Influence of seasonal variations on physical activity in older people living in mountainous agricultural areas.

Objectives: Increasing activity levels in older people is important for maintaining quality of life and ameliorating the risks of morbidity related to falls, depression, and dementia. This study aimed to clarify the seasonal variation effects on total energy expenditure, number of steps, time spent in low- and moderate- or high-intensity physical activities, and daily activities performed. Patients and Methods: This was a cross-sectional study of 22 community-dwelling older individuals (3 men, 19 women; mean age, 75.1 ± 7.3 years) living in three districts of Gero, Gifu, who participated in the Gero Salon Project hosted by the Social Welfare Councils. Evaluations were conducted in each season from September 2016 to August 2017. We used a uniaxial accelerometer, the Lifecorder device, which measures physical activity, and the Physical Activity Scale for the Elderly to evaluate activities of daily living. Data were analyzed using the multiple comparisons (Bonferroni correction) method. Results: Total energy expenditure and time spent in moderate- or high-intensity activities did not show seasonal variations. However, the lowest number of steps was taken during the winter, and the number of steps increased significantly from winter to spring. The time spent in low-intensity physical activities was significantly longer in the spring and summer than in the winter. There was no significant seasonal difference in total Physical Activity Scale for the Elderly score, leisure activities, domestic activities, or work-related activities. However, there was a significant difference between the summer and winter scores in "outdoor gardening," with the lowest score observed during the winter. Conclusions: With climate changes in the winter months, "outdoor gardening" becomes difficult, thus decreasing the number of steps taken. Therefore, it is necessary to identify other ways for older people to maintain physical activity during the winter season.

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J-SSCG 2016).

BACKGROUND AND PURPOSE: The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J-SSCG 2016), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in February 2017 and published in the Journal of JSICM, [2017; Volume 24 (supplement 2)] 10.3918/jsicm.24S0001 and Journal of Japanese Association for Acute Medicine [2017; Volume 28, (supplement 1)] http://onlinelibrary.wiley.com/doi/10.1002/jja2.2017.28.issue-S1/issuetoc.This abridged English edition of the J-SSCG 2016 was produced with permission from the Japanese Association of Acute Medicine and the Japanese Society for Intensive Care Medicine. METHODS: Members of the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine were selected and organized into 19 committee members and 52 working group members. The guidelines were prepared in accordance with the Medical Information Network Distribution Service (Minds) creation procedures. The Academic Guidelines Promotion Team was organized to oversee and provide academic support to the respective activities allocated to each Guideline Creation Team. To improve quality assurance and workflow transparency, a mutual peer review system was established, and discussions within each team were open to the public. Public comments were collected once after the initial formulation of a clinical question (CQ) and twice during the review of the final draft. Recommendations were determined to have been adopted after obtaining support from a two-thirds (> 66.6%) majority vote of each of the 19 committee members. RESULTS: A total of 87 CQs were selected among 19 clinical areas, including pediatric topics and several other important areas not covered in the first edition of the Japanese guidelines (J-SSCG 2012). The approval rate obtained through committee voting, in addition to ratings of the strengths of the recommendation, and its supporting evidence were also added to each recommendation statement. We conducted meta-analyses for 29 CQs. Thirty-seven CQs contained recommendations in the form of an expert consensus due to insufficient evidence. No recommendations were provided for five CQs. CONCLUSIONS: Based on the evidence gathered, we were able to formulate Japanese-specific clinical practice guidelines that are tailored to the Japanese context in a highly transparent manner. These guidelines can easily be used not only by specialists, but also by non-specialists, general clinicians, nurses, pharmacists, clinical engineers, and other healthcare professionals.

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J-SSCG 2016).

