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Biomedical subjects

Akihiko Hirose

Publications and source records attributed to Akihiko Hirose.

14 recordsLinked to original sources
PubMed2006

Developmental toxicity of dibutyltin dichloride in cynomolgus monkeys.

Dibutyltin dichloride (DBTCl) has been shown to be teratogenic in rats. The present study was conducted to determine the teratogenic potential of DBTCl given to pregnant monkeys during the entire period of organogenesis. Cynomolgus monkeys were dosed once daily by nasogastric intubation with DBTCl at 0, 2.5 or 3.8 mg/kg on days 20-50 of pregnancy, the whole period of organogenesis. The pregnancy outcome was determined on day 100 of pregnancy. In both DBTCl-treated groups, a significant increase in the incidence of pregnant females with soft stool and/or diarrhea, and with yellowish stool was observed. Maternal body weight gain at 3.8 mg/kg and food consumption at 2.5 and 3.8 mg/kg were decreased during the administration period. The survival rate of fetuses at terminal cesarean sectioning was decreased in the DBTCl-treated groups and significantly decreased at 2.5 mg/kg. There were no changes in the developmental parameters of surviving fetuses, including fetal body weight, crown-rump length, tail length, sex ratio, anogenital distance and placental weight, in the DBTCl-treated groups. No external, internal or skeletal malformations were found in the fetuses in any group. Although internal and skeletal variations were found, no difference in the incidence of fetal variation was noted between the control and DBTCl-treated groups. No effect on skeletal ossification was observed in fetuses in the DBTCl-treated groups. The data demonstrate that DBTCl is embryolethal but not teratogenic in cynomolgus monkeys.

Administration, Oral↗
PubMed2006

Prenatal developmental toxicity study of the basic rubber accelerator, 1,3-di-o-tolylguanidine, in rats.

Pregnant rats were given 1,3-di-o-tolylguanidine (DTG) by gavage at 0, 10, 20 or 40 mg/kg bw/day on days 6-19 of pregnancy and the pregnancy outcome was determined on day 20 of pregnancy. At 40 mg/kg bw/day, deaths were observed in four out of 24 females. The incidences of females showing mydriasis at 20 and 40 mg/kg bw/day and showing decreased locomotor activity at 40 mg/kg bw/day were significantly increased. Alopecia, bradypnea, prone position and tremor were also observed at mg/kg bw/day. The maternal body weight gain at 20 and 40 mg/kg bw/day and food consumption at 40 mg/kg bw/day were significantly reduced. A significantly decreased weight of the gravid uterus, increased incidence of postimplantation loss, decreased number of live fetuses, and lowered weights of fetuses and placentae were found at 40 mg/kg bw/day. The incidences of the total number of fetuses with external malformations at 40 mg/kg bw/day and with skeletal malformations at 20 and 40 mg/kg bw/day were significantly increased. Significantly higher incidences of fetuses with brachydactyly and short tail and defects of caudal vertebrae, phalanges and metacarpals were observed at 40 mg/kg bw/day. Delayed ossification was also noted at 40 mg/kg bw/day. The data indicate that DTG is teratogenic at maternal toxic doses and the NOAELs of DTG for maternal and developmental toxicity are 10 mg/kg bw/day in rats.

Abnormalities, Drug-Induced↗
PubMed2006

Evaluation of developmental toxicity of ultraviolet absorber 2-(3',5'-di-tert-butyl-2'-hydroxyphenyl)-5-chlorobenzotriazole in rats.

2-(3',5'-Di-tert-butyl-2'-hydroxyphenyl)-5-chlorobenzotriazole (DBHCB) is widely used as a UV absorber. In this study, the developmental toxicity of DBHCB was evaluated in rats. Pregnant rats were given DBHCB at 0, 62.5, 250, or 1000 mg kg(-1) day(-1) by gavage on days 5-19 of pregnancy. No deaths were observed in the pregnant rats of any group. No effect of DBHCB on the general conditions, body weight gain, or feed consumption was observed in the pregnant rats. There were no changes in the ovarian weight, gravid uterine weight, or necropsy findings in the maternal rats of the DBHCB-treated groups. No significant effects of DBHCB were found in the number of corpora lutea, implantations, live fetuses, resorptions or dead fetuses, incidence of pre- or postimplantation embryonic loss, viability of fetuses, fetal weight, or sex ratio of live fetuses. No significant difference in the incidence of fetuses with malformations or variations or degree of ossification was detected between the DBHCB-treated and control groups.

