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Fifty-five children aged 2 years from a birth cohort in the largest dioxin-contaminated area in Bien Hoa city, Vietnam participated in this survey to examine gaze behavior. Exposure levels were indicated by 2,3,7,8-tetrachlorodibenzo-p-dibenzodioxin (TCDD) and toxic equivalent of polychlorinated dibenzo-p-dioxin and polychlorinated dibenzofuran (TEQ-PCDD/Fs) levels in maternal breast milk. The percentage of the total fixation duration on the face (% Face), mouth (% Mouth), and eye areas (% Eyes) when viewing silent and conversation scenes was used as gaze behavior indices. When they reached 3-year-old, autistic behavior was assessed using the Autism Spectrum Rating Scale (ASRS). A general linear model adjusted for confounding factors was used to compare gaze indices and ASRS scores between high and low dioxin exposure groups. Effects of perinatal dioxin exposure on gaze behavior were found only when viewing conversation scenes indicated by lower % Face for boys in high TCDD exposure group and lower % Eyes for girls in high TEQ-PCDD/Fs group. Increased autistic traits showed by higher ASRS scores at 3-year-old were found in both gender in the high TCDD exposure group. These findings indicate that perinatal TCDD and TEQ-PCDD/Fs exposure may reduce gaze behavior in 2-year-old children, predicting increased autistic traits at 3-year-old. [ABSTRACT FROM AUTHOR]

Bien Hoa airbase is the most contaminated area of dioxin contamination from Agent Orange in Vietnam, but little is known about the neurodevelopmental effects of perinatal dioxin exposure on children living nearby. We recruited 210 mother–newborn resident pairs in 2012 and 78 pairs in 2015 and followed them for 2 years to assess the children's neurodevelopment. As a control group, we used 120 mother–child pairs recruited in 2014 in the Ha Dong district of Ha Noi City, an unexposed area. Perinatal dioxin exposure levels were indicated by levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and toxic equivalency values of polychlorodibenzodioxins, polychlorodibenzofurans, and nonortho-polychlorinated biphenyls (TEQ-PCDD/Fs/noPCBs) in maternal breast milk. The Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) were used to assess neurodevelopment, and scores in each domain were compared between children with different exposure levels using general linear regression models and stratification by sex. Decreased expressive and composite language scores in boys and gross motor scores in girls were found in children exposed to TCDD ≥ 5.5 (pg/g lipid) compared with children with TCDD < 1.8. However, in matched pair analysis between children with TCDD ≥ 5.5 and <1.8 (pg/g lipid), lower expressive and composite language scores in boys exposed to TCDD ≥ 5.5 were significant, but lower gross motor scores in girls did not reach statistical significance. In addition, significant association was found between levels of PCDD congeners other than TCDD and gross motor scores in boys. These findings suggest that perinatal exposure of TCDD and other PCDD congeners affects development of language and gross motor skills, respectively, in boys at 2 years of age exposed to dioxins originating from Agent Orange in Vietnam. Unlabelled Image • Decreased language scores were found in boys exposed to high TCDD. • Gross motor scores decreased at borderline significance in girls with high TCDD. • Gross motor scores decreased in boys with high PCDD congeners other than TCDD. [ABSTRACT FROM AUTHOR]

Abstract We previously reported the adverse effects of perinatal dioxin exposure on child neurodevelopment around a former US military airbase in Vietnam. In the present study, we investigated the effects of maternal dioxin exposure on fetal brain development, which may predict neurodevelopmental outcomes in early childhood. A total of 55 newborns with mothers from dioxin-contaminated areas were recruited in the prefecture hospital in Bien Hoa, Vietnam. Dioxins in maternal breast milk collected 1 month after birth were used as a maternal exposure marker. Relative powers and coherence were computed from neonatal electroencephalogram (EEG) records during active sleep stages. Relationships between the EEG parameters and dioxin exposure markers were analyzed using linear regression and a general linear model after adjusting for gestational age, body length, and head circumference of infants at birth. Using data from 47 infants whose neurodevelopment was examined in a 2-year follow-up study, associations between EEG parameters and neurodevelopment were analyzed after adjusting for confounding factors. On the right frontal and parietal regions, relative delta powers were significantly decreased, and relative alpha and beta powers were significantly increased with increasing dioxin exposure. Increases in delta power and decreases in alpha power on the right frontal and parietal regions were associated with an increase in language scores at 2 years of age. Furthermore, intra- and inter-hemispheric coherence in theta and alpha bands were positively and inversely correlated with dioxin exposure, respectively, and increased intra-coherence in the right hemisphere was associated with lower language scores. These findings suggest that prenatal dioxin exposure affects neuronal activity and functional connectivity between brain regions, and may lead to poor language development. Graphical abstract Unlabelled Image Highlights • Prenatal dioxin exposure affects neuronal activity estimated from neonatal EEG. • Relative power and coherence of neonatal EEG are good markers for brain development. • Alteration of neonatal EEG might lead to poor language development at 2 years of age. [ABSTRACT FROM AUTHOR]

We investigated dioxin concentrations in the blood of residents living in areas with different sources of dioxin pollution in Vietnam. A total of 823 individual blood samples were collected in 2014–2015 from residents of 16 provinces in Vietnam who were born between 1972 and 1976, and who lived in rural unsprayed areas (the control area), industrialized unsprayed areas (the industrialized area), and areas in which herbicides were sprayed during the Vietnam War (the sprayed area). After blood collection, pooled samples were obtained by combining 10–25 individual samples by age and sex for each area. A total of 6, 10, and 26 pooled blood samples were obtained for the control area, industrialized area, and sprayed area, respectively. The concentrations of 17 polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans were quantified in each pooled blood sample. The concentrations of TCDD, 1,2,3,7,8,9-HxCDD, 1,2,3,7,8-PeCDF, and OCDF were significantly higher in the sprayed area than in the unsprayed area, which comprised the control and industrialized areas. The toxic equivalents of PCDDs, TCDD, 1,2,3,7,8-PeCDF, and 1,2,3,6,7,8-HxCDF were significantly higher in the sprayed area than in the control area. No significant difference in dioxin concentration was found between the sprayed and industrialized areas after adjusting for sex. The 1,2,3,6,7,8-HxCDF concentration was significantly higher in the industrialized area than in the control area. The findings indicate that there are different dioxin congener blood profiles in residents of industrialized areas and areas in which herbicides were historically sprayed during the Vietnam War. [Display omitted] • Dioxin congeners varied between the herbicide-sprayed and industrialized areas. • Higher TEQs of PCDDs, TCDD, 1,2,3,7,8-PeCDF, and 1,2,3,6,7,8-HxCDF in sprayed than unsprayed area. • Increased 1,2,3,6,7,8-HxCDF concentrations was found in the industrialized area. [ABSTRACT FROM AUTHOR]

Dioxin concentrations remain elevated in both the environment and in humans residing near former US Air Force bases in South Vietnam. This may potentially have adverse health effects, particularly on infant neurodevelopment. We followed 214 infants whose mothers resided in a dioxin-contaminated area in Da Nang, Vietnam, from birth until 1 year of age. Perinatal exposure to dioxins was estimated from toxic equivalent (TEQ) levels of polychlorinated dibenzodioxins and polychlorinated dibenzofurans (PCDDs/Fs-TEQ), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TetraCDD) concentrations in breast milk. In infants, daily dioxin intake (DDI) was used as an index of postnatal exposure through breastfeeding. Neurodevelopment of toddlers was assessed using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). No significant differences in neurodevelopmental scores were exhibited for cognitive, language or motor functions between four exposure groups of PCDDs/Fs-TEQ or 2,3,7,8-TetraCDD. However, social–emotional scores were decreased in the high PCDDs/Fs-TEQ group and the high 2,3,7,8-TetraCDD group compared with those with mild exposure, after adjusting for confounding factors. Cognitive scores in the mild, moderate, and high DDI groups were significantly higher than those in low DDI group, but there were no differences in cognitive scores among the three higher DDI groups. These results suggest that perinatal exposure to dioxins may affect social–emotional development of 1-year-old toddlers, without diminishing global neurodevelopmental function. [ABSTRACT FROM AUTHOR]

