Faculty Bibliography

Chromosome aberrations in peripheral blood lymphocytes have been used for many years to monitor human populations exposed to potential carcinogens. Recent reports have confirmed the validity of this approach by demonstrating that elevated levels of chromosome aberrations in lymphocytes are associated with subsequent increased cancer risk, especially for increased mortality from hematological malignancies including acute myeloid leukemia (AML). We postulated that this approach could be improved in two ways: (a) by detecting oncogenic disease-specific aberrations; and (b) by using chromosome painting so that many more metaphases could be analyzed. Numerical and structural aberrations in chromosomes 8 and 21 are commonly observed in AML. In the present study, we painted chromosomes 8 and 21 in lymphocyte metaphases from 43 healthy workers exposed to benzene, an established cause of AML, and from 44 matched controls. To examine dose-response relationships the workers were divided into two groups at the median exposure level, a lower-exposed group (< or = 31 ppm; n = 21), and a higher-exposed group (> 31 ppm; n = 22). Benzene exposure was associated with significant increases in hyperdiploidy of chromosomes 8 (1.2, 1.5, and 2.4 per 100 metaphases; P < 0.0001) and 21 (0.9, 1.1, and 1.9 per 100 metaphases; P < 0.0001). Translocations between chromosomes 8 and 21 were increased up to 15-fold in highly exposed workers (0.01, 0.04, and 0.16 per 100 metaphases; P < 0.0001). In one highly exposed individual, these translocations were reciprocal and were detectable by reverse transcriptase-PCR. These data indicate a potential role for t(8;21) in benzene-induced leukemogenesis and are consistent with the hypothesis that detection of specific chromosome aberrations may be a powerful approach to identify populations at increased risk of leukemia

Electron paramagnetic resonance spectroscopy (EPR) was used to study synthetic hydroxyapatite and approximately 1, 2, and 6% synthetic carbonated apatites, deorganified dentine, and enamel. The carbonated apatites were synthesized by hydrolysis of dicalcium phosphate. Comparisons were made with spectra from enamel and deorganified dentine. Microwave power saturation and dose responses were determined for the synthetic materials. The Marquardt version of the Levenberg decomposition method was used to extract individual signals from the apatite data. Two samples of dentine were irradiated with 25 and 100 Gy, respectively, from a 60Co source. The first sample was then deorganified at 200 degreesC using the Soxhlet extraction technique. A third sample was irradiated with 100 Gy after deorganification. The resulting EPR spectra were then compared. It was determined that the dosimetric signal of 2% synthetic carbonated apatite was approximately the same as that of enamel. It was also verified that the dosimetric signal saturates at about 2% in synthetic carbonated apatites. The study established that the precenters responsible for the dosimetric signal (g perpendicular = 2.0018, g parallel = 1.9985) are preferentially concentrated in the surface-accessible region of the mineral component, as shown by the approximately 80% attenuation of the dosimetric signal in dentine following deorganification. The precenters responsible are not destroyed by the deorganification since the magnitude of the dosimetric signal from the dentine specimen irradiated following deorganification was approximately twice that of the comparable untreated, irradiated sample. Finally, the dose response of 2 and 6% synthetic carbonated apatites was determined

We conducted a methodologic study to validate a quantitative retrospective exposure assessment method used in a follow-up study of workers exposed to benzene. Assessment of exposure to benzene was carried out in 672 factories in 12 cities in China. Historical exposure data were collected for 3179 unique job titles. The basic unit for exposure assessment was a factory/work-unit/job-title combination over seven periods between 1949 and 1987. A total of 18,435 exposure estimates was developed, using all available historical information, including 8477 monitoring data. Overall, 38% of the estimates were based on benzene monitoring data. The highest time-weighted average exposures occurred in the rubber industry (30.7 ppm), particularly for rubber glue applicators (52.6 ppm). Because of its recognized link with benzene exposure, the association between a clinical diagnosis of benzene poisoning (hematotoxicity) and benzene exposure was evaluated (412 cases and 614,509 person-years) to validate the exposure-assessment method. Relative risks of benzene hematotoxicity increased very sharply with increasing estimated intensity of benzene exposure. Odds ratios were 2.2 (95% CI: 1.7-2.9), 4.7 (95% CI: 3.4-6.5), and 7.2 (95% CI: 5.3-9.8) for the intensity levels of less than 5 ppm, 5-19 ppm, 20-39 ppm, and 40 and more ppm, respectively. This sharp trend between benzene hematotoxicity and estimated exposure to benzene indicated that the exposure-estimation method used in this cancer epidemiology study is reliable