Abnormalities, Drug-Induced↗
PubMed2006

Semi-quantitative immunohistochemical analysis of male rat-specific alpha2u-globulin accumulation for chemical toxicity evaluation.

We purified male rat urinary alpha(2u)-globulin, prepared the antibody in rabbits, and improved an immunohistochemical detection method using this antibody for male rat-specific alpha(2u)-globulin accumulation appearing as hyaline droplets in the kidneys. Our prepared antibody reacted specifically with alpha(2u)-globulin in both immunohistochemical and Western blotting analyses, furthermore, and the graded immuno-reactivities on the slide were well associated with computational image analyzing results. Using this method, we retrospectively analyzed the renal sections from the toxicity studies of 12 nephrotoxic chemicals, which had already been conducted under the Japanese Existing Chemicals Survey Program. We demonstrated that the hyaline droplets induced by treatment with 10 chemicals (1,4-dibromobenzene, dicyclopentadiene, 3,4-dimethylaniline, 1,4-dicyanobenzene, tetrahydrothiophene-1,1-dioxide, 1,3-dicyanobenzene, acenaphthene, 3,4-dichloro-1-butene, 3a,4,7,7a-tetrahydro-1H-indene and 3,5,5-trimethylhexan-1-ol) were directly associated with alpha(2u)-globulin accumulation. This immunohistochemical method is convenient for applying, even retrospectively, paraffin sections from general toxicity studies and could be useful for qualifying male rat-specific hyaline droplets consisting of alpha(2u)-globulin and renal risk in humans.

Alpha-Globulins↗
PubMed2005

Reproductive and developmental toxicity screening test of basic rubber accelerator, 1,3-di-o-tolylguanidine, in rats.

Twelve male and female rats per group were exposed to the rubber accelerator 1,3-di-o-tolylguanidine (DTG) by gavage at 0, 8, 20 or 50 mg/kg bw/day. Males were dosed for a total of 49 days beginning 14 days before mating. Females were dosed for a total of 40-49 days beginning 14 days before mating to day 3 of lactation throughout the mating and gestation period. At 50 mg/kg bw/day, deaths were observed in two males and three females. Lowered body weight gain and food consumption were noted in males at 50 mg/kg bw/day and females at 20 and 50 mg/kg bw/day. Mydriasis, decreased locomotor activity, bradypnea, prone position, tremor and/or salivation were observed in males and females at 20 and 50 mg/kg bw/day. No effects of DTG were found on the estrous cyclicity, precoital interval, copulation, fertility and gestational indices, numbers of corpora lutea and implantations, or gestation length. A significant decrease in the number, body weight and viability of offspring and increase in the incidence of fetuses with external malformations were found at 50 mg/kg bw/day. Oligodactyly, anal atresia and tail anomalies were observed. These data suggest that DTG may be teratogenic. The NOAELs of DTG for general and developmental toxicity in rats are 8 and 20 mg/kg bw/day, respectively.

Abnormalities, Drug-Induced↗
PubMed2005

In silico assessment of chemical mutagenesis in comparison with results of Salmonella microsome assay on 909 chemicals.

