Biomedical subjects

Makoto Ema

Publications and source records attributed to Makoto Ema.

At least 19 recordsLinked to original sources

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

Susceptibility of newborn rats to 3-ethylphenol and 4-ethylphenol compared with that of young rats.

Newborn rat studies were conducted with oral administration of 3-ethylphenol (3EP) and 4-ethylphenol (4EP) on postnatal days (PND) 4-21 to allow comparison of no observed adverse effect level (NOAEL) and unequivocally toxic level (UETL) with those from 28-day studies of young rats starting at 5-6 weeks of age. In the newborn rat studies, slightly lowered body weight was observed after 3EP treatment, and deaths, hypoactivity, Straub tail, deep respiration and delayed righting reflex were clearly observed after 4EP treatment. In the young rat studies, salivation, staggering gait, changes in the liver including high values of liver weight and alanine aminotransferase or total cholesterol and the lesions in the forestomach were clearly observed after 3EP and 4EP treatments. NOAELs of 3EP and 4EP in the newborn rat studies appeared to be almost 3 times lower than those in the young rat studies. As a clear toxicity of 3EP was not observed in newborn rats, UETLs were not established for 3EP. Regarding 4EP, UETL of young rats was 4-5 times higher than that of newborn rats. In conclusion, newborn rats were 3-5 times more susceptible to 3EP and 4EP than young rats.

Administration, Oral↗

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

Comparative susceptibility of newborn and young rats to six industrial chemicals.

To elucidate the comparative susceptibility of newborn rats to chemicals, newborn and young animals were administered six industrial chemicals by gavage from postnatal days (PND) 4 to 21, and for 28 days starting at 5-6 weeks of age respectively, under the same experimental conditions as far as possible. As two new toxicity endpoints specific to this comparative analysis, presumed no-observed-adverse-effect-levels (pNOAELs) were estimated based on results of both main and dose-finding studies, and presumed unequivocally toxic levels (pUETLs) were also decided. pNOAELs for newborn and young rats were 40 and 200 for 2-chlorophenol, 100 and 100 for 4-chlorophenol, 30 and 100 for p-(alpha,alpha-dimethylbenzyl) phenol, 100 and 40 for (hydroxyphenyl)methyl phenol, 60 and 12 for trityl chloride, and 100 and 300 mg/kg/day for 1,3,5-trihydroxybenezene, respectively. To determine pUETLs, dose ranges were adopted in several cases because of the limited results of experimental doses. Values for newborn and young rats were thus estimated as 200-250 and 1000 for 2-chlorophenol, 300 and 500 for 4-chlorophenol, 300 and 700-800 for p-(alpha,alpha-dimethylbenzyl) phenol, 140-160 and 1000 for (hydroxyphenyl)methyl phenol, 400-500 and 300 for trityl chloride, and 500 and 1000 mg/kg/day for 1,3,5-trihydroxybenzene, respectively. In most cases, newborn rats were 2-5 times more susceptible than young rats in terms of both the pNOAEL and the pUETL. An exception was that young rats were clearly more susceptible than their newborn counterparts for trityl chloride.

Animals↗

PubMed2005

Elevated susceptibility of newborn as compared with young rats to 2-tert-butylphenol and 2,4-di-tert-butylphenol toxicity.

In order to determine the susceptibility of newborn rats to 2-tert-butylphenol (2TBP) and 2,4-di-tert-butylphenol (DTBP) toxicity, studies were conducted with oral administration from postnatal days (PND) 4 to 21 and the findings were compared with results for young rats exposed from 5 or 6 weeks of age for 28 days. In the newborn rats, specific effects on physical and sexual development and reflex ontogeny were not observed. While there were no clear differences in toxicological profiles between newborn and young rats, the no-observed-adverse-effect levels (NOAELs) differed markedly. For 2TBP, clinical signs such as ataxic gait, decrease in locomotor activity and effects on liver, such as increase in organ weight, were observed and the NOAELs were concluded to be 20 and 100 mg/kg/day in newborn and young rats, respectively. Based on hepatic and renal toxicity (histopathological changes and increase in organ weight with blood biochemical changes), the respective NOAELs for DTBP were concluded to be 5 and 20 mg/kg/day. Therefore, the susceptibility of newborn rats to 2TBP and DTBP was found to be 4-5 times higher than that of young rats.