Background and Purpose: The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J-SSCG 2016), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in February 2017 in Japanese. An English-language version of these guidelines was created based on the contents of the original Japanese-language version. Methods: Members of the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine were selected and organized into 19 committee members and 52 working group members. The guidelines were prepared in accordance with the Medical Information Network Distribution Service (Minds) creation procedures. The Academic Guidelines Promotion Team was organized to oversee and provide academic support to the respective activities allocated to each Guideline Creation Team. To improve quality assurance and workflow transparency, a mutual peer review system was established, and discussions within each team were open to the public. Public comments were collected once after the initial formulation of a clinical question (CQ), and twice during the review of the final draft. Recommendations were determined to have been adopted after obtaining support from a two-thirds (>66.6%) majority vote of each of the 19 committee members. Results: A total of 87 CQs were selected among 19 clinical areas, including pediatric topics and several other important areas not covered in the first edition of the Japanese guidelines (J-SSCG 2012). The approval rate obtained through committee voting, in addition to ratings of the strengths of the recommendation and its supporting evidence were also added to each recommendation statement. We conducted meta-analyses for 29 CQs. Thirty seven CQs contained recommendations in the form of an expert consensus due to insufficient evidence. No recommendations were provided for 5 CQs. Conclusions: Based on the evidence gathered, we were able to formulate Japanese-specific clinical practice guidelines that are tailored to the Japanese context in a highly transparent manner. These guidelines can easily be used not only by specialists, but also by non-specialists, general clinicians, nurses, pharmacists, clinical engineers, and other healthcare professionals.

Combined repeated-dose and reproductive/developmental toxicity screening test of benzene, 1,1'-oxybis-, tetrapropylene derivs. in rats.

We have conducted animal toxicity tests of chemicals for a chemical safety program implemented by the Ministry of Economy, Trade and Industry of Japan. Here we conducted a combined repeated-dose and reproductive/developmental toxicity screening test of benzene, 1,1'-oxybis-, tetrapropylene derivs. (BOTD). BOTD was administered to 9-week-old Crl:CD(SD) male and female rats by gavage at 0, 40, 200, or 1000 mg/kg/day. Males were treated for 42 days including mating period. Females were treated for 42-53 days through the premating, mating, pregnancy, and until Day 4 of lactation periods. Increases in prothrombin time and activated partial thromboplastin time values were observed only in males at 200 and 1000 mg/kg/day. Hypertrophy of centrilobular hepatocytes was observed with increased liver weight in both sexes at 200 and 1000 mg/kg/day, but there was no histologic evidence of hepatotoxicity. Diffuse hypertrophy of follicular cells in thyroid glands was observed in females at 200 mg/kg/day and in both sexes at 1000 mg/kg/day, with an increased blood cholesterol level in females at 1000 mg/kg/day. The conception index was decreased for females at 1000 mg/kg/day; and no abnormalities were detected in the reproductive indices of implantation, delivery, or pups' condition, although a slight increase in the pups' body weight was noted at birth. Our data indicate a no-observed-adverse-effect level of 40 mg/kg/day for repeated-dose toxicity on the basis of the prolongation of blood coagulating time, and of 200 mg/kg/day for reproductive/developmental toxicity on the basis of the decreased conception index.

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J-SSCG 2016)

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (JSSCG 2016), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in February 2017 in Japanese. An English-language version of these guidelines was created based on the contents of the original Japanese-language version. Members of the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine were selected and organized into 19 committee members and 52 working group members. The guidelines were prepared in accordance with the Medical Information Network Distribution Service (Minds) creation procedures. The Academic Guidelines Promotion Team was organized to oversee and provide academic support to the respective activities allocated to each Guideline Creation Team. To improve quality assurance and workflow transparency, a mutual peer review system was established, and discussions within eachteam were open to the public. Public comments were collected once after the initial formulation of a clinical question (CQ), and twice during the review of the final draft. Recommendations were determined to have been adopted after obtaining support from a twothirds (>66.6%) majority vote of each of the 19 committee members. A total of 87 CQs were selected among 19 clinical areas, including pediatric topics and several other important areas not covered in the first edition of the Japanese guidelines (J-SSCG 2012). The approval rate obtained through committee voting, in additionto ratings of the strengths of the recommendation and its supporting evidence were also added to each recommendation statement.We conducted meta-analyses for 29 CQs. Thirty seven CQs contained recommendations in the form of an expert consensus due to insufficient evidence. No recommendations were provided for 5 CQs.Based on the evidence gathered, we were able to formulate Japanese-specific clinical practice guidelines that are tailored to the Japanese context in a highly transparent manner. These guidelines can easily be used not only by specialists, but also by non-specialists, general clinicians, nurses, pharmacists, clinical engineers, and other healthcare professionals.