We evaluated the influence of urine pH on the proportion of urinary benzidine (BZ) and N-acetylbenzidine present in the free, unconjugated state and on exfoliated urothelial cell DNA adduct levels in 32 workers exposed to BZ in India. Postworkshift urine pH was inversely correlated with the proportions of BZ (r = -0.78; P < 0.0001) and N-acetylbenzidine (r = -0.67; P < 0.0001) present as free compounds. Furthermore, the average of each subject's pre- and postworkshift urine pH was negatively associated with the predominant urothelial DNA adduct (P = 0.0037, adjusted for urinary BZ and metabolites), which has been shown to cochromatograph with a N-(3'-phosphodeoxyguanosin-8-yl)-N'-acetylbenzidine adduct standard. Controlling for internal dose, individuals with urine pH < 6 had 10-fold higher DNA adduct levels compared to subjects with urine pH > or = 7. As reported previously, polymorphisms in NAT1, NAT2, and GSTM1 had no impact on DNA adduct levels. This is the first study to demonstrate that urine pH has a strong influence on the presence of free urinary aromatic amine compounds and on urothelial cell DNA adduct levels in exposed humans. Because there is evidence that acidic urine has a similar influence on aromatic amines derived from cigarette smoke, urine pH, which is influenced by diet, may be an important susceptibility factor for bladder cancer caused by tobacco in the general population

BACKGROUND: The consumption of alcoholic beverages is a strong risk factor for cancers of the oral cavity and pharynx (oral cancers). Alcohol dehydrogenase type 3 (ADH3) metabolizes ethanol to acetaldehyde, a carcinogen. We evaluated whether individuals homozygous for the fast-metabolizing ADH3(1) allele (ADH3[1-1]) have a greater risk of developing oral cancer in the presence of alcoholic beverage consumption than those with the slow-metabolizing ADH3(2) allele (ADH3[1-2] and ADH3[2-2]). METHODS: As part of a population-based study of oral cancer conducted in Puerto Rico, the ADH3 genotypes of 137 patients with histologically confirmed oral cancer and of 146 control subjects (i.e., individuals with no history of oral cancer) were determined by molecular genetic analysis of oral epithelial cell samples. Risks were estimated by use of multiple logistic regression analyses. RESULTS: Compared with nondrinkers with the ADH3(1-1) genotype, consumers of at least 57 alcoholic drinks per week with the ADH3(1-1), ADH3(1-2), and ADH3(2-2) genotypes had 40.1-fold (95% confidence interval [CI] = 5.4-296.0), 7.0-fold (95% CI = 1.4-35.0), and 4.4-fold (95% CI = 0.6-33.0) increased risks of oral cancer, respectively; the risk associated with the ADH3(1-1) genotype, compared with the ADH3(1-2) and ADH3(2-2) genotypes combined, was 5.3 (95% CI = 1.0-28.8) among such drinkers. Considering all levels of alcohol consumption, the risk of oral cancer per additional alcoholic drink per week increased 3.6% (95% CI = 1.9%-5.4%) for subjects with the ADH3(1-1) genotype and 2.0% (95% CI = 0.9%-3.0%) for subjects with the ADH3(1-2) or ADH3(2-2) genotype (two-sided P = .04). CONCLUSIONS: The ADH3(1-1) genotype appears to substantially increase the risk of ethanol-related oral cancer, thus providing further evidence for the carcinogenicity of acetaldehyde

