Association of renal function and delta-aminolevulinic acid dehydratase polymorphism among Vietnamese and Singapore workers exposed to inorganic lead

Objectives

To investigate the effect of δ‐aminolevulinic acid dehydratase (ALAD) polymorphisms on the association between blood lead and renal function among Vietnamese and Singaporean workers who were exposed to low to medium levels of inorganic lead, and to study the distribution of ALAD polymorphism among Vietnamese, Chinese, Malays and Indians.

Methods

A total of 459 male and female workers were studied. Blood and urine were collected for each worker in order to determine ALAD genotype, blood lead, and urinary δ‐aminolevulinic acid (ALAU). Renal function tests included urine albumin (Ualb), urine β2 microglobulin (Uβ2m), urinary α1 microglobulin (Uα1m), N‐acetyl‐glucosaminidas (NAG), and urine retinol blinding protein (RBP). A multiple regression model with interaction term was applied to fit the entire data and to explore the modifying effect of ALAD polymorphism on the relation of blood lead to each renal function parameter.

Results

ALAD1‐1 was the predominant genotype for all the ethnic groups while ALAD2‐2 was the rarest. The frequency of ALAD2 allele was higher among Malays (8.8%) and Indians (10.6%) compared to the Chinese (5.0%) and Vietnamese (4.3%). The geometric mean of blood lead for all workers was 19.0 μg/dl. The models for Uβ2m, Uα1m, and NAG showed that the ALAD1‐2/2‐2 group had higher β coefficients than the ALAD1‐1 group. Corresponding to 10 μg/dl blood lead, ALAD1‐1 homozygotes had an increment of 1.288 μg/g Cr, 1.175 mg/g Cr, and 1.995 U/g Cr for Uβ2m, Uα1m, and NAG, respectively. ALAD1‐2/2‐2 subjects had higher increments of 3.802 μg/g Cr, 2.138 mg/g Cr, and 3.89 U/g Cr for Uβ2m, Uα1m, and NAG, respectively.

Conclusion

The frequency of the ALAD2 allele is as low in Vietnamese workers as in Chinese. Workers with the ALAD2 allele appeared more susceptible to the effects of lead (especially at higher levels) on renal function.     

Polymorphisms in Iron Homeostasis Genes and Urinary Cadmium Concentrations among Nonsmoking Women in Argentina and Bangladesh

Background: Cadmium (Cd) is a human toxicant and carcinogen. Genetic variation might affect long-term accumulation. Cd is absorbed via iron transporters.Objectives: We evaluated the impact of iron homeostasis genes [divalent metal transporter 1 (SLC11A2), transferrin (TF), transferrin receptors (TFR2 and TFRC), and ferroportin (SLC40A1)] on Cd accumulation.Methods: Subjects were nonsmoking women living in the Argentinean Andes [n = 172; median urinary Cd (U-Cd) = 0.24 µg/L] and Bangladesh (n = 359; U-Cd = 0.54 µg/L) with Cd exposure mainly from food. Concentrations of U-Cd and Cd in whole blood or in erythrocytes (Ery-Cd) were measured by inductively coupled plasma mass spectrometry. Fifty polymorphisms were genotyped by Sequenom. Gene expression was measured in whole blood (n = 72) with Illumina DirectHyb HumanHT-12 v4.0.Results: TFRC rs3804141 was consistently associated with U-Cd. In the Andean women, mean U-Cd concentrations were 22% (95% CI: –2, 51%), and they were 56% (95% CI: 10, 120%) higher in women with GA and AA genotypes, respectively, relative to women with the GG genotype. In the Bangladeshi women, mean U-Cd concentrations were 22% (95% CI: 1, 48%), and they were 58% (95% CI: –3, 157%) higher in women with GA and AA versus GG genotype, respectively [adjusted for age and plasma ferritin in both groups; p_trend = 0.006 (Andes) and 0.009 (Bangladesh)]. TFRC expression in blood was negatively correlated with plasma ferritin (r_S = –0.33, p = 0.006), and positively correlated with Ery-Cd (significant at ferritin concentrations of < 30 µg/L only, r_S = 0.40, p = 0.046). Rs3804141 did not modify these associations or predict TFRC expression. Cd was not consistently associated with any of the other polymorphisms evaluated.Conclusions: One TFRC polymorphism was associated with urine Cd concentration, a marker of Cd accumulation in the kidney, in two very different populations. The consistency of the findings supports the possibility of a causal association.     

