/kg/day. Effects on estrous cycles, corpora lutea and implantations, and unsuccessfully mated females, despite additional mating, were observed at 180 mg/kg/day. Delayed initiation of delivery, dystocia, and deaths or mori-bundities of pregnant females were observed at 180 mg/kg/day, and only two pregnant rats delivered live pups at that dose. The NOAEL for reproductive/developmental toxicity was concluded to be 30 mg/kg/day.
    Reproductive Toxicology 11/2012; 35. DOI:10.1016/j.reprotox.2012.10.014 · 2.77 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The available toxicity information for boron was reevaluated and four appropriate toxicity studies were selected in order to derive a tolerable daily intake (TDI) using newly proposed uncertainty factors (UFs) presented in Hasegawa et al. (2010). No observed adverse effect levels (NOAELs) of 17.5 and 8.8 mg B/kg/day for the critical effect of testicular toxicity were found in 2-year rat and dog feeding studies. Also, the 95% lower confidence limit of the benchmark doses for 5% reduction of fetal body weight (BMDL(05)) was calculated as 44.9 and 10.3 mg B/kg/day in mouse and rat developmental toxicity studies, respectively. Measured values available for differences in boron clearance between rats and humans and variability in the glomerular filtration rate (GFR) in pregnant women were used to derive chemical specific UFs. For the remaining uncertainty, newly proposed default UFs, which were derived from the latest applicable information with a probabilistic approach, and their subdivided factors for toxicokinetic and toxicodynamic variability were applied. Finally, overall UFs were calculated as 68 for rat testicular toxicity, 40 for dog testicular toxicity, 250 for mouse developmental toxicity and 78 for rat developmental toxicity. It is concluded that 0.13 mg B/kg/day is the most appropriate TDI for boron, based on rat developmental toxicity.
    Regulatory Toxicology and Pharmacology 11/2012; 65(1). DOI:10.1016/j.yrtph.2012.10.013 · 2.14 Impact Factor
  • Toxicology Letters 06/2012; 211:S184-S185. DOI:10.1016/j.toxlet.2012.03.665 · 3.36 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Three female Crl:CD(SD) rats/group were dosed with single wall carbon nanotube (SWCNT) or multi wall carbon nanotube (MWCNT) four times by gavage at a total of 50 mg/kg bw or 200 mg/kg bw (four equally divided doses at one-hour intervals). Acute oral doses of SWCNT and MWCNT caused neither death nor toxicological effects, and thus the oral LD 50 values for SWCNT and MWCNT were considered to be greater than 50 mg/kg bw and 200 mg/kg bw, in rats respectively. Five or ten Crl:CD(SD) rats/sex were dosed with SWCNT once daily by gavage at a dose of 0 (control), 0.125, 1.25 or 12.5 mg/kg bw/day for 28 days with a 14-day recovery period (0 and 12.5 mg/kg bw/day groups). Six or twelve Crl:CD(SD) rats/sex were dosed with MWCNT once daily by gavage at a dose of 0 (control), 0.5, 5.0 or 50 mg/kg bw/day for 28 days with a 14-day recovery period (0 and 50 mg/kg bw/day groups). Based on no toxicological effects, the no observed adverse effect levels (NOAELs) of repeated dose toxicity of SWCNT and MWCNT were considered to be 12.5 mg/kg bw/day and 50 mg/kg bw/day (the highest dose tested), respectively. It was suggested that SWCNT and MWCNT dosed by gavage reached the gastro-intestinal tract as agglomerates and were mostly excreted via feces.
    The Journal of Toxicological Sciences 01/2012; 37(3):463-74. DOI:10.2131/jts.37.463 · 1.38 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Phthalate esters are widely used as plasticizers in polyvinyl chloride products. Because of human health concerns, regulatory authorities in Japan, US, Europe and other countries control the use of di(2-ethylhexyl) phthalate, diisononyl phthalate, di-n-butyl phthalate, butylbenzyl phthalate, diisodecyl phthalate and di-n-octyl phthalate for the toys that can be put directly in infants' mouths. While these regulatory actions will likely reduce the usage of phthalate esters, there is concern that other plasticizers that have not been sufficiently evaluated for safety will be used more frequently. We therefore collected and evaluated the toxicological information on di(2-ethylhexyl) terephthalate (DEHT), 1,2-cyclohexanedicarboxylic acid, diisononyl ester (DINCH), diisononyl adipate (DINA), 2,2,4-trimetyl-1,3-pentanediol diisobutyrate (TXIB), tri-n-butyl citrate (TBC) and acetyl tri-n-butyl citrate (ATBC) which were detected at a relatively high frequency in toys. The collected data have shown that chronic exposure to DEHT affects the eye and nasal turbinate, and DINCH exerts effects on the thyroid and kidney in rats. DINA and TXIB have been reported to have hepatic and renal effects in dogs or rats, and ATBC slightly affected the liver in rats. The NOAELs for repeated dose toxicity are relatively low for DINCH (40 mg/kg bw/day) and TXIB (30 mg/kg bw/day) compared with DEHT, DINA and ATBC. DEHT, TXIB and ATBC have been reported to have reproductive/developmental effects at relatively high doses in rats. For DINA and TBC, available data are insufficient for assessing the hazards, and therefore, adequate toxicity studies should be conducted. In the present review, the toxicity information on 6 alternatives to phthalate plasticizers is summarized, focusing on the effects after oral exposure, which is the route of most concern.
