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Purpose: To clarify the current use of unapproved and unproven cancer treatment (UUCT) among the bereaved families of patients with cancer who died in palliative care units, the financial burden and psychological experiences of the families, and the relationship between patients in palliative care who used UUCT and communication with their physicians'., Methods: This study was conducted as part of a cross-sectional, anonymous nationwide survey of the bereaved family members of cancer patients who died in palliative care unit in Japan., Results: Questionnaires were sent to 1,039 bereaved family members, and responses were received from 661 (64%). Of these, 558 were included in the study after excluding the 103 who did not complete the questionnaire. A total of 7.3% (41 of 558) of patients received UUCT. Of these, 34% (14 of 41) of patients were informed that the treatment was in the research phase, and 49% (20 of 41) were informed that the efficacy of the treatment was unknown. Regarding expectations for UUCT, 61% (25/41) expected to be cured, and 80% (33/41) expected it to slow disease progression. In multivariate logistic regression analysis, use of complementary and alternative medicine (CAM) was associated with receiving UUCT (p = 0.024), and patients who could discuss CAM with their doctors tended to receive UUCT (p = 0.054)., Conclusion: Patients in palliative care unit who expect to cure tended to receive UUCT. These results highlight the challenge of telling patients that UUCT is ineffective and informing them of their prognosis and severe medical conditions., Competing Interests: Declarations. Ethical approval: Ethical approval for the study was granted by the ethics committee of Tohoku University Hospital and all participating institutions (2017–2-236–1). Ethics accordance: Our study was conducted in accordance with the Henschilki Declaration. Consent to participate: The return of the questionnaires was considered as informed consent for this study. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The Yatsushiro Sea in Japan is contaminated with mercury in wastewater discharge from the Chisso Company, which produced acetaldehyde from 1932 onwards. In this study, we investigated the current spatial distribution of total mercury (T-Hg) in sediments, both at the surface and at different depths, using 43 sediment cores and 22 surface sediment samples collected from the Yatsushiro Sea in August 2017. Altogether, 821 surface and core samples were analyzed for their T-Hg concentrations. Most of the mercury that was discharged from Chisso remained either in, or around the exit of, Minamata Bay, but some had been transported from Minamata Bay to the Nagashima Sea. We estimated that almost 51 and 6 tons of mercury had accumulated in the Yatsushiro and the Amakusa Sea areas, respectively. The amount of acetaldehyde produced in Chisso over time was correlated with the T-Hg concentrations in the sediments from the Yatsushiro Sea., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The human fetus is known to be exposed to methylmercury (MeHg), but little is known about the risk of infant exposure via breast milk. To evaluate the lactational exposure to MeHg via breast milk in Japanese infants, the levels of total mercury (THg) and MeHg were determined in breast milk and maternal blood using samples from a birth cohort study at the Tohoku Study of Child Development. Maternal blood and breast milk were collected one day postpartum and one month after delivery, respectively. The median THg (and MeHg) concentrations in maternal RBCs, plasma and breast milk were 17.8 ng g(-1) (17.8 ng g(-1)), 1.51 ng g(-1) (1.33 ng g(-1)) and 0.81 ng g(-1) (0.45 ng g(-1)), respectively (n=27). The median percentage of MeHg in THg was 54% in breast milk. Breast milk contained substantial amounts of MeHg, which was strongly associated with the internal accumulation of MeHg and the lipid content of the milk (r=0.684). The range of lipid contents in milk varied widely from 0.50 to 6.60 g/100 g of milk, with a median of 3.60 g/100 g. The median (range) weekly average intake of MeHg via breast milk was estimated to be 0.63 μg kg(-1) (0.08-1.68 μg kg(-1)) BW/week. Because the MeHg and lipid contents in milk substantially fluctuate, an investigation of the variations of MeHg and lipid content in breast milk may be required for a more precise risk assessment., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Methylmercury (MeHg) is one of the most risky substances to affect humans through fish consumption, and the fetus is known to be in the most susceptible group. Our objective in this study is to examine the relationships of total mercury (THg) and MeHg concentrations between umbilical cord tissue and other tissues as biomarkers of fetal exposure to MeHg in the Japanese population. In total, 116 paired samples were collected in three Japanese districts, the Tsushima Islands, Fukuoka City, and Katsushika ward of metropolitan Tokyo. THg was measured for hair and THg and MeHg were measured in cord tissues, maternal blood, and cord blood. The relationships among tissues in Hg concentrations were similar among districts. Therefore, we analyzed the relationships using all the samples. More than 90% of Hg in cord tissue, cord blood, and maternal blood was MeHg. THg and MeHg in cord blood was about two times higher than in maternal blood. A strong correlation was found between THg and MeHg in cord tissue. The cord tissue THg and MeHg showed a strong correlation with cord blood Hg, which is recognized as the best biomarker for fetal exposure to MeHg. The findings of this study indicate the significance of cord tissue THg and MeHg as biomarkers for fetal exposure to MeHg at parturition.

