Re-evaluation of the reduced heart weights in male rats in a 28-day oral repeated-dose toxicity study of tetramethylammonium hydroxide.

We recently conducted a detailed hazard assessment of tetramethylammonium hydroxide (TMAH), a priority chemical substance under the Japan Chemical Substances Control Law. During this assessment, there was debate regarding the reduced heart weight observed in the treated male groups in the 28-day rat oral repeated-dose toxicity study. This finding was not observed in females in this study and in both sexes of oral toxicity studies for tetramethylammonium chloride (TMAC) or tetramethylammonium hydrogen phthalate (TMAHP). Unpublished individual data from the oral TMAH developmental and reproductive toxicity (DART) screening study were also obtained; no effect on heart weight was observed. In addition, background data on rat heart weight from six 28-day oral toxicity studies conducted in the same facility, year, strain, age, and breeder as the TMAH study were obtained from the Japan Existing Chemical Substances Database (JECDB). These investigations suggest that the statistically significant lower heart weight in the treated males in the 28-day toxicity study is likely caused by an incidental skewing of individuals with heavier heart weights toward control male groups and is not due to TMAH treatment. Thus, it is worthwhile to include as much relevant data as possible to confirm or refute unexpected findings in toxicity studies.

The acceptance of the potential use of social robots for children with autism spectrum disorder by Indonesian occupational therapists: a mixed methods study.

PURPOSE: Social robots have shown positive effects in treating children with autism spectrum disorder. The development of social robots in Indonesia has enabled their potential use in occupational therapy. This study aimed to investigate the factors influencing the acceptance of the potential use of social robots by Indonesian occupational therapists in clinical practice. METHODS: This study employed a mixed methods explanatory sequential design. An adapted unified theory of acceptance and use of technology model was utilised for the quantitative phase. The questionnaire explored the acceptance of social robots. The data were analysed using structural equation modelling. In the qualitative phase, semi-structured interviews with reflexive thematic analysis were conducted. The second phase aimed to explain the reasons behind the quantitative results and factors related to the acceptance of social robots in therapy. RESULTS: Occupational therapists showed high interest in using social robots in their sessions, as indicated by the significant positive relationship between performance expectancy and potential use. Three influential factors affecting acceptance emerged in the qualitative phase: occupational therapists' characteristics and competencies, social robots and occupational therapy interventions, and environmental influence. CONCLUSIONS: Indonesian occupational therapists have shown interest in using social robots. However, there are challenges regarding the practical application of social robots concerning individual differences in the factors that influence acceptance.

Social robots have been perceived as beneficial intervention tools for improving occupational therapists' performance with children with autism spectrum disorder.Environmental factors significantly influence the acceptance of social robots.The attitudes of occupational therapists influence their acceptance towards the potential use of social robots.

Occupation-focused wheelchair training interventions to support the activity participation of children with mobility limitations: a rapid review of literature.

New types of wheelchairs are being introduced in the market to maximize opportunities for children to participate in meaningful occupations. However, interventions to support the inclusion of children with mobility limitations by using mobility support are desirable as these children continue to experience barriers to community and school participation, happiness, and inclusion. Little is known about the training programs and interventions designed to effectively integrate wheelchair use into the occupations of children with mobility limitations. This rapid review identified 10 studies addressing programs and interventions to equip children with mobility limitations with wheelchair-related skills and competencies. Three overarching themes, including (1) technology-mediated simulation, (2) custom-made wheelchairs, and (3) skills training and exercises, based on the type of intervention were identified. The development, safety, and playfulness of children with mobility limitations are crucial factors when providing wheelchair-related interventions.

Analysis and risk assessment of vinyl chloride emitted from aerosol products.

The objectives of this study were to develop a novel analytical method for quantifying vinyl chloride (VC) emitted from aerosol products, to provide analytical data on VC in aerosol products, and to evaluate consumer VC exposure by aerosol products. Our quantitative method involves absorbing VC into dimethyl sulfoxide and analyzing it using headspace gas chromatography/mass spectrometry. The correlation coefficients of the VC calibration curves were ≥ 0.9994 in the range of 0.16-80 µg/mL VC standard gases, which were prepared under either nitrogen or emission gases containing dimethyl ether or liquid petroleum gas. VC concentrations in these emission gases were calculated using a VC calibration curve from standard gases prepared under nitrogen; they were within ± 10% of the actual concentrations. We analyzed 39 household aerosol products; VC concentrations of 0.095, 0.098, and 0.28 µg/L were detected in three polyvinyl chloride spray paints. Consumer VC inhalation exposure level was estimated through an exposure scenario, and the hazard quotient was confirmed to be very low when comparing the exposure level with a cancer risk level of 10-5 for inhaled VC. These results suggest that the human health risk from VC in spray paint was low.

