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Background: Lactoferrin (bLF) is an iron-binding multifunctional protein that is abundant in milk. In mice, it inhibits catechol-O-methyltransferase (COMT) activity and increases blood levodopa levels. However, the clinical effects are unknown. Objective: The objective of this study was to determine the effect of bLF on the kinetics of levodopa in blood. Design: The effects of the concomitant administration of a combined formulation of levodopa and an aromatic amino acid decarboxylase inhibitor and bLF on the concentration of levodopa in blood and its metabolism were assessed in eight healthy subjects. In addition, we analyzed the association with clinical factors and evaluated whether clinical factors affected the COMT inhibitory activity of bLF in vitro. Results: Although not statistically significant, the peak plasma concentration (Cmax) of levodopa increased by 18.5%. From the results of the stratified analysis of total cholesterol, a relationship with ΔCmax was predicted. Therefore, bLF was reacted with cholesterol in the presence of lecithin and sodium deoxycholate in vitro to evaluate COMT inhibitory activity, and an increase in inhibitory activity was observed. By contrast, the ester compound cholesteryl oleate had no effect. The inhibitory activity of free fatty acids, which are known to interact with bLF, was also enhanced. Conclusion: The COMT inhibitory activity of bLF is not effective in elevating blood levodopa levels. However, in humans with high lipid levels, such as cholesterol, interactions may enhance the inhibitory effect, resulting in the enhanced absorption of levodopa. Trial registration: ID, UMIN000026787, registered 30 March 2017; URL, Trial registration: UMIN Japan identifier: UMIN000026787 [ABSTRACT FROM AUTHOR]

Aims: In 2008, the US Food and Drug Administration (FDA) issued a guidance requiring that cardiovascular outcome trials (CVOTs) be conducted for newer hypoglycaemic drugs for type 2 diabetes (T2D). We aimed to examine the decisions by 3 regulatory authorities in response to identical CVOT data. Methods: We surveyed ClinicalTrials.gov to identify CVOTs and examined the revision histories of drug labels in databases from the FDA, the European Medicines Agency, and the Pharmaceuticals and Medical Devices Agency in Japan. Results: We selected 14 drugs and corresponding CVOTs, 12 of which were conducted as postmarketing trials. In the USA and the EU, the pre‐CVOT indication on all 14 labels was "improvement in glycaemic control". Six drugs showed significant cardiovascular risk reduction, which led to an additional indication regarding reduction of cardiovascular adverse events in the USA, and a change to the EU indication to specify treatment of adults with T2D. The initial indication in Japan, T2D, remained unchanged. Regarding safety, significant increases in heart failure were observed only in the saxagliptin trial. A warning was added to the saxagliptin labels in the EU and Japan, whereas the FDA required a class effect warning to be added to the labels of all 4 dipeptidyl peptidase‐4 inhibitors. Conclusions: Regulatory authorities using identical trial data made substantially different decisions regarding both safety and efficacy of hypoglycaemic drugs. The differences in initial indication wording between Japan and the other authorities suggest that trial data and T2D are interpreted differently in these regions. [ABSTRACT FROM AUTHOR]

Reports of cerebral venous sinus thrombosis and intracranial hemorrhage (ICH) following the administration of coronavirus vaccines have raised concerns regarding their safety. Although no regulatory authority has recognized ICH as an adverse event associated with tozinameran (BNT162b2, Pfizer-BioNTech), fatal and non-fatal cases have been reported. In Japan, 10 fatal cases (five men and women) have been reported to date. Four of the five women died of ICH and the other died of aspiration pneumonia, whereas all five men died of causes other than stroke. This imbalance is incompatible with the mortality data on cardiovascular diseases in the National Statistics, which show no apparent disparity between sexes or between hemorrhagic and ischemic stroke. Cumulatively, our analysis reveals a disproportionately high incidence of death by ICH in Japanese women who received tozinameran, suggesting a potential association of ICH with the vaccine. Although we understand that the benefits of tozinameran still outweigh the risks, we believe that a causal link with the vaccine is not proven but possible and warrants further analysis. [ABSTRACT FROM AUTHOR]

Background: Cadmium (Cd) is a wide-spread environmental pollutant with insidious toxicity to kidneys, and children are considered to be a high-risk group. Lead (Pb) is suspected to induce retardation in mental development in children. Daily foods are an important source of both Cd and Pb exposure for general population. Nevertheless, data on dietary exposure of children to Cd and Pb are still scarce in Japan. Objectives: This study was initiated to clarify the extent of exposure of children to Cd. Exposure to Pb, another environmental pollutant element, was also studied in combination. Methods: Twenty-four-hour food duplicates and the first morning urine samples were collected from 296 children (159 boys and 137 girls at the ages of 3-6 years) in 15 kindergartens in Miyagi prefecture on the Pacific coast in north-east Japan; no environmental pollution with Cd has been known in the prefecture. Cd, Pb and iron in food duplicates and Cd in urine were analyzed by inductively coupled plasma-mass spectrometry. α-Microglobulin (α-MG) in urine was measured by the latex method. Log-normal distributions were confirmed for these analytes. Results: The geometric mean (GM) values for dietary intake of Cd and Pb were 11.8 and 2.28 μg/day, or 4.20 and 0.84 μg/kg body weight/week, respectively, for total children studied. No significant difference was detected in dietary Cd and Pb intake between boys and girls of the same age (except for Pb on a μg/day basis at 6 years) as well as of all ages in combination. Trends of increase in Cd and Pb intake were observed parallel to age when calculated on a daily intake basis, but the trends disappeared after correction for body weight. No age-dependent increase was observed in α-MG, despite there was an age-dependent increase in Cd. Conclusions: The dietary intake of Cd and Pb for children studied were 4.20 and 0.84 μg/kg body weight/week, respectively. International comparison of the present results with values reported in literature suggested that exposure of children in Japan was higher with regard to Cd, and lower regarding Pb, reproducing the observation in adult Japanese populations. For better health of children, efforts may be necessary to reduce high dietary exposure to Cd. [ABSTRACT FROM AUTHOR]

Abstract: Because dietary intakes of some minerals (including trace elements), especially iron (Fe), are insufficient for the needs of the general Japanese population, accurate estimation of mineral intake is important. This capability is especially necessary to preserve the health of Japanese children. Therefore, the current version of food composition tables (FCT) in Japan was evaluated for validity as tools to estimate dietary intake of minerals for children. For this purpose, 24h food duplicate samples were collected from 292 pre-school children in Miyagi prefecture, Japan. From the weights of items and food codes, intakes of nine minerals were estimated taking advantage of the FCT. In parallel, amounts of minerals in each duplicate samples were instrumentally measured by ICP-AES for Ca, Cu, Fe, Mg, Mn, P and Zn, and by flame AAS for K and Na, both after wet-ashing. The distributions of the mineral amounts were essentially normal. The comparison of the FCT-based estimates (E) and instrumental measures (M) showed that the E/M ratio was close to 1 for Ca, K, Mn, P and Zn, suggesting that E may be a surrogate of M for Ca, K, Mn, P and Zn on a group basis. The ratio being larger than 1.2 for Cu, Fe, Mg and Na indicates that a risk of over-estimation exists when E is relied upon in place of M. On an individual basis, significant differences were detected for all 9 minerals suggesting that the use of E as a surrogate for M should be practiced with care for the estimation of mineral intake. [Copyright &y& Elsevier]