Bisphenol A exposure is associated with in vivo estrogenic gene expression in adults

Background: Bisphenol A (BPA) is a synthetic estrogen commonly used in polycarbonate plastic and resin-lined food and beverage containers. Exposure of animal and cell models to doses of BPA below the recommended tolerable daily intake (TDI) of 50 μg/kg/day have been shown to alter specific estrogen-responsive gene expression, but this has not previously been shown in humans.Objective: We investigated associations between BPA exposure and in vivo estrogenic gene expression in humans.Methods: We studied 96 adult men from the InCHIANTI population study and examined in vivo expression of six estrogen receptor, estrogen-related receptor, and androgen receptor genes in peripheral blood leukocytes.Results: The geometric mean urinary BPA concentration was 3.65 ng/mL [95% confidence interval (CI): 3.13, 4.28], giving an estimated mean excretion of 5.84 μg/day (95% CI: 5.00, 6.85), significantly below the current TDI. In age-adjusted models, there were positive associations between higher BPA concentrations and higher ESR2 [estrogen receptor 2 (ER beta)] expression (unstandardized linear regression coefficient = 0.1804; 95% CI: 0.0388, 0.3221; p = 0.013) and ESRRA (estrogen related receptor alpha) expression (coefficient = 0.1718; 95% CI: 0.0213, 0.3223; p = 0.026): These associations were little changed after adjusting for potential confounders, including obesity, serum lipid concentrations, and white cell subtype percentages. Upper-tertile BPA excretors (urinary BPA > 4.6 ng/mL) had 65% higher mean ESR2 expression than did lower-tertile BPA excretors (0–2.4 ng/mL).Conclusions: Because activation of nuclear-receptor–mediated pathways by BPA is consistently found in laboratory studies, such activation in humans provides evidence that BPA is likely to function as a xenoestrogen in this sample of adults.     

Significance of the excretion of urinary indicator proteins for a low level of occupational exposure to cadmium

Summary Urinary cadmium (Cd), N-acetyl-β-D-glucosaminidase (NAG), metallothionein (MT), β₂-microglobulin (BMG), and blood cadmium were determined in 79 workers who had been employed at a Cd pigment factory in Japan. The workers who had been dealing with Cd pigment manufacturing processes were estimated to be exposed to cadmium pigment dust at a maximum concentration of 3.0 [μg/m³/8 h for about 20 years. The urinary Cd level ranged from 0.2 to 9.7 μg/g creatinine with a geometric mean of 1.02 μg/g creatinine. Pearson's correlation coefficients between logarithm of urinary Cd and that of NAG, MT, and BMG in urine were 0.45, 0.62, and 0.05, respectively. The correlation coefficients between blood Cd and urinary NAG, MT, and BMG were 0.21, 0.40, and −0.074, respectively. When partial correlation coefficients were calculated to exclude the contribution of age factor, urinary Cd turned out to be significantly correlated with urinary MT (r = 0.55) and NAG (r = 0.52). The present results indicate that urinary Cd is more closely associated with urinary MT and NAG than with BMG, and suggest that MT and NAG could be good indicators of Cd absorption in a Cd-exposed population whose mean urinary Cd level is relatively low, or less than 10 μg/g creatinine.     

Estimated short-term effects of coarse particles on daily mortality in Stockholm, Sweden

Background: Although serious health effects associated with particulate matter (PM) with aerodynamic diameter ≤ 10 μm (PM₁₀) and ≤ 2.5 μm (PM_2.5; fine fraction) are documented in many studies, the effects of coarse PM (PM_2.5–10) are still under debate.Objective: In this study, we estimated the effects of short-term exposure of PM_2.5–10 on daily mortality in Stockholm, Sweden.Method: We collected data on daily mortality for the years 2000 through 2008. Concentrations of PM₁₀, PM_2.5, ozone, and carbon monoxide were measured simultaneously in central Stockholm. We used additive Poisson regression models to examine the association between daily mortality and PM_2.5–10 on the day of death and the day before. Effect estimates were adjusted for other pollutants (two-pollutant models) during different seasons.Results: We estimated a 1.68% increase [95% confidence interval (CI): 0.20%, 3.15%] in daily mortality per 10-μg/m³ increase in PM_2.5–10 (single-pollutant model). The association with PM_2.5–10 was stronger for November through May, when road dust is most important (1.69% increase; 95% CI: 0.21%, 3.17%), compared with the rest of the year (1.31% increase; 95% CI: –2.08%, 4.70%), although the difference was not statistically significant. When adjusted for other pollutants, particularly PM_2.5, the effect estimates per 10 μg/m³ for PM_2.5–10 decreased slightly but were still higher than corresponding effect estimates for PM_2.5.Conclusions: Our analysis shows an increase in daily mortality associated with elevated urban background levels of PM_2.5–10. Regulation of PM_2.5–10 should be considered, along with actions to specifically reduce PM_2.5–10 emissions, especially road dust suspension, in cities.     