Previously, we reported that the global brain volume was significantly higher in men with estimated perinatal dioxin exposure in Vietnam. In this study, we aimed to clarify which brain lobes, consisting of several gyri, contributed to the increased global brain volume. We then analyzed associations between changes in brain volume and social anxiety symptoms to investigate the role of structural changes of the brain on social anxiety following perinatal dioxin exposure. Thirty-three men living near the dioxin-contaminated Bien Hoa airbase, underwent MRI examination. The regional gray matter volumes were extracted using the SPM12 in a MATLAB environment, and compared between subgroups with and without perinatal dioxin exposure estimated from their maternal residency in Bien Hoa during pregnancy. The social anxiety questionnaire for adults (SAQ-A30) was used to assess social anxiety. In both hemispheres, higher gray matter volume in the frontal and temporal lobes, particularly in the superior frontal gyrus, superior temporal gyrus, and temporal pole were found in men with perinatal dioxin exposure. Superior temporal gyrus volume was significantly higher in men with perinatal exposure also after adjusting for reduction of its volume associated with increasing 1,2,3,7,8-PentaCDD levels in blood. Increased volume of these gyri, which showed higher volume in men with perinatal exposure, was associated with increased SAQ-A30 scores. Perinatal dioxin exposure may increase the brain volume of gyri involved in social behavior, which was associated with increased social anxiety symptoms, suggesting functional effects accompanied the morphological effects of dioxin exposure. [ABSTRACT FROM AUTHOR]

In our previous study of 3-year-old children in a dioxin contamination hot spot in Vietnam, the high total dioxin toxic equivalent (TEQ-PCDDs/Fs)-exposed group during the perinatal period displayed lower Bayley III neurodevelopmental scores, whereas the high 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-exposed group displayed increased autistic traits. In autistic children, urinary amino acid profiles have revealed metabolic alterations in the amino acids that serve as neurotransmitters in the developing brain. Therefore, our present study aimed to investigate the use of alterations in urinary amino acid excretion as biomarkers of dioxin exposure-induced neurodevelopmental deficits in highly exposed 3-year-old children in Vietnam. A nested case-control study of urinary analyses was performed for 26 children who were selected from 111 3-year-old children whose perinatal dioxin exposure levels and neurodevelopmental status were examined in follow-up surveys conducted in a dioxin contaminated hot spot. We compared urinary amino acid levels between the following 4 groups: (1) a high TEQ-PCDDs/Fs and high TCDD-exposed group; (2) a high TEQ-PCDDs/Fs but low TCDD-exposed group; (3) a low TEQ-PCDDs/Fs exposed and poorly developed group; and (4) a low TEQ-PCDDs/Fs exposed and well-developed group. Urinary levels of histidine and tryptophan were significantly decreased in the high TEQ-PCDDs/Fs and high TCDD group, as well as in the high TEQ-PCDDs/Fs but low TCDD group, compared with the low TEQ-PCDDs/Fs and well-developed group. However, the ratio of histidine to glycine was significantly lower only in the high TEQ-PCDDs/Fs and high TCDD group. Furthermore, urinary histidine levels and the ratio of histidine to glycine were significantly correlated with neurodevelopmental scores, particularly for language and fine motor skills. These results indicate that urinary histidine is specifically associated with dioxin exposure-induced neurodevelopmental deficits, suggesting that urinary histidine may be a useful marker of dioxin-induced neurodevelopmental deficits and that histaminergic neurotransmission may be an important pathological contributor to dioxin-mediated neurotoxicity. [ABSTRACT FROM AUTHOR]

Background: The aim of the present study was to estimate the benchmark doses (BMD) for renal effects for health risk assessment of residents living in Cd-polluted and non-polluted areas in a Thai population. Methods: The study participants consisted of inhabitants aged 40 years or older who lived in a non-polluted area (40 men and 41 women) and in the environmentally polluted Mae Sot District (230 men and 370 women) located in northwestern Thailand. We measured urinary and blood cadmium (Cd) as markers of long-term exposure and urinary β2-microglobulin (β2-MG) and N-acetyl-β-D-glucosaminidase (NAG) as renal tubular effect markers. An updated hybrid approach was applied to estimate the benchmark doses (BMD) and their 95% lower confidence limits (BMDL) of urinary and blood Cd for Cd-induced renal effects in these subjects. BMD and BMDL corresponding to an additional risk (BMR) of 5% were calculated with the background risk at zero exposure set to 5% after adjusting for age and smoking status. Results: The estimated BMDLs of urinary Cd for renal effect markers were 6.9 for urinary β2-MG and 4.4 for NAG in men and 8.1 for β2-MG and 6.1 for NAG μg/g creatinine (Creat) in women. These BMDLs of urinary Cd (μg/g Creat) for NAG were less than the geometric mean urinary Cd in the polluted area (6.5 in men and 7.1 in women). The estimated BMDLs of blood Cd (μg/L) were 6.2 for urinary β2-MG and 5.0 for NAG in men and 5.9 for β2-MG and 5.8 for NAG in women. The calculated BMDLs were similar or less compared with the geometric mean blood Cd (μg/L) in the polluted Thai area (6.9 in men and 5.2 in women). Conclusion: The BMDLs of urinary and blood Cd for renal effects were estimated to be 4.4 − 8.1 μg/g Creat and 4.4 − 6.2 μg/L in the Thai population aged ≥ 40 years old, suggesting that more than 40% of the residents were at risk of adverse renal effects induced by Cd exposure in Thailand. [ABSTRACT FROM AUTHOR]

Abstract: Previous studies have reported that maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces socioemotional and cognitive disturbances in rat offspring. In the present study, the effects of maternal TCDD exposure on putative inhibitory interneurons were investigated in the medial prefrontal cortex (mPFC), basolateral amygdala (BLA), hippocampus (HP), and superior colliculus (SC) in rat offspring. Dams were given TCDD (1.0μg/kg) on gestational day 15. When offspring rats reached adulthood (14 weeks old), parvalbumin (PV)- and calbindin (Calb)-immunoreactive neurons were immunohistochemically investigated. The histological investigations indicated that the mean area of the mPFC had increased, whereas the mean area of the SC decreased in the exposed male rats. In the exposed female rats, the mean SC area increased. Furthermore, the number and area of PV-immunoreactive neurons increased in the mPFC of the female exposed rats. In contrast, the number of PV-immunoreactive neurons in the BLA, HP, and SC decreased in the male and female exposed rats. The number of Calb-immunoreactive neurons decreased in the HP of the male and female exposed rats and the SC of the female exposed rats. Because PV- and Calb-immunoreactive neurons, which are putatively GABAergic, have been implicated in various higher brain functions, the effects of TCDD on socioemotional and cognitive functions might be mediated partly through these alterations in PV- and Calb-immunoreactive neurons in these areas. [Copyright &y& Elsevier]

Dioxin exposure levels remain elevated in residents living around former US Air Force bases in Vietnam, indicating potential adverse impacts on infant growth. In this study, 210 mother-infant pairs in dioxin-contaminated areas in Vietnam were recruited at the infants' birth and followed up for 4 months. Perinatal dioxin exposure levels were estimated by measurement of polychlorinated dibenzo-p-dioxins/furans toxic equivalent (PCDDs/Fs-TEQ) in breast milk. The infants' size was measured at birth and 1 and 4 months after birth, and neurodevelopment was evaluated using the Bayley Scales III at 4 months of age. Among 4 dioxin groups (<25, 25-50, 50-75, ≥75 percentile of PCDDs/Fs-TEQ), cross-sectional comparisons of body size and neurodevelopment scales and comparisons of longitudinally assessed body size were performed respectively. At birth, head circumference of girls in the ≥75 percentile group was significantly larger than those in the <25 and 50-75 percentile groups. At 4 months of age, the weight and body mass index (BMI) of boys in the ≥75 percentile group were significantly lower than those in the other groups. Increase in weight was significantly lower in the ≥75 percentile group in both sexes from birth to 1 month but only in boys at 1-4 months of age. Estimated marginal mean values in a mixed model of weight and BMI during the first 4 months of life were significantly lower in the ≥75 percentile group in boys. In girls, marginal mean values for head circumference were increased with increase in dioxin levels. Only in boys, cognitive, language, and fine motor scores in the≥75 percentile group were significantly lower than those in the other groups. These results suggested a considerable impact of perinatal dioxin exposure on infant growth, particularly in boys exposed to dioxins at high level of PCDDs/Fs-TEQ. [ABSTRACT FROM AUTHOR]

Abstract: This study evaluated residual congener patterns of dioxin/furan (=PCDD/DF) related to tactical herbicides aerially sprayed over the regions of southern Vietnam through Operation Ranch Hand. The study focused on Cam Chinh (CC) commune, Quang Tri province (an area sprayed with tactical herbicides), and the Cam Phuc (CP) commune, Ha Tinh province (a non-sprayed area). Breast milk samples for analysis were collected in September 2002 and July 2003 from lactating primiparous and multiparous mothers born after the war (<31years old). We found the levels of each congener in the CC commune were higher than in the CP commune, and determined specificity in the PCDD/DF congener pattern in CC commune samples by cluster analysis. The congener pattern is characterized by higher (the hexa-, the hepta-, and the octa-) chlorinated PCDD/DFs; this appears to be the same profile as that presented by pentachlorophenol (PCP), rather than 2,4,5-trichlorophenoxy acid (2,4,5-T) contaminated with 2,3,7,8-TCDD. A GC/MS study in the 1970s detected the chlorophenols 2,4-di and 2,4,6-trichlorophenol in some Agent Orange samples, which contained, like PCP, a wide variety of PCDD/DF congeners. In this context, it may be expected that certain tactical herbicides contaminated with various chlorophenol impurities, have a unique congener pattern when compared with pure 2,4,5-T formulations. [Copyright &y& Elsevier]