Age Factors↗

PubMed2005

Susceptibility of newborn rats to hepatotoxicity of 1,3-dibromopropane and 1,1,2,2-tetrabromoethane, compared with young rats.

Newborn rat studies were conducted with oral administration of 1,3-dibromopropane (DBP) and 1,1,2,2-tetrabromoethane (TBE) from postnatal Days 4 to 21 to allow comparison of NOAELs and unequivocally toxic levels with those from 28-day young rat studies starting at 5-6 weeks of age. The unequivocally toxic level was estimated by our specified criteria, requiring simultaneous change of organ weights, histopathology, some biochemical parameters and body weights, because in this study only hypertrophy of hepatocytes was observed as a major histopathological change. DBP caused centrilobular hypertrophy of hepatocytes with alteration in biochemical parameters, as well as lowering of body weights, regardless of sex, in both newborn and young rats. NOAELs and unequivocally toxic levels were considered to be 50 and 150 mg/kg/day in newborn rats and 10 and 250 mg/kg/day in young rats, respectively. In the newborn rat study of TBE, some hepatic effects observed at the top dose of 50 mg/kg were not considered adverse because of the lack of histopathological changes. Significant lowering of body weight was noted at 200 mg/kg in the dose-finding study but histopathological data were not available. In the young rat study, there was no definite toxicity at 6 mg/kg and hypertrophic changes in liver and thyroids without body weight change occurred at 200 mg/kg. There were no clear sex differences in both the newborn and young rat studies. NOAELs were considered to be 50 and 6 mg/kg/day in newborn and young rats, respectively, but unequivocally toxic levels for both rats could not be estimated. Abnormalities of external and sexual development and reflex ontogeny in the newborn were not observed with either chemical. Based on these results, it can be concluded that the target organ of DBP and TBE is the liver in both newborn and young rats, and that while the doses at which toxic signs began to appear are higher in newborn rats, those causing clear toxicity may be paradoxically lower in the newborn case.

Age Factors↗

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

Unexpected nephrotoxicity induced by tetrabromobisphenol A in newborn rats.

The repeated dose toxicity of tetrabromobisphenol A (TBBPA), a flame retardant, was examined in male and female newborn rats given TBBPA orally at 0, 40, 200, or 600 mg/kg per day for 18 days from 4 days of age until weaning at 21 days of age. Half the rats in each dose group were sacrificed for a full gross necropsy and a histopathology on the organs and the tissues at 22 days of age and the remaining rats were reared without any treatment from post-weaning until 84 days of age to examine the recovery and the delayed occurrence of toxic effects. Treatment with 200 or 600 mg/kg TBBPA-induced nephrotoxicity characterized by the formation of polycystic lesions, and some deaths occurred in the 600 mg/kg group. There was no gender difference of nephrotoxicity and there were no other critical toxicities. At 85 days of age, nephrotoxic lesions were still present in the 200 and 600 mg/kg groups, but no abnormalities indicating delayed occurrence of toxic effects were found in the treated groups. In order to investigate the specificity of the nephrotoxicity induced by TBBPA in newborn rats, TBBPA was given to male and female young rats (5 weeks old) by oral administration at 0, 2000, or 6000 mg/kg per day for 18 days. The kidneys showed no histopathological changes even at the high dose. These results clearly indicate that the nephrotoxicity of TBBPA is specific for newborn rats although the toxic dose level was relatively high. To gain insight into the possible effects on human infants, the mechanism of this unexpected nephrotoxicity of TBBPA in newborn rats should be examined.