Acute respiratory inflammation in children and black carbon in ambient air before and during the 2008 Beijing Olympics

Background: Epidemiologic evidence for a causative association between black carbon (BC) and health outcomes is limited.Objectives: We estimated associations and exposure–response relationships between acute respiratory inflammation in schoolchildren and concentrations of BC and particulate matter with an aerodynamic diameter of ≤ 2.5 μm (PM_2.5) in ambient air before and during the air pollution intervention for the 2008 Beijing Olympics.Methods: We measured exhaled nitric oxide (eNO) as an acute respiratory inflammation biomarker and hourly mean air pollutant concentrations to estimate BC and PM_2.5 exposure. We used 1,581 valid observations of 36 subjects over five visits in 2 years to estimate associations of eNO with BC and PM_2.5 according to generalized estimating equations with polynomial distributed-lag models, controlling for body mass index, asthma, temperature, and relative humidity. We also assessed the relative importance of BC and PM_2.5 with two-pollutant models.Results: Air pollution concentrations and eNO were clearly lower during the 2008 Olympics. BC and PM_2.5 concentrations averaged over 0–24 hr were strongly associated with eNO, which increased by 16.6% [95% confidence interval (CI), 14.1–19.2%] and 18.7% (95% CI, 15.0–22.5%) per interquartile range (IQR) increase in BC (4.0 μg/m³) and PM_2.5 (149 μg/m³), respectively. In the two-pollutant model, estimated effects of BC were robust, but associations between PM_2.5 and eNO decreased with adjustment for BC. We found that eNO was associated with IQR increases in hourly BC concentrations up to 10 hr after exposure, consistent with effects primarily in the first hours after exposure.Conclusions: Recent exposure to BC was associated with acute respiratory inflammation in schoolchildren in Beijing. Lower air pollution levels during the 2008 Olympics also were associated with reduced eNO.     

Traffic-related air pollution and acute changes in heart rate variability and respiratory function in urban cyclists

Background: Few studies have examined the acute health effects of air pollution exposures experienced while cycling in traffic.Objectives: We conducted a crossover study to examine the relationship between traffic pollution and acute changes in heart rate variability. We also collected spirometry and exhaled nitric oxide measures.Methods: Forty-two healthy adults cycled for 1 hr on high- and low-traffic routes as well as indoors. Health measures were collected before cycling and 1–4 hr after the start of cycling. Ultrafine particles (UFPs; ≤ 0.1 μm in aerodynamic diameter), particulate matter ≤ 2.5 μm in aerodynamic diameter (PM_2.5), black carbon, and volatile organic compounds were measured along each cycling route, and ambient nitrogen dioxide (NO₂) and ozone (O₃) levels were recorded from a fixed-site monitor. Mixed-effects models were used to estimate associations between air pollutants and changes in health outcome measures relative to precycling baseline values.Results: An interquartile range increase in UFP levels (18,200/cm³) was associated with a significant decrease in high-frequency power 4 hr after the start of cycling [β = –224 msec²; 95% confidence interval (CI), –386 to –63 msec²]. Ambient NO₂ levels were inversely associated with the standard deviation of normal-to-normal (NN) intervals (β = –10 msec; 95% CI, –20 to –0.34 msec) and positively associated with the ratio of low-frequency to high-frequency power (β = 1.4; 95% CI, 0.35 to 2.5) 2 hr after the start of cycling. We also observed significant inverse associations between ambient O₃ levels and the root mean square of successive differences in adjacent NN intervals 3 hr after the start of cycling.Conclusions: Short-term exposures to traffic pollution may contribute to altered autonomic modulation of the heart in the hours immediately after cycling.     