Reflection on feasibility and usability of interactive online international exchange program for occupational therapy students.

The COVID-19 pandemic affected international exchange programs due to travel restrictions. There are few reports of online international exchange programs in medical area and no report of interactive activities among students together for several months. To the best of our knowledge, we needed to seek the feasible approach to conduct online exchange program. We experienced online collaboration works to promote internationalization in occupational therapy (OT) undergraduate education. The aim of this study is to examine the feasibility and usability of an interactive online international exchange program, and discuss its challenges and advantages. The three-month program was newly developed, and aimed at cultivating an international perspective, understanding OT, and learning basic research skills. Students' interests and the development of their motivation were considered in the program consisting of synchronous and asynchronous lectures, a collaboration research project, group work, and report assignments. Through the program, students were satisfied with the program contents and had the precious experience to develop international relationships. The online exchange program provided students with the opportunity to experience and learn OT education internationally at an economical cost, and to achieve program goal during the regular semester. In this program, students not only acquired knowledge in their professional field, but also cultivated their international communication skills in English from small group activities and social activities. Considering various communication methods was an important aspect in the virtual environment leading to a successful program. In medical education, an online program can be an effective and practical measure for international exchange. Supplementary Information: The online version contains supplementary material available at 10.1007/s44217-023-00031-4.

DUX4 double whammy: The transcription factor that causes a rare muscular dystrophy also kills the precursors of the human nose.

SMCHD1 mutations cause congenital arhinia (absent nose) and a muscular dystrophy called FSHD2. In FSHD2, loss of SMCHD1 repressive activity causes expression of double homeobox 4 (DUX4) in muscle tissue, where it is toxic. Studies of arhinia patients suggest a primary defect in nasal placode cells (human nose progenitors). Here, we show that upon SMCHD1 ablation, DUX4 becomes derepressed in H9 human embryonic stem cells (hESCs) as they differentiate toward a placode cell fate, triggering cell death. Arhinia and FSHD2 patient-derived induced pluripotent stem cells (iPSCs) express DUX4 when converted to placode cells and demonstrate variable degrees of cell death, suggesting an environmental disease modifier. HSV-1 may be one such modifier as herpesvirus infection amplifies DUX4 expression in SMCHD1 KO hESC and patient iPSC. These studies suggest that arhinia, like FSHD2, is due to compromised SMCHD1 repressive activity in a cell-specific context and provide evidence for an environmental modifier.

History of assistive devices and home modification services under long-term care insurance system in Japan across 20 years: A narrative review.

In this aging society, support services for older adults through the social welfare system have been introduced in many countries; in Japan, the long-term care insurance (LTCI) system was introduced in 2000. This review examined research of the past 20 years to investigate the history of assistive devices and home modification services and discussed future directions for health professionals through a narrative review. We selected 86 Japanese papers and six English papers: a total of 92 papers were analyzed by three researchers. This review revealed that assistive devices and home modification services contributed to helping users and decreased caregiver burden. Many studies have shown the importance of appropriate and sufficient cooperation among professionals. However, some issues related to LTCI were identified such as the regulation of subsidies and little flexibility considering local area conditions. The effectiveness and issues of assistive devices and home modification services were shown, and adjustments were suggested for the system and professional education according to the changes in a social situation. In addition, systematic research seems to be a small number; hence, studies with reliable research methods and analyses are needed to show the effectiveness of services and examine intervention by professionals.

Usability of Public Play Spaces for Children with Disabilities.

Purpose: To investigate the usability of public play spaces for children with disabilities by exploring their experiences in accessing and using these spaces and to further discuss recommendations for designing such spaces that are usable for these children. Methods: A hermeneutic phenomenological approach was employed to explore the experience of children with disabilities regarding the public play spaces. Seven children and their caregivers from two inclusive elementary schools in Central Java Province, Indonesia, participated in the study. Online semistructured interviews with the children were held using Zoom, followed by telephonic interviews with their parents. In addition, video recordings of the observation of the children's participation in the play spaces were gathered. The interview and video observation data were analyzed using van Manen's hermeneutic phenomenology thematic analysis method. Results: Five themes arose regarding the experiences of children with disabilities of accessing and using the public play spaces: (1) where time appeared to speed up, (2) "I like the tall one … I like extreme," (3) fostering connectedness, (4) the need for a safe space, and (5) how a play space should be. Conclusion: The public play spaces have meaningful values for the children with disabilities and their family, as they offered the opportunities to play, explore, interact with friends and families, enjoy nature, interact with animals, and learn. However, it is essential to provide a safe space in which children are free from physical and emotional harm, so that they can fully participate with confidence and a sense of autonomy. Nevertheless, it was also found that children, regardless of their abilities, craved risky and challenging play opportunities. This study also highlights the necessity of awareness-raising intervention programs to foster the inclusion of children with disabilities in public play space settings.