Administration, Oral↗

PubMed2004

Comments from the Behavioral Teratology Committee of the Japanese Teratology Society on OECD guideline for the testing of chemicals, proposal for a new guideline 426, developmental neurotoxicity study, draft document (September 2003).

In September 2003, a new revision of the draft guideline (Organization for Economic Co-operation and Development [OECD] Guideline for the Testing of Chemicals, Proposal for a New Guideline 426, Developmental Neurotoxicity Study) was distributed. The draft guideline consists of 51 paragraphs and an appendix. The National Coordinators were requested to arrange national expert reviews of the guideline proposal in their member countries. The member of the Behavioral Teratology (BT) Committee of the Japanese Teratology Society (JTS) reviewed, discussed and commented on the draft Test Guideline proposal. The BT Committee of the JTS also commented that the International Collaborative Study to validate this protocol should be definitely performed. These comments were sent to the OECD Secretariat. The BT Committee of the JTS expects that the comments are useful for further discussion.

Behavior↗

PubMed2004

Comparative toxicity study of 2,4,6-trinitrophenol (picric acid) in newborn and young rats.

The toxicity of oral 2,4,6-trinitrophenol (TNP) was determined in newborn rats, and compared with that in young rats. In newborn rats, males and females were given TNP at 0, 16.3, 81.4 or 407 mg/kg per day on postnatal days (PND) 4-17 for the dose-finding study, and at 0, 4.1, 16.3 or 65.1 mg/kg per day on PND 4-21 for the main study. Deaths, lower body weight (BW) and behavioral changes were found at 81.4 and 407 mg/kg per day in the dose-finding study, and lower BW was observed in males at 65.1 mg/kg per day during the dosing period of the main study. In young rats, 5-week-old males and females were given TNP at 0, 20, 100 or 500 mg/kg per day for 14 days as the dose-finding study and at 0, 4, 20 or 100 mg/kg per day for 28 days as the main study. Deaths were observed at 500 mg/kg per day in the dose-finding study. Deaths or changes in BW were not found at 100 mg/kg per day or less. At 100 mg/kg per day, hemolytic anemia and testicular toxicity were found. In conclusion, toxicity profiles induced by TNP were markedly different between newborn and young rats.

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↗

PubMed2003

Higher susceptibility of newborn than young rats to 3-methylphenol.

To determine susceptibility of infants to 3-methylphenol, a repeated dose toxicity study was conducted with oral administration to newborn and young rats. In an 18-day newborn study from postnatal days 4 to 21 at doses of 30, 100 and 300 mg/kg/day, various clinical signs including deep respiration, hypersensitivity on handling and tremors under contact stimulus, and depressed body weight gain were observed at 300 mg/kg. At 100 mg/kg, hypersensitivity and tremors were also noted in a small number of males only on single days during the dosing period. No adverse effects were observed in the 30 mg/kg group. There were no abnormalities of physical development, sexual maturation and reflex ontogeny. The no observed adverse effect level (NOAEL) for newborn rats was considered to be 30 mg/kg/day and the unequivocally toxic level 300 mg/kg/day. In a 28-day study starting at 5 weeks of age, clinical signs and depression of body weight gain, as observed in the newborn rats, appeared in both sexes at 1000 mg/kg but not 300 mg/kg. The NOAEL and the unequivocally toxic level were 300 mg/kg/day and 1,000 mg/kg/day, respectively. From these results, newborn rats were concluded to be 3 to 10 times more susceptible to 3-methylphenol than young rats. However, the realistic no adverse effect dose for the newborn must be slightly lower than 100 mg/kg/day, at which the toxicity incidence was very low, rather than 30 mg/kg/day. Based on this speculation and the equal toxicity at unequivocally toxic levels, the differences in the susceptibility to 3-methylphenol could be concluded to be 3 to 4 times. This is consistent with the results of our previous comparative studies on 4-nitrophenol, 2,4-dinitrophenol and 3-aminophenol, which showed 2 to 4 times differences in the susceptibility between newborn and young rats.

Aging↗