Bronchial damage and diffuse alveolar hemorrhage following chlorine gas inhalation: A case report.

Chlorine is a toxic inhalant and sources of exposure for individuals include accidental releases of chlorine vapor due to industrial or chemical transportation accidents. Inhalation of a large quantity of gas may cause circulatory and respiratory disorders or even mortality; however, the effects of a small amount of chlorine gas may be asymptomatic. The present case study presents a successfully treated 55-year-old male patient exposed to chlorine gas, resulting in bronchial damage and diffuse alveolar hemorrhage. Endobronchial and alveolar injuries were evaluated by direct observation using fiberoptic bronchoscopy (FB) and analyzing bronchoalveolar lavage fluid obtained by FB. Taking a precise medical history from the patient is crucial to correctly diagnose toxic gas inhalation. In addition, a timely and proper evaluation with chest imaging as well as FB may provide useful clinical information. Therefore, clinicians should consider performing FB if the circumstances permit.

Consideration of pain felt by patients in the ICU.

Patients in the ICU are often treated under extreme conditions, with the patient often fearful of losing his life or experiencing severe pain. As a result, high-quality pain management is required. However, response to pain is often inadequate due to continuous administration of sedatives, difficulties in communicating with intubated patients, and/or poor awareness of pain in patients not receiving surgery. Reports on difficulties in pain management in the ICU are many, but few consider the correlation between pain management and patient prognosis. Consequently, consideration on how to implement pain control activities in the ICU to improve patient prognosis is needed.

Combined repeated-dose and reproductive/developmental toxicity screening test of 1-tert-butoxy-4-chlorobenzene in rats.

We have carried out animal toxicity tests of chemicals for a chemical safety program implemented by the Ministry of Economy, Trade, and Industry of Japan. Here, we tested 1-tert-butoxy-4-chlorobenzene in a combined repeat-dose and developmental and reproductive toxicity test. The test chemical was administered daily by gavage to 9-week-old Crl:CD (SD) rats at doses of 0, 20, 100, and 500 mg/kg/d. Males were treated for 42 d beginning 14 d before mating. Females were treated from 14 d before mating to day 4 of lactation. Decreased spontaneous locomotion, decreased respiratory rate, and incomplete eyelid opening were observed at 500 mg/kg/d (both sexes), but resolved within 30 min of administration, suggesting central nervous system depression. No notable changes were observed in body weight, food consumption, functional battery tests, or blood test. Increased liver weight with centrilobular or diffuse hepatocyte hypertrophy was observed at 100 and 500 mg/kg/d (both sexes). There were no biochemical or histopathological changes related to hepatotoxicity. Increased kidney weight with basophilic tubules, tubule dilatation, and increased hyaline droplets were observed in males dosed at 100 and 500 mg/kg/d. Immunohistochemical staining indicated α2u-globulin nephropathy, a male rat-specific toxicity. Although kidney weight was also increased in females dosed at 500 mg/kg/d, it was not considered to be an adverse effect because there were no histopathological changes. Pup weights on postnatal day 0 were decreased at 500 mg/kg/d and still decreased on postnatal day 4. Our data indicated the no-observed-adverse-effect-level for repeated-dose and reproductive/developmental toxicity for 1-tert-butoxy-4-chlorobenzene was 100 mg/kg/d.

A possible role for HLA-DRB1*04:06 in statin-related myopathy in Japanese patients.