Factors influencing implementation of assistive technology services for older adults from the perspectives of Thai occupational therapists: a mixed methods study.

PURPOSE: Occupational therapists are crucial in providing assistive technology (AT) services for older adults. However, evidence has shown limited provision of such services in Thailand. This study aimed to investigate the factors that influence the implementation of AT services for older adults from the perspectives of Thai occupational therapists. METHODS: An explanatory sequential mixed-methods design was guided by the measurement instrument for determinants of innovations and literature review. This study was conducted in two phases: quantitative and qualitative. During the quantitative phase, an adapted version of the Measurement Instrument for Determinants of Innovations was administered to 96 occupational therapists (OTs). A subsample of 5 OTs completed a semi-structured interview during the qualitative phase to explain the findings in the quantitative one. RESULTS: Factors were categorized into three sections: personal, organizational and socio-political context levels. At the personal level, integrating knowledge and experience could contribute to awareness and professional competency. Client satisfaction influenced OTs to utilize AT, based on a client centred manner. With coordinator and performance feedback within the organization, OTs indicated that consultants supported them in their decision-making. In contrast, availability of AT for older adults is determined by time and resources. Moreover, at the socio-political context level, legislation and regulations may permit or prohibit accessibility of assistive devices. CONCLUSION: In order to address current challenges, education or training programmes are needed to increase the awareness and competence of OTs. In addition, collaboration with other professionals in community settings is necessary to improve access to AT services.IMPLICATIONS FOR REHABILITATIONAT service for older adults is limited by the availability of time and resources. To handle with these challenges, occupational therapists could advocate for village health volunteers to be a part of the AT services for older adults in the community to increase AT accessibility for older adults.Additional education or training programs should be developed to build competencies and increase occupational therapists' awareness of providing AT services to older adults, as well as to strengthen their roles in AT services.Future research and health policies should focus on access to sufficient funding, and resources for occupational therapists relative to their role in implementing AT services.

Characterization of synthetic turf rubber granule infill in Japan: Rubber additives and related compounds.

We have conducted several studies with an overall goal of assessing the effects of rubber granules in synthetic turf on the health of athletes, other players, and children in Japan. As part of these studies, the investigation reported herein was aimed at analyzing the concentrations of rubber additives (vulcanization accelerators, antioxidants, and cross-linking agents) and related chemicals in 46 rubber infills prior to their use in synthetic turf fields in Japan. Of the 36 chemicals selected for targeted analysis, 26 were detected and quantified. Nontargeted analyses further identified and quantified 16 compounds derived from vulcanization accelerators, plasticizers, and other additives. The types and concentrations of the detected compounds varied both between products and within the same product; in the case of rubber infill products made from recycled rubber, this variation was caused by the different types of rubber products recycled as raw materials. Elution tests with four simulated biofluids (gastric juice, intestinal juice, saliva, and perspiration) revealed that the elution rates varied between compounds and were affected by the presence of coatings. Most compounds had low elution rates in all the simulated biofluids, with many at or below the limit of quantification. The data reported herein will be utilized in the risk characterization part of our subsequent study on the health risk assessment of rubber infill.

Characterization of synthetic turf rubber granule infill in Japan: Polyaromatic hydrocarbons and related compounds.