Background and objectives: Cd absorption may be enhanced in association with iron (Fe) deficiency. Women have increased risks of Fe loss at the time of child birth as well as breast-feeding of children. Possible effects of these two factors were investigated in the present study. Methods: Data were drawn from previous publications from this group on Cd and tubular dysfunction markers (i.e., α-microglobulin, β-microglobulin, and N-acetyl-β- d-glucosaminidase) in urine of adult women in non-polluted areas in Japan. Information including age, smoking, number of children, and types of child feeding was obtained by self-administered questionnaires at the time of urine sampling. In practice, 17,468 cases were available, from which 12,869 cases were employed in the present analyses after exclusion of smokers, former or current patients of anemia or hypertension, and those with incomplete answers. Lactation burden was scored after coding of breast, mixed, and bottle feeding with 2, 1, and 0 for each child followed by summation for all children born to a mother. In order to exclude possible effect of aging, women were stratified by 5 years of age to randomly select equal numbers of cases and controls, followed by summation for all ages for comparison. Results: The arithmetic mean age and the geometric mean Cd (as observed) were 49.7 years and 1.13 μg/l urine. The number of children was 0-7, and lactation burden score ranged from 0-12. Multiple regression analyses were conducted with age and either number of children or lactation burden scores as independent variables and Cd as a dependent variable. The results showed that age was an influential variable. Comparison after matching for age showed that having 1, 2, or 3 children or lactation burden score up to 2 were associated with a significant increase in Cd. Lactation burden score up to 2 was also associated with increased Cd in urine and such trend persisted up to the highest score of 5-12. The results of trend tests were generally in agreement with these observations. Further comparison after age-matching showed that women having 2 or 3 children but no lactation burden had higher Cd than those with no children. In contrast, Cd was not higher for those having 2 or 3 children with substantial lactation scores (i.e., 2-4 or 3-6) than for those with the same number of children without lactation burden. Conclusions: Giving birth to 1-3 children was associated with an increase in urinary Cd, suggesting that child birth might be associated with elevation in Cd body burden. The effect of lactation is probably attributable to that of number of children. Further studies are necessary to examine whether the association is also observable in mothers who have 3 or more children. [ABSTRACT FROM AUTHOR]

Background: The use of benchmark dose (BMD) and the 95% lower confidence limit of benchmark dose (BMDL) have been gaining popularity not only in experimental studies but also in epidemiological studies including those on toxicology of cadmium (Cd), a ubiquitous hazardous element in the environment. However, the reproducibility of BMD and BMDL values has seldom been examined. Objectives: This study was initiated to determine whether consistent BMD and BMDL values are obtained for similar non-exposed populations, i.e., the populations with no anthropogenic exposure to Cd in a single nation of Japan. Methods: Cd (an exposure marker), α-microglobulin (α-MG), β-microglobulin (β-MG) and N-acetyl-β-D-glucosaminidase (NAG) (three effect markers of tubular dysfunction) levels in the urine of adult Japanese women from five previous publications of this study group were examined. Overall, data were available for 17,375 cases (in 16 prefectures) regarding Cd, α-MG and β-MG, and 6,409 cases (in ten prefectures) regarding NAG. The data were used to calculate BMD and BMDL values taking advantage of the hybrid approach (Budtz-Jǿrgensen et al. in Biometrics 57:698-706, ). It was possible to calculate BMD and BMDL values for α-MG and β-MG for all of the 16 prefectures with 17,375 cases, whereas the values for NAG were successfully calculated for nine prefectures with 5,843 cases. Results: The application gave BMD values of 1.92, 2.46 and 2.32 μg Cd/g cr for α-MG, β-MG and NAG, respectively, and BMDL values of 1.83, 2.32 and 2.09 μg Cd/g cr. Large inter-prefectural variations were observed in the BMD and BMDL; there was about fourfold difference both in BMD and in BMDL calculated for α-MG and β-MG in 16 prefectures, and the variation was greater (i.e., by about sevenfold) in BMD and BMDL for NAG in nine prefectures. A survey of relevant literature revealed variation in BMD and BMDL values of similar folds as observed in the present analyses in five studies of Japanese populations. Multiple regression analyses taking BMD or BMDL as a dependent variable and age, CR concentration and Cd concentration as independent variables showed both BMD and BMDL were significantly influenced by Cd concentration in cases of α-MG and β-MG, whereas BMD and BMDL for NAG was by CR. Conclusions: Even when the analysis was conducted in a single nation, both BMD and BMDL for the Cd effect markers varied by ca. fourfold when examining α-MG or β-MG and the values varied by ca. sevenfold for NAG among Cd-non-exposed populations. The most influential factors in the study population may include urine density and Cd levels in the urine. [ABSTRACT FROM AUTHOR]

Abstract: Background: Although approved elsewhere, many drug indications remain unapproved in Japan. Many of these unapproved indications are off-label, which, despite strong supporting evidence, are not covered by the Japanese health insurance system. To address this situation, the Ministry of Health, Labour and Welfare of Japan announced in 1999 that, under certain conditions, it would approve a new supplement for a drug indication without clinical trials. This approval scheme involved application evaluation using literature-based evidence; however, the type of indications and the kind of evidence used in practical applications remain to be clarified. Objective: This commentary sought to investigate the factors that contribute to the approval of individual applications through an analysis of review reports and to assess the outcome of efforts to facilitate the approval of off-label drugs by this approval system that has been used for over a decade in Japan. Methods: Data from 80 approvals granted under this scheme were obtained from the official review reports of the Japanese regulatory agency. The following criteria were selected for the analysis of individual applications: review time, therapeutic class, application category under Japanese regulations, international approval status, postapproval monitoring plan, and variety and quantity of literature evidence. The literature used as a source of evidence was categorized into 4 types: (I) standard textbooks, (II) standard guidelines, (III) reviews, and (IV) application dossier submitted to the foreign regulatory authorities. Results: The number of approvals and applications per year showed no consistent trend. The median (SD) review time was 16.4 (9.0) months, which was not affected by the international approval status or the literature evidence. This approval scheme was applied to not only a new indication (56 applications [70%]) or dosage (9 [11%]) but also a new route of administration (13 [16%]). Of the 80 applications, 46 (58%) had been approved in the United States, the United Kingdom, or both; 11 (14%), in other countries; and 23 (29%), in no country. For 2 approvals, the review reports were not released; the other 78 were based on either standard textbooks or guidelines, while 67 (84%) were based on both. The variety and quantity of literature evidence provided in the application showed no consistent trend with respect to international approval status. Conclusions: Prior approval by foreign authorities, although important, did not appear to be essential for approval in Japan. However, substantiating safety and effectiveness of agents by means of standard textbooks or guidelines was used consistently to obtain approval for off-label use. [Copyright &y& Elsevier]