Statin-related myopathy (SRM) is a clinically important adverse reaction. Recent pharmacogenetic research, mainly in non-Asian populations, have indicated clinical relevance of some of genetic biomarkers to SRM, but predictive markers for SRM in Asian populations including Japanese has not yet been established. This study was aimed to identify clinically important genetic markers associated with SRM in Japanese patients. Allele frequencies of the three reported candidate markers - SLCO1B1 rs4149056, RYR2 rs2819742, and GATM rs9806699 - and carrier frequencies of HLA types were compared between patients with SRM patients (n = 52) and healthy Japanese subjects (n = 2878 or 86 (for rs9806699) as controls). No significant association of RYR2, SLCO1B1, and GATM variants with SRM were observed in our Japanese patients, but a significant association was detected for HLA-DRB1*04:06 with SRM (odds ratio: 3.19; 95% confidence interval: 1.53-6.66). This study suggested that HLA-DRB1*04:06 might be associated with SRM onset in a Japanese population. Further studies are required to validate these results.

Tetanus in the Elderly: The Management of Intensive Care and Prolonged Hospitalization.

Tetanus is a potentially fatal infection. Approximately 100 cases are reported in Japan each year; however, little is known about its clinical course and outcomes in the current era of treatment. We herein report three cases of tetanus in elderly patients who survived after mechanical ventilation and intensive care. These patients, together with six other similar cases, had a median weaning period of 31 days and median length of stay of 77 days. In elderly patients, severe systemic forms of tetanus require prolonged mechanical ventilation and hospitalization. To improve prevention, tetanus vaccination should be promoted more aggressively among those who are susceptible to the disease.

Acute respiratory distress syndrome due to severe pulmonary tuberculosis treated with extracorporeal membrane oxygenation: A case report and review of the literature.

Mortality in patients with pulmonary tuberculosis remains high, especially in those who develop acute respiratory distress syndrome (ARDS). We report on a-48-year-old man with ARDS due to severe pulmonary tuberculosis who was rescued by extracorporeal membrane oxygenation (ECMO). He was initially hospitalized in the intensive care unit and noninvasive positive-pressure ventilation started. He was also administered anti-tuberculosis drugs and received systemic corticosteroid therapy. Six days later, further deterioration of gas exchange prompted the decision to intubate. However, he experienced progressive deterioration of arterial oxygenation despite conventional ventilatory support. We therefore decided to administer ECMO on day 9. After initiation of these treatments and ECMO support, pulmonary infiltrate and oxygenation status gradually improved and ECMO was discontinued on day 52. The patient was finally discharged from our hospital without severe disability. ECMO should be considered one of the treatment options for the management of ARDS due to severe pulmonary tuberculosis.

Combined repeated dose and reproductive/developmental toxicity screening test of 4-methoxy-2-nitroaniline in rats.

4-Methoxy-2-nitroaniline (4M2NA) is widely used as an intermediate for the synthesis of dyes, pigments and other chemical compounds. Since 4M2NA has amino-group and nitro-group on the benzene ring, it was expected that it induced obvious hemolytic anemia. We conducted a combined repeated dose and reproductive/developmental toxicity screening test according to Organisation for Economic Co-operation and Development (OECD) Test Guideline No. 422 (OECD TG 422) to enrich the toxic information and ensure the safety of 4M2NA. 4M2NA was administered to Crl:CD(SD) male and female rats by gavage at 0, 12.5, 75 or 450 mg/kg/day for 42 to maximum of 54 days through pre-mating, mating, pregnancy and lactation periods. An extramedullary hematopoiesis and congestion in spleen, and higher reticulocyte ratio were noted in only females at 450 mg/kg/day without decreased anemic parameters in the hematological examination. Hypertrophy of centrilobular hepatocytes in both sexes was observed with increased relative liver weight at 450 mg/kg/day. Furthermore, the diffuse follicular cell hypertrophy of the thyroid was observed in females at 450 mg/kg/day. No abnormalities were detected in the reproductive indices of copulation, delivery or fetal viability. We concluded the no-observed-adverse-effect level (NOAEL) for repeated-dose toxicity was 75 mg/kg/day based on the trace evidences of hemolytic anemia, and the NOAEL for reproductive/developmental toxicity as 450 mg/kg/day based on no toxicological concerns for reproductive endpoints. The hemolytic anemia was much milder than expected. Thus, we discussed the reason of this much less hemolytic effect from the point of view of the structural characteristics of 4M2NA.

Development of a category approach to predict the testicular toxicity of chemical substances structurally related to ethylene glycol methyl ether.