Mercury-contaminated effluent was discharged into Minamata Bay from a chemical plant over a period of approximately 40 years until 1968. In October 1977, the Minamata Bay Pollution Prevention Project was initiated to dispose of sedimentary sludge containing mercury concentrations higher than 25 mg kg(-1). In March 1990, the project was completed. In an effort to estimate current contamination in the bay, the vertical and horizontal distributions of mercury in sediment were investigated. Sediment core samples were collected on June 26, 2002 at 16 locations in Minamata Bay and Fukuro Bay located in the southern part of Minamata Bay. The sediment in Fukuro Bay had not been dredged. The total mercury concentration in surface sediment was 1.4-4.3 mg kg(-1) (2.9+/-0.9 mg kg(-1), n=9) for the dredged area of Minamata Bay and 0.3-4.8 mg kg(-1) (3.6+/-1.6 mg kg(-1), n=4) for Fukuro Bay. In the lower layers of long cores taken from both areas, the total mercury concentration decreased with depth and finally showed relatively uniform low values. These values can be considered to represent the background concentration absent of anthropogenic influence, which was estimated for the study area to be 0.068+/-0.012 mg kg(-1) (n=10). From the surface, the total mercury concentration in Fukuro Bay increased with depth and reached a maximum at 8-14 cm. In Minamata Bay, several centimeters from the surface the total mercury concentration did not change significantly having considerably higher values than the background level. At six stations, the methylmercury concentration was determined. Although the vertical variations were similar to those for total mercury, Fukuro Bay sediment showed a higher concentration of methylmercury than Minamata Bay sediment.

The purpose of this retrospective study was to examine the effect of methylmercury pollution on the sex ratio of offspring at birth and of fetuses at stillbirth in Minamata City, Japan, in the 1950s when severe and widespread methylmercury pollution was experienced. In 4 of 5 years from 1955 to 1959 when methylmercury pollution was most severe, lower numbers of male offspring at birth were observed in the city population. The offspring sex distributions from 1950 to 1969 by 5-year period were calculated in the overall population of Minamata City, in the most prevalent area, in fishermen (most heavily exposed occupation group) and among Minamata disease patients using data from birth certificates. We also similarly calculated the sex ratio of stillborn fetuses in the city population using Kumamoto Prefecture's vital statistics on still-birth. Decreases in male births were observed in offspring in the overall city population, in fishermen, and in maternal Minamata disease patients in the city in 1955-1959, when the methylmercury pollution was most severe. An increase in the proportion of male stillborn fetuses in the city was observed at the time. It is possible that male fetuses were more susceptible to the pollution than their female counterparts, and this could be a cause for the lower numbers of male offspring at birth., (Copyright 2001 Academic Press.)

