Faculty Bibliography

While this study is larger than previous investigations and includes workers with a wide range of exposures to benzene, the estimates of risk, as measured by statistical confidence intervals, are still fairly broad, and would benefit from the larger numbers that could be provided by continued follow-up of this population. Nevertheless, the study confirms earlier findings of increased risk for ANLL and aplastic anemia among benzene-exposed workers, provides the first substantial evidence that MDS is linked to benzene exposure, and provides evidence that benzene increases risk for ANLL/MDS at lower levels of exposure than had previously been demonstrated. Currently we are evaluating the potential for extending the follow-up of workers included in this study. A new study would include expanded data collection for cases of hematopoietic malignancy and related disorders and for an appropriate control series

The objectives of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial are to determine in screenees ages 55-74 at entry whether screening with flexible sigmoidoscopy (60-cm sigmoidoscope) can reduce mortality from colorectal cancer, whether screening with chest X-ray can reduce mortality from lung cancer, whether screening men with digital rectal examination (DRE) plus serum prostate-specific antigen (PSA) can reduce mortality from prostate cancer, and whether screening women with CA125 and transvaginal ultrasound (TVU) can reduce mortality from ovarian cancer. Secondary objectives are to assess screening variables other than mortality for each of the interventions including sensitivity, specificity, and positive predictive value; to assess incidence, stage, and survival of cancer cases; and to investigate biologic and/or prognostic characterizations of tumor tissue and biochemical products as intermediate endpoints. The design is a multicenter, two-armed, randomized trial with 37,000 females and 37,000 males in each of the two arms. In the intervention arm, the PSA and CA125 tests are performed at entry, then annually for 5 years. The DRE, TVU, and chest X-ray exams are performed at entry and then annually for 3 years. Sigmoidoscopy is performed at entry and then at the 5-year point. Participants in the control arm follow their usual medical care practices. Participants will be followed for at least 13 years from randomization to ascertain all cancers of the prostate, lung, colorectum, and ovary, as well as deaths from all causes. A pilot phase was undertaken to assess the randomization, screening, and data collection procedures of the trial and to estimate design parameters such as compliance and contamination levels. This paper describes eligibility, consent, and other design features of the trial, randomization and screening procedures, and an outline of the follow-up procedures. Sample-size calculations are reported, and a data analysis plan is presented

The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial is enrolling 148,000 men and women ages 55-74 at ten screening centers nationwide with balanced randomization to intervention and control arms. For prostate cancer, men receive a digital rectal examination and a blood test for prostate-specific antigen. For lung cancer, men and women receive a posteroanterior view chest X-ray. For colorectal cancer, men and women undergo a 60-cm flexible sigmoidoscopy. For ovarian cancer, women receive a blood test for the CA125 tumor marker and transvaginal ultrasound. Members of the control arm continue with their usual care. Follow-up in both groups will continue for at least 13 years from randomization to assess health status and cause of death. The primary endpoint is mortality from the four PLCO cancers, which accounts for about 53% of all cancer deaths in men and 41% of cancer deaths in women in the United States each year. Blood specimens are collected from screened participants, buccal cell DNA from controls, and histology slides from cases; these are maintained in a biorepository. Participants complete a baseline questionnaire (covering health status and risk factors) and a dietary questionnaire. More than 12,000 participants were enrolled in the pilot phase (concluded in September 1994). Changes in the eligibility criteria followed. As of April 2000, enrollment exceeded 144,500. Data are scanned into designated on-site computers for uploading by participant identification number to the coordinating center for quality checks, archival storage, and preparation of analysis datasets for use by the National Cancer Institute (NCI). Scientific direction is provided by NCI scientists, trial investigators, external consultants, and an independent data safety and monitoring board. Performance and data quality are monitored via data edits, site visits, random record audits, and teleconferences. The PLCO trial is formally endorsed by the American Cancer Society and has been ranked by the American Urological Association as one of the most important prostate cancer studies being conducted. Special efforts to enroll black participants are cosponsored by the U.S. Centers for Disease Control and Prevention