Although the health effects of artificial turf fillings have been investigated in Europe and the United States, the actual situation in Japan is unclear. To address this issue, the concentrations of 46 polyaromatic hydrocarbons (PAHs) and related compounds in rubber infills were analyzed prior to their use in synthetic turf fields in Japan. Based on information obtained from the sample suppliers, the investigated samples were divided into five categories: discarded tires, industrial rubber, combinations of these products or unidentified components (mixture/unknown), synthetic rubber specifically manufactured for synthetic turf, and special-purpose thermoplastic elastomers (TPEs). The industrial rubber samples were mixtures of styrene butadiene rubber, natural rubber, and ethylene propylene diene rubber (EPDM). The synthetic rubber samples consisted only of EPDM. A few or none of the PAHs were detected in the synthetic rubber and TPE samples. However, in the discarded tire and industrial rubber samples, benzo[a]pyrene, cyclopenta[cd]pyrene, and 30 other compounds were detected. A comparison between these two categories indicated that the discarded tire samples exhibited higher concentrations of the target compounds than the industrial rubber samples. This finding can be attributed to the presence of EPDM in almost all of the industrial rubber samples, which were not present in the discarded tire samples. The maximum PAH concentrations obtained in the present study were equivalent to or lower than the previously reported PAH concentrations. The total concentrations of the eight PAHs included in the European Chemical Agency (ECHA) assessment of health risks were lower in the present study than those reported by the ECHA. Furthermore, elution testing was performed with four simulated biofluids (gastric and intestinal juices, saliva, and perspiration). The actual elution amounts of all compounds were less than the limits. This report provides basic data for the risk assessment of PAHs in rubber infills.

Characterization of synthetic turf rubber granule infill in Japan: Total content and migration of metals.

We evaluated the total content of 28 metals in synthetic turf rubber granule infill and performed extraction tests using four types of simulated biofluids to assess the health effects of synthetic turf crumb rubbers used in Japan. The highest median metal concentration was obtained for Zn, with median concentrations above 100 µg/g, followed by Al, Fe, and Mn. The highest median Pb concentration was 19.9 µg/g. The metal concentrations of the samples were different depending on the origin/material. Among high-concentration metals, Al, Fe, and Mn were higher in ethylene propylene diene monomer rubber, and Zn was higher in tires. Significantly higher Sb and Sr concentrations were observed in other materials, including industrial rubber, synthetic rubber, and thermoplastic elastomer, compared with tires. However, significantly higher Sn, Co, Pb, and Cd concentrations were detected in tires compared with other materials. Metals with high concentrations independent of the origin/material were considered derived from materials added during the manufacturing process. To evaluate the bioaccessibility, extraction tests were conducted using simulated biofluids. In gastric fluid, many metals were detected in higher concentrations than in other biofluids, intestinal fluid, saliva, and sweat, and the extraction rate of most metals exceeded 10% in artificial gastric fluid. Because the amount of metals leached into the simulated biofluids was much lower than several standards on the amount of certain metals that have the potential to be extracted from the object if ingested, the risk related to the exposure to metals from synthetic turf rubber granule infill is considered low.

Characterization of synthetic turf rubber granule infill in Japan: Volatile organic compounds.

There has been extensive studies on the composition of tires and industrial rubber. However, there is insufficient information on volatile organic compounds (VOCs) emitted from rubber granule products used to fill synthetic turf fields. In this study, we applied a passive sampling method for assessing the VOCs emitted from rubber granule products used for filling synthetic turf fields. We also performed a quantitative component analysis using a gas chromatography-mass spectrometer (GC-MS). The component analysis results of 46 rubber granule-based products showed the predominant presence of benzothiazole and methyl isobutyl ketone. The level of benzene, which the International Agency for Research on Cancer classifies as a substance with sufficient evidence for carcinogenicity to humans, was below the lower quantification limit in the products tested in this study. Our study included most of the rubber granule products used for synthetic turf fields in Japan (>95% of the products in the current domestic market of Japan). Therefore, we obtained a comprehensive overview of the VOCs emitted from the rubber granule-based products used in Japan's synthetic turf fields. Estimating the exposure to these airborne VOCs is essential to evaluate the adverse health effects of the VOCs emitted from these rubber granule-based products. Our sampling method and results can help provide key data for such risk assessment studies in the future.

Cross-sectional Neuromuscular Phenotyping Study of Patients With Arhinia With SMCHD1 Variants.