Dioxins are known to affect infant growth and neurodevelopment in both humans and animals. In this study, we examined the relationship between neonatal head circumference, which is related to fetal brain development, and the concentration of dioxins in breast milk as an indicator of maternal exposure. A total of 42 milk samples were obtained on the fifth to eighth postpartum day from mothers in Japan exposed to dioxins in the environment. The levels of seven dioxins and 10 furan isomers were measured in each milk sample using an HR-GC/MS system. The relationships between the concentration of each dioxin isomer and newborn size, including head circumference, were then investigated after adjustment for confounding factors. The concentration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most toxic dioxin isomer, negatively correlated with newborn head circumference, even after adjustment for gestational age, infant sex, parity and other confounding factors. However, there were no significant relationships between the concentration of other dioxin and furan isomers in maternal breast milk and infant height, weight and chest circumference at birth. These facts suggested that fetal brain development might be influenced by maternal exposure to TCDD in the environment.Journal of Exposure Science and Environmental Epidemiology (2008) 18, 246–251; doi:10.1038/sj.jes.7500589; published online 6 June 2007 [ABSTRACT FROM AUTHOR]

Abstract: The effects of maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during pregnancy on fetal brain growth and neurobehavioral development in early developmental stages were investigated using rat offspring. TCDD in corn-oil (0.1μg/kg) was orally administrated to the dams from the 9th to 19th gestational day. When TCDD effects on the fetal brain weight were analyzed on the 19th gestational day, weight ratio of the brain to the whole body, and that of the forebrain without the cerebral cortex to the whole brain were larger in the exposed group than those of the control group, suggesting premature fetal brain development. TCDD effects on motor functions were investigated using newborns in an inclined plane task. Motor development assessed by righting response on an inclination was delayed in the exposed offspring in the 8th–12th postnatal day, especially in male. Also, TCDD effects on active avoidance behavior in a shuttle box were investigated using the offspring after weaning. Latency in the active avoidance learning was longer, and locomotor activity was reduced in the exposed male offspring in the 41st–44th postnatal day. The results demonstrated that maternal TCDD exposure delayed fetal brain growth and neurodevelopment of the offspring in early stage, especially in male rats. [Copyright &y& Elsevier]

Abstract: This study evaluated the utility of single and combined measurements of cadmium toxicity markers for surveillance purposes, using a sample of 224 individuals, 30–87 years of age, who were residents of cadmium polluted area in Mae Sot District, Tak Province, Thailand. Urinary cadmium levels excreted by them ranged between 1 and 58μg/g creatinine with geometric mean of 8.2μg/g creatinine which was 16-fold greater than the average for the general Thai population of 0.5μg/g creatinine. The urinary markers evaluated were total protein, albumin, N-acetyl-β-d-glucosaminidase (NAG), lysozyme, β2-microglobulin (β2-MG) and α1-microblobulin (α1-MG). Among these markers, only NAG showed a positive correlation with urinary cadmium in both male and female subjects with and without disease (r =0.43–0.71). Further, the prevalence rates for urinary NAG above 8units/g creatinine (NAG-uria) increased with exposure levels in a dose dependent manner (p =0.05) among subjects with disease. In contrast, however, increased prevalence of β2-MG above 0.4mg/g creatinine (β2-MG-uria) was associated with cadmium above 5μg/g creatinine only in those without disease (POR=10.6 and 7.8 for 6–10 and >10μg/g creatinine). Prevalence rates for abnormal excretion of all other markers, except albumin, were markedly increased among those having β2-MG-uria with and without disease (χ 2-test, p ≤0.001–0.02). Thus, urinary β2-MG and NAG should be used together with urinary cadmium in the monitoring of renal toxicity in a population exposed to high-level cadmium coupled with high prevalence of chronic diseases. [Copyright &y& Elsevier]

Abstract: The influence of cadmium (Cd) body burden on mortality remains controversial. Excess mortality and the dose–response relationship between mortality and urinary cadmium excretion were investigated in this study among environmentally exposed subjects. A 15-year follow-up study was carried out on 3119 inhabitants (1403 men and 1716 women) of the Cd-polluted Kakehashi River basin, whose urinary Cd concentration was examined in a 1981–1982 health impact survey. The mortality risk of high urinary Cd (⩾10μg/g Cr) subjects after adjustment for age using Cox''s proportional hazard model was higher than that of moderate urinary Cd (<10μg/g Cr) subjects in both sexes. When the subjects were divided into five groups according to the amount of urinary Cd (<3, 3–5, 5–10, 10–20, ⩾20μg/g Cr), the mortality risk was significantly increased among the subjects with urinary Cd⩾3μg/g Cr in proportion to the increases in the amount of urinary Cd concentration after adjustment for age, especially in women. Furthermore, special causes of death among high and moderate urinary Cd were investigated, and mortality risk ratio for heart failure, which is a cause of death often diagnosed in cases with a gradual deterioration culminating in death, was significantly increased in both sexes, compared with the moderate urinary Cd subjects. Also, in women the mortality risk for renal diseases in the high urinary Cd subjects was significantly higher than that in the moderate urinary Cd subjects. These results suggest that a causal association between Cd body burden and mortality exists among inhabitants environmentally exposed to Cd but that no special disease may be induced except renal diseases. [Copyright &y& Elsevier]

Abstract: In recognition of a central role of the kidney in long-term blood pressure control, we undertook an in-depth analysis of the relationship between blood pressure and kidney damage caused by environmental exposure to the common pollutants cadmium and lead. The subjects were 200 healthy Thais, 16 and 60 years of age (100 female non-smokers, 53 male non-smokers, and 47 male smokers). None of these subjects had been exposed to Cd or Pb in the workplace and their urinary Cd concentrations ranged from 0.4 to 37nM, whereas their urinary Pb concentrations ranged from 0.1 to 30nM. The prevalence of high blood pressure was 2%, 8% and 19%, respectively in subjects with low, average and high Cd-burden (linear trend χ 2 =6.4, P =0.01). Multiple regression analysis revealed a significant positive association between Cd-burden and blood pressure in male non-smokers (adjusted β =0.31, P =0.02) and an inverse association between blood pressure and urinary Pb excretion rate in male smokers (adjusted β =−0.38, P =0.005). Associations between Cd-burden and nephropathies were evidenced by increases in urinary excretion of β2-microglobulin (P =0.02) and N-acetyl-β-d-glucosaminidase (P =0.005) in subjects with high Cd-burden, compared with the subjects with average Cd-burden. In addition, an association between Cd-related nephropathy and high blood pressure was evidenced by a 20% increase in the prevalence of high blood pressure in people with NAG-uria (linear trend χ 2 =4.3, P =0.04). Our present study provides first evidence for a possible link between renal tubular damage and dysfunction caused by environmental Cd exposure and increased risk of high blood pressure. [Copyright &y& Elsevier]

Abstract: Female rats were exposed by intragastric administration with a cannula 1mg/kg/day or 10mg/kg/day CdCl2 for the 11 days from the 9th to 19th day of pregnancy, and the effects of Cd exposure on eight elements, Na, K, Ca, Mg, P, Fe, Zn, and Cu in fetal liver, kidney, brain, fetal membrane and placenta then examined. We found that: (1) although Cd was not detected in fetal kidney and brain, significant Cd accumulation was found in fetal liver, fetal membrane and placenta in the 10mg/kg Cd group, (2) the Zn and Fe concentrations in fetal liver in the 10mg/kg Cd group were significantly lower than those in the control group, but no difference was found in the placenta, (3) the Cu concentrations in the placenta, fetal membrane and liver in the 10mg Cd groups were significantly lower than those in the control group, (4) Na/K ratio in the placenta and fetal kidney and the Ca concentration in the placenta in the 10mg/kg Cd group were lower than those in the controls. These results suggest that Cd exposure inhibits Zn and Fe transportation from the placenta to fetus, as well as Cu, Ca, Na and K uptake and transportation across the placenta, possibly influencing fetal growth and metabolism. [Copyright &y& Elsevier]

