Faculty Bibliography

Based on the first National Study of Coal Workers' Pneumoconiosis (CWP) and the U.S. Geological Survey database of coal quality, we show that the prevalence of CWP in seven coal mine regions correlates with levels of bioavailable iron (BAI) in the coals from that particular region (correlation coefficient r = 0.94, p < 0.0015). CWP prevalence is also correlated with contents of pyritic sulfur (r = 0.91, p < 0.0048) or total iron (r = 0.85, p < 0.016) but not with coal rank (r = 0.59, p < 0.16) or silica (r = 0.28, p < 0.54). BAI was calculated using our model, taking into account chemical interactions of pyrite, sulfuric acid, calcite, and total iron. That is, iron present in coals can become bioavailable by pyrite oxidation, which produces ferrous sulfate and sulfuric acid. Calcite is the major component in coals that neutralizes the available acid and inhibits iron's bioavailability. Therefore, levels of BAI in the coals are determined by the available amounts of acid after neutralization of calcite and the amount of total iron in the coals. Using the linear fit of CWP prevalence and the calculated BAI in the seven coal mine regions, we have derived and mapped the pneumoconiotic potencies of 7,000 coal samples. Our studies indicate that levels of BAI in the coals may be used to predict coal's toxicity, even before large-scale mining

Numerous studies have reported short-term associations between ambient air pollution concentrations and mortality and morbidity. Particulate matter (PM) was often implicated as the most significant predictor of the health outcomes among the various air pollutants. However, a question remains as to the potential role played by the relative error of exposure estimation associated with each pollutant in defining their relative strengths of association. While most of the recent studies on PM exposure measurements have focused on the temporal correlation between personal exposures and the concentrations observed at ambient air quality monitors (within a few miles from the subjects), there have been few studies that systematically evaluated spatial uniformity of temporal correlation of air pollution within the scale of a city (several tens of miles) for which mortality or morbidity outcomes are aggregated in time-series studies. In this study, spatial uniformity of temporal correlation was examined by computing monitor-to-monitor correlation using available multiple monitors for PM(10) and gaseous criteria pollutants (NO(2), SO(2), CO, and O(3)) in the nationwide data between 1988 and 1997. For each monitor, the median of temporal correlation with other monitors within the Air Quality Control Region (AQCR) was computed. The resulting median monitor-to-monitor correlation was modeled as a function of qualitative site characteristics (i.e., land-use, location-setting, and monitoring-objective) and quantitative information (median separation distance, longitude/latitude or regional indicators) for each pollutant. Generalized additive models (GAM) were used to fit the smooth function of the separation distance and regional variation. The intercepts of the models across pollutants showed the overall rankings in monitor-to-monitor correlation on the average to be: O(3), NO(2), and PM(10), (r approximately 0.6 to 0.8)>CO (r<0.6)>SO(2) (r<0.5). Both the separation distance and regional variation were important predictors of the correlation. For PM(10), for example, the correlation for the monitors along the East Coast was higher by approximately 0.2 than western regions. The qualitative monitor characteristics were often significant predictors of the variation in correlation, but their impacts were not substantial in magnitude for most categories. These results suggest that the apparent regional heterogeneity in PM effect estimates, as well as the differences in the significance of health outcome associations across pollutants, may in part be contributed to by the differences in monitor-to-monitor correlations by region and across pollutants.Journal of Exposure Analysis and Environmental Epidemiology advance online publication, 16 June 2004; doi:10.1038/sj.jea.7500386

Epidemiology studies suggest that exposure to air pollution increases the frequency of cardiac arrhythmias. A limitation of these studies is that it is difficult to link an increased risk of arrhythmias to a specific air pollutant. Animal exposure studies offer the opportunity to examine the effects of concentrated ambient fine particulate matter (PM), ultrafine PM, and copollutant gases separately. Male Fischer 344 rats, aged 18 mo, with implanted electrocardiograph (ECG) transmitters were used to determine the effects of PM on the frequency of arrhythmias. We found that old F344 rats had many spontaneous arrhythmias. An arrhythmia classification system was developed to quantify arrhythmia frequency. Arrhythmias were broadly grouped into two categories: premature beats and delayed beats. The rats were exposed to concentrated ambient PM (CAPS) or air for 4 h. The rats were exposed twice with a crossover design so each rat could serve as its own control. The CAPS concentrations were 160 microg/m(3) and 200 microg/m(3) for the first and second exposures, respectively. There was a significant increase in the frequency of irregular and delayed beats after exposure to CAPS. The same rats were subsequently exposed to laboratory-generated ultrafine carbon particles, to SO(2), or to air with a repeated crossover design. In these experiments there was no significant change in the frequency of any category of spontaneous arrhythmia following exposure to ultrafine carbon or SO(2). Thus, this study adds supporting evidence that acute exposure to elevated levels of ambient PM increases the frequency of cardiac arrhythmias