We propose a category approach to assessing the testicular toxicity of chemicals with a similar structure to ethylene glycol methyl ether (EGME). Based on toxicity information for EGME and related chemicals and accompanied by adverse outcome pathway information on the testicular toxicity of EGME, this category was defined as chemicals that are metabolized to methoxy- or ethoxyacetic acid, a substance responsible for testicular toxicity. A Japanese chemical inventory was screened using the Hazard Evaluation Support System, which we have developed to support a category approach for predicting the repeated-dose toxicity of chemical substances. Quantitative metabolic information on the related chemicals was then considered, and seventeen chemicals were finally obtained from the inventory as a shortlist for the category. Available data in the literature shows that chemicals for which information is available on the metabolic formation of EGME, ethylene glycol ethyl ether, methoxy- or ethoxyacetic acid do in fact possess testicular toxicity, suggesting that testicular toxicity is a concern, due to metabolic activation, for the remaining chemicals. Our results clearly demonstrate practical utility of AOP-based category approach for predicting repeated-dose toxicity of chemicals.

Effects of periodic task-specific test feedback on physical performance in older adults undertaking band-based resistance exercise.

The purpose of this study was to determine the effects of periodic task-specific test feedback on performance improvement in older adults undertaking community- and home-based resistance exercises (CHBRE). Fifty-two older adults (65-83 years) were assigned to a muscular perfsormance feedback group (MPG, n = 32) or a functional mobility feedback group (FMG, n = 20). Both groups received exactly the same 9-week CHBRE program comprising one community-based and two home-based sessions per week. Muscle performance included arm curls and chair stands in 30 seconds, while functional mobility was determined by the timed up and go (TUG) test. MPG received fortnightly test feedback only on muscle performance and FMG received feedback only on the TUG. Following training, there was a significant (P < 0.05) interaction for all performance tests with MPG improving more for the arm curls (MPG 31.4%, FMG 15.9%) and chair stands (MPG 33.7%, FMG 24.9%) while FMG improved more for the TUG (MPG-3.5%, FMG-9.7%). Results from this nonrandomized study suggest that periodic test feedback during resistance training may enhance task-specific physical performance in older persons, thereby augmenting reserve capacity or potentially reducing the time required to recover functional abilities.

Specific HLA types are associated with antiepileptic drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Japanese subjects.

AIM: This preliminary study investigated genomic biomarkers for Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), related to three antiepileptic drugs, zonisamide, phenobarbital and phenytoin. PATIENTS & METHODS: HLA class I and HLA-DRB1 loci were genotyped for Japanese patients with zonisamide-, phenobarbital- or phenytoin-induced SJS/TEN (n = 12, 8 and 9, respectively) and for healthy Japanese volunteers (n = 2878). RESULTS: Carrier frequencies of HLA-A*02:07 in patients with zonisamide-induced SJS/TEN and in the general Japanese population were 41.7 and 6.81%, respectively. Carrier frequencies of HLA-B*51:01 in patients with phenobarbital- and phenytoin-induced SJS/TEN and in controls were 75.0, 55.6 and 15.2%, respectively. HLA-A*02:07 and HLA-B*51:01, in a dominant model, were significantly associated with zonisamide- and phenobarbital-induced SJS/TEN, respectively (Pc = 0.0176 and 0.0042, respectively). CONCLUSION: Our data suggest that HLA-A*02:07 and HLA-B*51:01 are potential biomarkers for zonisamide- and phenobarbital-induced SJS/TEN, respectively, in Japanese individuals.

Combined repeated-dose and reproductive/developmental toxicity screening test of 3-amino-5-mercapto-1,2,4-triazole in rats.