BACKGROUND AND OBJECTIVES: Facioscapulohumeral muscular dystrophy type 2 (FSHD2) and arhinia are 2 distinct disorders caused by pathogenic variants in the same gene: SMCHD1. The mechanism underlying this phenotypic divergence remains unclear. In this study, we characterize the neuromuscular phenotype of individuals with arhinia caused by SMCHD1 variants and analyze their complex genetic and epigenetic criteria to assess their risk for FSHD2. METHODS: Eleven individuals with congenital nasal anomalies, including arhinia, nasal hypoplasia, or anosmia, underwent a neuromuscular examination, genetic testing, muscle ultrasound, and muscle MRI. Risk for FSHD2 was determined by combined genetic and epigenetic analysis of 4q35 haplotype, D4Z4 repeat length, and methylation profile. We also compared expression levels of pathogenic DUX4 mRNA in primary myoblasts or dermal fibroblasts (upon myogenic differentiation or epigenetic transdifferentiation, respectively) in these individuals vs those with confirmed FSHD2. RESULTS: Among the 11 individuals with rare, pathogenic, heterozygous missense variants in exons 3-11 of SMCHD1, only a subset (n = 3/11; 1 male, 2 female; age 25-51 years) met the strict genetic and epigenetic criteria for FSHD2 (D4Z4 repeat unit length <21 in cis with a 4qA haplotype and D4Z4 methylation <30%). None of the 3 individuals had typical clinical manifestations or muscle imaging findings consistent with FSHD2. However, the patients with arhinia meeting the permissive genetic and epigenetic criteria for FSHD2 displayed some DUX4 expression in dermal fibroblasts under the epigenetic de-repression by drug treatment and in the primary myoblasts undergoing myogenic differentiation. DISCUSSION: In this cross-sectional study, we identified patients with arhinia who meet the full genetic and epigenetic criteria for FSHD2 and display the molecular hallmark of FSHD-DUX4 de-repression and expression in vitro-but who do not manifest with the typical clinicopathologic phenotype of FSHD2. The distinct dichotomy between FSHD2 and arhinia phenotypes despite an otherwise poised DUX4 locus implies the presence of novel disease-modifying factors that seem to operate as a switch, resulting in one phenotype and not the other. Identification and further understanding of these disease-modifying factors will provide valuable insight with therapeutic implications for both diseases.

Promoting Sports Engagement during the COVID-19 Pandemic via Virtual Reality Games.

OBJECTIVE: To examine sports engagement and health changes of young adults when utilizing a VR sports game and investigate the relationship between sports engagement and health. METHOD: This study used a single-group design with 20 participants, aged 19-29 years, with no preexisting health conditions. The VR game "Sports Scramble" was used thrice within a span of one week. Outcomes sought include sports engagement and health, measured through the Sports Engagement Scale (SES) and Short Form 36 (SF-36), respectively. RESULTS: A significant difference (p < 0.001) was found between the pre-posttest scores of the SES. Moreover, a positive trend was observed in terms of health with a significant difference (p < 0.05) between pre-posttest scores of the SF-36's vitality dimension. There were positive correlations among the dedication and vigor subscales of the SES with the dimensions of health. CONCLUSION: This study showed the potential of VR sports games in positively influencing sports engagement and health among participants with the vigor and dedication positively influencing health. Future studies may involve the exploration of the effectiveness of VR to promote engagement and health through a randomized controlled trial with a longer timeframe and across various populations.

Multimodal regulatory elements within a hormone-specific super enhancer control a heterogeneous transcriptional response.

The hormone-stimulated glucocorticoid receptor (GR) modulates transcription by interacting with thousands of enhancers and GR binding sites (GBSs) throughout the genome. Here, we examined the effects of GR binding on enhancer dynamics and investigated the contributions of individual GBSs to the hormone response. Hormone treatment resulted in genome-wide reorganization of the enhancer landscape in breast cancer cells. Upstream of the DDIT4 oncogene, GR bound to four sites constituting a hormone-dependent super enhancer. Three GBSs were required as hormone-dependent enhancers that differentially promoted histone acetylation, transcription frequency, and burst size. Conversely, the fourth site suppressed transcription and hormone treatment alleviated this suppression. GR binding within the super enhancer promoted a loop-switching mechanism that allowed interaction of the DDIT4 TSS with the active GBSs. The unique functions of each GR binding site contribute to hormone-induced transcriptional heterogeneity and demonstrate the potential for targeted modulation of oncogene expression.

Developing an international research of health-care ICT applied for rehabilitation and daily living support between Japan and the Netherlands.

While many health-care issues and technological solutions are viewed locally, developing new technological solutions might benefit from lessons learned globally. The aim of this study was to develop a shared international research agenda of health-care ICT, applied to rehabilitation and daily living support. This study was focused on sensor technology and social robots used for supporting older persons in the Netherlands (Amsterdam) and Japan (Tokyo). Three researchers from Amsterdam University of Applied Sciences visited Japan and four researchers from Tokyo Metropolitan University visited the Netherlands and conducted field-visits and mutual presentations. Using a nominal group technique (NGT) facilitated the expert panel deliberations. Research priorities were identified qualitatively through in-action critical reflection on emerging ideas, and quantitatively by ranking of identified knowledge gaps (using the Mentimeter© app). The resulting joint research agenda identified topics around the utility of sensor monitoring and processes of acceptance of health-care ICT among older persons and occupational therapists. The agenda was complemented by formulating underlying assumptions prescribing such research to be embedded in real-life situations with the participation of stakeholders.