Inference on the time of onset and the duration of a treatment effect is a challenging problem in biomedical research. These studies often generate repeated measurements from subjects in a treated group and a control group during the same time period. We propose a simple approach, called the 'Fishing License' method, to test for a treatment effect occurring during an unspecified time interval. The method is based on a statistic of the largest absolute value of the t statistic between two groups obtained by considering every possible time interval in the observed time period. A bootstrapped null distribution of the test statistic is used to determine the critical value. The method also provides estimates of onset and ending times, when the null hypothesis of no effect is rejected. Simulated and real experimental data sets were generated for assessing the performance of the method

Hexavalent chromium (Cr (VI)) is a well known-human carcinogen with exposures occurring in both occupational and environmental settings. Although lung carcinogenicity has been well documented for occupational exposure via inhalation, the carcinogenic hazard of drinking water exposure to Cr (VI) has yet to be established. We used a hairless mouse model to study the effects of K(2)CrO(4) in the drinking water on ultraviolet radiation (UVR)-induced skin tumors. Hairless mice were unexposed or exposed to UVR alone (1.2 kJ/m(2)), K(2)CrO(4) alone at 2.5 and 5.0 ppm, or the combination of UVR and K(2)CrO(4) at 0.5, 2.5, and 5.0 ppm. Mice were observed on a weekly basis for the appearance of skin tumors larger than 2 mm. All the mice were euthanized on day 182. The skin tumors were excised and subsequently analyzed microscopically for malignancy by histopathology. There was a total absence of observable skin tumors in untreated mice and in mice exposed to chromate alone. However, there was a dose-dependent increase in the number of skin tumors greater than 2 mm in mice exposed to K(2)CrO(4) and UV compared with mice exposed to UV alone. The increase in tumors larger than 2 mm was statistically significant (P < 0.05) for UV and K(2)CrO(4) at the two highest K(2)CrO(4) doses (2.5 and 5.0 ppm), and there was a statistically significant increase in the numbers of malignant tumors per mouse in the UVR plus K(2)CrO(4) (5 ppm) group compared with UV alone. The data presented here indicate that K(2)CrO(4) increases the number of UV-induced skin tumors in a dose-dependent manner, and these results support the concern that regulatory agencies have relative to the carcinogenic health hazards of widespread human exposure to Cr (VI) in drinking water

The present study was designed to establish the form of the dose-response relationship for dietary sodium arsenite as a co-carcinogen with ultraviolet radiation (UVR) in a mouse skin model. Hairless mice (strain Skh1) were fed sodium arsenite continuously in drinking water starting at 21 days of age at concentrations of 0.0, 1.25, 2.5, 5.0, and 10 mg/L. At 42 days of age, solar spectrum UVR exposures were applied three times weekly to the dorsal skin at 1.0 kJ/m2 per exposure until the experiment ended at 182 days. Untreated mice and mice fed only arsenite developed no tumors. In the remaining groups a total of 322 locally invasive squamous carcinomas occurred. The carcinoma yield in mice exposed only to UVR was 2.4 +/- 0.5 cancers/mouse at 182 days. Dietary arsenite markedly enhanced the UVR-induced cancer yield in a pattern consistent with linearity up to a peak of 11.1 +/- 1.0 cancers/mouse at 5.0 mg/L arsenite, representing a peak enhancement ratio of 4.63 +/- 1.05. A decline occurred to 6.8 +/- 0.8 cancers/mouse at 10.0 mg/L arsenite. New cancer rates exhibited a consistent-with-linear dependence on time beginning after initial cancer-free intervals ranging between 88 and 95 days. Epidermal hyperplasia was elevated by arsenite alone and UVR alone and was greater than additive for the combined exposures as were growth rates of the cancers. These results demonstrate the usefulness of a new animal model for studying the carcinogenic action of dietary arsenite on skin exposed to UVR and should contribute to understanding how to make use of animal data for assessment of human cancer risks in tissues exposed to mixtures of carcinogens and cancer-enhancing agents. Key words: arsenic, arsenite, cancer, hairless, mouse, radiation, skin, ultraviolet, UV

Antibodies (Abs) against the V3 loop of the human immunodeficiency virus type 1 gp120 envelope glycoprotein were initially considered to mediate only type-specific neutralization of T-cell-line-adapted viruses. However, recent data show that cross-neutralizing V3 Abs also exist, and primary isolates can be efficiently neutralized with anti-V3 monoclonal Abs (MAbs). The neutralizing activities of anti-V3 polyclonal Abs and MAbs may, however, be limited due to antigenic variations of the V3 region, a lack of V3 exposure on the surface of intact virions, or Ab specificity. For clarification of this issue, a panel of 32 human anti-V3 MAbs were screened for neutralization of an SF162-pseudotyped virus in a luciferase assay. MAbs selected with a V3 fusion protein whose V3 region mimics the conformation of the native virus were significantly more potent than MAbs selected with V3 peptides. Seven MAbs were further tested for neutralizing activity against 13 clade B viruses in a single-round peripheral blood mononuclear cell assay. While there was a spectrum of virus sensitivities to the anti-V3 MAbs observed, 12 of the 13 viruses were neutralized by one or more of the anti-V3 MAbs. MAb binding to intact virions correlated significantly with binding to solubilized gp120s and with the potency of neutralization. These results demonstrate that the V3 loop is accessible on the native virus envelope, that the strength of binding of anti-V3 Abs correlates with the potency of neutralization, that V3 epitopes may be shared rather than type specific, and that Abs against the V3 loop, particularly those targeting conformational epitopes, can mediate the neutralization of primary isolates