    Kokuritsu Iyakuhin Shokuhin Eisei Kenkyūjo hōkoku = Bulletin of National Institute of Health Sciences 01/2012;
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To obtain initial information on the possible repeated-dose oral toxicity of fullerene C60, Crl:CD(SD) rats were administered fullerene C60 by gavage once daily at 0 (vehicle: corn oil), 1, 10, 100, or 1,000 mg/kg/day for 29 days, followed by a 14-day recovery period. No deaths occurred in any groups, and there were no changes from controls in detailed clinical observations, body weights, and food consumption in any treatment groups. Moreover, no treatment-related histopathological changes were found in any organs examined at the end of the administration period and at the end of the recovery period. Blackish feces and black contents of the stomach and large intestine were observed in males and females at 1,000 mg/kg/day in the treatment group. There were no changes from controls in the liver and spleen weights at the end of the administration period, but those weights in males in the 1,000 mg/kg/day group increased at the end of the recovery period. Using liquid chromatography-tandem mass spectrometry, fullerene C60 were not detected in the liver, spleen or kidney at the end of the administration period and also at the end of the recovery period. In conclusion, the present study revealed no toxicological effects of fullerene C60; however, the slight increases in liver and spleen weights after the 14-day recovery period may be because of the influence of fullerene C60 oral administration. In the future, it will be necessary to conduct a long-term examination because the effects of fullerene C60 cannot be ruled out.
    The Journal of Toxicological Sciences 01/2012; 37(2):353-61. DOI:10.2131/jts.37.353 · 1.38 Impact Factor
  • Fuel and Energy Abstracts 08/2011; 205. DOI:10.1016/j.toxlet.2011.05.351
  • Fuel and Energy Abstracts 08/2011; 205. DOI:10.1016/j.toxlet.2011.05.961
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aluminium ammonium sulfate (AAS) was tested for reproductive/developmental toxicity in a two-generation study. Male and female rats were continuously given AAS in drinking water at 0, 50, 500 or 5000 ppm. Water consumption was decreased in all AAS-treated groups, and the body weight of parental animals transiently decreased in the 5000 ppm group. In either generation, no compound-related changes were found in estrous cyclicity, sperm parameters, copulation, fertility and gestation index, number of implantations and live birth pups, sex ratios of pups or viability during the preweaning period. Male and female F1 pups in the 5000 ppm group showed a lower body weight on postnatal day 21, while there were no differences in the birth weight of F1 and F2 pups between the control and AAS-treated groups. Preweaning body weight gain in F2 males and females indicated a similar decreasing tendency at 5000 ppm. In F1 and F2 weanlings, the weight of the liver, spleen and thymus decreased at 5000 ppm, but no histopathological changes were found in these organs. In F1 females in the 5000 ppm group, vaginal opening was delayed slightly. There were no compound-related changes in male preputial separation or in other developmental landmarks. In behavioral tests conducted for F1 animals at 4-6 weeks of age, no compound-related changes were found in spontaneous locomotor activity and performance in a water-filled multiple T-maze. In conclusion, the NOAEL of AAS for two-generation reproductive/developmental toxicity was considered to be 500 ppm in rats. Considering the aluminium content in the basal diet, the total ingested dose of aluminium from drinking water and food in this 500 ppm group was calculated to be 5.35 mgAl/kgbw/day.
    Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 05/2011; 49(9):1948-59. DOI:10.1016/j.fct.2011.04.035 · 2.61 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In a two-generation reproductive toxicity study, male and female rats were given aluminium sulfate (AS) in drinking water at 0, 120, 600 or 3000 ppm. AS reduced water consumption in all treatment groups, and body weight was transiently decreased in the 3000 ppm group. In the F1 and F2 pups, preweaning body weight gain was inhibited at 3000 ppm, and the liver and spleen weight was decreased at weaning. At this dose, vaginal opening was slightly delayed. There were no compound-related changes in other reproductive/developmental parameters, including developmental neurobehavioral endpoints. The data indicated that the NOAEL of AS in this two-generation study is 600 ppm for parental systemic toxicity and reproductive/developmental toxicity. The total ingested dose of aluminium from drinking water and food (standard rat diet, containing 25-29 ppm of aluminium) combined for this 600 ppm group was calculated to be 8.06 mg Al/kg bw/day.
