Judy L. Mumford

Inhalable particles and pulmonary host defense: In vivo and in vitro effects of ambient air and combustion particles

The ability of particulate air pollutants (and possible constituents) to alter pulmonary host defenses was examined using an in vitro alveolar macrophage cytotoxicity assay and an in vivo bacterial infectivity screening test which employed intratracheal injection of the particles. A wide range of response between particles was seen at the 1.0-mg/ml level in vitro and the 0.1-mg/mouse level in vivo. A sample of fluidized-bed coal fly ash, bentonite, asbestos, some ambient air particles, and heavy metal oxides greatly increased susceptibility to pulmonary bacterial infection. Most coal fly ash samples and some air particles caused moderate increases in infectivity, while diesel particulates, volcanic ash, and crystalline silica caused only small increases. Cytotoxic effects on macrophages in vitro were observed with most of the particles. The in vivo and in vitro assays produced a similar ranking of toxicity; however, not all particles that were highly cytotoxic were potent in increasing bacterial infectivity. Increased toxicity measurable by either assay often appeared to be associated with small size or with the presence of metal in the particles.

Polymorphisms in the DNA nucleotide excision repair genes and lung cancer risk in Xuan Wei, China†

The lung cancer mortality rate in Xuan Wei County is among the highest in China and has been attributed to exposure to indoor smoky coal emissions that contain very high levels of polycyclic aromatic hydrocarbons (PAHs). Nucleotide excision repair (NER) plays a key role in reversing DNA damage from exposure to environmental carcinogens, such as PAHs, that form bulky DNA adducts. We studied single nucleotide polymorphisms (SNPs) and their corresponding haplotypes in 6 genes (ERCC1, ERCC2/XPD, ERCC4/XPF, ERCC5/XPG, RAD23B and XPC) involved in NER in a population‐based case‐control study of lung cancer in Xuan Wei. A total of 122 incident primary lung cancer cases and 122 individually matched controls were enrolled. Three linked SNPs in ERCC2 were associated with lung cancer with similar ORs; e.g., persons with the Gln allele at codon 751 had a 60% reduction of lung cancer (OR = 0.40, 95% CI 0.18–0.89). Moreover, one haplotype in ERCC2 was associated with a decreased risk of lung cancer (OR = 0.40, 95% CI 0.19–0.85) compared to the most common haplotype. In addition, subjects with one or 2 copies of the Val allele at codon 249 of RAD23B had a 2‐fold increased risk of lung cancer (OR = 1.91, 95% CI 1.12–3.24). In summary, our results suggest that genetic variants in genes involved in the NER pathway may play a role in lung cancer susceptibility in Xuan Wei. However, due to the small sample size, additional studies are needed to evaluate these associations within Xuan Wei and in other populations with substantial environmental exposure to PAHs.

Chronic Arsenic Exposure and Oxidative Stress: OGG1 Expression and Arsenic Exposure, Nail Selenium, and Skin Hyperkeratosis in Inner Mongolia

Arsenic, a human carcinogen, is known to induce oxidative damage to DNA. In this study we investigated oxidative stress and As exposure by determining gene expression of OGG1, which codes for an enzyme, 8-oxoguanine DNA glycosylase, involved in removing 8-oxoguanine in As-exposed individuals. Bayingnormen (Ba Men) residents in Inner Mongolia are chronically exposed to As via drinking water. Water, toenail, and blood samples were collected from 299 Ba Men residents exposed to 0.34–826 μg/L As. RNA was isolated from blood, and mRNA levels of OGG1 were determined using real-time polymerase chain reaction. OGG1 expression levels were linked to As concentrations in drinking water and nails, selenium concentrations in nails, and skin hyperkeratosis. OGG1 expression was strongly associated with water As concentrations (p < 0.0001). Addition of the quadratic term significantly improved the fit compared with the linear model (p = 0.05). The maximal OGG1 response was at the water As concentration of 149 μg/L. OGG1 expression was also significantly associated with toenail As concentrations (p = 0.015) but inversely associated with nail Se concentrations (p = 0.0095). We found no significant differences in the As-induced OGG1 expression due to sex, smoking, or age even though the oldest group showed the strongest OGG1 response (p = 0.0001). OGG1 expression showed a dose-dependent increased risk of skin hyperkeratosis in males (trend analysis, p = 0.02), but the trend was not statistically significant in females. The results from this study provide a linkage between oxidative stress and As exposure in humans. OGG1 expression may be useful as a biomarker for assessing oxidative stress from As exposure.

Indoor air sampling and mutagenicity studies of emissions from unvented coal combustion.