Autopsy specimens from the historic cat experiment were recently discovered in a storage area at the Kumamoto University School of Medicine. The specimens were from an experiment prompted by physicians in the Chisso Minamata Plant following the announcement made by the Study Group for Minamata disease. On July 14, 1959 the Group announced that the disease was most likely caused by a kind of organic mercury. In order to prove or disprove that industrial waste from the Chisso Factory was the culprit in Minamata disease, a total of ten cats were fed food mixed with industrial waste produced in the acetaldehyde-producing plant. One of the ten cats, No. 717, was subsequently autopsied but the autopsy findings have never been published or recorded in the literature despite their historic significance. The rediscovered specimens were studied pathologically and biochemically, and were analyzed chemically with currently available techniques. Characteristic lesions of methylmercury poisoning were observed in the central nervous system, and the mercury levels in the cerebrum, cerebellum, liver and kidney were found to be markedly elevated in this animal.

Based on our previous finding that the concentrations of total mercury in mussel adductor muscle approximated those of methylmercury, we compared concentrations of total mercury in the adductor muscle of the mussel Mytilus galloprovincialis, collected from four sites around Minamata City from 1993 to 1995 and four sites in Kagoshima Bay from 1997 to 1998, to assess the level of localized methylmercury contamination. Though the input of mercury from the chemical plant had stopped by around 1970, concentrations of total mercury in the mussel adductor muscle were higher at two sites (26-121 ng/g, n = 135) near the main fallout of wastewater from the chemical plant in Minamata Bay than at the other sites, i.e. two sites 1-5 km from the former sites in Minamata City (6-28 ng/g, n = 52), and all sites in Kagoshima Bay (2-30 ng/g, n = 287). The localized methylmercury contamination around the chemical plant in Minamata Bay was documented also by our sensitive analysis of mercury concentrations in seawater and sediment samples. The survey of concentrations of total mercury in the mussel adductor muscle seems to be useful for monitoring the methylmercury contamination in coastal areas.

Mercury-contaminated effluent was discharged into Minamata Bay from a chemical plant over a 20-year period until 1965 (from 1958 to 1959, effluent was discharged into Minamata River), causing Minamata disease. In an effort to characterize the extent of the contamination in the Yatsushiro Sea, the vertical and horizontal distributions of mercury in sediment were investigated. Sediment was sampled at 62 locations in the southern part of the sea from 4 to 6 March 1996. In the lower layers of the long cores of sediment, the total amount of mercury was at a relatively uniform low concentration. We interpret these low values to represent the background concentration absent of anthropogenic influence. The background value thus estimated for the Yatsushiro Sea was 0.059 +/- 0.013 mg kg(-1) (mean +/- S.D., n = 51). The highest concentration in each sample ranged from 0.086 to 3.46 mg kg(-1) (mean, 0.57 mg kg(-1)). The higher values were obtained at stations near Minamata Bay and the Minamata River (the sources of the pollution). Concentrations decreased with distance from the source. An inspection of the vertical profiles of mercury concentration in cores suggested that the deposited mercury had not been fixed in sediment but had been transported, despite 30 years having past since the last discharge of contaminated effluent. At nine stations, extractable inorganic and organic mercury concentrations were determined differentially. Inorganic mercury is the predominant species in sediment and organic mercury comprising approximately 1% of the total.

A total of 151 umbilical cords during the period from 1950 to 1969 were collected from the residents of the Minamata area (including 25 patients with congenital Minamata disease) for methylmercury (MeHg) analysis. When the MeHg discharge from the Chisso Company's Minamata factory into the Minamata Bay is compared with the incidence of congenital Minamata disease, the abrupt increase of the former in 1952 [Nishimura H. Chem. Today 1998;323:60-66] was found to precede that of the latter by approximately 2 years, thereby indicating that MeHg is the cause of the disaster. This was confirmed by the elevated levels of MeHg in the umbilical cords from residents of the Minamata area [from 0.35 +/- 0.30 (S.D.) ppm in 1952 to 0.96 +/- 0.75 ppm in 1955], the MeHg levels (1.60 +/- 1.00 ppm) in the cords from patients with congenital Minamata disease showing the highest values [P < 0.01 vs. acquired Minamata disease (0.72 +/- 0.65 ppm), mental retardation (0.74 +/- 0.64 ppm), other diseases (0.22 +/- 0.15 ppm), and no symptoms (0.28 +/- 0.20 ppm), respectively]. Thus, in order to fill a gap, which extends over a long period of time, in studies on environmental Hg pollution, umbilical cord samples were considered to be a useful tool.