    Reproductive Toxicology 11/2010; 31(2):219-30. DOI:10.1016/j.reprotox.2010.11.004 · 2.77 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We propose new uncertainty factors (UFs) and a new subdivision of default factors in chemical risk assessment using a probabilistic approach based on the latest applicable information. Rounded values of 150 for mice, 100 for hamsters and rats, and 40 for rabbits, monkeys and dogs for inter- and intra-species differences (UF(AH)) were derived from the probabilistic combination of two log-normal distributions. Further calculation of additional UFs when chronic data (UF(S)) or NOAEL (UF(L)) are lacking was conducted using available log-normal distribution information. The alternative UF(S) and UF(L) values of 4 are considered to be appropriate for both cases where data are lacking. The default contributions of inter-species difference (UF(A)) and intra-species difference (UF(H)) to the UF(AH) of 100 for hamsters and rats as an example are considered to be 25 and 4, respectively. The UF(A) of 25 was subdivided into 25(0.6) (i.e., 7.0) for pharmacokinetics (PK) (UF(A,PK)) and 25(0.4) (i.e., 3.6) for pharmacodynamics (PD) (UF(A,PD)), and the UF(H) of 4 was evenly subdivided into 4(0.5) (i.e., 2) (UF(H,PK) and UF(H,PD)), to account for chemical-specific difference data between humans and laboratory animals for PK and/or PD. These default UFs, which come from actual experimental data, may be more appropriate than previous default UFs to derive tolerable daily intake values.
    Regulatory Toxicology and Pharmacology 11/2010; 58(2):237-42. DOI:10.1016/j.yrtph.2010.06.006 · 2.14 Impact Factor
  • Toxicology Letters 07/2010; 196. DOI:10.1016/j.toxlet.2010.03.714 · 3.36 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: 2-(2'-hydroxy-3',5'-di-tert-butylphenyl)benzotriazole (HDBB) is an ultraviolet absorber used in plastic resin products, such as building materials and automobile components. In oral repeated dose toxicity studies using 5- or 6-week-old rats, this chemical induced hepatic histopathological changes, such as hypertrophy accompanied with eosinophilic granular changes and focal necrosis of hepatocytes, and male rats showed nearly 25 times higher susceptibility to the toxic effects than females. Castration at approximately 4 weeks of age markedly reduced the sex-related variation in HDBB toxicity, but some difference, less than five times, remained between male and female castrated rats. Following oral HDBB administration to male and female juvenile rats from postnatal days 4-21, such gender-related difference in toxic susceptibility was not detected; therefore, it is speculated that the determinants of susceptibility to HDBB toxicity are differentiated between sexes after weaning. In young rats given HDBB, there was no gender-related difference in plasma HDBB concentration, and no metabolites were detected in the plasma of either sex. HDBB induced lauric acid 12-hydroxylase activity in the liver and this change was more pronounced in males than in females. These findings indicate that HDBB could show hepatic peroxisome proliferation activity, and the difference in the susceptibility of male and female rats to this effect might lead to marked gender-related differences in toxicity.
    Congenital Anomalies 12/2009; 49(4):247-52. DOI:10.1111/j.1741-4520.2009.00248.x · 0.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The present study was performed to determine experimental conditions for thalidomide induction of fetal malformations and to understand the molecular mechanisms underlying thalidomide teratogenicity in cynomolgus monkeys. Cynomolgus monkeys were orally administered thalidomide at 15 or 20mg/kg-d on days 26-28 of gestation, and fetuses were examined on day 100-102 of gestation. Limb defects such as micromelia/amelia, paw/foot hyperflexion, polydactyly, syndactyly, and brachydactyly were observed in seven of eight fetuses. Cynomolgus monkeys were orally administered thalidomide at 20mg/kg on day 26 of gestation, and whole embryos were removed from the dams 6h after administration. Three embryos each were obtained from the thalidomide-treated and control groups. Total RNA was isolated from individual embryos, amplified to biotinylated cRNA and hybridized to a custom Non-Human Primate (NHP) GeneChip((R)) Array. Altered genes were clustered into genes that were up-regulated (1281 genes) and down-regulated (1081 genes) in thalidomide-exposed embryos. Functional annotation by Gene Ontology (GO) categories revealed up-regulation of actin cytoskeletal remodeling and insulin signaling, and down-regulation of pathways for vasculature development and the inflammatory response. These findings show that thalidomide exposure perturbs a general program of morphoregulatory processes in the monkey embryo. Bioinformatics analysis of the embryonic transcriptome following maternal thalidomide exposure has now identified many key pathways implicated in thalidomide embryopathy, and has also revealed some novel processes that can help unravel the mechanism of this important developmental phenotype.
    Reproductive Toxicology 09/2009; 29(1):49-56. DOI:10.1016/j.reprotox.2009.09.003 · 2.77 Impact Factor

Publication Stats

423 Citations
101.70 Total Impact Points

Institutions

  • 2005–2014
    • National Institute of Health Sciences, Japan
      • • Division of Risk Assessment
      • • Division of Pathology at Biological Safety Research Center
      • • Division of Medical Safety Science
      Edo, Tōkyō, Japan
  • 2013
    • Shin Nippon Biomedical Laboratories, Ltd.
      Kagosima, Kagoshima, Japan
  • 2007–2008
    • National Institute of Occupational Safety and Health JAPAN
      Edo, Tōkyō, Japan