To develop sampling strategies and bioassay protocols for indoor air containing emissions from coal combustion in homes of the rural Xuan Wei County in China, the authors developed a medium-volume sampler to collect the <10-..mu..m particles and semivolatile organics by a filter and an XAD-2 resin, respectively. A high-volume particulate sampler was used for comparison. The coal was burned under conditions that simulated the open-pit combustion that occurs in Xuan Wei. High-volume and medium-volume sampling yielded similar, high particulate concentrations 38-39 mg/m/sup 3/. Fifteen percent of the total extractable organic mass was collected in the XAD-2 resin, and the remaining 85% was retained in the filter. The polycyclic aromatic hydrocarbons found in the XAD were composed of four or fewer rings. In the Ames Salmonella assay, the XAD sample showed low mutagenic activity, and most of the mutagenic activity was found in the filter. The coal combustion emitted both direct- and indirect-acting mutagens, most of which were frameshift mutagens. 12 references, 2 figures, 3 tables.

Chronic Arsenic Exposure and Cardiac Repolarization Abnormalities with QT Interval Prolongation in a Population-based Study

Background Chronic arsenic exposure is associated with cardiovascular abnormalities. Prolongation of the QT (time between initial deflection of QRS complex to the end of T wave) interval and profound repolarization changes on electrocardiogram (ECG) have been reported in patients with acute promyelocytic leukemia treated with arsenic trioxide. This acquired form of long QT syndrome can result in life-threatening arrhythmias. Objective The objective of this study was to assess the cardiac effects of arsenic by investigating QT interval alterations in a human population chronically exposed to arsenic. Methods Residents in Ba Men, Inner Mongolia, have been chronically exposed to arsenic via consumption of water from artesian wells. A total of 313 Ba Men residents with the mean arsenic exposure of 15 years were divided into three arsenic exposure groups: low (≤ 21 μg/L), medium (100–300 μg/L), and high (430–690 μg/L). ECGs were obtained on all study subjects. The normal range for QTc (corrected QT) interval is 0.33–0.44 sec, and QTc ≥ 0.45 sec was considered to be prolonged. Results The prevalence rates of QT prolongation and water arsenic concentrations showed a dose-dependent relationship (p = 0.001). The prevalence rates of QTc prolongation were 3.9, 11.1, 20.6% for low, medium, and high arsenic exposure, respectively. QTc prolongation was also associated with sex (p < 0.0001) but not age (p = 0.486) or smoking (p = 0.1018). Females were more susceptible to QT prolongation than males. Conclusions We found significant association between chronic arsenic exposure and QT interval prolongation in a human population. QT interval may potentially be useful in the detection of early cardiac arsenic toxicity.

ANALYSES OF MICRONUCLEI IN EXFOLIATED EPITHELIAL CELLS FROM INDIVIDUALS CHRONICALLY EXPOSED TO ARSENIC VIA DRINKING WATER IN INNER MONGOLIA, CHINA

The groundwater in Bayingnormen (Ba Men), located in Central West Inner Mongolia, China, is naturally contaminated with arsenic at concentrations ranging from 50 w g/L to 1.8 mg/L. Various adverse health effects in this region, including cancer, have been linked to arsenic exposure via drinking water. A pilot study was undertaken to evaluate frequencies of micronuclei (MN), as measures of chromosomal alterations, in multiple exfoliated epithelial cell types from residents of Ba Men chronically exposed to arsenic via drinking water. Buccal mucosal cells, airway epithelial cells in sputum, and bladder urothelial cells were collected from 19 residents exposed to high levels of arsenic in drinking water (527.5 - 24 w g/L), and from 13 control residents exposed to relatively low levels of arsenic in drinking water (4.4 - w g/L). Analytical results from these individuals revealed that MN frequencies in the high-exposure group were significantly elevated to 3.4-fold over control levels for buccal and sputum cells, and to 2.7-fold over control for bladder cells (increases in MN frequency significant at p < .001 for buccal cells; p < .01 for sputum cells; p < .05 for bladder cells). When smokers were excluded from high-exposure and control groups the effects of arsenic were observed to be greater, although only in buccal and sputum cells; approximately 6-fold increases in MN frequency occurred in these tissues. The results indicate that residents of Ba Men chronically exposed to high levels of arsenic in drinking water reveal evidence of genotoxicity in multiple epithelial cell types; higher levels of induced MN were observed in buccal and sputum cells than in bladder cells.