The methylmercury exposure of patients with congenital or infantile Minamata disease is known only from a small number of analyses of umbilical cords. Four laboratories in Japan have analyzed a total of 176 samples of umbilical cord tissue obtained from Minamata. The highest concentrations were seen in cord tissue from children born during 1950-1965, i.e., the peak period of acetaldehyde production in Minamata before installation of waste water treatment. Twenty-four samples from patients diagnosed with Minamata disease showed a median mercury concentration of 1.63 microg/g and differed significantly from levels seen in cord tissue from control children. However, children diagnosed with mental retardation had mercury concentrations in cord that were intermediate between the two other groups. Using regression coefficients obtained at a study conducted at the Faroe Islands, the median cord mercury concentration from the children with Minamata disease is estimated to correspond to about 216 microg/L cord blood and 41 microg/g in maternal hair. Based on correlations reported in the literature, the median daily mercury intake of the women whose children developed Minamata disease can then be estimated at about 225 microg. Although these children had fully developed Minamata disease, the estimates of median mercury levels are only four to five times higher than current mercury exposure limits., (Copyright 1998 Academic Press.)

The hair-organ relationship of mercury concentration was investigated in 46 autopsy samples in Tokyo, Japan. Hair mercury levels were highly significantly correlated with organ Hg levels in the cerebrum, cerebellum, heart, spleen, liver, kidney cortex, and kidney medulla, when the total mercury or methyl mercury value in the organ was compared with the hair total mercury or organic mercury, respectively. When the inorganic mercury value was tested, significant correlations remained, with weaker coefficients in all the organs but the spleen. Stepwise multiple regression analysis evidenced that the hair organic mercury value was the major explanatory variable for the organ total mercury or organ methyl mercury value in all the organs. To explain the organ inorganic mercury value, the hair organic mercury value was the major variable for the cerebrum and kidney (both cortex and medulla), the hair inorganic mercury value was the major variable for the cerebellum and heart, and the hair phosphorous and hair organic mercury were the major variables for the liver; no explanatory variable existed for the spleen. Auxiliary explanatory variables accounted for the organ total mercury and inorganic mercury levels, among which the hair selenium value was conspicuous with negative regression coefficients.

Multi-element analyses were conducted on internal organs (cerebrum, cerebellum, heart, spleen, liver and kidney) of Japanese obtained from 45 forensic medical autopsy cadavers. Elements analyzed and analytical methods were as follows: Ca, Cd, Cu, Fe, K, Mg, Na, P and Zn by inductively coupled plasma atomic emission spectrometry; total Hg (T-Hg) and inorganic Hg (I-Hg) by cold vapour atomic absorption spectrometry; methyl Hg (MeHg) by gas chromatography; and Se by fluorometry. A significantly positive correlation between Se and T-Hg was observed in kidney, liver, heart and spleen. The T-Hg/Se molar ratio was less than 1 in all the organs examined. The correlation between Zn and Cd was significant in liver and kidney. Multiple regression analyses using Se as a dependent and I-Hg, MeHg, Zn, Cd, Cu as independent variables were conducted on each organ. Inorganic Hg was a significant independent variable in kidney, whereas in liver and spleen it was MeHg. Cadmium was significant in explaining the variations in Se in liver and kidney medulla, indicating Cd-Se co-accumulation in humans.