We examined the interrelationships between phenotype of hepatic cytochrome P450 2A6 (CYP2A6), nephropathy, and exposure to cadmium and lead in a group of 118 healthy Thai men and women who had never smoked. Their urinary Cd excretion ranged from 0.05 to 2.36 μg/g creatinine, whereas their urinary Pb excretion ranged from 0.1 to 12 μg/g creatinine. Average age and Cd burden of women and men did not differ. Women, however, on average showed a 46% higher urinary Pb excretion (p < 0.001) and lower zinc status, suggested by lower average serum Zn and urinary Zn excretion compared with those in men. Cd-linked nephropathy was detected in both men and women. However, Pb-linked nephropathy was seen only in women, possibly because of higher Pb burden coupled with lower protective factors, notably of Zn (p < 0.001), in women compared with men. In men, Pb burden showed a negative association with CYP2A6 activity (adjusted β = -0.29, p = 0.003), whereas Cd burden showed a positive association with CYP2A6 activity (adjusted β = 0.38, p = 0.001), suggesting opposing effects of Cd and Pb on hepatic CYP2A6 phenotype. The weaker correlation between Cd burden CYP2A6 activity in women despite similarity in Cd burden between men and women is consistent with opposing effects of Pb and Cd on hepatic CYP2A6 phenotypic expression. A positive correlation between Cd-linked nephropathy (urinary N-acetyl-β-D-glucosaminidase excretion) and CYP2A6 activity in men (r = 0.39, p = 0.002) and women (r = 0.37, p = 0.001) suggests that Cd induction of hepatic CYP2A6 expression and Cd-linked nephropathy occurred simultaneously. [ABSTRACT FROM AUTHOR]

Relationships between cadmium (Cd) body burden, kidney function and coumarin metabolism were investigated using two groups of 197 and 200 healthy Thais with men and women in nearly equal numbers. A mean age of one group was 30.5 years and it was 39.3 years for the other group. Of 397, 20 subjects (5%) excreted urine Cd between 1.4 μg/g and 3.8 μg/g creatinine and these subjects faced 10–15% increase in the probability of having abnormal urinary excretion of N-acetyl-β-d-glucosaminidase (NAG-uria). The prevalence of NAG-uria varied with Cd body burden in a dose-dependent manner (χ2=22, P<0.008). Also NAG-nuria was one of the three kidney effect markers tested that showed the greatest strength of correlation with urine Cd in both men and women (r=0.48, P<0.001). In addition, urine Cd excretion of men and women showed a positive correlation (r=0.46 to 0.54, P<0.001) with urine 7-hydroxycoumarin (7-OHC) excretion which was used as a marker of liver cytochrome P450 2A6 (CYP2A6) enzyme activity. Urinary Cd excretion accounted for 25% of the total variation in urine 7-OHC excretion (P<0.001). These data suggest that Cd may increase the expression of CYP2A6 in liver, resulting in enhanced coumarin metabolism in subjects with high Cd body burden. [Copyright &y& Elsevier]

A study to clarify the food composition and nutritional factors that contribute to the levels of blood and urinary cadmium (Cd) was conducted on 50 pregnant Japanese women with mean age of 29 years. The mean iron (Fe) intake of subjects was 9.2 mg, which is much lower than the recommended level of 20 mg for pregnant women. Cd in urine samples collected at 30–32 weeks of gestation were correlated (r=0.354), but urinary Cd was related to age more than blood Cd. Urinary Cd and blood Cd levels were inversely related to total energy (rpartial=−0.325, and −0.334, respectively) and fat intake (rpartial=−0.419,and −0.379, respectively), even after adjustment for age. Blood Cd was also correlated to protein and iron intake (rpartial=−0.299, and −0.353, respectively). These results indicate that Cd exposure levels of pregnant women with low energy intake, especially less fat intake, were higher than those of women with more energy and fat intake. In particular, blood Cd may be affected by protein and iron intake in pregnant women with increased these nutrients demand. [Copyright &y& Elsevier]

The article cites a study on the relationship between newborn size and mother's blood cadmium (Cd) levels. The effect of blood Cd, which reflects not only Cd body burden but also recent Cd exposure and communicates with fetal blood in the placenta, on newborn size at birth was investigated. The correlation between maternal blood Cd and infant birth weight also showed an inverse relationship, but it was not significant. On the other hand, the mean birth weight of eight infants whose maternal blood Cd was more than 13.4 nmol/l was 2889 g, and significantly lower than that of infants whose maternal blood Cd was under 13.4 nmol/l. These facts suggest that maternal Cd exposure might affect infant size, which was expressed as either weight or height, but its effect on the infant height is clearer even in lower levels than the exposure level to affect the weight. A larger population including highly exposed women will be necessary to clarify the relationship with birth weight in a future study. In addition, an effect of Cd on bone and calcium metabolism has been reported in adults, but not in the maternal-fetal unit.

For 8 years, we have followed up a birth cohort comprising 241 mother-and-infant pairs living around the Da Nang airbase, a hot spot of dioxin contamination in Vietnam, and have reported the impacts of perinatal dioxin exposure on the neurodevelopment of children at various ages. In the present study, 9 years after birth, we investigated the effects of perinatal dioxin exposure on mu and theta rhythms by analyzing EEG power during the execution and observation of hand movements, which indicate mirror neuron system activity. One hundred fifty-five 9-year-old children (86 boys and 69 girls) from the Da Nang birth cohort participated in the EEG examination with free viewing of hand movements. The dioxin levels in their mothers' breast milk, measured 1 month after birth, were used as perinatal dioxin exposure markers. A log transform of the ratio of EEG power during execution or observation of the hand movements relative to the power during observation of a bouncing ball for theta and mu rhythms was used to evaluate mirror neuron activity. In both brain hemispheres, the log power ratio in the theta band was significantly higher (i.e., less reduction of power) during observation of hand movements in girls exposed to high levels of TCDD. In boys, however, dioxin congeners other than TCDD, including HxCDDs and several PCDF congeners, contributed to increased log power ratios in the theta band. Particularly for PCDF congeners, the log power ratios in the lowest group among 4 exposure groups were lowest and significantly increased (i.e., decreasing reduction of power) with increasing dose. Perinatal TCDD exposure may influence the mirror neuron system of the brain, which plays an important role for social-emotional behavior in children, particularly in girls living in a hot spot of dioxin contamination in Vietnam. [Display omitted] • Perinatal TCDD exposure decreased mirror neuron activity in 9-year-old girls. • Increasing some PCDF congeners significantly decreased mirror neuron activity in boys. • Mirror neuron impairment may be involved in developmental deficits due to dioxin exposure. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of perinatal dioxin exposure indicated by dioxins in breast milk on neonatal electroencephalography (EEG) power in the quiet sleep stage, and associations with neurodevelopmental outcomes at 2 years of age.Study Design: Fifty-one mother-newborn pairs were enrolled for neonatal EEG analysis in the quiet sleep stage from a birth cohort recruited at a prefecture hospital in Bien Hoa city, Vietnam. Relative EEG power in intra-burst-intervals and high-voltage-bursts in the trace alternant pattern were computed from EEG data during the quiet sleep stage. Forty-three mother-child pairs participated in a 2-year follow-up survey to examine neurodevelopment using the Bayley-III scale and gaze behavior exhibited by fixation duration on the face of a child talking in videos. The general linear model and regression linear model were used for data analysis after adjusting for confounding factors.Results: Perinatal dioxin exposure, particularly 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure, influenced relative EEG power values mainly in the intra-burst-interval part of the trace alternant pattern in the quiet sleep stage. In intra-burst-intervals, decreased frontal delta power and increased frontal and parietal alpha power values in the left hemisphere and temporal beta power values in the right hemisphere were associated with increased TCDD exposure, with significant dose-response relationships. Almost none of the relative power values in these brain regions were associated with Bayley III scores, but relative delta power values were significantly associated with face fixation duration in left frontal and parietal regions at 2 years of age.Conclusion: Perinatal dioxin exposure influences neuronal activity in the quiet sleep stage, leading to poor communication ability indicated by gaze behavior in early childhood. [ABSTRACT FROM AUTHOR]