Neuropsychological measures of attention and impulse control among 8-year-old children exposed prenatally to organochlorines

Background: We previously reported associations between organochlorines and behaviors related to attention deficit hyperactivity disorder among boys and girls at 8 years of age using a teacher’s rating scale for a birth cohort in New Bedford, Massachusetts (USA).Objectives: Our goal was to corroborate these findings using neuropsychological measures of inattentive and impulsive behaviors.Methods: We investigated the association between cord serum polychlorinated biphenyls (PCBs) and p,p´-dichlorodiphenyl dichloroethylene (p,p´-DDE) and attention and impulse control using a Continuous Performance Test (CPT) and components of the Wechsler Intelligence Scale for Children, 3rd edition (WISC-III). Participants came from a prospective cohort of children born during 1993–1998 to mothers residing near a PCB-contaminated harbor in New Bedford. Median (range) cord serum levels for the sum of four prevalent PCBs [congeners 118, 138, 153, and 180 (ΣPCB₄)] and p,p´-DDE were 0.19 (0.01–2.59) and 0.31 (0–14.93) ng/g serum, respectively.Results: We detected associations between PCBs and neuropsychological deficits for 578 and 584 children with CPT and WISC-III measures, respectively, but only among boys. For example, boys with higher exposure to ΣPCB₄ had a higher rate of CPT errors of omission [rate ratio for the exposure interquartile range (IQR) = 1.12; 95% confidence interval (CI): 0.98, 1.27] and slower WISC-III Processing Speed (change in score for the IQR = –2.0; 95% CI: –3.5, –0.4). Weaker associations were found for p,p´-DDE. For girls, associations were in the opposite direction for the CPT and null for the WISC-III.Conclusions: These results support an association between organochlorines (mainly PCBs) and neuropsychological measures of attention among boys only. Sex-specific effects should be considered in studies of organochlorines and neurodevelopment.     

Prenatal arsenic exposure and DNA methylation in maternal and umbilical cord blood leukocytes

Background: Arsenic is an epigenetic toxicant and could influence fetal developmental programming.Objectives: We evaluated the association between arsenic exposure and DNA methylation in maternal and umbilical cord leukocytes.Methods: Drinking-water and urine samples were collected when women were at ≤ 28 weeks gestation; the samples were analyzed for arsenic using inductively coupled plasma mass spectrometry. DNA methylation at CpG sites in p16 (n = 7) and p53 (n = 4), and in LINE-1 and Alu repetitive elements (3 CpG sites in each), was quantified using pyrosequencing in 113 pairs of maternal and umbilical blood samples. We used general linear models to evaluate the relationship between DNA methylation and tertiles of arsenic exposure.Results: Mean (± SD) drinking-water arsenic concentration was 14.8 ± 36.2 μg/L (range: < 1–230 μg/L). Methylation in LINE-1 increased by 1.36% [95% confidence interval (CI): 0.52, 2.21%] and 1.08% (95% CI: 0.07, 2.10%) in umbilical cord and maternal leukocytes, respectively, in association with the highest versus lowest tertile of total urinary arsenic per gram creatinine. Arsenic exposure was also associated with higher methylation of some of the tested CpG sites in the promoter region of p16 in umbilical cord and maternal leukocytes. No associations were observed for Alu or p53 methylation.Conclusions: Exposure to higher levels of arsenic was positively associated with DNA methylation in LINE-1 repeated elements, and to a lesser degree at CpG sites within the promoter region of the tumor suppressor gene p16. Associations were observed in both maternal and fetal leukocytes. Future research is needed to confirm these results and determine if these small increases in methylation are associated with any health effects.     

Causes of death and renal tubular dysfunction in residents exposed to cadmium in the environment

Objectives

To clarify the causes of death of residents with renal tubular dysfunction induced by cadmium (Cd) in the environment.

Methods

A 15 year follow up study was performed with the inhabitants living in the Cd polluted Kakehashi River basin in Japan. Standardised mortality ratios (SMRs) for causes of death, classified by ICD‐9, were computed using the person‐years method to investigate the excess mortality of subjects with urinary β2‐MG (microglobulin) ⩾1000 μg/gCr. Mortality risk analysis was performed using Cox''s proportional model to compare mortality between subjects with urinary β2‐MG ⩾1000 and <1000 μg/gCr, and to investigate the relationship between the degree of urinary β2‐MG and mortality.

Results

Excess mortality due to heart failure and cerebral infarction in both sexes, and nephritis and nephrosis in men, was observed among subjects with urinary β2‐MG ⩾1000 μg/gCr. Significant increases in mortality risk for cerebral infarction in men and for malignant neoplasms in women with urinary β2‐MG ⩾1000 μg/gCr were observed during the first five year observation period. For nephritis and nephrosis, the mortality risks for men and women with urinary β2‐MG ⩾1000 μg/gCr significantly increased over the 15 year observation period. The mortality risks for heart failure and cerebral infarction increased in proportion to the increased urinary β2‐MG in both sexes. Increased mortality risks for nephritis and nephrosis were identified in the subjects with urinary β2‐MG ⩾10000 μg/gCr in both sexes.