Constructing a developmental and reproductive toxicity database of chemicals (DART NIHS DB) for integrated approaches to testing and assessment.

Developmental and reproductive toxicity (DART) is an important endpoint, and databases (DBs) are essential for evaluating the risk of untested substances using alternative methods. We have constructed a reliable and transparent DART DB, which we named DART NIHS DB, using the publicly available datasets of DART studies of industrial chemicals conducted by Japanese government ministries in accordance with the corresponding OECD test guidelines (OECD TG421 and TG422). This DB is unique because its dataset chemicals have little overlap with those of ToxRefDB, which compiles large-scale DART data, and it is reliable because the included datasets were created after reviewing the individual study reports. In DART NIHS DB, 171 of 404 substances exhibited signs of DART, which occurred during fertility and early embryonic development (49 substances), organogenesis (59 substances), and the perinatal period (161 substances). When the lowest-observed-adverse-effect level (LOAEL) of DART was compared with that of repeated-dose toxicity (RDT), 15 substances (12%) had a lower LOAEL for DART than for RDT. Of these, five substances displayed significant DART at doses of ≤ 50 mg/kg bw/day. The chemical and toxicity information in this DB will be useful for the development of stage-specific adverse outcome pathways (AOPs) via integration with mechanistic information. The whole datasets of the DB can be implemented in read-across support tools such as the OECD QSAR Toolbox, which will further lead to future integrated approaches to testing and assessment based on AOPs.

Exploring the applicability of the robotic seal PARO to support caring for older persons with dementia within the home context.

OBJECTIVE: To (1) examine the potentiality of using the robot PARO to mediate care provided by the family and (2) identify problems when utilizing PARO in the home context. METHODS: Family members of 7 households were asked to use PARO for at least three times per week, over 1 to 3 months. Research data, including standardized assessments, interviews, and observations, were collected at initial and subsequent monthly visits. Collected data were analyzed through descriptive statistics and inductive thematic content analysis. RESULTS: Out of the seven participants, five responded positively to PARO, thereby achieving their goals of improving activity engagement, relaxation, a respite from supervision, and improved mood. A positive initial interaction with PARO showed continued interest to it. Participants were observed to communicate with caregivers and relate to PARO. DISCUSSION: The application of PARO at home is possibly influenced by the persons' initial level of interest toward PARO. It is crucial to perform careful observation and assessment before deciding to use PARO within the home context to support the life of older persons with dementia.

[Application of the Benchmark Dose Method to the Incidence Data for Various Pathological Findings and Its Validation Analysis].

Benchmark dose (BMD) method have been used in the toxicological assessment of chemical substances so that the point of departure can be derived, as an alternative to the use of no observable adverse effect level (NOAEL), and the method is often applied to the incidence data of histopathological findings in the toxicity studies. In the present study, the BMD method was applied to various patterns of incidence data derived from some toxicity studies as case studies, and the validity of each application was discussed. Five independent applications including toxicity studies of madder color or semicarbazide hydrochloride were prepared and model averaging over the three models with the lowest three AIC (Akaike information criteria) values (MA-3), a recently proposed model averaging method, was employed. The series of case studies indicated, for the better application of the BMD method to histopathological findings, the following points:(i) If there are incidence data with severity grading of pathologically significant lesions, we must discuss whether the BMD method should be applied to the total incidence data or the incidence data above certain grade with or without data aggregation.(ii) If a lesion of interest had higher toxicological significance rather than the secondary lesions with higher severity, the BMD method should be applied to the incidence data of the lesion of interest.(iii) If it is highly necessary to apply the BMD method to obtained incidence data without toxicological and statistical validity, toxicological pathologists are advised to review individual datasets of histopathology and associated data, and provide new incidence data of comprehensive findings (diagnostic name) such as hepatocellular injury or nephropathy, if possible. In all cases, toxicological significance and mechanism of a lesion of interest need to be considered in light of the dose-dependence. In view of both toxicology and statistics, sufficient discussions must be made on the validity of applying BMD method and its estimate.