Previous studies have reported that dioxin exposure alters sexual dimorphism of play behavior in pre-pubertal children. We aimed to investigate the effects of perinatal dioxin exposure, indicated by dioxins in breast milk, on sexual dimorphism of gaze behavior after adjusting for salivary testosterone (T). Participants were pre-pubertal children in a hot spot for dioxin contamination originating from herbicide spraying in Vietnam. We used eye tracking to assess gaze behavior in 172 children (100 boys and 72 girls) aged 8–9 years. Two sets of 15 pairs of pictures, one oriented towards boys and one oriented towards girls, containing 5 pairs of toy photos (non-biological stimuli) and 10 pairs of human line drawings (biological stimuli) were shown to all children. The total fixation duration for each picture was extracted using Tobii studio software and a feminine index of gaze behavior was defined as the ratio of the summed fixation duration for the girl- vs boy-oriented versions of each stimuli. When viewing non-biological stimuli, feminine index scores significantly increased with TCDD (β = 0.294) in girls only. For biological stimuli, however, feminine index scores significantly increased with TEQ-PCDD/Fs (β = 0.269) in boys and with TCDD in girls (β = 0.286). These associations were significant even after adjusting for salivary T levels, which were inversely associated with some dioxin congeners in girls. In addition, increased feminine index scores for biological stimuli were associated with lower cognitive scores for hand-movement and word-order tests in boys and for face-recognition tests in girls examined at 5 years of age. In conclusion, these results suggest that perinatal dioxin exposure may increase visual interest in girl-oriented objects through impairment of cognitive abilities in pre-pubertal Vietnamese children. PCDD congeners were associated with gaze behavior independently of T levels in boys, while this was only the case for TCDD levels in girls. Unlabelled Image • Dioxin effects on behavioral sexual dimorphism were investigated in Vietnamese 8-year-olds. • Salivary testosterone was significantly decreased with increasing TEQ-PCDFs in girls. • Feminine scores for any stimuli were increased with increasing TCDD in girls. • Feminine scores for biological stimuli were increased with increasing TEQ-PCDD/Fs in boys. • Increased feminine gaze behavior may be associated with impairment of cognitive abilities. [ABSTRACT FROM AUTHOR]

The aim of the present study was to evaluate the effect of environmental cadmium (Cd) exposure indicated by urinary Cd (U-Cd) on cancer mortality in the general Japanese population. A 19-year cohort study was conducted in 1107 men and 1697 women who lived in three Cd non-polluted areas in Japan. Mortality risk ratio and 95% confidence interval (95%CI) for continuous U-Cd were estimated for all malignant neoplasms and specific cancers using a Fine and Gray competing risks regression model. The all-cause, including cancer and non-cancer mortality rates per 1000 person-years were 29.8 and 13.9 in men and women, respectively. By using Fine and Gray's method, continuous U-Cd adjusted for creatinine (+1 μg/g cre) was significantly related to mortalities for all malignant neoplasms (risk ratio = 1.06, 95%CI: 1.02-1.11) and pancreas (risk ratio = 1.13, 95%CI: 1.03-1.24) in women. In the present study, U-Cd was significantly associated with increased cancer mortality in the general Japanese population, indicating that environmental Cd exposure adversely affects the life prognosis in Cd non-polluted areas in Japan. [ABSTRACT FROM AUTHOR]

Urinary β2-microgroblin (β2-MG) excretion levels above 300 μg/g creatinine are used to indicate defective tubular reabsorption. Arguably, increased urinary β2-MG excretion could also reflect glomerular filtration rate decline. Thus, we investigated an association between urinary β2-MG and estimated glomerular filtration rate (eGFR). We studied 527 subjects, aged 30–87 years (mean 51.2), who lived in a rural area of Thailand polluted with cadmium (Cd). Of this cohort, 10.3% had urinary Cd levels <2 μg/g creatinine and 53.5% had urinary Cd levels ≥5 μg/g creatinine. Half (53.1%) of the participants had urinary β2-MG levels ≥ 300 μg/g creatinine, and 11.6% had low GFR, defined as eGFR <60 mL/min/1.73 m2. Lower eGFR values were associated with older age (β = −0.568, P < 0.001), higher urinary β2-MG (β = −0.170, P < 0.001), higher urinary Cd (β = −0.103, P = 0.005) and diabetes (β = 0.074, P = 0.032). An inverse association between eGFR and urinary β2-MG was evident in subjects with low GFR (β = −0.332, P = 0.033), but not in those with GFR >90 mL/min/1.73 m2 (β = −0.008, P = 0.896). These findings suggested Cd-induced nephron loss and reduced tubular reabsorption in low eGFR subjects. Urinary β2-MG levels <300 μg/g creatinine were associated with 4.66 (95% CI: 1.92, 11.32) fold increase in the POR for low GFR, compared with urinary β2-MG levels <100 μg/g creatinine. Findings in the present study cast doubt on a cut-off value for urinary β2-MG, while lending support to the notion that elevated urinary β2-MG excretion could indicate a fall of GFR. • Higher urinary β2-MG levels are associated with lower eGFR. • An elevated urinary β2-MG could be a result of nephrons loss. • The cut-off value for β2-MG excretion should be reassessed. • Cd exposure limit should be reassessed. [ABSTRACT FROM AUTHOR]

Dioxins are endocrine-disrupting chemicals, and their effects on reproductive functions are well-documented. The aim of the present study was to measure the levels of reproductive hormones in 42 men residing near a dioxin-contaminated area in Vietnam. We measured levels of 17 2,3,7,8-substituted congeners of polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) and four non-ortho polychlorinated biphenyls (PCBs) in blood. Levels of follicle-stimulating hormone, luteinizing hormone, progesterone, prolactin, estradiol, and total testosterone were measured in serum. Blood dioxin levels were elevated; the levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin was 7.3 pg/g fat. Seven of the men had testosterone levels below 250 ng/dL, and nine men had prolactin levels above 9.7 ng/mL. Four PCDD congeners, two PCDF congeners, one PCB congener, and the sum TEQ of PCDDs, PCDDs/Fs, and PCDDs/Fs/PCBs were positively and significantly correlated with prolactin levels. Two PCDD congeners, six PCDF congeners, two PCB congeners, and the TEQs of PCDFs and PCBs were negatively and significantly correlated with testosterone levels. There were no significant correlations between dioxin congeners and follicle-stimulating hormone, luteinizing hormone, or progesterone levels. [ABSTRACT FROM AUTHOR]

Background Exposure to cadmium (Cd) via food is supposed to affect life prognosis of inhabitants of Cd-polluted area in Japan. However, there have been few reports demonstrating a significant relationship between the amount of Cd intake and mortality. We aimed to investigate the relationship between mortality and individual lifetime Cd intake (LCd) in inhabitants of the polluted Jinzu River basin, Toyama, Japan. Methods We conducted a 26-year follow-up survey in 2407 inhabitants (1208 men and 1199 women) who participated in health examinations for screening of renal dysfunction from 1979 to 1984. The calculation of LCd in each inhabitant was based on the formula of Nogawa (Nogawa et al., 1989): (mean Cd concentration in rice of the present hamlet × 333.5 g/day + 34 μg/day) × 365 days/year × number of years of residence in the present hamlet + 50 μg/day × 365 days/year × number of years living in Cd non-polluted regions. In this formula, 333.5 g/day is the 1970 average daily intake of rice in this area, 34 µg/day is the Cd intake from foods other than rice in this area, and 50 μg/day is the average intake of Cd in non-polluted areas in Japan. Mortality risk ratios of LCd for all and specific causes were estimated after adjustments for age at baseline, smoking status, and history of hypertension using a Cox hazard model or Fine and Gray competing risks regression model. Results The mortality risk ratios of LCd (+ 1 g) for all causes in women were significantly dose-dependently increased (risk ratio: 1.08). Relative risk of LCd for kidney and urinal tract disease, renal diseases, renal failure and toxic effects of cadmium were significantly higher in women. Conclusions The present study documents that individual LCd dose-dependently decreased life prognosis over long-term observation in women. LCd was significantly related to the increased mortality for renal disease and toxic effect of Cd in women. The result provides clear evidence that life prognosis was adversely affected by Cd-exposure, especially in women. [ABSTRACT FROM AUTHOR]

Dioxin concentrations remain elevated in the environment and humans residing near the former US Air Force base in Bien Hoa city, South Vietnam. We recruited 210 mother-infant pairs for whom breast milk dioxin levels were reported in our previous study. Cord blood samples were collected from 162 mother-infant pairs. We selected 16 cord blood samples with a volume over 20 mL and fat content of ≥ 0.03 g. Toxic equivalent levels of polychlorinated dibenzodioxins and polychlorinated dibenzofurans (TEQ-PCDD/Fs) and concentrations of 17 congeners, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD), in cord blood were measured and compared with levels in breast milk (Study 1). Levels of 2,3,7,8-TCDD and TEQ-PCDD/Fs in cord blood samples were highly and significantly correlated with those in breast milk samples in the same pairs. This suggests dioxins in breast milk reflect prenatal dioxin exposure. Estradiol (E2) and testosterone (TS) were measured in cord blood serum from 162 samples. Associations between dioxins in breast milk and cord blood sex hormones were analyzed by infant sex, after adjusting for confounding factors (Study 2). Increased levels of TEQ-PCDD/Fs in breast milk were associated with decreased cord blood TS in girls. In boys, a significant reduction of cord blood TS was observed in those exposed to 2,3,7,8-TCDD at high levels (≥ 5.5 pg/g lipid). There was no significant association between E2 and dioxins in breast milk in either sex. These results suggest increased prenatal dioxin exposure is associated with decreased cord TS, but in boys, only high level of 2,3,7,8-TCDD influence cord blood TS. [ABSTRACT FROM AUTHOR]

