Mina Suh

A chronic oral reference dose for hexavalent chromium-induced intestinal cancer

High concentrations of hexavalent chromium [Cr(VI)] in drinking water induce villous cytotoxicity and compensatory crypt hyperplasia in the small intestines of mice (but not rats). Lifetime exposure to such cytotoxic concentrations increases intestinal neoplasms in mice, suggesting that the mode of action for Cr(VI)‐induced intestinal tumors involves chronic wounding and compensatory cell proliferation of the intestine. Therefore, we developed a chronic oral reference dose (RfD) designed to be protective of intestinal damage and thus intestinal cancer. A physiologically based pharmacokinetic model for chromium in mice was used to estimate the amount of Cr(VI) entering each intestinal tissue section (duodenum, jejunum and ileum) from the lumen per day (normalized to intestinal tissue weight). These internal dose metrics, together with corresponding incidences for diffuse hyperplasia, were used to derive points of departure using benchmark dose modeling and constrained nonlinear regression. Both modeling techniques resulted in similar points of departure, which were subsequently converted to human equivalent doses using a human physiologically based pharmacokinetic model. Applying appropriate uncertainty factors, an RfD of 0.006 mg kg–1 day–1 was derived for diffuse hyperplasia—an effect that precedes tumor formation. This RfD is protective of both noncancer and cancer effects in the small intestine and corresponds to a safe drinking water equivalent level of 210 µg l–1. This concentration is higher than the current federal maximum contaminant level for total Cr (100 µg l–1) and well above levels of Cr(VI) in US drinking water supplies (typically ≤ 5 µg l–1).

Prevalence of Allergic Diseases among Korean School-age Children: A Nationwide Cross-Sectional Questionnaire Study

The purpose of this study was to investigate the nationwide prevalence of childhood asthma, eczema and other allergic diseases in Korean school-age children (8-11 yr old) and to assess the difference between residential areas. Among 6,279 elementary schools, 427 schools were randomly selected according to residential area (metropolitan, provincial, rural, and industrial area) by the cluster sampling method. Parents of students completed a modified Korean version of a questionnaire formulated by the International Study of Asthma and Allergies in Childhood (ISAAC). Among 50,200 subjects, 31,026 (61.8%) responded, and 30,893 (99.6%) were analyzed. The 12-month prevalence of wheeze, flexural rash, and allergic rhinitis symptoms were 4.8%, 15.3%, and 32.9%, respectively. The prevalence of diagnosis of allergic diseases in boys was higher than that in girls, with the exception of eczema. In both boys and girls, the difference of the prevalence of allergic diseases among industrial, metropolitan and provincial areas was not statistically significant, but the differences between rural area and other areas were significant. Our results support the importance of contextual effect associated with residential area as causative agents of allergic diseases among Korean school-age children.

Assessment of Cr(VI)-Induced Cytotoxicity and Genotoxicity Using High Content Analysis

Oral exposure to high concentrations of hexavalent chromium [Cr(VI)] induces intestinal redox changes, villus cytotoxicity, crypt hyperplasia, and intestinal tumors in mice. To assess the effects of Cr(VI) in a cell model relevant to the intestine, undifferentiated (proliferating) and differentiated (confluent) Caco-2 cells were treated with Cr(VI), hydrogen peroxide or rotenone for 2–24 hours. DNA damage was then assessed by nuclear staining intensity of 8-hydroxydeoxyguanosine (8-OHdG) and phosphorylated histone variant H2AX (γ-H2AX) measured by high content analysis methods. In undifferentiated Caco-2, all three chemicals increased 8-OHdG and γ-H2AX staining at cytotoxic concentrations, whereas only 8-OHdG was elevated at non-cytotoxic concentrations at 24 hr. Differentiated Caco-2 were more resistant to cytotoxicity and DNA damage than undifferentiated cells, and there were no changes in apoptotic markers p53 or annexin-V. However, Cr(VI) induced a dose-dependent translocation of the unfolded protein response transcription factor ATF6 into the nucleus. Micronucleus (MN) formation was assessed in CHO-K1 and A549 cell lines. Cr(VI) increased MN frequency in CHO-K1 only at highly cytotoxic concentrations. Relative to the positive control Mitomycin-C, Cr(VI) only slightly increased MN frequency in A549 at mildly cytotoxic concentrations. The results demonstrate that Cr(VI) genotoxicity correlates with cytotoxic concentrations, and that H2AX phosphorylation occurs at higher concentrations than oxidative DNA damage in proliferating Caco-2 cells. The findings suggest that in vitro genotoxicity of Cr(VI) is primarily oxidative in nature at low concentrations. Implications for in vivo intestinal toxicity of Cr(VI) will be discussed.

