Relationship Between Stress Coping Mechanisms and Depression in Kidney Transplant Recipients.

BACKGROUND: It has been reported that transplant recipients are exposed to physical and psychosocial stresses even after transplant surgery and exhibit psychological disorders such as depression. PURPOSE: In this study, we extracted trends concerning how recipients of kidney transplants cope with stress, and we also examined how they cope with depression and its countermeasures. METHOD: We administered questionnaire surveys to 109 kidney transplant recipients. These included items on personal attributes, medical information, depression, and stress-coping type scales. Statistical analysis was performed using factor analysis and multiple regression analysis. RESULTS: Fifteen out of 109 (13.8%) were found to be high-risk patients for depression based on responses to the questionnaire using the depression scale. We extracted 2 factors of stress-coping type, namely Factor 1, "Directly coping with the problem," of patients who try to directly resolve the problem in a positive manner and Factor 2, "Stress-release while avoiding the problem," for those who relieve their feelings in response to the stress without resolving the problem itself. When multiple regression analysis was conducted with the depression scale as the dependent variable and the stress-coping factor as the independent variable, Factor 1 tended to be associated with reduced depression and Factor 2 with increased depression. CONCLUSIONS: Results showed that to improve the mental health of those who receive kidney transplants, it is necessary to examine the depression and stress-coping types of such patients at an early stage and carry out education on stress-coping, focusing on resolving the actual problem.

Characteristics of histologically confirmed endometriosis in cynomolgus monkeys.

STUDY QUESTION: What are the characteristics of spontaneous endometriosis in cynomolgus monkeys? SUMMARY ANSWER: Spontaneous endometriosis in cynomolgus monkeys exhibited similar characteristics to the human disease. WHAT IS KNOWN ALREADY: One previous report described the prevalence and the basic histopathology of spontaneous endometriosis in cynomolgus monkeys. STUDY DESIGN, SIZE, DURATION: Endometriotic lesions that had been histologically confirmed in 8 female cynomolgus monkeys between 5 and 21 years old were subjected to study. PARTICIPANTS/MATERIALS, SETTING, METHODS: The monkeys died of, or were sacrificed because of, sickness consequent on endometriosis. Specimens were evaluated histopathologically with haematoxylin and eosin staining, iron staining and immunohistochemistry (CD10, CD31, α-SMA and PGP9.5), and by observing them under a microscope. MAIN RESULTS AND THE ROLE OF CHANCE: Endometriotic and stromal cells (CD10-positive) with haemorrhage and inflammation were observed. Smooth muscle metaplasia and nerve fibres were also noted in the endometriotic lesions. Endometriotic lesions in lymph nodes were incidentally found. LIMITATIONS AND REASONS FOR CAUTION: Since laparoscopic analysis for monitoring the disease state was not set as a parameter of the current study, time course changes (progression) of the disease were not assessed. WIDER IMPLICATIONS OF THE FINDINGS: Further investigation of spontaneous endometriosis in cynomolgus monkeys may contribute to better understanding of the disease pathobiology. STUDY FUNDING/COMPETING INTERESTS: No external funds were used for this study. A.N.K., S.M., S.H., T.I., O.K., A.K. and M.S. are full-time employees of Chugai Pharmaceutical Co., Ltd. R.K. received lecture fees from Chugai Pharmaceutical Co., Ltd., unrelated to the submitted work. S.N., S. O., L.Y., K.Y. and T.S. have nothing to declare. TRIAL REGISTRATION NUMBER: N/A.

Efficacy and Safety of High-Dose Mizoribine Combined With Cyclosporine, Basiliximab, and Corticosteroids in Renal Transplantation: A Japanese Multicenter Study.