After the severest mass extinction event in the Phanerozoic, biotic recovery from the extinction at the Permian-Triassic boundary required approximately 5 my, which covers the entire Early Triassic. It is important to obtain information on the superocean Panthalassa, which occupied most of the world ocean, to explore paleoenvironmental changes during the Early Triassic at the global scale. In order to establish the continuous lithostratigraphy of pelagic sediments in Panthalassa during the Early Triassic, high-resolution reconstruction of the Lower Triassic pelagic sequence in Japan was conducted for the first time based on detailed field mapping and lithostratigraphic correlation in the Inuyama area, central Japan. The reconstructed Early Triassic sequence is approximately 9.5 m thick, consists of five rock types, and is divided into eight lithological units. For the reconstructed continuous sequence, measurement of carbon isotopic composition of sedimentary organic matter (δ13Corg) was carried out. Stratigraphic variation of the δ13Corg value shows large-amplitude fluctuations between −34.4 and −21.0‰ throughout the sequence. In order to establish a higher resolution age model for the reconstructed Lower Triassic pelagic sequence, we correlated δ13Corg records in the Inuyama area with high-resolution isotopic profiles of carbonate carbon (δ13Ccarb) from shallow-marine carbonate sequences in southern China based on the similarity in general variation patterns with age constraints by radiolarian and conodont biostratigraphy. The result provides a high-resolution time scale for the pelagic sequence of Panthalassa during the Smithian and Spathian. The age model suggests a drastic increase in sedimentation rate during the late Smithian, which should have been caused by the increase in terrigenous input to this site. [ABSTRACT FROM AUTHOR]

Background and objectives: Previous findings suggest that the dose (e.g., cadmium in urine)-response (e.g., tubular dysfunction markers in urine) relationship after environmental exposure to cadmium (Cd) may be in a shape of a hockey stick with a steep slope when Cd exposure exceeds a certain level, i.e., the point of flexion. However, less attention has been paid to the relation below the flexion point whether it is linear or not. The present study was initiated to examine through epidemiological analyses whether the assumption of linearity holds true when Cd exposure is low. Methods: Data were cited from previous publications of this research group on Cd, α-microglobulin (α-MG), β-microglobulin (β-MG), N-acetyl-β- d-glucosaminidase (NAG), and creatinine (CR) in urine from more than 17,000 adult Japanese women. The cases were selected for age (50-59 years), urine specific gravity (1.010-1.030) and CR (0.3-3.0 g/l), and 5,306 cases were available after selection (the group selected in terms of age and urine density, or the AD-selected group). Results: Statistical analyses of the AD-selected group revealed that the relation was not linear. In case of β-MG, the slope of the regression line between Cd as an independent variable and β-MG a dependent variable was steeper at lower Cd level (i.e., <2.5 μg/l) and shallower when Cd was higher, showing a clear trend of leveling off. The same was also the case for α-MG and NAG. When Cd was 2.0-2.1 μg/l or higher, α-MG, β-MG, and NAG were in excess of the 95%-tile values for the markers in more than 5% of the population. The significance of the observation was discussed in reference to existing criteria for Cd such as 2.5 or 5.2 μg/g cr or for β-MG of 300 μg/g cr. Conclusions: When the present observation of bilinear relation at low Cd exposure levels was combined with the previous observation of very sharp increase in responses among heavily exposed cases, it appeared likely that the overall relationship is tri-phasic in Cd dose-response relationship in humans. A substantial fraction (>5%) of the populations had the marker levels in excess of the 95%-tile values when Cd was ≥2 μg/l. Comparison with findings in reported literature suggests that the presence of such cases by itself may not necessarily mean a risk of tubular dysfunction and that other factors including Cd levels in urine should be considered together. [ABSTRACT FROM AUTHOR]

The article focuses on a study on the elucidation of organic solvents used in enterprises in Japan through a comparison of current solvent types with historical data. It informs that adhesives spreading was relatively common in small-scale enterprises, printing and painting work in middle-scale ones, and solvent use for testing and research purpose in large-scaled enterprises.

Objectives: The objectives of the present study are to investigate whether cadmium in blood (Cd-B) and cadmium in urine (Cd-U) correlate with each other irrespective of age among general populations and which one of Cd-B or Cd-U correlates more closely with three renal tubular dysfunction markers in urine of α-microglobulin (α-MG-U), β-microglobulin (β-MG-U) and N-acetyl-β- d-glucosaminidase (NAG-U). Methods: Data on two exposure markers (Cd-B and Cd-U) and three effect markers (α-MG-U, β-MG-U and NAG-U) were collected for 1,403 adult women in non-polluted areas all over Japan. Possible significance of correlation between the parameters and dependency on age was examined by simple and multiple regression analysis. Results: Both Cd-B and Cd-U increased as a function of age. The two exposure markers correlated significantly with each other, and the Cd-U over Cd-B ratio also increased as a function of age. Although both Cd-B and Cd-U correlated significantly with the three effect markers, the correlation was closer for Cd-U than for Cd-B. Conclusions: Cd-U rather than Cd-B should be recommended as an exposure marker of choice in Cd biological monitoring of general populations. Effects of aging should be taken into account when evaluating study results. [ABSTRACT FROM AUTHOR]

Background: Background levels of metals of toxicological or industrial importance have been reported for several populations in the world. The information on the levels of metals of industrial, occupational or clinical importance in blood of general Japanese populations is however still scarce. Objectives: The objectives of the study were to establish background levels of Cd, Cr, Mn, Ni and Pb in blood of Japanese population using inductively coupled plasma-sector field mass spectrometry (ICP-SF-MS), which was expected to be sensitive enough to measure low-level Pb in blood of general populations. For this purpose, women, rather than men, were studied to minimize the effect of smoking. An additional objective was to examine possible contamination from devices in phlebotomy process. Methods: Blood samples were collected in 2000's from 1,420 adult women in eight prefectures of no known anthropogenic environmental metal pollution in Japan, and the samples were subjected to ICP-SF-MS analyses after wet digestion with extra-pure nitric acid. Ultra pure water samples aspirated into blood sampling vacuum tubes were analyzed to detect possible metal contamination. Results: Contamination of blood samples from phlebotomy device was detected for Cr and possibly for Mn and Ni, whereas it was below measurable levels with regard to Cd, Ni and Pb. Under this limitation, GM metal concentrations in blood were 1.23 μg/l for Cd, 0.55 μg/l for Cr, 13.2 μg/l for Mn, 1.81 μg/l for Ni and 15.8 μg/l for Pb. Cd and Pb tended to increase in association with age, whereas Cr, Mn and Ni tended to decrease. Smoking induced elevation both in Cd and in Pb in blood. It was also made clear that the ICP-SF-MS is reliable for measurements of Cd, Mn and Pb in blood allowing evaluation even on an individual basis, while the results of Cr and Ni should be reliable on a group basis (e.g., n ≥ 5). Limitation in compatibility was discussed between the results by ICP-SF-MS and that by traditional graphite furnace atomic absorption spectrometry. Conclusions: ICP-SF-MS is a reliable method of blood analysis for Cd, Mn and Pb even for the evaluation on an individual basis. Cr and Ni analyses should be reliable on a group basis, probably due to limited performance inherent to the analysis principle and matrix. Possible contamination from phlebotomy devices with Cr should be taken into account in evaluating the results. [ABSTRACT FROM AUTHOR]

The article discusses a study that determines the metabolic syndrome-related risks among obese workers in Japan. The researchers analyze the data from 804 workers who pathological findings in 12 MS-related and other health parameters in 2003. Study reveals that metabolic syndrome-related risks are not only revealed in obese but also among non-obese workers.