Conclusion

Renal tubular dysfunction induced by Cd affected the causes of death, and mortality for heart failure, cerebral infarction, and nephritis and nephrosis was increased among inhabitants living in a Cd polluted area in Japan. In women, cancer mortality may have been increased while Cd pollution was ongoing.     

Low-level environmental cadmium exposure is associated with DNA hypomethylation in Argentinean women

Background: Cadmium, a common food pollutant, alters DNA methylation in vitro. Epigenetic effects might therefore partly explain cadmium’s toxicity, including its carcinogenicity; however, human data on epigenetic effects are lacking.Objective: We evaluated the effects of dietary cadmium exposure on DNA methylation, considering other environmental exposures, genetic predisposition, and gene expression.Methods: Concentrations of cadmium, arsenic, selenium, and zinc in blood and urine of nonsmoking women (n = 202) from the northern Argentinean Andes were measured by inductively coupled mass spectrometry. Methylation in CpG islands of LINE-1 (long interspersed nuclear element-1; a proxy for global DNA methylation) and promoter regions of p16 [cyclin-dependent kinase inhibitor 2A (CDKN2A)] and MLH1 (mutL homolog 1) in peripheral blood were measured by bisulfite polymerase chain reaction pyrosequencing. Genotyping (n = 172) for the DNA (cytosine-5-)-methyltransferase 1 gene (DNMT1 rs10854076 and rs2228611) and DNA (cytosine-5-)-methyltransferase 3 beta gene (DNMT3B rs2424913 and rs2424932) was performed with Sequenom iPLEX GOLD SNP genotyping; and gene expression (n = 90), with DirectHyb HumanHT-12 (version 3.0).Results: Cadmium exposure was low: median concentrations in blood and urine were 0.36 and 0.23 µg/L, respectively. Urinary cadmium (natural log transformed) was inversely associated with LINE-1 methylation (β = –0.50, p = 0.0070; β = –0.44, p = 0.026, adjusted for age and coca chewing) but not with p16 or MLH1 methylation. Both DNMT1 rs10854076 and DNMT1 rs2228611 polymorphisms modified associations between urinary cadmium and LINE-1 (p-values for interaction in adjusted models were 0.045 and 0.064, respectively). The rare genotypes demonstrated stronger hypomethylation with increasing urinary cadmium concentrations. Cadmium was inversely associated with DNMT3B (r_S = –0.28, p = 0.0086) but not with DNMT1 expression (r_S = –0.075, p = 0.48).Conclusion: Environmental cadmium exposure was associated with DNA hypomethylation in peripheral blood, and DNMT1 genotypes modified this association. The role of epigenetic modifications in cadmium-associated diseases needs clarification.     

Lithium in drinking water and thyroid function

Background

High concentrations of lithium in drinking water were previously discovered in the Argentinean Andes Mountains. Lithium is used worldwide for treatment of bipolar disorder and treatment-resistant depression. One known side effect is altered thyroid function.

Objectives

We assessed associations between exposure to lithium from drinking water and other environmental sources and thyroid function.

Methods

Women (n = 202) were recruited in four Andean villages in northern Argentina. Lithium exposure was assessed based on concentrations in spot urine samples, measured by inductively coupled plasma mass spectrometry. Thyroid function was evaluated by plasma free thyroxine (T₄) and pituitary gland thyroid-stimulating hormone (TSH), analyzed by routine immunometric methods.

Results

The median urinary lithium concentration was 3,910 μg/L (5th, 95th percentiles, 270 μg/L, 10,400 μg/L). Median plasma concentrations (5th, 95th percentiles) of T₄ and TSH were 17 pmol/L (13 pmol/L, 21 pmol/L) and 1.9 mIU/L, (0.68 mIU/L, 4.9 mIU/L), respectively. Urine lithium was inversely associated with T₄ [β for a 1,000-μg/L increase = −0.19; 95% confidence interval (CI), −0.31 to −0.068; p = 0.002] and positively associated with TSH (β = 0.096; 95% CI, 0.033 to 0.16; p = 0.003). Both associations persisted after adjustment (for T₄, β = −0.17; 95% CI, −0.32 to −0.015; p = 0.032; for TSH: β = 0.089; 95% CI, 0.024 to 0.15; p = 0.007). Urine selenium was positively associated with T₄ (adjusted T₄ for a 1 μg/L increase: β = 0.041; 95% CI, 0.012 to 0.071; p = 0.006).

Conclusions

Exposure to lithium via drinking water and other environmental sources may affect thyroid function, consistent with known side effects of medical treatment with lithium. This stresses the need to screen for lithium in all drinking water sources.     