Effect of endoscopy screening on stage at gastric cancer diagnosis: results of the National Cancer Screening Programme in Korea

Background:Although gastric cancer screening is common among countries with a high prevalence of gastric cancer, there is little data to support the effectiveness of this screening. This study was designed to determine the differences in stage at diagnosis of gastric cancer according to the screening history and screening method (upper gastrointestinal series (UGIS) vs endoscopy).Methods:The study population was derived from the National Cancer Screening Programme (NCSP), a nationwide organised screening programme in Korea. The study cohort consisted of 19 168 gastric cancer patients who had been diagnosed in 2007 and who were invited to undergo gastric cancer screening via the NCSP between 2002 and 2007.Results:Compared with never-screened patients, the odds ratios for being diagnosed with localised gastric cancer in endoscopy-screened patients and UGIS-screened patients were 2.10 (95% CI=1.90–2.33) and 1.24 (95% CI=1.13–1.36), respectively.Conclusions:Screening by endoscopy was more strongly associated with a diagnosis of localised stage gastric cancer compared with screening by UGIS.

Air pollution as a risk factor for depressive episode in patients with cardiovascular disease, diabetes mellitus, or asthma

BACKGROUND There is currently insufficient evidence to confirm the effect of ambient air pollution on mental disorders, especially among susceptible populations. This study investigated the short-term effect of ambient air pollution on the risk of depressive episode and the effect modification across disease subpopulations. METHODS Subjects who visited the emergency department (ED) for depressive episode from 2005 to 2009 (n=4985) in Seoul, Republic of Korea were identified from medical claims data. We conducted a time-stratified case-crossover study using conditional logistic regression. Subgroup analyses were conducted after the subjects were stratified by underlying disease (cardiovascular disease, diabetes mellitus, chronic obstructive pulmonary disease, asthma, and depressive disorder). The risk was expressed as an odds ratio (OR) per 1 standard deviation of each air pollutant. RESULTS SO2, PM10, NO2, and CO were positively associated with ED visits for depressive episode. The maximum risk was observed in the distributed lag 0-3 model for PM10 (OR, 1.120; 95% confidence interval, 1.067-1.176). PM10, NO2, and CO significantly increased the risks of ED visits for depressive episode in subjects with either underlying cardiovascular disease, diabetes mellitus, asthma, or depressive disorder. LIMITATIONS Our data may include a misclassification bias due to the validity of a diagnosis determined from medical services utilization data. CONCLUSIONS SO2, PM10, NO2, and CO significantly increased the risk of ED visits for depressive episode, especially among individuals with pre-existing cardiovascular disease, diabetes mellitus, or asthma.