Abstract: Astronomical forcing is one of the main drivers of climate change, and astronomical cyclicity recorded in sediments provides a clue to understand the dynamics of the global climate system. Bedded cherts consist of rhythmic alternations of chert and shale beds. Although previous studies have hypothesized that the origin of bedded chert is related to astronomical cycles (e.g. Fischer, 1976; Hori et al., 1993), conclusive proof remains elusive. To explore this possibility, we established a continuous, high-resolution lithostratigraphy of middle Triassic bedded chert in Central Japan. The average duration of each chert–shale couplet is 20kyr, similar to that of the precession cycle. Spectral analysis of a bed number series of thickness variations in chert beds was performed assuming that each chert–shale couplet represents a 20-kyr precession cycle. The results reveal cycles involving approximately 200, 20, 5, and 2–3 beds, corresponding to periodicities of approximately 4000, 400, 100, and 40–60kyr, respectively. By further assuming that the 20-bed cycle represents a 405-kyr eccentricity cycle of constant and stable periodicity, we converted the bed number series to a time series. Spectral analysis of the time series revealed distinct periodicities of 3600, 117, 97, and 38kyr, in addition to 405kyr. Besides 3600kyr, these periodicities agree well with the 120, 95, and 37kyr periodicities for eccentricity cycles and the obliquity cycle during the Triassic. Moreover, we detected amplitude modulation of the approximately 100-kyr cycle of thickness variations in chert beds with a 405-kyr periodicity, which may correspond to amplitude modulation of 100-kyr climatic precession cycle with the 405-kyr periodicity. The approximately 3600-kyr periodicity described above and 1800-kyr periodicity manifested as the amplitude modulation of the 405-kyr cycle are correlated to present-day long-term eccentricity cycles of 2400 and 4800kyr evolved by chaotic behavior of solar planets. Collectively, these similarities in the periodicities of dominant cycles, their hierarchy, and the nature of amplitude modulation of cycles in chert bed thickness with those of astronomical cycles strongly support the hypothesis that the sedimentary rhythm of bedded chert is paced by astronomical cycles, thereby indicating the potential of bedded chert as a template for a Mesozoic cyclostratigraphy. [Copyright &y& Elsevier]

Occupational health service (OHS) for small-scale enterprises (SSEs) is still limited in many countries. Both Japan and the Netherlands have universal OHS systems for all employees. The objective of this survey was to examine the activities of occupational physicians (OPs) in the two countries for SSEs and to investigate their proposals for the improvement of service. Questionnaires on types and sizes of the industries they serve, allocation of service hours (current and desired), sources of information for occupational health activities etc. were mailed in 2006 to 461 and 335 Japanese and Dutch OPs, respectively, who have served in small- and medium-scale enterprises. In practice, 107 Japanese (23%) and 106 Dutch physicians (32%) replied, respectively. Total service time per month was longer for OPs in the Netherlands than OPs in Japan. Japanese OPs spent more hours for health and safety meetings, worksite rounds, and prevention of overwork-induced ill health (14–16% each). Dutch OPs used much more hours for the guidance of absent workers (48%). Thus, service conditions were not the same for OPs in the two countries. Nevertheless, both groups of OPs unanimously considered that employers are the key persons for the improvement of OHS especially in SSEs and their education is important for better OHS. The conclusions should be taken as preliminary, however, due to study limitations including low response rates in both groups of physicians. [ABSTRACT FROM AUTHOR]

Literature survey has suggested that cadmium (Cd) in the general environment is more abundant in the northern part of the coast on the sea of Japan. The present survey was initiated to examine if the exposure to Cd in the area has been higher than other parts of Japan, and if so, the higher exposure has been associated with tubular dysfunction among the local residents. In three prefectures of Akita, Yamagata and Ishikawa in the region, adult women (about 700 subjects per prefecture) were invited to participate in the survey. Each of the participants provided informed consents, offered spot urine samples and filled questionnaires (on age etc.). The urine samples were analyzed for Cd, α1-microglobulin (α1-MG), β2-microglobulin (β2-MG) and N-acetyl-β- d-glucosaminidase, together with creatinine and specific gravity. The results were combined with published data on two other prefectures of Niigata and Toyama (both in the area), as well as Japan as a whole (all Japan-A excluding Niigata prefecture, which was studied separately in the present study), and subjected to analysis for possible difference from all Japan-A in terms of the levels of internal Cd burden, and prevalence of β2-MG-uria. Geometric means (GMs) for urinary Cd in the five prefectures were in a range from a low of 1.20 to a high of 2.65 μg/l, being higher than the GM (0.99 μg/l) for all Japan-A. GMs for α1-MG (2.15–2.80 mg/l) and β2-MG (99–107 μg/l) were only slightly higher or even lower than all Japan-A values depending on the prefectures. Elevation in the prevalence of β2-MG-uria was significant in Akita prefecture, but the elevation in β2-MG was not associated with elevation in Cd in urine. Literature survey on general population Cd epidemiology showed that Cd, α1-MG and β2-MG levels in urine of the residents in the five prefectures were within the levels reported for non-polluted areas, and such was also the case for prevalence of β2-MG-uria. In an over-all evaluation, no clear-cut evidence was available for increased prevalence of Cd exposure-associated renal tubular dysfunction among general populations in the five prefectures in the northern part on the coast of Sea of Japan than in other prefectures in Japan, despite moderate elevation in urinary Cd levels. [ABSTRACT FROM AUTHOR]

This study was initiated to investigate if and to what extent the elevations in urinary α1-and β2-microglobulins (α1-MG and β2-MG, respectively) are specific to Cd nephro-toxicity. Stored urine samples, collected from 1,000 adult women in 11 prefectures all over Japan, were analysed for eight elements (Ca, Cd, Co, Cu, Mg, Mn, Ni and Zn), α1-MG, β2-MG, creatinine (CR) and specific gravity (SG); the data were cited from previous publications. The levels of eight elements and two MGs were expressed as observed and after correction for CR or SG (1. 016). Age, CR and SG distributed normally, whereas two MGs and eight elements distributed log-normally. The 1,000 cases were classified into quartiles (i. E. , 250 cases/group) of the lowest to the highest values (Groups A to D) for each element. Α1-MG and β2-MG increased as a function of Ca, Cd and Cu when corrected for CR, and the two MGs increased in parallel only with Cd and Cu after SG correction. Prevalence of α1-MG-uria (cut-off values; 5. 3 and 6. 5 mg/g cr or l) and β2-MG-uria (cut-off values; 300 and 400 μg/g cr or l) was elevated with increasing Ca, Cd and Cu when corrected for CR, but only with Cd and Cu when corrected for SG. Multiple regression analysis of 353 cases of 50–59 year-old women with the eight element levels as independent variables and one of the two MGs as a dependent variable showed that Cu was the most influential element, and both Cd and Zn were less influential. Urinary levels of α1-MG and β2-MG among women with no environmental Cd exposure correlated more closely with Cu levels than Cd levels in urine. The observation suggests that sub-clinical elevation in α1-MG and β2-MG is not always attributable to nephro-toxicity of Cd, and that consideration on possible effects of other elements such as Cu is necessary. [ABSTRACT FROM AUTHOR]