Background: The aim of the present study was to estimate the benchmark doses (BMD) for renal effects for health risk assessment of residents living in Cd-polluted and non-polluted areas in a Thai population.Methods: The study participants consisted of inhabitants aged 40 years or older who lived in a non-polluted area (40 men and 41 women) and in the environmentally polluted Mae Sot District (230 men and 370 women) located in northwestern Thailand. We measured urinary and blood cadmium (Cd) as markers of long-term exposure and urinary β2-microglobulin (β2-MG) and N-acetyl-β-D-glucosaminidase (NAG) as renal tubular effect markers. An updated hybrid approach was applied to estimate the benchmark doses (BMD) and their 95% lower confidence limits (BMDL) of urinary and blood Cd for Cd-induced renal effects in these subjects. BMD and BMDL corresponding to an additional risk (BMR) of 5% were calculated with the background risk at zero exposure set to 5% after adjusting for age and smoking status.Results: The estimated BMDLs of urinary Cd for renal effect markers were 6.9 for urinary β2-MG and 4.4 for NAG in men and 8.1 for β2-MG and 6.1 for NAG μg/g creatinine (Creat) in women. These BMDLs of urinary Cd (μg/g Creat) for NAG were less than the geometric mean urinary Cd in the polluted area (6.5 in men and 7.1 in women). The estimated BMDLs of blood Cd (μg/L) were 6.2 for urinary β2-MG and 5.0 for NAG in men and 5.9 for β2-MG and 5.8 for NAG in women. The calculated BMDLs were similar or less compared with the geometric mean blood Cd (μg/L) in the polluted Thai area (6.9 in men and 5.2 in women).Conclusion: The BMDLs of urinary and blood Cd for renal effects were estimated to be 4.4-8.1 μg/g Creat and 4.4-6.2 μg/L in the Thai population aged ≥ 40 years old, suggesting that more than 40% of the residents were at risk of adverse renal effects induced by Cd exposure in Thailand. [ABSTRACT FROM AUTHOR]

Background: We aimed to investigate the mortality and causes of deaths of inhabitants with renal dysfunction induced by cadmium (Cd) exposure caused by heavy environmental contamination.Methods: We conducted a 26-year follow-up survey targeting 7529 inhabitants of the Cd-polluted Jinzu River basin and 2149 controls from non-polluted areas who participated in urinary examinations for proteinuria and glucosuria conducted in 1979 to 1984. When the residents were divided into 4 groups, no finding group, glucosuria group, proteinuria group, glucoproteinuria group, mortality risk ratios for all and specific causes of these groups in the polluted area were compared with that of controls without glucosuria and/or proteinuria after adjustments for age at baseline, smoking status, and history of hypertension using Cox's proportional hazard model.Results: The mortality risk ratios for all causes of proteinuria and glucoproteinuria in men and glucosuria, proteinuria, and glucoproteinuria in women of the polluted areas significantly increased compared with those of the controls with no urinary findings. Respiratory, renal, and cardiovascular diseases and diabetes in men, and all diseases except cerebrovascular diseases in women contributed toward an increased mortality of exposed glucoproteinuria groups, which involved chronic Cd toxicosis with renal tubular dysfunction. In women, the mortality risks for cancer of the colon and rectum, uterus and kidney and urinary tract were significantly higher in the exposed proteinuria and glucoproteinuria groups, suggesting associations between renal damage and cancer risk. In exposed women, the no finding group and glucoproteinuria group also showed increased mortality from ischemic heart diseases, indicating that all exposed women may be at risk for ischemic heart diseases. Although the control glucosuria and/or proteinuria group also showed high mortality for diabetes and renal diseases, the increased risk ratio for renal disease mortality was much higher in exposed subjects with urinary findings, particularly in women.Conclusions: These findings indicate that inhabitants with renal effects caused by Cd exposure had a poor life prognosis over long-term observation in both genders. Particularly in women, renal tubular dysfunction indicated by glucoproteinuria may increase mortality from cancer, ischemic heart diseases, and renal diseases. [ABSTRACT FROM AUTHOR]

The adverse health effects of cadmium (Cd) are well known in human populations; however, much of what is known about biological mechanisms of Cd comes from in vitro and animal studies. The adverse health outcomes due to high levels of Cd exposure in the population of Mae Sot, Thailand have been extensively characterized. Here, for the first time, this population is being studied in an epigenetic context. The objective of this study was to characterize the association between DNA methylation markers and Cd exposure, taking into account sex and smoking differences, in an adult population at an increased risk of experiencing adverse health outcomes from high body burden of Cd. One hundred and sixty-nine residents from known exposure areas of Mae Sot, Thailand and one hundred residents from non-exposed areas nearby were surveyed in 2012. Urine and blood samples were collected for measurement of urinary Cd (UCd) and DNA methylation of Cd-related markers ( DNMT3B , MGMT , LINE-1, MT2A ). UCd levels were 7 times higher in the exposed compared to the unexposed populations (exposed median: 7.4 μg/L, unexposed median: 1.0 μg/L, p < 0.001). MGMT hypomethylation was associated with increasing levels of UCd in the total population. Sex-specific associations included MT2A and DNMT3B hypomethylation in women and LINE-1 hypermethylation in men with increasing UCd. Upon subanalysis, these associations separated by smoking status. In summary, environmental Cd exposure is associated with gene-specific DNA methylation in a sex and smoking dependent manner. [ABSTRACT FROM AUTHOR]

Examines the effects of environmental cadmium on the health of people living at Kakehashi River basin in Ishiskawa, Japan. Mortality ratios of the urinary beta[sub 2]-microglobulin-positive (MG) subjects; Impact of the severity of renal dysfunction on mortality rate; Causes of the high mortality of beta[sub 2]-MG-positive groups.

Objectives: Japan has a relatively high prevalence of smoking in men. Despite the importance of behavioral patterns on successful smoking cessation, only limited information is available in Japan. The present study collected data from former smokers in a rural community in Japan in order to identify health status at the time of cessation, predominant motivating factors, and the role of smoking cessation aids in individuals who successfully stopped smoking. Methods: This cross-sectional study collected data using a self-reported questionnaire from 149 randomly-selected former smokers (119 men and 30 women, aged 20-79 years) who were residents of Nanao, Ishikawa Prefecture, Japan. Results: Of the male participants, 14.3% quit due to serious personal health problems, including cardiovascular disease, cancer, or respiratory tract disease, while 20.8% of former smokers experienced mild personal health problems or were pregnant at the time of cessation. An approximately equal number stopped smoking due to fear of illness in the absence of immediate health concerns. Compared to personal health motivations, a smaller number of male smokers quit due to anti-smoking social pressure or expense. We also observed a marked increase in former smokers who quit for these reasons in recent years. Smoking lost its appeal in 19.3% of male and 10.0% of female smokers. Approximately, 95% of quitters did not utilize health professional counseling or pharmacological therapy. Conclusions: Personal health concerns in former smokers in Nanao, Japan were the predominant motivation for quitting smoking, with the vast majority of former smokers achieving successful smoking cessation by themselves. [ABSTRACT FROM AUTHOR]

Abstract: High levels of cadmium (Cd) in paddy soil and rice, and a concurrent increase in urinary Cd of inhabitants in the Mae Sot District, Tak Province, Thailand first emerged in 2003. Risk factors such as occupation, sources of staple food and drinking water as well as biomarkers of adverse renal effects of the increased body burden of Cd were investigated in 795 residents, 30 years or older, whose urinary Cd levels were between 0.02 and 106μg/g creatinine. Farmers who consumed their own rice and residents who sourced drinking water from wells and/or the river demonstrated increased urinary Cd. Age-adjusted mean urinary cadmium for male and female subjects who consumed well water was 5.7μg/g vs. 6.1μg/g creatinine while the corresponding value for male and female subjects who did not consume well water was 3.7μg/g vs. 4.8μg/g creatinine, respectively. Increased urinary levels of β2-microglobulin and N-acetyl-β-d-glucosaminidase were observed with the increase in urinary Cd, indicating tubular dysfunction and renal damage associated with increase in Cd body burden. Consumption of well water and rice grown in the contaminated area increase the body burden of Cd. Cessation of exposure is essential to prevent and possibly recover from Cd toxicity, especially among the residents whose kidney damage and malfunction may be reversible. [ABSTRACT FROM AUTHOR]