Assessment of the mode of action underlying development of rodent small intestinal tumors following oral exposure to hexavalent chromium and relevance to humans

Abstract Chronic exposure to high concentrations of hexavalent chromium (Cr(VI)) in drinking water causes intestinal adenomas and carcinomas in mice, but not in rats. Cr(VI) causes damage to intestinal villi and crypt hyperplasia in mice after only one week of exposure. After two years of exposure, intestinal damage and crypt hyperplasia are evident in mice (but not rats), as are intestinal tumors. Although Cr(VI) has genotoxic properties, these findings suggest that intestinal tumors in mice arise as a result of chronic mucosal injury. To better understand the mode of action (MOA) of Cr(VI) in the intestine, a 90-day drinking water study was conducted to collect histological, biochemical, toxicogenomic and pharmacokinetic data in intestinal tissues. Using MOA analyses and human relevance frameworks proposed by national and international regulatory agencies, the weight of evidence supports a cytotoxic MOA with the following key events: (a) absorption of Cr(VI) from the intestinal lumen, (b) toxicity to intestinal villi, (c) crypt regenerative hyperplasia and (d) clonal expansion of mutations within the crypt stem cells, resulting in late onset tumorigenesis. This article summarizes the data supporting each key event in the MOA, as well as data that argue against a mutagenic MOA for Cr(VI)-induced intestinal tumors.

Assessment of the mode of action for hexavalent chromium-induced lung cancer following inhalation exposures.

Inhalation of hexavalent chromium [Cr(VI)] is associated with increased lung cancer risk among workers in several industries, most notably chromate production workers exposed to high concentrations of Cr(VI) (≥100 μg/m(3)), for which clear exposure-response relationships and respiratory irritation and tissue damage have been reported. Data from this industry are used to assess lung cancer risk associated with environmental and current occupational exposures, occurring at concentrations that are significantly lower. There is considerable uncertainty in the low dose extrapolation of historical occupational epidemiology data to assess risk at current exposures because no published or well recognized mode of action (MOA) for Cr(VI)-induced lung tumors exists. We conducted a MOA analysis for Cr(VI)-induced lung cancer evaluating toxicokinetic and toxicological data in humans and rodents and mechanistic data to assess plausibility, dose-response, and temporal concordance for potential MOAs. Toxicokinetic data support that extracellular reduction of Cr(VI), which limits intracellular absorption of Cr(VI) and Cr(VI)-induced toxicity, can be overwhelmed at high exposure levels. In vivo genotoxicity and mutagenicity data are mostly negative and do not support a mutagenic MOA. Further, both chronic bioassays and the epidemiologic literature support that lung cancer occurs at exposures that cause tissue damage. Based on this MOA analysis, the overall weight of evidence supports a MOA involving deposition and accumulation of particulate chromium in the bifurcations of the lung resulting in exceedance of clearance mechanisms and cellular absorption of Cr(VI). Once inside the cell, reduction of Cr(VI) results in oxidative stress and the formation of Cr ligands. Subsequent protein and DNA damage lead to tissue irritation, inflammation, and cytotoxicity. These effects, concomitant with increased cell proliferation, result in changes to DNA sequences and/or methylation status that can lead to tumorigenesis. This MOA supports the use of non-linear approaches when extrapolating lung cancer risk occurring at high concentration occupational exposures to environmentally-relevant exposures.

Validity of fecal occult blood test in the national cancer screening program, Korea.

Aim The aims of the current study were to assess the validity of the fecal occult blood test (FOBT) in an organized screening setting in Korea and to determine factors associated with FOBT validity, such as screening round, age group, and anatomical location of the cancer. Methods Study participants were those who were 50 years and older who received an FOBT through the National Cancer Screening Program between 2004 and 2007. Colorectal cancer diagnoses were ascertained through linkage with the Korean National Cancer Incidence Database. The positivity rate, colorectal cancer detection rate, interval cancer rate, sensitivity, specificity, and positive predictive value of the FOBT were calculated. Results A total of 2,193,093 tests were included in the analysis. Overall, the sensitivity of the FOBT for colorectal cancer was 59.7% for the first round and 56.1% for the subsequent round. Sensitivity was highest for distal colon cancer (65.9%) in the first round, and for rectal cancer (58.4%) for the subsequent round. The sensitivity and positive predictive value of the FOBT generally improved between 2004 and 2008. Conclusions The FOBT showed reasonable validity in an organized screening setting, and the validity of the FOBT varied by screening round, anatomical location, and screening year.