This paper was presented at a workshop addressing the potential of biodosimetry techniques for use in the interplanetary space program. Some of the concerns for adequate dosimetry in space include: (1) a dosimeter that provides a permanent record of the cumulative dose and can be read independently on return to Earth; (2) a dosimeter which cannot be lost, forgotten or inadvertently removed by an individual; and (3) appropriate assessments of radiation exposures that pose an acute health risk and could jeopardize the success of an interplanetary mission. Tooth enamel is a permanent, stable biological dosimeter showing great promise in retrospective dosimetry of radiation accidents. With a proper technique, the minimum detectable dose can be in the range of tens of milligrays in extracted, prepared teeth. In addition to transient accidental doses, the cumulative dose from chronic low-level exposures (which individually may be below reportable limits) is recorded in the enamel of teeth. While many teeth remain with an individual over all or most of a lifetime, one or more are often removed due to dental problems and provide an opportunity to make dosimeteric measurements. The collection and analysis of extracted teeth in later life allows measurement of cumulative lifetime dose using the high-sensitivity techniques described in this paper. The goal of a lightweight, high-sensitivity, in vivo EPR spectrometer has not yet been realized, but its benefit to all aspects of retrospective dosimetry, terrestrial or otherwise, would be great. This paper reviews the current status of EPR dosimetry of teeth as applied to retrospective measurements of accidental exposures and outlines future research directions which will further reduce the limits of detection

In a cross-sectional study of 33 workers exposed to benzidine and benzidine dyes and 15 non-exposed controls, we previously reported that exposure status and internal dose of benzidine metabolites were strongly correlated with the levels of specific benzidine-DNA adducts in exfoliated urothelial cells. We also evaluated DNA adduct levels in peripheral white blood cells (WBC) of a subset of 18 exposed workers and 7 controls selected to represent a wide range of adducts in exfoliated urothelial cells. Samples were coded and then DNA was analyzed using 32P-postlabeling, along with n-butanol extraction. One adduct, which co-chromatographed with a synthetic N-(3'-phospho-deoxyguanosin-8-yl)-N'-acetylbenzidine standard, predominated in those samples with adducts present. The median level (range) of this adduct in WBC DNA was 194.4 (3.2-975) RAL x 10(9) in exposed workers and 1.4 (0.1-6.4) in the control subjects (p = 0.0002, Wilcoxon Rank Sum Test). There was a striking correlation between WBC and exfoliated urothelial cell adduct levels (Pearson r = 0.84, p < 0.001) among exposed subjects. In addition, the sum of urinary benzidine, N-acetylbenzidine and N,N'-diacetylbenzidine correlated with the levels of this adduct in both tissues. This is the first study in humans to show a relationship for a specific carcinogen adduct in a surrogate tissue and in urothelial cells, the target for urinary bladder cancer

Effects of tobacco smoking and alcohol use on risks of cancers of the larynx and lung have been evaluated extensively in industrialized countries. Few studies on the effect of these risk factors have been reported from developing countries. We conducted a case-control study to evaluate risks of laryngeal and lung cancers in men by subsite and cell type in relation to smoking and alcohol drinking in Turkey, a country where smoking and alcohol consumption patterns are different from those in industrialized countries. We identified 832 laryngeal and 1,210 lung cancer cases and 829 controls with information on smoking and alcohol use (amount and duration) and histologic cell type from an oncology treatment center of a Social Security Agency hospital in Istanbul, Turkey, admitted between 1979 and 1984. Both laryngeal and lung cancer showed significant associations with smoking and alcohol drinking, but no monotonic dose-response was obtained for alcohol drinking. Among smokers, the highest risks were observed in the supraglottis region of the larynx (odds ratio [OR] = 4.1) after adjustment for age and alcohol use. Among alcohol drinkers, the highest risks were observed in the glottis region of the larynx (OR = 1.7) after adjustment for age and smoking. In the analysis by the cell type of lung cancer among ever-smokers, small cell type showed the highest risk (OR = 5.4), while it showed no association with alcohol drinking. Cumulative cigarette use (pack-years) and number of cigarettes per day showed stronger associations than years smoked for both cancer sites. The relative risks of joint exposure to smoking and alcohol were 12.2 for laryngeal cancer and 14.1 for lung cancer among heavy smokers and heavy alcohol drinkers. This study provides epidemiologic evidence from Turkey that smoking and alcohol use are associated with risks of cancers of the larynx and lung