Survival analysis of long-term exposure to different sizes of airborne particulate matter and risk of infant mortality using a birth cohort in Seoul, Korea

Background

Several studies suggest that airborne particulate matter (PM) is associated with infant mortality; however, most focused on short-term exposure to larger particles.

Objectives

We evaluated associations between long-term exposure to different sizes of particles [total suspended particles (TSP), PM ≤ 10 μm in aerodynamic diameter (PM₁₀), ≤ 10–2.5 μm (PM_10–2.5), and ≤ 2.5 μm (PM_2.5)] and infant mortality in a cohort in Seoul, Korea, 2004–2007.

Methods

The study includes 359,459 births with 225 deaths. We applied extended Cox proportional hazards modeling with time-dependent covariates to three mortality categories: all causes, respiratory, and sudden infant death syndrome (SIDS). We calculated exposures from birth to death (or end of eligibility for outcome at 1 year of age) and pregnancy (gestation and each trimester) and treated exposures as time-dependent variables for subjects’ exposure for each pollutant. We adjusted by sex, gestational length, season of birth, maternal age and educational level, and heat index. Each cause of death and exposure time frame was analyzed separately.

Results

We found a relationship between gestational exposures to PM and infant mortality from all causes or respiratory causes for normal-birth-weight infants. For total mortality (all causes), risks were 1.44 (95% confidence interval, 1.06–1.97), 1.65 (1.18–2.31), 1.53 (1.22–1.90), and 1.19 (0.83–1.70) per interquartile range increase in TSP, PM₁₀, PM_2.5, and PM_10–2.5, respectively; for respiratory mortality, risks were 3.78 (1.18–12.13), 6.20 (1.50–25.66), 3.15 (1.26–7.85), and 2.86 (0.76–10.85). For SIDS, risks were 0.92 (0.33–2.58), 1.15 (0.38–3.48), 1.42 (0.71–2.87), and 0.57 (0.16–1.96), respectively.

Conclusions

Our findings provide supportive evidence of an association of long-term exposure to PM air pollution with infant mortality.     

Air pollution and stillbirth: a population-based case-control study in Taiwan

Background: There is limited evidence suggesting that prenatal exposure to ambient air pollutants may increase the risk of stillbirth, but previous epidemiological studies have not elaborated the most susceptible gestational period for the effects of air pollution exposure on stillbirth.Objectives: We estimated associations between exposure to ambient air pollutants and stillbirth, with special reference to the assessment of gestational periods when the fetus is most susceptible.Methods: We conducted a population-based case–control study in Taiwan. The case group consisted of 9,325 stillbirths, and the control group included 93,250 births randomly selected from 1,510,064 Taiwanese singleton newborns in 2001–2007. Adjusted logistic regression models were used to estimate odds ratios (ORs) per 10-ppb change for ozone and nitrogen dioxide, 1-ppb change for sulfur dioxide (SO₂), 10-μg/m³ change for particulate matter with aerodynamic diameter ≤ 10 μm (PM₁₀), and 100-ppb change for carbon monoxide during different gestational periods and according to term or preterm (< 37 weeks) birth status.Results: Stillbirth increased in association with a 1-ppb increase in first-trimester SO₂ [adjusted OR = 1.02; 95% confidence interval (CI), 1.00–1.04], particularly among preterm births (adjusted OR = 1.04; 95% CI, 1.01–1.07). Stillbirth was also associated with a 10-μg/m³ increase in PM₁₀ during the first (adjusted OR = 1.02; 95% CI, 1.00–1.05) and second (adjusted OR = 1.02; 95% CI, 1.00–1.04) month of gestation, and, as with SO₂, associations appeared to be restricted to preterm births (first-trimester adjusted OR = 1.03; 95% CI, 1.00–1.07).Conclusion: The study provides evidence that exposure to outdoor air SO₂ and PM₁₀ may increase the risk of stillbirth, especially among preterm births, and that the most susceptible time periods for exposure are during the first trimester of gestation.     