Gastric cancer screening uptake trends in Korea: results for the National Cancer Screening Program from 2002 to 2011: a prospective cross-sectional study.

Abstract Although the effectiveness of mass screening for gastric cancer remains controversial, several countries with a high prevalence of gastric cancer have implemented nationwide gastric cancer screening programs. This study was conducted to assess trends in the use of either upper gastrointestinal series (UGIS) or endoscopy to screen for gastric cancer, as well as to assess factors strongly associated with changes therein, over a 10-year period. Data were obtained from the National Cancer Screening Program (NCSP) database from 2002 to 2011 in Korea. The NCSP provides biennial gastric cancer screening with either UGIS or endoscopy for men and women aged ≥40 years. Using the NCSP database, overall screening rates for gastric cancer and percentages of endoscopy use among participants were analyzed from 2002 to 2011. To estimate changes in participation rates and endoscopy use over time, we assessed the average annual percentage change (APC) by comparing the rates from 2002 and 2011 as relative rates. Participation rates for gastric cancer screening increased 4.33% annually from 2002 to 2011. In terms of screening method, a substantial increase in endoscopy use was noted among the gastric cancer screening participants over the 10-year period. The percentage of participants who had undergone endoscopy test increased from 31.15% in 2002 to 72.55% in 2011, whereas the percentage of participants who underwent UGIS decreased tremendously. Increased endoscopy test use was greatest among participants aged 40 to 49 (APC = 4.83%) and Medical Aid Program recipients (APC = 5.73%). Overall, men, participants of ages 40 to 49 years, and National Health Insurance beneficiaries of higher socioeconomic status were more likely to undergo screening via endoscopy. This study of nationwide empirical data from 2002 to 2011 showed that endoscopy is increasingly being used for gastric cancer screening in Korea, compared with UGIS. Nevertheless, further study of the impact of endoscopy on gastric cancer mortality is needed, and future evaluations of screening methods should take into account both cost and any associated reduction in gastric cancer mortality.

The effects of perchlorate, nitrate, and thiocyanate on free thyroxine for potentially sensitive subpopulations of the 2001-2002 and 2007-2008 National Health and Nutrition Examination Surveys.

Among women with urinary iodine concentration <100 μg/l in the 2001–2002 National Health and Nutrition Examination Survey (NHANES), urinary perchlorate was associated with significant changes in thyroid stimulating hormone and total thyroxine (T4). Although perchlorate, nitrate, and thiocyanate all potentially act to inhibit iodide uptake, free T4 was not found to be associated with exposure to these chemicals in the same data. Fetuses of pregnant mothers with iodine deficiency are thought to be a sensitive subpopulation for perchlorate exposure, but the potential associations between free T4 and exposure to these chemicals among pregnant mothers in NHANES 2001–2002 and 2007–2008 have not been specifically evaluated to date. This study investigates the potential associations between urinary perchlorate, nitrate, and thiocyanate and serum free T4 in individuals with low urinary iodine levels and pregnant women. Multivariate regression models of free T4 were conducted and included urinary perchlorate, nitrate, thiocyanate, and covariates known to have an impact on the thyroid (anti-thyroid peroxidase (TPO) antibodies, age, race/ethnicity, body mass index, and hours of fasting). Meta-analyses were also conducted on non-pregnant and on pregnant women from the two survey cycles. Urinary nitrate was associated with serum free T4 in non-pregnant women of NHANES 2001–2002 who had urinary iodine ≥100 μg/l. In the meta-analysis, urinary perchlorate, nitrate, and thiocyanate were significant predictors of serum free T4 in non-pregnant women. No association was found in men and pregnant women. TPO antibodies were significant predictors of free T4 among non-pregnant women only when the models included urinary perchlorate, nitrate, or thiocyanate. Risk assessment for perchlorate exposure should consider co-exposure to nitrate and thiocyanate.