Some residents of the Mae Sot district in Thailand have suffered long-term exposure to elevated dietary levels of cadmium. To test the hypothesis that chronic dietary cadmium exposure can cause imbalance in calcium dynamics and accelerate bone resorption, a group of these residents (156 men and 256 women aged ≥ 50) were selected on the basis of previous records of elevated urinary cadmium and tested for urinary and blood cadmium, bone formation and resorption markers, and the renal tubular dysfunction markers. Both genders had high levels of blood and urinary cadmium and high urinary levels of the markers for renal dysfunction and bone resorption in a dose–response relationship to urinary cadmium. The excretion of bone resorption markers was positively correlated to the ratio of excreted calcium and urinary cadmium. The results of a multivariate regression analysis indicated that bone resorption was accelerated by impaired calcium reabsorption in renal tubules. [ABSTRACT FROM AUTHOR]

The aim of the present study was to clarify the relationship between urinary cadmium concentration (U-Cd) and total cadmium intake (T-Cd) based on individual data of Cd in urine. Morning urine specimens were collected from 198 persons (100 men with average age of 45.8 years and 98 women with average age of 50.7 years) living in the Kakehashi River basin in Ishikawa Prefecture, Japan. The method used to calculate T-Cd basically mirrored that used in our previous study. Correlation coefficients between U-Cd and T-Cd of 0.879 and 0.835 were obtained in men and women, respectively, with both values statistically significant. Therefore, T-Cd is confirmed to be a useful indicator for external Cd exposure even on the basis of individual data of U-Cd. [Copyright &y& Elsevier]

The interrelations of the seven elements, calcium (Ca), magnesium (Mg), sodium (Na), potassium (K), phosphorus (P), copper (Cu), zinc (Zn), and cadmium (Cd) in human breast milk were examined in Japanese mothers to clarify the effects of Cd exposure on these important elements for infant growth. Breast milk and urine samples were obtained from 68 mothers, aged 19–38 years, at 5–8 days postpartum. The concentrations were determined by inductively-coupled plasma atomic emission spectrometry for Ca, Mg, Na, K, P, by flame atomic absorption spectrophotometry for Cu and Zn, and by flameless atomic absorption spectrophotometry for Cd. Geometrical mean Cd concentrations were 0.28 (geometrical standard deviation=1.82) μg/l in breast milk and 1.00 (1.93) μg/g creatinine in urine. Among the above elements only Cd concentration in breast milk was significantly correlated with urinary Cd concentration (r=0.451, P<0.001). Significant positive correlations were found between Cu and Ca (r=0.500, P<0.001), Cu and Mg (r=0.378, P<0.01), and Zn and Mg (r=0.355, P<0.01) in breast milk. Cd concentration in breast milk showed an inverse relationship with Ca concentration in breast milk (r=−0.248, P<0.05). These results indicate that the Cd concentration in breast milk closely reflects Cd body burden, with increased Cd in breast milk possibly affecting Ca secretion in breast milk. [Copyright &y& Elsevier]

Erroneous conclusions may result from normalization of urine cadmium and N-acetyl-β-D-glucosaminidase concentrations ([Cd]u and [NAG]u) to the urine creatinine concentration ([cr]u). In theory, the sources of these errors are nullified by normalization of excretion rates (ECd and ENAG) to creatinine clearance (Ccr). We hypothesized that this alternate approach would clarify the contribution of Cd-induced tubular injury to nephron loss. We studied 931 Thai subjects with a wide range of environmental Cd exposure. For x = Cd or NAG, Ex/Ecr and Ex/Ccr were calculated as [x]u/[cr]u and [x]u[cr]p/[cr]u, respectively. Glomerular filtration rate (GFR) was estimated according to the Chronic Kidney Disease (CKD) Epidemiology Collaboration (eGFR), and CKD was defined as eGFR < 60 mL/min/1.73m2. In multivariable logistic regression analyses, prevalence odds ratios (PORs) for CKD were higher for log(ECd/Ccr) and log(ENAG/Ccr) than for log(ECd/Ecr) and log(ENAG/Ecr). Doubling of ECd/Ccr and ENAG/Ccr increased POR by 132% and 168%; doubling of ECd/Ecr and ENAG/Ecr increased POR by 64% and 54%. As log(ECd/Ccr) rose, associations of eGFR with log(ECd/Ccr) and log(ENAG/Ccr) became stronger, while associations of eGFR with log(ECd/Ecr) and log(ENAG/Ecr) became insignificant. In univariate regressions of eGFR on each of these logarithmic variables, R2 was consistently higher with normalization to Ccr. Our tabular and graphic analyses uniformly indicate that normalization to Ccr clarified relationships of ECd and ENAG to eGFR. [ABSTRACT FROM AUTHOR]

Background: We have followed a birth cohort from 2008 to 2009 near a dioxin-contaminated area of Da Nang, Vietnam, and investigated the effects of perinatal dioxin exposure on neurodevelopment from infancy to pre-school age. The present study aimed to investigate the effects of perinatal dioxin exposure on the learning abilities of the elementary-school children from the Da Nang birth cohort.Methods: From 241 mother-infant pairs recruited at baseline (134 boys and 107 girls), 185 (76.8%) participated in a follow-up when the children were 8 years of age (108 boys and 77 girls). The children's perinatal dioxin exposure was estimated using the dioxin levels in their mothers' breast milk. The Colorado Learning Difficulties Questionnaire (CLDQ) was used to evaluate the children's learning difficulties. Math- and language-achievement scores were obtained using paper-based tests. Reading fluency was examined by having the children read passages in Vietnamese.Results: In boys exposed to high levels of 2,3,7,8-tetrachlorodibenzodioxin (2,3,7,8-TetraCDD), CLDQ reading scores were significantly higher (worse), and language achievement scores were significantly lower. Boys exposed to high levels of 2,3,7,8-TetraCDD as well as high levels of the toxic equivalent (TEQ) of polychlorodibenzodioxins and polychlorodibenzofurans (PCDDs/Fs) had higher numbers of reading errors. Reading errors were higher and math achievement scores were lower with increasing concentrations of 1,2,3,4,7,8-HexaCDD and 1,2,3,4,6,7,8-HeptaCDD. In girls, no significant differences of any learning ability markers were found between high and low exposure groups to TEQ-PCDDs/Fs and these 3 congeners.Conclusions: Perinatal dioxin exposure may have adverse effects on the learning abilities of school children, especially boys. [ABSTRACT FROM AUTHOR]

Although Vietnam's massive herbicide exposure in 1960s and 1970s was clearly injurious to health, not all causal relationships have been clarified. We therefore explored associations among dioxins, steroid hormones, age and prostate cancer risk in men. We compared serum levels of dioxin, steroid hormones and prostate specific antigen (PSA) in men aged 56–81 years from herbicide-exposed hotspots ( n = 50) with those from non-sprayed regions ( n = 48). Mean serum levels of dioxin congeners in the hotspot group were 1.5–11.3 times higher than the non-sprayed group depending on specific compound. Levels of testosterone, estradiol and 3β-hydroxysteroid dehydrogenase (3β-HSD) activity in the hotspot group were also significantly higher than in non-sprayed group. Estradiol levels were significantly related to levels of several specific dioxin derivatives in both group. Significant positive correlations were also found between DHT and 1234678-HpCDD or 1234678-HpCDF; and between 3β-HSD activity and 123678-HxCDD, 123478-HxCDF, 123678-HxCDF, or HxCB#169. After adjusting for age, body mass index, and tobacco use, multiple linear regressions showed levels of dihydrotestosterone (DHT), estradiol, testosterone and 3β-HSD activity were not associated with dioxins in the two groups; however, levels of DHT, testosterone and 3β-HSD activity increased significantly with age in the hotspot group. The hotspot and non-sprayed groups did not significantly differ in PSA levels. But six of the hotspot subjects had PSA levels > 3 ng/mL, 3 of whom were suspected to have prostate cancer (PC) after digital rectal examination. Our findings suggest that dioxin exposure can lead to increased levels of several sex steroid hormones with age. The correlation of dioxin with steroid hormone levels and prostate cancer risk should be studied further. [ABSTRACT FROM AUTHOR]