The study was initiated to identify the effects of recent changes in dietary pattern in Japan on nutrient intake. In the large city of Osaka, Japan, 24-h food duplicate samples were collected from 26 middle-aged women, and nutrients in the duplicates were estimated in reference to standard tables of food composition. The subjects took 1844 kcal (7.72 MJ) energy, 67.5 g protein, and 54.5 g lipid (37% from plants) per day. Micro-nutrient intakes were generally sufficient, but NaCl intake tended to be excessive, and the relatively high body mass index (>25 in six cases) suggested a possibility of over-eating. The food composition was rich in rice and fish, being basically of a traditional type. Consumption of bread, an acquired habit, was observed in 65% of the breakfasts but less so in lunch and none in dinner. Thus, the acceptance of bread in place of rice was limited and did not induce substantial alteration in nutrient intakes. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study is to examine if overall correlation exists among cadmium levels (Cd) in the general environment, dietary Cd intake, and Cd body burden of local residents. Methods: Eleven prefectures in Japan were selected as the areas where large-scale data on Cd levels in urine of adult women (40–49 and 50–59 years of age, respectively) were available to calculate geometric mean (GM) values for each of the prefecture. Other data were cited from published or previously established databases on Cd in the sediments of river bottoms (as a representative of Cd in the environment), Cd in rice for local consumption, and Cd in daily food duplicate samples collected from local women populations, and calculated for GM values for the prefectures. The GM values were subjected to correlation matrix and regression analysis. Results: Marginally significant ( P<0.10) correlation was detected between Cd in sediment and Cd in rice. Furthermore, correlation of Cd in sediment was significant with Cd in total foods ( P<0.05) and possibly with Cd in urine ( P<0.05–0.10). Importance of data on Cd in rice paddy soil as a missing link is discussed. Conclusions: Correlation was demonstrated in the flow of Cd transport from the environment (expressed as Cd contents in river sediments) to humans (in terms of Cd in urine) among general populations in Japan. [ABSTRACT FROM AUTHOR]

A revised edition of the standard tables of food composition was implemented in Japan in 2005; one of the major revision points is the change of retinol activity equivalents for pro-vitamin A carotenoids. This preliminary analysis was conducted to examine whether the revision affects the estimation of vitamin A intake; and if so, to what extent. Accordingly, a field survey was conducted to collect 24-h duplicates of daily foods of citizens, and 26 adult women volunteered. Application of the procedures in the new and previous standard tables of food composition gave 537 µg retinol activity equivalent and 704 µg retinol equivalence, respectively, for daily vitamin A intake. Thus, the changes in retinol activity equivalents induced substantial reduction (by 24%) in estimation of vitamin A intake among the Japanese population, for whom pro-vitamin A carotenoids in plant foods are the major sources (76%) for vitamin A, and retinol accounts for only 35% (on the retinol activity equivalent basis). [ABSTRACT FROM AUTHOR]

The present study was initiated to examine urinary α1-microglobulin (α1-MG-U) levels among non-smoking women in the general population in Japan. A previously established database on spot urine samples from adult woman volunteers in 10 non-polluted areas all over Japan was re-examined. The data examined were on α1-MG-U, cadmium, calcium, magnesium and zinc levels in urine (Cd-U, Ca-U, Mg-U and Zn-U, respectively), urinary creatinine (CR or cr), urine specific gravity (SG or sg), smoking habits and age. Thus, 8975 never-smoking women were selected for statistical analyses. The grand geometric mean (GM) for α1-MG-U among the population was 2.1 mg/L or 2.5 mg/g cr, depending on the correction for urine density. It was 1.1 µg/L or 1.3 µg/g cr for GM Cd-U. The inter-area difference in α1-MG-U was <1.5 mg/g cr or <0.7 mg/L; the area with the highest or lowest GM Cd-U was not always highest or lowest in GM α1-MG-U. The correlation coefficient (0.53) between log Cd-U and log α1-MG-U (both without urine density correction) became substantially smaller when the analyte levels were corrected for CR (0.25) or SG (0.26). In multiple regression analysis, the power of influence of the five independent variables (log Cd-U, Ca-U, Mg-U, Zn-U and age) in combination was small (R2 ≦ 0.13). In contrast, logistic regression analysis suggested that α1-MG-U might be elevated as a function of an increase in Cd-U, depending on the cut-off values. Discussion was made on dose (Cd-Ucr) and response (α1-MG-Ucr) relationship based on information available in literatures to show that the increment in α1-MG-Ucr per Cd-Ucr was much greater when Cd-Ucr was large, e.g., in excess of 10 µg/g cr. [ABSTRACT FROM AUTHOR]

Objective. The purpose of this data compilation is to overview past and current dietary exposure (primarily via rice) of general populations to cadmium (Cd) in environmentally polluted and non-polluted areas in Japan, and to compare the levels with counterpart levels in other areas in Asia. Methods. A literature survey was conducted for publications on this subject, in either Japanese or international languages, since the early 1970s. Most of the studies identified employed the food-duplicate method in combination with atomic absorption spectrometry for Cd determination, although a few studies utilized other methods, such as the market basket method and dithizon-colorimetry. Results. The highest estimate of dietary Cd intake (Cd-D), 600 μg Cd/day, was reported in the late 1960s for the local population in the Jinzu river basin, where Itai-itai disease had been endemic, and the Cd-D levels were 300 μg/day or higher in other polluted areas. Cd-D dropped to well below 100 μg/day when the polluted soil was replaced in the late 1970s and thereafter. In non-polluted areas, the Cd-D was reported to be approximately 100 μg/day in 1969, followed by a gradual decrease to approximately 40 μg/day in the late 1970s, to reach the current level of less than 30 μg/day. There is a trend of gradual reduction at the rate of 0.3 to 0.6 μg/day per year. Cd from rice accounted for 30 to 40% of the Cd-D in non-polluted areas, but a higher contribution was observed in some polluted areas. Nevertheless, the current Cd-D is still higher than the levels in other rice-dependent populations in east and south-east Asia. Conclusion. The Cd-D levels reported for polluted areas were in excess of 300 μg Cd/day. Substantial reduction in Cd-D to the level below 100 μg/day was observed after remediation, such as replacement of polluted paddy soil. In non-polluted areas, there has been a gradual decrease in Cd-D in the past 25 years. Nevertheless, the levels in the current intake of the general population in Japan (25 to 30 μg/day, or <1/10 of the levels in polluted areas in the past) is still higher than the levels in other rice-dependent areas in Asia. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this report is to outline current regulations to control chemical environmental pollution in Japan, with special references to internationally defined 12 persistent organic pollutants (POPs). Materials: Law concerning the Examination and Regulation of Manufacture, etc. of Chemical Substances [(LERCS); enacted in 1973] and related administrative activities of monitoring of the environment in Japan. Results: Among the existing chemicals identified by the 1972 Chemicals Inventory, LERCS designates aldrin, chlordanes, DDT, dieldrin, endrin, HCB, PCBs, poly(Cln; n=3 or more)-chlorinated naphthalene (PCNs) and bis(tributyltin) oxide (TBTO) as Class 1 specified chemical substances which are under strict regulation, such as prohibition of production, import, or use in principle. In addition LERCS designates 23 Class 2 specified chemical substances (including 13 tributyltin and seven triphenyltin compounds) for which notification of scheduled and past production, compliance with technical guidelines and compliance with labeling standards is requested. When compared with the 12 POPs, the designation covers most of them except for mirex and toxaphene, which have never been used in Japan. The regulation has been effective in reducing substantially the levels of the designated chemical substances (and therefore the 12 POPs except for dioxins and furans) in the general environment in Japan. Efforts are currently focused under a newly enacted law to reduce the emission of the two non-intentionally produced pollutants of dioxins and furans, especially from city waste incinerators, so that emission in 2002 should be 10% of that in 1997. Conclusion: Regulations to control chemical emissions have been effective in reducing POPs levels in the environment in Japan, and further efforts have been made under a new law to reduce the emission of dioxins, furans and co-planar PCBs. [ABSTRACT FROM AUTHOR]

The article presents a study which investigates the occurrence of motor neuron disease (MND) in Kii Peninsula, Japan associated with metal contamination in drinking water. The study use geometric means (GM) arithmetic means (AM) to evaluate the concentration of the eight metals including magnesium, calcium, and lead. Result shows a significant correlation of aluminum concentration in the incidence of MND.