Mizoribine (MZR) is an immunosuppressive agent that exhibits a less potent immunosuppressive effect at doses up to 3 mg/kg/d. We investigated whether high-dose MZR is effective and safe for renal transplant patients in conjunction with cyclosporine (CsA), basiliximab, and corticosteroids. Ninety Japanese renal transplant patients were administered MZR (6 mg/kg/d), CsA (7 mg/kg/d), prednisolone (maintenance dose, 10 mg/d), and basiliximab (20 mg/body). They were compared with a control group of 81 renal transplant patients who received mycophenolate mofetil (MMF; 1500 mg/d), CsA, prednisolone, and basiliximab. The 2-year patient and graft survival rates were 98.9% and 97.8% in the MZR group and 98.8% and 97.5% in the MMF group, respectively. The rejection rate within 2 years after transplantation was 21.1% in the MZR group and 16.0% in the MMF group; the difference was nonsignificant. None of the MZR group developed cytomegalovirus (CMV) disease, whereas 12.3% of the MMF group contracted CMV (P < .0001). CMV viremia developed in 28.9% of the MZR group vs 46.9% of the MMF group (P < .0001); their peak antigen levels were 20.4 ± 44.1 and 252.8 ± 527.0 (P < .01). Furthermore, the incidence of gastrointestinal disorder, hyperlipidemia, and blood disorder was significantly lower in the MZR group than in the MMF group. The combination of high-dose MZR with CsA, basiliximab, and corticosteroids not only provides satisfactory immunosuppression but is also associated with a low incidence of CMV infection and gastrointestinal and blood disorders.

Practices for Supporting and Confirming Decision-Making Involved in Kidney and Liver Donation by Related Living Donors in Japan: A Nationwide Survey.

This nationwide survey investigated the actual practices for supporting and confirming the decision-making involved in related living-organ donations in Japan, focusing on organ type and program size differences. Answers to a questionnaire survey were collected from 89 of the 126 (71%) kidney and 30 of the 35 (86%) liver transplantation programs in Japan that were involved in living-donor transplantations in 2013. In 70% of the kidney and 90% of the liver transplantation programs, all donors underwent "third-party" interviews to confirm their voluntariness. The most common third parties were psychiatrists (90% and 83%, respectively). Many programs engaged in practices to support decision-making by donor candidates, including guaranteeing the right to withdraw consent to donate (70% and 100%, respectively) and prescribing a set "cooling-off period" (88% and 100%, respectively). Most donors were offered care by mental health specialists (86% and 93%, respectively). Third parties were designated by more of the larger kidney transplant programs compared with the smaller programs. In conclusion, the actual practices supporting and confirming the decision to donate a living organ varied depending on the organ concerned and the number of patients in the program.

Evolution of registry and tracking system for organ transplantation in Japan.

Previously, the renal and liver transplantation registry in Japan was enforced yearly using registration and tracking papers only on recipients. The input of all patient data and announcement of statistical analysis to the public required a long time. Following The Declaration of Istanbul 2008, the committees planned to establish new registry and tracking systems for renal and liver transplantations on both recipients and donors. As the first step, for renal transplantation, we established a new registry and tracking system, JARTRE (JApan Renal Transplantation REgistry), using flash (USB) memory in 2009. The recipient and donor data were inputted into the USB memory in the transplantation centers. The memory was collected once a year by the committees with performed at 3 months at 1 year and every year after, the operation. As the second step, for liver transplantation, we established an online registry and tracking system, LITRE-J (LIver Transplantation REgistry in Japan), using the Internet in 2011. The recipient and donor data are inputted online in the centers just after transplantation. The tracking is performed at 3 months, at 1 year and every year after the operation. In 2012, we will convert the JARTRE system to an online registration and tracking system using the Internet like LITRE-J. The advantages of these system are the ease of input, scope of the data, and rapidly for statistical processing. Herein we have reported the details of JARTRE and LITRE-J, as well as the evaluation of the registry and tracking systems for renal and liver transplantation in Japan.

Excellent results with high-dose mizoribine combined with cyclosporine, corticosteroid, and basiliximab in renal transplant recipients: multicenter study in Japan.

We performed a multicenter study in Japan to assess the efficacy and safety of immunosuppressive therapy with high-dose mizoribine (MZR; 6 mg/kg) combined with basiliximab (Bas), cyclosporine (CyA), and a corticosteroid in 90 patients. MZR was adjusted to maintain a target trough level of 1 to 2 µg/mL. CyA was started at 7 mg/kg to maintain blood levels in the target therapeutic range of 200 ng/mL (trough [C0]), 1200 ng/mL (2-hour post-dose [C2]), and 6000 ng·h/mL (area under the curve(0-9)). Bas (20 mg/body weight) was administered on the day of transplantation and on postoperative day 4. Rejection was diagnosed by episode and protocol biopsies. Cytomegalovirus (CMV) antigenemia (direct immunological staining of leukocytes using peroxidase-labeled monoclonal antibody [C7-HRP]) levels were measured every 2 weeks for 6 months. At 12 months, all patients and grafts were surviving except for one death from infection: the 1-year patient and graft survival rate was 98.9%. The acute rejection rate was 21.1%. The mean serum creatinine level at 1 year was 1.51 ± 0.61 mg/dL. The incidence of CMV disease was 0% with 28.9%, CMV antigenemia and 5.6%, ganoyclovir treatment. The incidence of BK virus disease was 2.2%. The mean serum uric acid level was 7.15 ± 1.79 mg/dL at 1 month and 7.06 ± 1.78 mg/dL at 3 months. We observed that a high-dose MZR regimen in combination with CyA, Bas, and corticosteroid was safe and effective to reduce the frequency of CMV and BK virus-related events in renal transplant recipients.