Maternal drinking water arsenic exposure and perinatal outcomes in Inner Mongolia, China

Background Bayingnormen is a region located in western Inner Mongolia China, with a population that is exposed to a wide range of drinking water arsenic concentrations. The relationship between maternal drinking water arsenic exposure and perinatal endpoints (term birth weight, preterm birth, stillbirth and neonatal death) in this region was evaluated in this study. Methods An analysis was conducted of all singleton deliveries in a defined geographical area of Inner Mongolia from December 1996 to December 1999 (n=9890). Outcome and covariate data were abstracted from prenatal care records. Exposure was based on well-water measures for the maternal subvillage. Mean birth weight at term was compared across four arsenic categories using analysis of covariance. ORs for stillbirth, preterm birth and neonatal death were estimated by logistic regression with arsenic exposure dichotomised at 50 μg/l. Results Term birth weight was 0.05 kg higher (95% CI 0.02 to 0.08) in the highest exposure category (>100 μg/l) compared to the reference (below limit of detection to 20 μg/l). Arsenic >50 μg/l was associated with an increased risk of neonatal death (OR 2.01, 95% CI 1.12 to 3.59). No relationship was found between maternal arsenic exposure and preterm or stillbirth delivery. Conclusions At the levels observed in our study, arsenic does not appear to contribute to adverse birth outcomes. Exposure may play a role in neonatal death; however, the neonatal death rate in this population was low and this potential association merits further research.

Human Exposure to Arsenic and Health Effects in Bayingnormen, Inner Mongolia

Publisher Summary Arsenic (As) is naturally occurring in ground water in large areas of Inner Mongolia with concentrations ranging from 50 μg/l) in the west and Tumet (with 81 villages >50 μg/l) in central Inner Mongolia are the two major endemic areas with high concentrations of As in ground water. Drinking water is the only significant source of As contamination. This chapter reports As exposure and health effects associated with As exposure in Ba Men. Up to 1995, a total of 1,447 cases (81% of all cases in Inner Mongolia) of arsenicism (mainly skin hyperkeratosis, depigmentation, hyperpigmentation, and skin cancer) were confirmed in Ba Men and more cases have been reported since then. The prevalence of arsenicism shows a dose-response relationship with concentration of As in drinking water. Patients with arsenicism range from 5 to 80 years old with peak prevalence among the 40–49 age group. Other clinical symptoms among the people who are exposed to As in Ba Men are—the central and peripheral neuro effects, including peripheral neuritis, Raynauds Syndrome, gastroenteritis, hypertrophy and abnormal functions in liver, peripheral and cardiovascular effects, including myocardial ischemia, arrhythmia, pulmonary effects, hematological effects showing morphological changes and membrane damage in red blood cells, and Bowens Disease and skin tumors. These studies showed that arsenic exposure resulted in a wide range of health effects in Inner Mongolia.

A sensitive color ELISA for detecting polycyclic aromatic hydrocarbon-DNA adducts in human tissues

Human exposure to polycyclic aromatic hydrocarbons (PAHs) has been determined by measurement of DNA adducts in human tissues. Competitive enzyme-linked immunosorbent assays (ELISAs) using antisera recognizing benzo[a]pyrenediol-epoxide-modified DNA (BPDE-I-DNA) and color of fluorescence endpoint detection have been used extensively for quantifying PAH-DNA adducts. The fluorescence ELISA (limit of detection 1 adduct/10(8) nucleotides) was previously reported to be more sensitive than the color ELISA (1/10(7)) for measuring PAH adducts (Santella et al. (1988) Carcinogenesis, 9, 1265-1269). However, the fluorescence assay has the disadvantages of greater variation among the replicates and higher background levels than the color assay. Using a newly developed antiserum against BPDE-I-DNA, we have modified the color of ELISA so that it has the same sensitivity as the fluorescence ELISA and requires only 33% of the sample quantity needed for the fluorescence ELISA. The modifications included preincubation of the antiserum with the samples, using microtiter plates with half-size, flat bottom wells, and optimizing the assay conditions. The improved color ELISA was used to analyze DNA samples from human autopsy tissues, including heart, lung, liver, kidney, spleen, pancreas and stomach from smokers and nonsmokers. With the exception of spleen and stomach, all tissues from smokers showed higher PAH-DNA adducts (ranging from 0.3 to 19.0 adducts/10(7) nucleotides) than the tissues from the nonsmokers (0.3 to 3.7 adducts/10(7) nucleotides) in two separate experiments. Among the tissues from smokers, heart showed the highest level of DNA adducts. This study demonstrates that a stable color ELISA with high sensitivity can be useful in assessing human exposure to PAH.

Increased Mortality Associated with Well-Water Arsenic Exposure in Inner Mongolia, China

We conducted a retrospective mortality study in an Inner Mongolian village exposed to well water contaminated by arsenic since the 1980s. Deaths occurring between January 1, 1997 and December 1, 2004 were classified according to underlying cause and water samples from household wells were tested for total arsenic. Heart disease mortality was associated with arsenic exposure, and the association strengthened with time exposed to the water source. Cancer mortality and all-cause mortality were associated with well-water arsenic exposure among those exposed 10–20 years. This is the first study to document increased arsenic-associated mortality in the Bayingnormen region of Inner Mongolia.