The article presents a study which investigates the correlations among cadmium (Cd) levels in urine, diet, and blood in a general population in Japan. The study examined 37 female farmers aging from 28 to 54 years without any kidney diseases in three rural regions in Japan. Results show that the geometric mean (GM) of Cd-B ranged from the lowest of 2.92 nanogram (ng) per milliliter (ml) in Watari in summer of 1981 to the highest of 5.34 ng/ml in Kannari in summer of 1982.

Investigates the dietary intake of Lead among farmers in Japan. Detection of seasonal variation in females; Effects of smoking and alcohol consumption on lead absorption; Absence of significant correlation between dietary intake and blood lead levels.

Analyzes the baseline level of blood lead concentration among farmers in Japan. Determination of lead concentration; Collection of blood samples from several Japanese farmers; Analysis on the blood lead levels.

The early Aptian Oceanic Anoxic Event (OAE 1a; ca. 120 Ma) was accompanied by a massive eruption of the Ontong Java Plateau, doubling atmospheric p CO₂, and increasing sea surface temperature by 4–8 °C. In this study, we attempted a palynological analysis of the Hauterivian to Cenomanian deep–sea chert from the Goshikinohama site, and successfully obtained a variety of microremains, mainly represented by amorphous organic matter, aggregations of organic and inorganic particles, and cuticle fragments. One Hauterivian and many Aptian samples unexpectedly yielded terrestrial plant material, such as resins and wood fragments with tracheids, which represent the first record of terrestrial plant microremains from deep-sea pelagic chert. The occurrence of wood fragments within the negative and positive δ13C excursions during the OAE 1a can be correlated with an interval of increased atmospheric CO₂ level. We can also suggest that the occurrence of resins, mainly within the mudstone-rich chert intervals of the early Aptian negative δ13C peak and the middle-upper Aptian interval, are possibly related with periods with sea-level drops. Similar massive resin deposition events have been linked with intensified hydrological cycling during other abrupt climatic disruptions, such as the Carnian Pluvial Event, the Triassic−Jurassic boundary, and the Paleocene−Eocene Thermal Maximum. Therefore, an increase of terrestrial plant burial in deep–sea chert is likely linked with a massive plant discharge related with enhanced hydrological cycles, such as intensified storms and/or some sea–level change during the OAE 1a. • This is the first palynological study of pelagic deep-sea chert. • First record of terrestrial plant burial in pelagic deep-sea chert during the OAE 1a. • Increased resins and wood tracheids abundance may relate to environmental changes across the OAE 1a. [ABSTRACT FROM AUTHOR]

Abstract: α1-Microglobulin (α1-MG), β2-microglobulin (β2-MG) and N-acetyl-β-d-glucosaminidase (NAG) are tubular dysfunction markers often used in cadmium (Cd) epidemiology. The purpose of the present study was to identify the best maker among the above-referred three that correlates most closely with Cd in urine of residents with no known Cd pollution. Survey was conducted in 2007–2008 in three prefectures in Japan. Adult women, 2163 in total, participated in the survey; they provided informed consents, offered spot urine samples and filled questionnaires on possible confounders of Cd burden. Urine samples were analyzed for Cd, α1-MG, β2-MG and NAG together with calcium (Ca), magnesium (Mg), creatinine (CR) and specific gravity (SG). The analyte levels, as observed (e.g., Cdob) or after correction for CR (e.g., Cdcr) or SG (e.g., Cdsg) were subjected to simple and multiple regression analysis. Correlation matrix analysis with observed values for total cases showed that the coefficients of correlation with Cd were highest for NAG, followed by α1-MG, and lowest for β2-MG. Multiple regression analysis by three prefectures either separately or in combination (thus four analyses) disclosed that Cd was the independent variable most influential to NAG (as the dependent variable) throughout the four analysis conditions with high R 2 values (>0.3), whereas the most influential variables were not the same depending on the analysis conditions in cases with α1-MG and β2-MG. When coefficients of correlation for the three dysfunction markers with Cd were compared among the observed, CR- and SG-corrected values, the coefficients for the observed values were higher than the counterpart values for CR- or SG-corrected values. In conclusion, NAG rather than α1-MG or β2-MG should be recommended for monitoring Cd exposure-related tubular effects among general populations. Observed (i.e., un-corrected) values rather than CR- or SG-corrected values should be used. [Copyright &y& Elsevier]

The Late Miocene global cooling (LMGC; approximately 7.9-5.8 Ma) was associated with remarkable changes in monsoon dynamics, biogenic bloom in the global oceans, and the rise of modern ecosystems at the expense of old biota. However, the possible linkage between the environmental changes and ecosystem shifts during the LMGC is still debated. In this paper, we show the high-resolution changes in the fluxes of selected radiolarian species, suggesting a drastic reorganization in the paleoceanography and ecosystem in the Japan Sea during the LMGC. The endemic radiolarian Cycladophora nakasekoi dominated the Japan Sea until 7.4 Ma when the Japan Sea sediment changed from dark radiolarian-rich sediment to organic-poor diatom ooze. Changes in the fluxes of C. nakasekoi and Tricolocapsa papillosa, the latter related to changes in the Pacific central water (PCW), show 100, 200, and ~ 500 ka cycles with their high flux mostly within the darker sediment intervals during the low-eccentricity period until 7.4 Ma, suggesting that orbitally paced PCW inflow might have been the major nutrient source into the Japan Sea. At about 7.4 Ma, these species decreased at the expense of increased Larcopyle weddellium, a radiolarian related to the North Pacific intermediate water (NPIW), and Cycladophora sphaeris, a subarctic radiolarian species, implying a decrease in PCW inflow and an increase in the inflow of NPIW and subarctic shallow water. Such a change would have been related to the LMGC-induced weakening in the Pacific Meridional overturning circulation and the southward shift of the subarctic front due to intensified East Asian winter monsoon. Such a drastic reorganization in the hydrography in the Japan Sea probably caused changes in nutrient provenance from the PCW to the NPIW and resulted in faunal turnover, marked by the disappearance of the old regional and endemic faunal components, such as C. nakasekoi., (© 2022. The Author(s).)