Analysis of mortality of 439 deaths that occurred among 1483 patients with Minamata disease (MD) in Kumamoto Prefecture, Japan was performed from the end of 1981. Causes of death and survival rates were studied by means of the standardized mortality ratio (SMR) and life-table technique. Of the 439 deaths (29.6%) in MD cases, the first death occurred in 1954. There was a first peak incidence in 1956 when MD was initially reported, however, the majority of deaths occurred after 1972 when a second and much larger peak was evident. In 1970 an important milestone occurred when the Public Nuisance Relief Law (an anti-pollution law) was enacted. Among its provisions, this law required and enabled verification of MD among people suspected of having been exposed. In contrast to the early cases, later cases of MD were older and their mean age-at-death was not different from that of the general population. The mortality rate for all causes of death was significantly higher in both sexes compared to the general population. Significantly lower survival rates were noted for older patients. The cause-specific mortality rates also showed significantly increased SMRs for liver diseases and nephritis-nephrosis-nephrotic syndrome in male patients, and for nephritis-nephrosis-nephrotic syndrome and other diseases in females. On the other hand, the SMR for senility without mention of psychosis was significantly lower than expected in both sexes.

The causes of death in Minamata disease were analyzed and compared with those of control subjects. Of the 1422 Minamata disease patients in the Kumamoto Prefecture, 378 had died by the end of 1980. Of these 378, the first death occurred in 1954 with a peak incidence in 1956 when Minamata disease was officially reported for the first time. The number of deaths increased rapidly after 1972 with a second peak in 1976. The male:female ratio was 1.8:1 and the mean age-at-death was 67.2 years (SD = +/- 18.65). The mean age-at-death was younger in the cases of the initial outbreak than in those recently. There were, on the average, 2.8 causes of death per person. Of these cases, 157 (41.5%) had Minamata disease indicated on the death certificate, though 64 (16.9%) had Minamata disease coded as the underlying cause. Minamata disease and the noninflammatory diseases of the central nervous system (CNS) were the main underlying causes of death between 1954 and 1969, while, in the multiple cause data, pneumonia and non-ischemic heart disease were the most prevalent. Cerebrovascular diseases (18.0%) were the main underlying causes of death followed by malignant neoplasms (14.7%), cardiovascular diseases (14.1%) and Minamata disease (14.1%) in 1970 or later, while cardiovascular diseases (18.6%), Minamata disease (14.5%), cerebrovascular diseases (10.4%) and malignant neoplasms (7.1%) were the major multiple causes of death. As compared with the control, the proportions of deaths due to noninflammatory diseases of CNS and pneumonia were higher in the initial outbreak. Although the difference in the causes of death was less apparent recently, malignant neoplasms and hypertensive diseases tended to be lower. These results suggest that there is a need for a long-term follow-up of Minamata disease patients. The data also show the potential value of multiple causes of death coding in analyses of mortality.

Concentrations of inorganic mercury (IHg), methylmercury (MeHg), and total mercury (THg) were determined for autopsy samples from 46 Japanese subjects. Two laboratories (Labs A and B) participated in Hg analyses: Lab A for THg and IHg and Lab B for THg and MeHg. Total mercury concentration values were in good agreement between the two laboratories: the averages were several hundreds of ng/g in kidney cortex, kidney medulla, and liver, and were several tens of ng/g in cerebrum, cerebellum, heart, and spleen. Inorganic mercury accumulated more in kidney and liver: its percentage THg was 81-84% in the kidney, 67% in the liver, 25% in the heart, 22% in the spleen, 20% in the cerebrum, and 14% in the cerebellum. Methylmercury levels in tissues were uniform through all organs except the liver. Approximately 80% was in the form of MeHg in the cerebrum, cerebellum, heart, and spleen, whereas the values were 33%, 15%, and 11% in the liver, kidney medulla, and kidney cortex, respectively. Age was a significant factor in increased IHg concentrations in the cerebrum and heart, decreased values of %MeHg in the cerebrum, cerebellum, and heart, and increased values of %IHg in the cerebrum and heart.