New registry and tracking system for renal transplantation in Japan.

Following The Declaration of Istanbul 2008, a registration committees of The Japan Society for Transplantation and The Japanese Society for Clinical Renal Transplantation planned to establish a new registry and tracking system for renal transplant recipients and donors supported by a Health Labor Sciences Research Grant by The Ministry of Health Labour and Welfare. In place of the previous paper-based system, we established the new registry and tracking system, JARTRE (Japan Renal Transplantation Registry), using USB memory in 2009. Recipient and donor data were inputted into the USB memory at the transplantation centers. The memory was reviewed a yearly by committees. The recipient and donor registration included details from both. The tracking is performed centrally 3 months, 1 year, and every year after the operation. The advantages of this system are the ease of input, adequacy of the data, and rapid statistical processing. In 2009, we registered 97.9% of new renal transplantation recipients and donors; in 2008 it was more than 81.9% of all past renal transplantation recipients in Japan.

Low survival rate of renal transplant recipients from unrelated living donors with renal diseases.

In three hospitals within a restricted area in Japan in November, 2006, 42 patients were revealed to have received kidneys transplanted from unrelated living donors who displayed renal diseases. All of these cases were performed by one doctor without any ethical discussion in the hospitals nor any reports to the public. Almost all medical records were discarded legally in two hospitals. Only one hospital, Uwajima City Hospital, kept the almost complete records including the survivals of 25 cases. The Japan Society for Transplantation was asked to analyze these cases leading to this report on the long-term outcome of cases at Uwajima City Hospital. The diseased kidney grafts were procured in four hospitals. The cases of removal of the kidneys from the donors were malignant diseases (n = 11) or benign diseases (n = 14). The survival rates of the donors were 86.1% at 1, 70.8% at 5, and 57.7% at 10 years. The survival rates of the recipients transplanted from donors with malignant versus benign diseases were 80.8% versus 92.3% in 1, 48.5% versus 84.6% at 5% and 48.5% versus 76.2% at 10 years, respectively. The survival rates of the grafts from donors with malignant versus benign diseases were 71.6% versus 71.4% at 1, 15.3% versus 50.0% at 5, and 15.3% versus 33.3% at 10 years, respectively. In conclusion, we have reported herein the low survival rates of renal transplantation recipients and grafts from unrelated living donors with preexistent renal diseases.

Toxicological evaluation of L-proline in a 90-day feeding study with Fischer 344 rats.

L-proline (L-Pro) is a non-essential amino acid, and has become widely used as supplements and health foods, recently. A subchronic oral toxicity study of L-Pro was conducted with groups of 10 male and 10 female Fischer 344 rats fed a powder diet containing 0%, 0.625%, 1.25%, 2.5% and 5.0% of L-Pro for 90 days. No treatment-related clinical signs and mortality were noted. We observed no clear treatment-related effects with regard to body weight, food intake or urinalysis data. The average daily water intakes of the treated female groups were significantly increased compared to the controls. The hematology (red blood cell parameter) and serum biochemistry (glucose, blood urea nitrogen, creatinine or uric acid) of the treated male and/or female groups were lower than those of the control groups. However, these changes were lacked dose-dependence, and no abnormalities were found in corresponding pathological findings. In conclusion, the no-observed-adverse-effect-level (NOAEL) for L-Pro was determined to be a dietary dose of 5.0% (2772.9 mg/kg body weight/day for males and 3009.3mg/kg body weight/day for females) under the present experimental conditions.

National survey of laparoscopic live donor nephrectomy in Japan from 2002 to 2008.