BACKGROUND: Benzene is a widely distributed environmental contaminant known to cause leukemia, particularly acute nonlymphocytic leukemia, and perhaps other hematologic neoplasms and disorders. Few epidemiologic studies, however, have been able to address relationships between the extent of benzene exposure and the level of risk. PURPOSE: A large cohort study was carried out in China to evaluate the risks of developing specific hematologic neoplasms and selected related disorders in relationship to quantitative estimates of occupational benzene exposure. METHODS: A cohort of 74828 benzene-exposed and 35805 unexposed workers employed from 1972 through 1987 in 12 cities in China was identified and followed to determine the incidence of hematologic neoplasms and related disorders. Estimates of benzene exposure were derived from work histories and available historic benzene measurements. Existing pathologic material and supporting medical records were reviewed to establish diagnoses of disease. Relative risks (RRs) (i.e., ratios of incidence rates for specific hematologic neoplasms and related disorders in the benzene-exposed group to incidence rates in the unexposed group) were determined by use of Poisson regression analysis, with stratification by age and sex. RESULTS: For workers historically exposed to benzene at average levels of less than 10 parts per million (ppm), the RR for all hematologic neoplasm combined was 2.2 (95% confidence interval [CI] = 1.1-4.2), and, for the combination of acute nonlymphocytic leukemia and related myelodysplastic syndromes, the RR was 3.2 (95% CI = 1.0-10.1). For individuals who were occupationally exposed to benzene at constant levels of 25 ppm or more, the RR for the combination of acute nonlymphocytic leukemia and related myelodysplastic syndromes was 7.1 (95% CI = 2.1-23.7). Workers with 10 or more years of benzene exposure had an RR of developing non-Hodgkin's lymphoma of 4.2 (95% CI = 1.1-15.9), and the development of this neoplasm was linked most strongly to exposure that had occurred at least 10 years before diagnosis (i.e., distant exposure) (P for trend = .005, two-sided). In contrast, the risk for the combination of acute nonlymphocytic leukemia and related myelodysplastic syndromes was significantly increased among those with more recent benzene exposure (P for trend = .003, two-sided), but it was not linked to distant exposure (P for trend = .51, two-sided). CONCLUSIONS: The results of this study suggest that benzene exposure is associated with a spectrum of hematologic neoplasms and related disorders in humans. Risks for these conditions are elevated at average benzene-exposure levels of less than 10 ppm and show a tendency, although not a strong one, to rise with increasing levels of exposure. The temporal pattern of benzene exposure appears to be important in determining the risk of developing specific diseases

Benzene is a ubiquitous occupational hematotoxin and leukemogen, but people vary in their response to this toxic agent. To evaluate the impact of interindividual variation in enzymes that activate (i.e., CYP2E1) and detoxify (i.e., NQO1) benzene and its metabolites, we carried out a case-control study in Shanghai, China, of occupational benzene poisoning (BP; i.e., hematotoxicity), which we show is itself strongly associated with subsequent development of acute nonlymphocytic leukemia and the related myelodysplastic syndromes (relative risk, 70.6; 95% confidence interval, 11.4-439.3). CYP2E1 and NQO1 genotypes were determined by PCR-RFLP, and CYP2E1 enzymatic activity was estimated by the fractional excretion of chlorzoxazone (fe(6-OH)) for 50 cases of BP and 50 controls. Subjects with both a rapid fe(6-OH). and two copies of the NQO1 609C-->T mutation had a 7.6-fold (95% confidence interval, 1.8-31.2) increased risk of BP compared to subjects with a slow fe(6-OH) who carried one or two wild-type NQO1 alleles. In contrast, the CYP2E1 PstI/RsaI polymorphism did not influence BP risk. This is the first report that provides evidence of human susceptibility to benzene-related disease. Further evaluation of susceptibility for hematotoxicity and hematological malignancy among workers with a history of occupational exposure to benzene is warranted