Genotoxicity is one of the important endpoints for risk assessment of environmental chemicals. Many short-term assays to evaluate genotoxicity have been developed and some of them are being used routinely. Although these assays can generally be completed within a short period, their throughput is not sufficient to assess the huge number of chemicals, which exist in our living environment without information on their safety. We have evaluated three commercially available in silico systems, i.e., DEREK, MultiCASE, and ADMEWorks, to assess chemical genotoxicity. We applied these systems to the 703 chemicals that had been evaluated by the Salmonella/microsome assay from CGX database published by Kirkland et al. We also applied these systems to the 206 existing chemicals in Japan that were recently evaluated using the Salmonella/microsome assay under GLP compliance (ECJ database). Sensitivity (the proportion of the positive in Salmonella/microsome assay correctly identified by the in silico system), specificity (the proportion of the negative in Salmonella/microsome assay correctly identified) and concordance (the proportion of correct identifications of the positive and the negative in Salmonella/microsome assay) were increased when we combined the three in silico systems to make a final decision in mutagenicity, and accordingly we concluded that in silico evaluation could be optimized by combining the evaluations from different systems. We also investigated whether there was any correlation between the Salmonella/microsome assay result and the molecular weight of the chemicals: high molecular weight (>3000) chemicals tended to give negative results. We propose a decision tree to assess chemical genotoxicity using a combination of the three in silico systems after pre-selection according to their molecular weight.

Biological Assay↗
PubMed2005

[Progress on OECD chemicals programme (7)--SIAM 15 in Boston, 2002].

The 15th Screening Information Data Set (SIDS) Initial Assessment Meeting (SIAM 15) was held in Boston, USA. The initial assessment documents of twelve substances at SIAM 15 (CAS numbers: 79-39-0, 88-60-8, 92-70-6, 102-76-1, 110-83-8, 135-19-3, 7647-01-0, 8007-18-9, 10043-52-4, 11070-44-3, 25321-09-9, 68186-90-3) were submitted by the Japanese Government with or without the International Council of Chemical Associations (ICCA) and all of them on the human health effect parts were agreed at the meeting. In this report, the human health effect parts in their 12 substance documents are introduced.

Animals↗
PubMed2004

Principles of risk assessment for determining the safety of chemicals: recent assessment of residual solvents in drugs and di(2-ethylhexyl) phthalate.

Risk assessment of chemicals is essential for the estimation of chemical safety, and animal toxicity data are typically used in the evaluation process, which consists of hazard identification, dose-response assessment, exposure assessment, and risk characterization. Hazard identification entails the collection of all available toxicity data and assessment of toxicity endpoints based on findings for repeated dose toxicity, carcinogenicity or genotoxicity and species-specificity. Once a review is compiled, the allowable lifetime exposure level of a chemical is estimated from a dose-response assessment based on several measures. For non-carcinogens and non-genotoxic carcinogens, the no-observed-adverse-effect-level (NOAEL) is divided by uncertainty factors (e.g. with environmental pollutants) or safety factors (e.g. with food additives) to derive a tolerable daily intake (TDI) or acceptable daily intake (ADI), respectively. These factors include interspecies and individual differences, duration of exposure, quality of data, and nature of toxicity such as carcinogenicity or neurotoxicity. For genotoxic carcinogens, low dose extrapolation is accomplished with mathematical modeling (e.g. linearized multistage model) from the point of departure to obtain exposure levels that will be associated with an excess lifetime cancer risk of a certain level. Data for levels of chemicals in food, water and air, are routinely used for exposure assessment. Finally, risk characterization is performed to ensure that the established 'safe' level of exposure exceeds the estimated level of actual exposure. These principles have led to the evaluation of several existing chemicals. To establish a guideline for residual solvents in medicine, the permitted daily exposure (PDE), equivalent to TDI, of N,N-dimethylformamide was derived on the basis of developmental toxicity (malformation) and of N-methylpyrrolidone on the basis of the developmental neurotoxicity. A TDI for di(2-ethylhexyl)phthalate was derived from assessment of testicular toxicity.

Animals↗
PubMed2004

Revision and establishment of Japanese drinking water quality guidelines for di(2-ethylhexyl) phthalate, toluene and vinyl chloride -- differences from the latest WHO guideline drafts.

The revision of the Japanese drinking water quality guidelines was established in May 2003. The WHO drinking water quality guidelines for the 3(rd) edition were also revised and the draft has been open to the public since last year. Most guideline values of each chemical in both Japan and WHO were quite similar; however, there are different overt values for three chemicals. In this short communication, we describe them and discuss the reason for taking the different toxicity endpoints and derivation method for these three chemicals, di(2-ethylhexyl) phthalate, toluene and vinyl chloride.