Laparoscopic nephrectomy (LN) has been accepted for live donor kidney transplantation. Continuous surveys on the status of LN in live donors were made from 2002 to 2008 in Japan. At first, we reported the status in 2008 at 148 Japanese kidney transplantation centers. Of 148 centers, 109 responded, and 58 performed LN. These centers performed 764 live donor nephrectomies, including 659 LN and 105 open nephrectomies. In 58 centers, 20 were performed as hand-assisted (HA) LN, 27 as non-HA (pure laparoscopic), 2 as both HA and non-HA, and 8 as laparoscope-assisted. There were 24 centers that carried out a peritoneal approach and 34 had a retro-peritoneal approach. Among 764 LN donors, not 1 had a life-threatening complication. Blood transfusions were performed in only 1 donor. Open conversions from LN were required in 13 (2.0%) cases. Minor complications not requiring a prolonged hospital stay were reported in 20 cases. The mortality after LN was 0. Among 659 recipients, 1 case was reported as primary nonfunction, but ten recipients (1.5%) needed hemodialysis after transplantation because of delayed graft function. Urinary tract complications were noted in 18 recipients (2.7%). We have discussed the trends in LN from 2002 to 2008 in Japan. At the beginning of LN, many surgeons performed LN, so the open conversion rate was low and the blood transfusion rate was high. But in the later years, surgeons performed LN in the same manner as general laparoscopic surgeries with high intention for donor safety.

Outcome of laparoscopic living donor nephrectomy in 2007: national survey of transplantation centers in Japan.

Laparoscopic nephrectomy (LN) has been accepted for a donor in living donor kidney transplantation. However, the current status of LN in living donors is not yet clarified in Japan. In this study, we surveyed 138 Japanese kidney transplantation centers to investigate the outcomes of living donor LN in 2007. Of 138 centers, 107 responded, and 48 performed LN. These centers performed 840 living donor nephrectomies, including 623 LN and 217 open nephrectomies. Among 47 centers, 23 performed hand-assisted (HA) LN, 18 non-HA (pure laparoscopic), 3 both HA and non-HA, and 3 laparoscope-assisted. Seventeen centers utilized a peritoneal approach, 26 a retroperitoneal approach, and 4 both approaches. Among 623 LN donors, the 2 who had the life-threatening complications of bleeding and intestinal injury both survived. Blood transfusions were performed in 5 donors (0.8%). There were 8 (1.3%) open conversions from LN. Minor complications not requiring a longer hospital stay were reported in 10. There was no donor mortality after LN. However, among the recipients, there was 1 case of primary nonfunction. Thirteen recipients (2.0%) required hemodialysis after transplantation because of delayed graft function. Urinary tract complications were noted in 13 recipients (2.0%). This survey presented the current status of this procedure among donors who provided informed consent.

Effect of glutathione on the development of rat embryos following microinsemination.

PURPOSE: The present study was carried out to evaluate the role of glutathione on rat embryo developmental potential after ICSI. We observed the effects of glutathione on the development of non-treated rat embryos, ICSI embryos and embryos with sham injection treatment. The development of glutathione-microinjected embryos was also observed. METHODS: Oocytes and fertilized embryos were obtained from superovulated Wistar-Imamichi rats and cultured in mR1ECM medium. Oocytes and embryos were then allowed to develop to assess the effect of glutathione on the development rate in intact embryos, micro-injected embryos and ICSI embryos. RESULTS: (1) In the intact embryo, the proportion of blastocyst stage development increased when 0.01 mM GSH was added to the medium compared to the control. (2) Microinjection of glutathione (GSSG, GSH) into the embryo increased development at each stage, and the addition of 0.2 nM GSSG or GSH significantly increased blastocyst development, in comparison to that of the control (P < 0.05). (3) Compared to the control, all the GSSG and GSH concentrations improved damaged blastocyst development, where 0.01 mM GSH improved significantly (P < 0.05). (4) The addition of glutathione in the medium increased the rate of blastocyst development after ICSI. A significantly higher number of TE and total cells were obtained in the micro-injected embryo with both of the 0.02 mM GSSG and GSH treatments (P < 0.05). CONCLUSIONS: The addition of glutathione into the culture media can improve early embryo development and is capable of repairing the damage of ICSI rat embryos.

Outcome of laparoscopic living donor nephrectomy: current status and trends in Japan.