The Ministry of Health, Labor, and Welfare of Japan recommends that an occupational physician (OP) play an important role in implementing the stress-check program since 2015. This study aimed to compare the activities and encountered difficulties of Japanese part-time OPs in 2008 and 2016, and to investigate the effects of the stress-check program. Questionnaires were sent via mail to 946 part-time OPs in Kyoto prefecture in 2016. Completed questionnaires were returned by 181 OPs who were private practitioners or physicians in hospitals, and served as OPs on a part-time basis. In 2016, OPs utilized long hours for activities related to general health examination and to stress-check. Hours for specific health examination, health and hygiene education, health promotion activity, development of a comfortable workplace, and guidance of workers on sick leave reduced from 2008 to 2016. A total of 62% OPs frequently encountered difficulties in the stress-check-related activities in 2016. Many OPs also reported difficulties in the mental health care and the prevention of health hazard due to overwork both in 2008 and 2016. Enforcement of the stress-check program in 2015 changed the activities of part-time OPs in Japan. OPs should be given opportunities to gain more information in this area.

Introduction: The 'one biomarker/one drug' scenario is unsustainable because cancer is a complex disorder that involves a number of molecular defects. In the past decade, major technological advances have lowered the overall cost and increased the efficiency of next-generation sequencing (NGS)., Areas Covered: We review recent regulations on NGS and complementary diagnostics in Japan, mainly focusing on high-quality studies that utilized these new diagnostic modalities and were published within the last 5 years. We highlight significant changes in regulation, and explain the direction of efforts to translate the results of NGS and complementary diagnostics into clinical practice., Expert Opinion: NGS holds a number of advantages over conventional companion and complementary diagnostics that enable simultaneous analyzes of multiple cancer genes to detect actionable mutations. Parallel technological developments and regulatory changes have led to the rapid adoption of NGS into clinical practice. NGS-based genomic data have been leveraged to better understand the characteristics of a disease that affects its patient's response to a given therapy. As NGS-based tests become more widespread, however, Japanese authorities will face significant challenges particularly with respect to the complexity of genomic data, which will have to be managed if NGS is to benefit patients.

The objective of the study is to establish exposure-excretion relationship between dichlorometane (DCM) in air (DCM-A) and in urine (DCM-U) in workplace to confirm a previous report. Male workers in a screen-printing plant participated in the study. Time-weighted average DCM-A was measured by diffusive sampling followed by gas-chromatography (GC), and DCM in end-of-shift urine samples was by head-space GC. The data were subjected to regression and other statistical analyses. In practice, 30 sets of DCM-A and DCM-U values were available. The geometric mean DCM-A was 8.4 ppm and that of DCM-U (as observed) was 41.1 µg/l. The correlation coefficients (0.70-0.85) were statistically significant across the correction for urine density. Thus, the analysis for un-metabolized DCM in end-of-shift urine samples is applicable for biological monitoring of occupational exposure to DCM, in support of and in agreement with the previous report. In conclusion, biological monitoring of occupational DCM exposure is possible by use of analysis for un-metabolized DCM in end-of-shift urine.

Background and Aim: Cadmium (Cd) is an ubiquitous environmental toxic pollutant. As daily foods are an almost exclusive source of exposure for general populations, it is of public health importance to know the level of dietary intake of cadmium (Cd-D). The purpose of this study is to examine whether Cd in blood (Cd-B) or urine (Cd-U) correlates with Cd-D in East Asia, and in case it is, whether it is possible to estimate Cd-D from Cd-B or Cd-U. It should be added that the measurement of Cd-D is quite hand-consuming in practice., Materials and Methods: Literature was retrieved for publication on Cd-B and Cd-U in combination with Cd-D. Twenty three data sets thus obtained for East Asia were subjected to regression analysis to investigate the possibility to estimate Cd-D from Cd-B or Cd-U., Results: In Japan and Korea, large correlation coefficients (p > 0.7) were observed between Cd-B and Cd-D, as well as between Cd-U and Cd-D. In China, the coefficient was >0.7 between Cd-B and Cd-D. Furthermore, correlation was significant for Cd-B and Cd-D, as well as Cd-U and Cd-D, when 19 sets for Japan, Korea and China were combined for analysis., Discussion: Major reasons for successful analysis may be predominant use of women-based data. Women have been less smoking than men in East Asia, and possible confounding effects of smoking on Cd exposure might be minimized., Conclusion: Based on significant correlations, Cd-D can be estimated from Cd-B or Cd-U in East Asia., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Background: New drug and medical device introduction in Japan usually lags behind that in the West. Many reports indicate that in Japan, the associated risks are considered greater than the benefits recognized in other countries. This study aimed to compare the relationship between risk-benefit perception and acceptance of medical technologies in 3 leading markets., Methods: A tripartite cross-sectional survey of the general public was used. In total, 3345 adults in the United Kingdom, the United States, and Japan participated, and sexes and age groups were equally represented. Questions about the perception of risk, benefit, and acceptance of medical and other scientific technologies, and trust of medical product providers or regulatory authorities were included., Results: Five-step Likert coding for risk/benefit/acceptance of 4 medical items (x-rays, antibiotics, vaccines, and cardiac pacemakers) and 6 general items (such as automobiles and airplanes) were collected. Relationships between benefit perception and acceptance were linear for 4 medical technologies. The relationship had a similar slope but was shifted downward in Japan compared with the UK and US ( P < .01), suggesting a lower acceptance in Japan for all benefit perceptions. The trend was the same between risk perception and acceptance, except for slopes that were negative. Correspondence analysis showed a strong correlation among acceptance of medical technologies, benefits of medical technologies, trust in doctors, and trust in the Department of Health. The UK and US attributes were clustered with positive responses such as "useful," "acceptable," and "trustworthy," whereas Japan was clustered with intermediate to negative responses such as "neither" and "untrustworthy.", Conclusions: Acceptance of medical technologies was low in Japan because of significant differences in trust for doctors and authorities compared with that in the UK and US. This is a possible basis for delays of 24 to 60 months for medical product approval in Japan.

Objectives: It would be quite convenient if daily dietary cadmium intake (Cd-D) can be estimated either from Cd in blood (Cd-B) or from Cd in urine (Cd-U). The aim of the study was to examine if Cd-D can be estimated from Cd-B or Cd-U., Methods: The data available in a previous publication were employed for regression analyses between Cd-D and Cd-B, and between Cd-D and Cd-U. 30 sites in various prefectures throughout Japan were surveyed and 20 adult women/site on average provided food duplicate, peripheral blood, and second morning urine samples. Geometric means were taken as representative values and employed in regression analyses., Results: Cd-D, Cd-B, and Cd-U(cr) [i.e., Cd-U after correction for creatinine (cr) concentration] distributed in ranges of 12.5-70.5 μg/day, 0.46-3.98 μg/l, and 1.16-11.02 μg/g cr, respectively. A close correlation was observed between Cd-D and Cd-B, and also between Cd-D and Cd-U(cr) with r = 0.76 and r = 0.79 (p < 0.001 for both), respectively. Both regression lines passed close to the origins. Application of 1.23 μg Cd/l blood and 1.26 μg Cd/g cr in urine (average levels for adult Japanese women) to the regression equations gave 16.5 and 11.5 μg Cd/day., Conclusions: The analyses suggested that it may be possible to estimate Cd-D from Cd-B or Cd-U. Cd-B-based estimation should be more respected. As variations in the estimation parameters and estimated values are inherent to field surveys, care should be taken in the application of the study results. Application on a group basis (and not on an individual basis) should be considered.