Studies of HIV-1 immunological relatedness have revealed that genetic diversity does not parallel antigenic diversity and have recently shown that HIV-1 strains from different geographic regions from around the world can be grouped into a small number of immunologically defined groups (immunotypes). Previously, the binding patterns of 28 monoclonal antibodies (mAbs) (specific for V3 and C5 of gp120 and cluster I of gp41) with 26 HIV-1 virions obtained globally were determined in a virus binding assay. Analysis of the binding patterns of these 728 mAb/virus combinations now reveals that a particular subset containing six of the 28 mAbs can correctly immunotype 24 of the 26 isolates (92%) into three immunotypes. Like the original panel of mAbs, the subset of six mAbs identified was directed against epitopes in the V3 and C5 regions of gp 120 as well as cluster I of gp41. The binding patterns ('profiles') of these six mAbs with 24 additional HIV-1 virions from Cameroon confirmed that epitopes in V3 and C5 of gp120 and cluster I of gp41 are well exposed on these viruses. Multivariate analysis of the binding patterns of these six mAbs with all 50 viruses (26 obtained globally and 24 obtained from Cameroon) indicates that the viruses from Cameroon have binding profiles similar to viruses from the rest of the world and can be classified into the same three immunotypes that were previously described. This study suggests that a vaccine against HIV-1 need not be based on geographic origin of the virus or on clade, but may better be based on antigenic properties that classify the plethora of different HIV-1 viruses into immunologically defined groups

Efforts to devise immunoassays for tuberculosis (TB) that can be adapted to rapid formats are ongoing. The present study was aimed at determining whether urinary anti-Mycobacterium tuberculosis antibodies are present in patients with TB, to evaluate the feasibility of developing a urine antibody-based diagnostic test. Urinary antibodies directed against the culture filtrate proteins of M. tuberculosis, MPT 32, and the 81-kDa GlcB protein were detectable in patients with TB, although the sensitivity of antibody detection was lower (53%-64%), compared with serum antibodies (68%-77%). Surprisingly, with all 3 antigens, the use of paired serum and urine samples provided higher sensitivities of antibody detection than either single specimen, and anti-GlcB antibodies were present in the serum and/or urine of 39 (90%) of 43 smear-positive patients with TB. Although, with the current methods and antigens, the level of sensitivity is insufficient to design a urinary antibody diagnostic test, these studies provide the foundation for further studies on the development of a urine antibody-based immunoassay for TB

OBJECTIVE: To evaluate HIV-1 antibody seroprevalence and risk factors for HIV seropositivity in rural areas of Cameroon. METHOD: The prevalences of HIV antibodies in 53 villages in rural Cameroon visited during May-October 2000 were determined with an HIV1/2 rapid assay, standard ELISA, and western blot. Demographic data and risk factors were elicited via face-to-face interviews with a structured questionnaire. RESULTS: HIV seroprevalence was 5.8% (243/4156, 95% confidence interval [CI] = 5.1-6.6) overall, 6.3% (151/2394, 95% CI = 5.4-7.4) among females and 5.2% (92/1762, 95% CI = 4.3-6.4) among males. HIV seroprevalence among persons aged 15 - 70 years did not differ significantly by province (5.6% in Center, 4.5% in East, 6.9% in South, and 5.8% in South-West) ( =.10). Analysis of age- and gender-standardized prevalence by village across provinces indicated a near-significant difference (nonparametric Wilcoxon signed rank test, =.06), with highest prevalence in South-West, followed by South, Center, and East. Multivariate analysis revealed that single women were significantly more likely to be HIV seropositive than were married or widowed women. Women with a history of sexual relations while traveling were at significantly increased risk of HIV seropositivity (OR adjusted for age and marital status = 2.4, 95% CI = 1.4-9.7). Among men, those who reported ever having a sexually transmitted disease were at significantly increased risk of HIV-seropositivity (OR adjusted for age = 1.8, 95% CI = 1.1-2.8). CONCLUSION: We have documented a wide range of HIV prevalences among rural villages of Cameroon. Age, marital status (in women) and sexual risk factors appear to be associated with HIV infection in this setting