Occupational exposure to cis-1,3-dichloropropene: biological effect monitoring of kidney and liver function

OBJECTIVES—To investigate the possible effects of occupational exposure to the nematocide cis-1,3-dichloropropene (cis-DCP) on function of the kidney and liver in the starch potato growing region in The Netherlands.
METHODS—The study involved 13 commercial application workers exposed to cis-DCP for 117 days, and 22 matched control workers. The inhalatory exposure of the application workers was estimated from biological monitoring data. All workers collected urine and serum samples before, during, and after the fumigation season for monitoring of variables for kidney and liver function. Renal effect variables were alanine aminopeptidase (AAP), N-acetyl-β-D-glucosaminidase (NAG), retinol binding protein (RBP), and albumin (ALB) in urine, and β₂-microglobulin (β₂M-S) and creatinine in serum (Creat-S). Liver variables were alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), γ-glutamyltranspeptidase (GGT), alkaline phosphatase (ALP), and total bilirubin (TBIL) in serum and the urinary ratio of 6-β-hydroxycortisol to free cortisol (βOHC/COR).
RESULTS—The geometric mean exposure of the application workers was 2.7 mg/m³ (8 hour time weighted average (8 hour TWA)); range 0.1-9.5 mg/m³. No differences were found between the values of the renal effect variables or the liver variables of the exposed group and the control group, except a lower urinary ratio of βOHC/COR in the exposed group. This was not considered to be related to the exposure to cis-DCP. No dose-effect relations were found between the exposure indices and the effect variables.
CONCLUSIONS—The present study does not provide evidence that occupational exposure to cis-DCP in the starch potato growing region causes adverse effects on the kidney or liver at 8 hour TWA exposure concentrations below 9.5 mg/m³ (2 ppm).


Keywords: cis-1,3-dichloropropene; occupational exposure; kidney; liver     

Dietary exposure to cadmium at close to the current provisional tolerable weekly intake does not affect renal function among female Japanese farmers

Dietary cadmium (Cd) exposure and renal tubular function were investigated in 1381 female farmers from five districts in Japan (Japanese Multi-centered Environmental Toxicant Study project; JMETS). Dietary Cd exposure of the five populations was assessed from the individual Cd concentrations of the rice consumed by the study participants and the quantities of rice consumed daily. The populations showed a sequential difference in dietary Cd exposure, ranging from a level as low as that of the general Japanese population to one close to the current provisional tolerable weekly intake (PTWI). The levels of urinary Cd excretion, an indicator of Cd accumulation in the kidneys, increased along the same sequential pattern as dietary Cd exposure. However, no differences were observed among the populations in levels of urinary alpha 1-microglobulin and beta 2-microglobulin excretion, which are indicators of renal tubular function. These results indicate that the current PTWI is sufficient to prevent Cd-induced renal dysfunction among the general population.     

Involvement of connexin43 hemichannel in ATP release after γ-irradiation

Ionizing radiation induces biological effects not only in irradiated cells but also in non-irradiated cells, which is called the bystander effect. Recently, in vivo and in vitro experiments have suggested that both gap junction hemichannel connexin43 (Cx43) and extracellular adenosine triphosphate (ATP) released from cells play a role in the bystander effect. We have reported that γ-irradiation induces ATP release from B16 melanoma cells, which is dependent on the P2X₇ receptor. However, the mechanism of ATP release caused by irradiation remains unclear. We here show the involvement of Cx43 in P2X₇ receptor-dependent ATP release after 0.5 Gy γ-irradiation. Inhibitors of gap junction hemichannels and an inhibitory peptide for Cx43 (gap26), but not an inhibitory peptide for pannexin1 (Panx1), significantly blocked γ-irradiation-induced ATP release from B16 melanoma cells. We confirmed high expression of Cx43 mRNA in B16 melanoma cells. These results suggest involvement of Cx43 in radiation-induced ATP release. We found that after 0.5 Gy γ-irradiation tyrosine phosphorylation was significantly blocked by P2X₇ receptor antagonist, but not gap26, suggesting that tyrosine phosphorylation is a downstream event from the P2X₇ receptor. Since tyrosine kinase inhibitor significantly suppressed radiation-induced ATP release, tyrosine phosphorylation appears to play an important role in the Cx43-mediated ATP release downstream of the P2X₇ receptor. In conclusion, the Cx43 hemichannel, which lies downstream of the P2X₇ receptor, is involved in ATP release in response to radiation. Our results suggest a novel mechanism for radiation-induced biological effects mediated by both ATP and Cx43.     