Laparoscopic nephrectomy (LN) has been accepted for donors in living donor kidney transplantation. But the current status of LN in living donors is not clarified yet in Japan. In this study, we surveyed 124 Japanese kidney transplantation centers to investigate the outcomes of living donor LN in 2006. Of 124 centers, 100 responded, and 52 performed LN. These centers performed 831 living donor nephrectomies, including 589 LN, and 242 open procedures. In 52 centers, 20 were performed as hand-assisted (HA) LNs, 23 non-HA (pure laparoscopic), five both HA and non-HA, and four laparoscope-assisted. Eighteen centers used a peritoneal approach, 31 used a retroperitoneal approach and three, both. Among 589 LN donors, three experienced life-threatening complications of bleedings and intestinal injury, but all of them survived. Blood transfusions were performed in nine donors (1.5%), and open conversions of LN in 33 (5.6%). Minor complications not requiring a long hospital stay were reported in 45. The mortality of LN was 0. Among the 589 recipients, there was one case of primary nonfunction after venous injury at the operation. Twenty eight recipients (4.8%) needed hemodialysis after transplantation because of delayed graft function. Urinary tract complications were noted in 11 recipients (2.5%). This survey presented the current status of LN in Japan.

Toxic effects of l-aspartic acid at high dose levels on kidneys and salivary glands in Fischer 344 rats detected in a 90-day feeding study.

A subchronic oral toxicity study of l-aspartic acid (l-Asp) was conducted with groups of 10 male and 10 female Fischer 344 rats fed a powder diet containing 0%, 0.05%, 1.25%, 2.5% and 5.0% concentrations for 90 days. Serum biochemistry showed treatment-related decreases of blood urea nitrogen, creatinine and uric acid levels in both sexes. In addition, incidences of urinary ketone and protein were significantly increased in treated both sexes, while relative kidney weight was significantly increased in the 5.0% male rat, and regenerative renal tubules with tubular dilation were histopathologically observed in male rats of the 2.5% or greater groups. The observed renal injury was confirmed not to be due to accumulation of alpha2u-globulin. Acinar cell hypertrophy of salivary glands was histopathologically evident in male and female rats of the 2.5% or greater groups. The present results indicate that l-Asp causes toxic effects on kidneys and possibly salivary glands at high dose levels in male and female Fischer 344 rats. Such toxic effects were observed only in animals given 2.5% and/or higher doses of l-Asp. In conclusion, the no-observed-adverse-effect-level (NOAEL) for l-Asp is 1.25% (696.6 mg/kg body weight/day for males and 715.2 mg/kg body weight/day for females) under the present experimental conditions.

Establishment of an animal model with side effects induced by mycophenolate mofetil and pharmacohistological analysis of them.

UNLABELLED: Mycophenolate mofetil (MMF) is used for immunosuppression after organ transplantation, but gastrointestinal side effects including diarrhea are sometimes observed with this drug. We sought to construct on animal model of diarrhea with MMF in rodents. MATERIALS AND METHODS: BALB/Cj mice, weighing 25 g received 500 mg /kg of MMF, 60 mg/kg of levofloxacin (LVFX), 1000 mg/kg of Hangeshashin-to (HST), which is traditional Kampo medicine. This cocktail was administered orally to MMF, LVFX, HST, MMF+LVFX, and MMF+LVFX+HST groups for 21 days. We measured the water content fecal collected on days 1, 4, 8, 11, 14, 18, and 21. Feces on day 21 were cultured for identification of fecal flora. Mice were sacrificed on day 21, with blood samples collected to measure mycophenolic acid (MPA) concentrations by HPLC. Jejunum, cecum, and colon were taken for histological evaluation. RESULTS: Significant weight loss of mice and increased fecal water content of were observed in MMF and MMF+LVFX but not in MMF+LVFX+HST groups. Serum MPA levels didn't differ in MMF-administered groups. Inflammatory changes in intestinal villi were observed in the cecum in MMF and MMF+LVFX groups. A change in fecal flora was observed in LVFX-administered groups. CONCLUSION: Diarrhea induced by MMF in a rodent model produced inflammatory changes in the cecum. LVFX seemed to change the activity of beta-glucuronidase in the fecal flora. HST suppressed fecal softening induced by MMF in this animal model.

Outcome of laparoscopic live donor nephrectomy in 2005: National survey of Japanese transplantation centers.