Diethylhexyl Phthalate↗
PubMed2004

[Progress on OECD chemicals programme].

The twelfth SIDS, the Screening Information Data Set, Initial Assessment Meeting (SIAM 12) was held at the Organisation for Economic Co-operation and Development (OECD) headquarters in Paris, France and SIAM 13 was held in Bern, Switzerland, hosted by the European Commission. Two substances at SIAM 12 (CAS No:91-15-6, 123-77-3) and 4 substances at SIAM 13 (CAS No:91-76-9, 112-85-6, 868-77-9, 1477-55-0) were submitted by the Japanese Government and/or International Council of Chemical Associations (ICCA). These substances were agreed at the meetings. In this report, the human health effects of 6 substances above-mentioned are introduced.

Animals↗
PubMed2004

[Recent TDI derivation of dioxin based on the reproductive and developmental toxicity].

In 1998, WHO-IPCS re-assessed the TDI of dioxin, which was derived from the body burdens of TCDD exposed to the experimental animals. Then, the international assessment agencies and governmental assessment agencies have conducted the dioxin fs health assessment using the similar method to the WHO-IPCS approach. The key endpoints were reproductive and developmental toxicity caused by in utero and lactational exposure. Each assessment agencies used the similar data set of the toxicity studies, however, there are some differences about the TDI derivation method and the selection of adverse endpoints. This report reviewed the recent reproductive and developmental toxicity studies of the dioxins and summarized the health assessment in the international or governmental agencies, and discussed the appropriate TDI derivation.

Animals↗
PubMed2003

Protective effects of progesterone on implantation failure induced by dibutyltin dichloride in rats.

We previously showed that dibutyltin dichloride (DBTCl) at 7.6 mg/kg and higher on days 0-3 of pregnancy caused implantation failure and a decline in serum progesterone levels in rats and hypothesized that the decline is responsible for the implantation failure. This study was conducted to determine the protective effects of progesterone on the DBTCl-induced implantation failure in rats. Rats were given oral DBTCl at 0, 7.6, or 15.2 mg/kg on days 0-3 of pregnancy and/or subcutaneous progesterone at 2 mg/rat on days 0-8 of pregnancy. The reproductive outcome was determined on day 9 of pregnancy. No effects of administration of progesterone alone on the pregnancy rate and number of implantations were found. The pregnancy rate and number of implantations were significantly decreased after administration of DBTCl alone. The pregnancy rate and number of implantations were higher in the groups given DBTCl and progesterone than the groups given DBTCl alone. The present data indicate that progesterone protects, at least in part, against the DBTCl-induced implantation failure and support our hypothesis that the decline in progesterone levels is a primary mechanism for the implantation failure due to DBTCl.

Animals↗
PubMedDate not supplied

Decreased anogenital distance and increased incidence of undescended testes in fetuses of rats given monobenzyl phthalate, a major metabolite of butyl benzyl phthalate.

The objective of this study was to determine the adverse effects of monobenzyl phthalate (MBeP), a major metabolite of butyl benzyl phthalate (BBP), on the development of the reproductive system, and to assess the role of MBeP in the antiandrogenic effects of BBP. Pregnant rats were given MBeP by gavage at 167, 250, or 375 mg/kg on days 15-17 of pregnancy. Fetuses were examined on day 21 of pregnancy. Maternal body weight gain and food consumption were significantly decreased at 167 mg/kg and higher. Fetal weight was significantly decreased at 375 mg/kg. A significant increase in the incidence of undescended testes and decrease in the anogenital distance (AGD) and ratio of AGD to the cube root of body weight was found in male fetuses at 250 mg/kg and higher. The AGD and ratio of AGD to the cube root of body weight of female fetuses in the MBeP-treated groups were comparable to those in the control group. The present data indicate that MBeP produces adverse effects on the development of the reproductive system in male offspring and suggest that MBeP may be responsible for the antiandrogenic effects of BBP.

Abnormalities, Drug-Induced↗