Inhibitory effects of calcium against intestinal cancer in human colon cancer cells and ApcMin/+ mice

The aim of the study was to investigate the inhibitory effects of calcium against intestinal cancer in vitro and in vivo. We first investigated the effects of calcium treatment in HCT116 and HT29 human colon cancer cells. At the concentration range of 0.8-2.4 mM, calcium significantly inhibited cell growth (by 9-29%), attachment (by 12-26%), invasion (by 15-31%), and migration (by 19-61%). An immunofluorescence microscope analysis showed that the treatment with calcium (1.6 mM) for 24 h increased plasma membrane β-catenin but decreased nuclear β-catenin levels in HT29 cells. We then investigated the effect of dietary calcium on intestinal tumorigenesis in Apc^Min/+ mice. Mice received dietary treatment starting at 6 weeks of age for the consecutive 8 weeks. The basal control diet contained high-fat (20% mixed lipids by weight) and low-calcium (1.4 mg/g diet) to mimic the average Western diet, while the treatment diet contained an enriched level of calcium (5.2 mg calcium/g diet). The dietary calcium treatment decreased the total number of small intestinal tumors (by 31.4%; P < 0.05). The largest decrease was in tumors which were ≥ 2 mm in diameter, showing a 75.6% inhibition in the small intestinal tumor multiplicity (P < 0.001). Immunohistochemical analysis showed significantly reduced nuclear staining of β-catenin (expressed as nuclear positivity), but increased plasma membrane staining of β-catenin, in the adenomas from the calcium-treated groups in comparison to those from the control group (P < 0.001). These results demonstrate intestinal cancer inhibitory effects of calcium both in human colon cancer cells and Apc^Min/+ mice. The decreased β-catenin nuclear localization caused by the calcium treatment may contribute to the inhibitory action.     

Gestational Diabetes and Preeclampsia in Association with Air Pollution at Levels below Current Air Quality Guidelines

Background: Several studies have estimated associations between air pollution and birth outcomes, but few have evaluated potential effects on pregnancy complications.Objective: We investigated whether low-level exposure to air pollution is associated with gestational diabetes and preeclampsia.Methods: High-quality registry information on 81,110 singleton pregnancy outcomes in southern Sweden during 1999–2005 was linked to individual-level exposure estimates with high spatial resolution. Modeled exposure to nitrogen oxides (NO_x), expressed as mean concentrations per trimester, and proximity to roads of different traffic densities were used as proxy indicators of exposure to combustion-related air pollution. The data were analyzed by logistic regression, with and without adjusting for potential confounders.Results: The prevalence of gestational diabetes increased with each NO_x quartile, with an adjusted odds ratio (OR) of 1.69 (95% CI: 1.41, 2.03) for the highest (> 22.7 µg/m³) compared with the lowest quartile (2.5–8.9 µg/m³) of exposure during the second trimester. The adjusted OR for acquiring preeclampsia after exposure during the third trimester was 1.51 (1.32, 1.73) in the highest quartile of NO_x compared with the lowest. Both outcomes were associated with high traffic density, but ORs were significant for gestational diabetes only.Conclusion: NO_x exposure during pregnancy was associated with gestational diabetes and preeclampsia in an area with air pollution levels below current air quality guidelines.     

Interlaboratory Evaluation of in Vitro Cytotoxicity and Inflammatory Responses to Engineered Nanomaterials: The NIEHS Nano GO Consortium

Background: Differences in interlaboratory research protocols contribute to the conflicting data in the literature regarding engineered nanomaterial (ENM) bioactivity.Objectives: Grantees of a National Institute of Health Sciences (NIEHS)-funded consortium program performed two phases of in vitro testing with selected ENMs in an effort to identify and minimize sources of variability.Methods: Consortium program participants (CPPs) conducted ENM bioactivity evaluations on zinc oxide (ZnO), three forms of titanium dioxide (TiO₂), and three forms of multiwalled carbon nanotubes (MWCNTs). In addition, CPPs performed bioassays using three mammalian cell lines (BEAS-2B, RLE-6TN, and THP-1) selected in order to cover two different species (rat and human), two different lung epithelial cells (alveolar type II and bronchial epithelial cells), and two different cell types (epithelial cells and macrophages). CPPs also measured cytotoxicity in all cell types while measuring inflammasome activation [interleukin-1β (IL-1β) release] using only THP-1 cells.Results: The overall in vitro toxicity profiles of ENM were as follows: ZnO was cytotoxic to all cell types at ≥ 50 μg/mL, but did not induce IL-1β. TiO₂ was not cytotoxic except for the nanobelt form, which was cytotoxic and induced significant IL-1β production in THP-1 cells. MWCNTs did not produce cytotoxicity, but stimulated lower levels of IL-1β production in THP-1 cells, with the original MWCNT producing the most IL-1β.Conclusions: The results provide justification for the inclusion of mechanism-linked bioactivity assays along with traditional cytotoxicity assays for in vitro screening. In addition, the results suggest that conducting studies with multiple relevant cell types to avoid false-negative outcomes is critical for accurate evaluation of ENM bioactivity.