The increased acceptance of laparoscopic nephrectomy (LN) has been a driving force for live donor kidney transplantation. However, the outcomes of LN in live donors has not yet been clarified in Japan. In this study, we surveyed 125 Japanese kidney transplantation centers to investigate the current status of live donor LN. Of 125 centers, the 98 that responded had performed 695 live donor nephrectomies. Among these centers, 43 had performed LN. Among the 695 nephrectomies, 441 donors had undergone LN and 254, open nephrectomies. In 43 centers, 16 were performed as hand-assisted (HA) LN; 20, non-HA; 3, both HA and non-HA; and 5 laparoscope-assisted. Ten centers used a peritoneal approach; 30, a retroperitoneal; and 3, both. In 441 LN donors, 1 had a life-threatening complication of deep venous thrombosis and survived. Blood transfusions were performed in 7 donors. Open conversions from LN were necessary in 24. Minor complications not requiring prolonged hospital stay were reported in 52. The mortality of LN was zero. In contrast, among the 441 recipients, 1 case was reported as primary nonfunction after venous misadventure in the operation and 30 recipients needed hemodialysis after transplantation because of delayed graft function. Urinary tract complications were noted in 11 recipients. This survey presented the current status of the procedure, providing a base for informed consent from potential donors.

Effects of tetrabromobisphenol A, brominated flame retardant, in ICR mice after prenatal and postnatal exposure.

Tetrabromobisphenol A (TBBPA), brominated flame retardant, is produced in the largest amounts globally for use in plastics or building materials. TBBPA has been detected in sediment, air at the dismantling plant or human serum samples. In the present study, we examined the effects of prenatal and postnatal exposure to TBBPA in mice. TBBPA (99.1% pure) in diet was administered to pregnant ICR mice at doses of 0% (control), 0.01%, 0.1% or 1.0% from gestational day 0 to weaning at postnatal day 27. The average daily food intake and body weight of dams showed no significant differences between the control and treated groups. There were no dose-related effects on reproductive data. Serum concentrations of total-cholesterol and liver weights of treated dams and offspring were higher than those of the control mice. Histological findings in treated dams or offspring showed the increase of focal necrosis of hepatocytes and inflammatory cell infiltration in the liver, and increase of dilation or atrophy of renal tubules and cyst in the kidney. TBBPA was developed as a new, safe class of flame retardant and was not highly toxic. However, the present data suggested that TBBPA caused a lipid metabolic disorder and hepatic or kidney lesion, under these conditions.

Backtransplantation for survival of the graft.

To assess survival of grafts after uncontrollable rejection, one performs backtransplantation from the recipient to the donor. This study investigated backtransplantation in an animal model. Hearts were transplanted heterotopically in rats. After a few days, the transplanted heart grafts were harvested from the recipients and backtransplanted to the donor strain heterotopically and a drug was administered. Cardiac grafts survived 6.2 days in the first recipients. After backtransplantation on day 5 or 6, all backtransplanted grafts survived well in the second recipients. After backtransplantation on day 7, when 4 of 5 grafts had no beat, 2 of 5 grafts recovered beating on day 3 after backtransplantation without any drug treatment. After backtransplantation on day 7, when 4 of 5 grafts had no beat, all (5 of 5 grafts) recovered beating well with the administration of FTY720 on day 3 after backtransplantation. CsA or FK506 had no effect on survival after backtransplantation. Pathological findings revealed mild cellular infiltration in the cases of FTY720 and severe necrosis in the cases of no drug, CsA, or FK506. After backtransplantation on day 8, no grafts (0 of 5 grafts in each drug) recovered beating with any drugs. These data document the possibility of backtransplantation.

Chronic toxicity of thiabendazole (TBZ) in CD-1 mice.

Male and female CD-1 mice (50 mice per group) were administered thiabendazole (TBZ) in diet at levels of 0 (control), 0.031, 0.125 and 0.5% for 78 weeks. A life time study was terminated after 78 weeks due to enhanced strain specific mortality. There were no significant differences in mortality between the control and treated groups. Mean body weights of high-dose groups showed significant decreases compared with the controls. The bladder weights of male and female mice of the 0.5% group were significantly higher than those of the control mice. Gross findings in treated mice included the renal atrophy, hydronephrosis, calculi in renal pelvis and/or bladder and ovarian atrophy. Microscopic findings in the kidneys of treated mice included the nephrosis, hydronephrosis or hyperplasia of transitional epithelium of renal pelvis or papilla. In the bladder of treated mice, hyperplasia or squamous metaplasia of transitional epithelium and one transitional cell papilloma were observed. Dose-dependent decreases in the incidence of spontaneous lesion in the male or female reproductive system were recognized. It is concluded that TBZ is not carcinogenic to CD-1 mice of both sexes. However, caution should be exercised in the long-term application of high TBZ doses.