To develop approval regulations for drugs against chemical, biological, radiological, or nuclear (CBRN) agents in Japan, and to help inform arguments about the development of anti-CBRN agents, we analyzed documentation describing approval processes and data for drugs against CBRN agents. Sixteen countermeasure products against 10 CBRN agents have been approved in Japan. Approval schemes were grouped into 3 categories: application for off-label uses, expedited review for antiterrorism measures, and expedited review. Ten drug applications were designated "priority reviews," and the median review time was 4.4 months. No application relied exclusively on clinical trials to expose patients to CBRN threats. Clinical experience with drugs in victims of unexpected exposure was not necessarily important for approval. The United States is the most advanced country in terms of developing medical countermeasure products against CBRN agents. Japan has similarities with the US in approved products and application packages, but there were 3 unapproved products or indications that were approved under the Animal Rule in the US. The Animal Rule might encourage development of a novel product by providing efficacy evaluation in animal studies. The US also has regulations that do not exist in Japan that authorize administration of an investigational drug outside a clinical trial for patients. Introduction of the Animal Rule and expanded access of investigational drugs could contribute to development and approvals of novel countermeasure products and improve an emergency response in a crisis in Japan.

Objectives: The present study was initiated to examine if application of the same biological occupational exposure limits (BOELs) for organic solvents is applicable across the sexes., Methods: A survey was conducted in 69 micro-scale enterprises in a furniture-producing industrial park. In practice, 211 men and 52 women participated in the survey. They worked in a series of production process, and were exposed to solvent vapor mixtures. The exposure intensities were monitored with two types of diffusive samplers, one with carbon cloth (for solvents in general) and the other with water (for methyl alcohol) as adsorbents. Solvents in the adsorbents and head-space air from urine samples were analyzed with capillary FID-GC. The measured values were subjected to linear regression analysis followed by statistical evaluation for possible sex-related differences in slopes., Results: Essentially no significant difference was detected between men and women in regression line parameters including slopes. Possible differences in the cases of acetone and toluene were discussed and excluded., Conclusions: With the exceptions for acetone and toluene, the present study did not detect any clear differences between men and women. In examinations of past reports, no support for the observed differences was found. The present findings deserve further study so that a solid conclusion can be formed.

Objectives: Standard Tables of Food Composition in Japan 2010 (FCT) remain incomplete for iodine contents. This survey was initiated to develop a method to cope with this shortage and to find daily iodine intake of preschool children in Japan., Methods: Data were available for one-day food intake for 296 3- to 6-year-old children (the total cases). 128 samples (the selected cases) were analyzed by ICP-MS for iodine (the measured values). Iodine intake was also calculated using FCT assuming that iodine contents in missing items were zero (the calculated values)., Results: Measured and calculated values for the selected 125 cases (after exclusion of 3 extreme cases) gave geometric means (GM) of 117.6 and 101.8 μg/day. The measured/calculated ratio in GM, 117.6/101.8 = 1.155, was applied to the calculated values for total 296 cases to estimate iodine intake (the estimated values). GM for the estimated value was 175.2 μg/day and it was 8.93 μg/kg/day after adjustment for body weight for 296 children. There was no significant difference between boys and girls., Discussion: The GM values for both the measured and estimated values (n = 125 pairs) were 117.6 μg/day. The agreement suggested that the factor employed, 1.155, was proper and adequate. Literature survey suggested that values on a body weight basis were comparable between the children and adults in Japan. The levels were higher than levels in east Asian countries., Conclusions: A correction method was developed for estimation of daily dietary iodine intake. The iodine intake level for preschoolers was comparable to levels for adult population.

Objectives: The present analyses were initiated to elucidate changes in types of prevalently used organic solvents in various solvent workplaces in Japan during the past 30 years., Methods: Five publications on industrial solvent use were employed as databases, which were supplemented by solvent workplace surveys in 2010-2012; the surveys were conducted following regulation-stipulated procedures. In practice, data on 500-600 unit workplaces/year were available; the data were classified by types of solvent work according to the regulation., Results: The use of aromatic solvents (typically toluene) has been gradually replaced in a recent few years with methyl alcohol and isopropyl alcohol in surface coating workplaces, whereas toluene has been essentially most prevalent in printing and painting workplaces. In cleaning workplaces, the use of chlorinated hydrocarbon solvents was almost terminated in the years before 2000., Conclusions: The present study may be the first report to note that the prevalence of toluene use has been decreasing in surface coating workplaces to be replaced by alcohols, although toluene has been most prevalent in printing and painting workplaces. In cleaning workplaces, there was a substantial reduction in the use of chlorinated hydrocarbon solvents.

Background and Objectives: Solvents used in production facility-affiliated private laboratories have been seldomly reported. This study was initiated to specify solvent use characteristics in private laboratories in comparison with the use in public research laboratories and on production floors. Elucidation of the applicability of conclusions from a public laboratory survey to private institutions is not only of scientific interest but also of practical importance., Materials: A survey on use of 47 legally stipulated organic solvents was conducted. The results were compiled for April 2011 to March 2013. Through sorting, data were available for 479 unit workplaces in private laboratories. Similar sorting for April 2012 to March 2013 was conducted for public research laboratories (e.g., national universities) and production floors (in private enterprises) to obtain 621 and 937 cases, respectively. Sampling of workroom air followed by capillary gas-chromatographic analyses for solvents was conducted in accordance with regulatory requirements., Results: More than one solvent was usually detected in the air of private laboratories. With regard to solvent types, acetone, methyl alcohol, chloroform and hexane were prevalently used in private laboratories, and this was similar to the case of public laboratories. Prevalent use of ethyl acetate was unique to private laboratories. Toluene use was less common both in private and public laboratories. The prevalence of administrative control class 1 (i.e., an adequately controlled environment) was higher in laboratories (both private and public) than production floors., Conclusions: Solvent use patterns are similar in private and public laboratories, except that the use of mixtures of solvents is substantially more popular in private laboratories than in public laboratories.

Objectives: Laboratories in research institutions use organic solvents in research and development. Nevertheless, the types of solvents in use have been seldom reported. This study was initiated to elucidate types of organic solvents used in large research institutions in Japan, with a focus on possible different use among research fields., Methods: In 2010-2011, 4517 laboratories in seven large research institutions were visited. In accordance with legal stipulations, air in each laboratory was collected in polyvinyl fluoride bags and analyzed by direct injection into a gas-chromatograph for 47 types of organic solvents. In evaluation, the laboratories were grouped by 5 research fields, i.e., agriculture, biology, medicine, natural science, and technology and engineering., Results: Types of organic solvents commonly used in research activities were not diverse. Those commonly used were chloroform and 1,2-dichloroethane out of 7 Group 1 organic solvents (with high toxicities); 6 organic solvents, i.e., acetone and methyl alcohol in general, ethyl acetate, hexane and toluene in technology and engineering laboratories; and xylenes in medical fields out of 40 Group 2 organic solvents (with relatively low toxicities). Judging from solvent vapor concentrations, work environments in more than 99 % of laboratories were considered adequate. Nevertheless, use of chloroform in high-performance liquid chromatography (HPLC) resulted in inadequate environments in 30 laboratories (0.7 %)., Conclusions: Organic solvents commonly used were not very diverse. Work environments in research laboratories were generally good, but the environment with use of chloroform in HPLC analysis remained yet to be improved.