The substance 3-amino-5-mercapto-1,2,4-triazole (AMT, CAS No. 16691-43-3) was daily administered by gavage to Crl:CD (SD)IGS rats at doses of 0 (control), 10, 50, and 250 mg/kg bw/day. Males (12/group) were treated for a total of 42 days beginning 14 days before mating. Females (12/group) were treated beginning 14 days before mating to day 4 of lactation throughout the mating and gestation periods. No deaths occurred in males but three females died on day 23 of gestation at 250 mg/kg/day. Only temporary decreases in body weight and food intake were found in both sexes at 250 mg/kg/day. There were no considerable changes in general appearance, the functional battery tests, biochemical analysis or urinalysis. Anemia was observed in both sexes at 250 mg/kg/day. The relative weight of thyroid glands was significantly increased in both sexes at 250 mg/kg/day and hypertrophy of thyroid follicular cells was observed in 50 and 250 mg/kg/day males and 250 mg/kg/day females. As this effect on thyroid glands was considered to be the major toxicity, the possible mechanism was discussed comparing with the toxicity of structural similar analogs. Other histopathological changes in males were hypertrophy of centrilobular hepatocytes at 250 mg/kg/day, and anterior pituitary glands at 50 mg/kg/day and more. Vacuolization in renal tubular epithelium of females was observed at 50 and 250 mg/kg/day. For reproduction, the gestation period was prolonged and the delivery index was decreased at 250 mg/kg/day. The number of pups born and the birth index were also reduced. It was thus concluded that the NOAEL for repeated-dose toxicity was 10 mg/kg/day based on the thyrotoxicity and renal toxicity, and that the NOAEL for reproductive/developmental toxicity was 50 mg/kg/day based on the reduced number of offspring, etc.

Combined repeated dose and reproductive/developmental toxicity screening test of tert-butylhydrazine monohydrochloride in rats.

tert-Butylhydrazine monohydrochloride was daily administered by gavage to groups of Crl:CD (SD)IGS rats at doses of 0 (control), 0.8, 4, or 20 mg/kg/day. Twelve males per group were treated for a total of 42 days from 14 days before mating. Twelve females per group were treated from 14 days before mating to day 4 of lactation throughout the mating and gestation periods. Recovery groups of five males and five non-pregnant females per group were dosed for 42 days followed by a 14-day recovery period. No deaths were observed in any groups of either sex. There were no considerable changes in body weight, food intake, general appearance, functional observations or biochemical analysis. Values of the anemic parameters were decreased in the 20 mg/kg/day males and in all female dose groups. The relative weight of the liver, kidneys and spleen was significantly increased in 20 mg/kg/day females. Histopathological examination showed congestion and hemosiderin deposition in the spleen at 20 mg/kg/day in both sexes, but there were no changes in the liver or kidneys in either sex. Anemic parameters with hemosiderin deposition did not completely recover in the 20 mg/kg/day group in both sexes after the recovery period. As for reproduction, a significant reduction was only observed in the number of corpora lutea at 20 mg/kg/day. It was thus concluded that the LOAEL was 0.8 mg/kg/day based on the decreased values of the anemic parameters of repeated-dose toxicity, and that the NOAEL was 4 mg/kg/day based on the low number of corpora lutea of reproductive/developmental toxicity.

New parameter that supports speculation on the possible mechanism of hypothyroidism induced by chemical substances in repeated-dose toxicity studies.

Hypothyroidism induced by xenobiotic treatment was analyzed for possible underlying mechanism(s) on the basis of different responses of the thyroid gland and the liver, using a newly-created database of repeated-dose toxicity of 500 chemicals. Two mechanisms are proposed: direct inhibition of thyroid hormone biosynthesis in the thyroid gland, and stimulated degradation of thyroid hormone by induction of hepatic drug-metabolizing enzymes. In the database there were 10 chemicals inducing hypertrophy/hyperplasia of follicular cells in the thyroid gland and having data on thyroid glands. On the basis of the chemical structure and information available in the literature, we judged three chemicals to be typical thioamide derivatives that act directly on the thyroid gland, and the others as non-thioamide derivatives that were unlikely to have any direct action on the thyroid gland. All these chemicals were classified into two groups using the ratios of relative weight increase rate of thyroid gland versus that of the liver. These values were at least 1.7, but 3.2 or more in the most of the cases for thioamide derivatives, and 1.2 or less for non-thioamide derivatives. This background analysis suggests the feasibility of parameter-supported speculation on the possible underlying mechanism when new repeated-dose toxicity data on hypothyroidism becomes available.