Dioxin concentrations remain elevated in the environment and in humans residing near former US Air Force bases in South Vietnam. Our previous epidemiological studies showed adverse effects of dioxin exposure on neurodevelopment for the first 3 years of life. Subsequently, we extended the follow-up period and investigated the influence of perinatal dioxin exposure on neurodevelopment, including motor coordination and higher cognitive ability, in preschool children. Presently, we investigated 176 children in a hot spot of dioxin contamination who were followed up from birth until 5 years old. Perinatal dioxin exposure levels were estimated by measuring dioxin levels in maternal breast milk. Dioxin toxicity was evaluated using two indices; toxic equivalent (TEQ)-polychlorinated dibenzo-p-dioxins/furans (PCDDs/Fs) and concentration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Coordinated movements, including manual dexterity, aiming and catching, and balance, were assessed using the Movement Assessment Battery for Children, Second Edition (Movement ABC-2). Cognitive ability was assessed using the nonverbal index (NVI) of the Kaufman Assessment Battery for Children, Second Edition (KABC-II). In boys, total test and balance scores of Movement ABC-2 were significantly lower in the high TEQ- PCDDs/Fs group compared with the moderate and low exposure groups. NVI scores and the pattern reasoning subscale of the KABC-II indicating planning ability were also significantly lower in the high TCDD exposure group compared with the low exposure group of boys. However, in girls, no significant differences in Movement ABC-2 and KABC-II scores were found among the different TEQ-PCDDs/Fs and TCDD exposure groups. Furthermore, in high risk cases, five boys and one girl highly exposed to TEQ-PCDDs/Fs and TCDD had double the risk for difficulties in both neurodevelopmental skills. These results suggest differential impacts of TEQ-PCDDs/Fs and TCDD exposure on motor coordination and higher cognitive ability, respectively. Moreover, high TEQ-PCDDs/Fs exposure combined with high TCDD exposure may increase autistic traits combined with developmental coordination disorder. [ABSTRACT FROM AUTHOR]

We investigated the biological half-life of urinary cadmium concentration (U-Cd) based on a 22-year follow-up study after cessation of environmental Cd pollution. Spot urine samples were obtained from the inhabitants (32 men and 36 women) in the target area in 1986, 1991, 1999, 2003 and 2008. These inhabitants were divided into higher or lower baseline U-Cd group by the cut-off of 5 μg l–1or 5 μg g–1creatinine. Biological half-life of U-Cd was estimated using a linear mixed model adjusted for the baseline age. In the higher baseline U-Cd groups, the estimated half-life and 95% confidence intervals were 12.4 years (9.3–18.8 years) and 11.4 years (9.3–14.6 years) for unadjusted U-Cd in men and women, respectively. For creatinine-adjusted U-Cd, they were 16.0 years (13.0–20.7 years) and 20.4 years (16.6–26.2 years) in men and women, respectively. In the lower baseline U-Cd groups, biological half-life for unadjusted U-Cd in men was solely significant (23.4 years) and longer than the corresponding half-life in the higher baseline U-Cd group. The biological half-lives of U-Cd obtained in this study were identical with the values for U-Cd or total body burden determined by a different method. [ABSTRACT FROM PUBLISHER]

The aim of this study was to establish the cause-effect relationship between renal tubular dysfunction and mortality. A 19-year cohort study was conducted in 900 men and 1313 women in 1993 or 1994 who lived in two cadmium non-polluted areas in Japan. Hazard ratio (HR) and 95% confidence interval (95% CI) of urinary β2-microglobulin (β2-MG) and N-acetyl-β-glucosaminidase (NAG) for mortality were calculated using a proportional hazard regression. Forward stepwise model selection was applied to the potential covariates such as age, body mass index, mean arterial pressure, various lifestyle factors and present illness. Simultaneously, the dose-effect relationship between renal tubular markers and urinary cadmium at baseline was evaluated using multiple regression analyses. In men, HR was significant for β2-MG (HR corresponding to an increase of 100 μg/g cre: 1.02) and NAG (HR corresponding to an increase of 1 IU/g cre: 1.05). In women, a significant HR was observed for β2-MG (HR corresponding to an increase of 100 μg/g cre: 1.01) and NAG (HR corresponding to an increase of 1 IU/g cre: 1.02). Dose-effect relationships were significant for urinary cadmium and all renal tubular markers in men and women. The present study indicated that renal tubular dysfunction was significantly related to mortality in the general population of cadmium non-polluted areas in Japan. [ABSTRACT FROM AUTHOR]

We determined polychlorinated dibenzodioxin (PCDD) and polychlorinated dibenzofuran (PCDF) levels in breast milk of 143 primiparae living around the three most dioxin-contaminated areas of Vietnam. The women sampled lived in the vicinity of former U.S. air bases at Bien Hoa (n = 51), Phu Cat (n = 23), and Da Nang (n = 69), which are known as dioxin hotspots. Breast milk samples from Bien Hoa City, where residents live very close to the air base, showed high levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), with 18% of the samples containing > 5 pg TCDD/g lipid. However, Phu Cat residents lived far from the air base and their samples showed lower TCDD levels, with none containing > 5 pg TCDD/g lipid. In Da Nang, TCDD levels in mothers from Thanh Khe (close to the air base, n = 43) were significantly higher than those in mothers from Son Tra (far from the air base, n = 26), but not other PCDD and PCDF (PCDD/F) congeners. Although TCDD levels in Bien Hoa were the highest among these hotspots, levels of other PCDD/F congeners as well as the geometric mean concentration of total PCDD/F level in Bien Hoa (9.3 pg toxic equivalents [TEQ]/g lipid) were significantly lower than the level observed in Phu Cat (14.1 pg TEQ/g lipid), Thanh Khe (14.3 pg TEQ/g lipid), and Son Tra (13.9 pg TEQ/g lipid). Our findings indicated that residents living close to former U.S. air bases were exposed to elevated levels of TCDD, but not of other PCDD/F congeners. [ABSTRACT FROM AUTHOR]

Purpose The aim of the present study was to evaluate the dose–effect relationship between urinary cadmium (U-Cd as an index of internal Cd exposure) and mortality in a cohort of the Japanese general population. Methods A 19-year cohort study was conducted in 897 men and 1307 women who lived in two non-polluted areas in Japan. The subjects were categorized into four quartiles based on creatinine adjusted U-Cd (μg/g cre). Hazard ratio (HR) and 95% confidence interval (95%CI) of the quartiles of U-Cd for mortality was calculated using a proportional hazards regression. Forward stepwise model selection was applied to the potential covariates such as age, body mass index, mean arterial pressure, various lifestyle factors and present illness. Results The mortality rates per 1000 person years were 27.8 and 12.5 in men and women, respectively. In men, the fourth quartile of U-Cd (≥2.919 μg/g cre) showed a significant, positive HR (1.50, 95%CI: 1.11–2.02) for mortality compared to the first quartile (<1.014). In women, the fourth quartile of U-Cd (≥3.943 μg/g cre) also showed a significant HR (1.50, 95%CI: 1.08–2.09) for mortality compared to the first quartile (<1.140). Conclusion The present study clarified that U-Cd was significantly associated with increased mortality, indicating the worsened life prognosis of the general population in Cd non-polluted areas in Japan. These results highlight the importance of further discussion of the health risk assessment of Cd exposure in the general population. [ABSTRACT FROM AUTHOR]

A recent study found an inverse correlation between serum TCDD levels and serum testosterone in the US veterans, while there is little known on the dioxin and steroid hormones about Vietnamese men. We collected blood samples from 48 men who had resided in a hotspot when exposure happened and 38 men in a non-sprayed area. Some steroid hormones levels showed significant differences between two areas. There were no correlations between steroid hormones and dioxin TEQ, after ajusting for age and other factors. Our findings indicate that steroid hormones of Vietnamese men did not correlate with dioxin TEQ in two areas. [ABSTRACT FROM AUTHOR]

The aim of this study was to clarify the relationship between dioxin concentrations in breast milk and the sister chromatid exchange (SCE) frequency in women from herbicide-sprayed and non sprayed areas. Blood samples were taken from 21 women with high TCDD (tetrachlorodibenzo-p-dioxin) levels from sprayed areas, 23 women with moderate TCDD levels from sprayed areas, and 19 women from non sprayed areas to determine their SCE frequency. The SCE frequencies for the high and moderate TCDD groups from the sprayed area and for the non sprayed area group were 2.40, 2.19, and 1.48 per cell, respectively. Multiple regression analysis showed that the standardized ß values for 1,2,3,6,7,8-hexaCDD (ß = 0.60), 1,2,3,4,6,7,8-heptaCDD (ß = 0.64), and octaCDD (ß = 0.65) were higher than those for TCDD (ß = 0.34) and 1,2,3,7,8-pentaCDD (ß = 0.42). The adjusted R2 value for polyCDDs (R2 = 0.38) was higher than that for polyCDD toxic equivalents (TEQ (toxic equivalents); R2 = 0.23). This study therefore shows that levels of hexa-, hepta-, and octaCDD, which were previously regarded as being less toxic than TCDD, are closely related to SCE frequency and that the level of dioxin (pg/g lipid) is potentially more useful as an indicator than TEQ value for explaining SCE frequency. [ABSTRACT FROM AUTHOR]