BACKGROUND: Earlier reports of the mortality experience of this cohort of automotive workers followed from 1938 to 1967 who were exposed to cutting oil mist noted an excess of gastrointestinal cancer. The present report describes the mortality experience of these workers followed for mortality through 1980. METHODS: Cause-specific standardized mortality ratios were calculated by comparing the observed number of deaths to the expected numbers based on rates for the U.S. male population. RESULTS: The SMRs for liver and biliary tract, and testicular cancers were significantly elevated. Among the subset of workers with heavy oil mist exposure, SMRs were significantly elevated for cancers of the lung and testis, and for Hodgkin's disease. The risk of death due to lung cancer was greatest among workers with heavy exposure to oil mist employed for 15 or more years. Mortality due to stomach cancer was in excess among workers with heavy exposure to oil mist who were employed for 5 or more years. There were significant excesses of deaths due to asthma and emphysema. CONCLUSIONS: Further studies with information on the presence of contaminants and additives in oil mists will help elucidate the relationship between oil mist exposure and cancer

We propose a new approach to the additive dose method in EPR dosimetry studies for tooth enamel specimens. We outline a specialized routine whereby the sample may be left for the most part unirradiated, while only a small aliquot of the sample will be additively irradiated to relatively large doses. The routine is done in such a way so as not to significantly compromise either precision or accuracy of the dose reconstruction. It is also demonstrated that the overall throughput of the dose reconstruction is not appreciably compromised. With this potential ability, the utility of an international dose/sensitivity standard for EPR dosimetry of teeth is considered

Tobacco use is an established cause of bladder cancer. The ability to detoxify aromatic amines, which are present in tobacco and are potent bladder carcinogens, is compromised in persons with the N-acetyltransferase 2 slow acetylation polymorphism. The relationship of cigarette smoking with bladder cancer risk therefore has been hypothesized to be stronger among slow acetylators. The few studies to formally explore such a possibility have produced inconsistent results, however. To assess this potential gene-environment interaction in as many bladder cancer studies as possible and to summarize results, we conducted a meta-analysis using data from 16 bladder cancer studies conducted in the general population (n = 1999 cases), Most had been conducted in European countries. Because control subjects were unavailable for a number of these studies, we used a case-series design, which can be used to assess multiplicative gene-environment interaction without inclusion of control subjects. A case-series interaction odds ratio (OR) > 1.0 indicates that the relationship of cigarette smoking and bladder cancer risk is stronger among slow acetylators as compared with rapid acetylators. We observed an interaction between smoking and N-acetyltransferase 2 slow acetylation (OR, 1.3; 95% confidence interval, 1.0-1.6) that was somewhat stronger when analyses were restricted to studies conducted in Europe (OR, 1.5; confidence interval, 1.1-1.9), a pooling that included nearly 80% of the collected data. Using the predominantly male European study population and assuming a 2.5-fold elevation in bladder cancer risk from smoking, we estimated that the population attributable risk percent was 35% for slow acetylators who had ever smoked and 13% for rapid acetylators who had ever smoked. These results suggest that the relationship of smoking and bladder cancer is stronger among slow acetylators than among rapid acetylators

A population-based case-control study was carried out among 981 men (479 black, 502 white) with pathologically confirmed prostate cancer and 1315 controls (594 black, 721 white). In-person interviews elicited information on sexual behaviour and other potential risk factors for prostate cancer. Blood was drawn for serologic studies in a subset of the cases (n = 276) and controls (n = 295). Prostate cancer risk was increased among men who reported a history of gonorrhoea or syphilis (odds ratio (OR) = 1.6; 95% confidence internal (CI) 1.2-2.1) or showed serological evidence of syphilis (MHA-TP) (OR = 1.8; 95% CI 1.0-3.5). Patterns of risk for gonorrhoea and syphilis were similar for blacks (OR = 1.7; 95% CI 1.2-2.2) and whites (OR = 1.6; 95% CI 0.8-3.2). Risks increased with increasing occurrences of gonorrhoea, rising to OR = 3.3 (95% CI 1.4-7.8) among subjects with three or more events (Ptrend = 0.0005). Frequent sexual encounters with prostitutes and failure to use condoms were also associated with increased risk. Syphilis, gonorrhoea, sex with prostitutes and unprotected sexual intercourse may be indicators of contact with a sexually transmissible factor that increases the risk of prostate cancer

Oral epithelial cells provide an easily accessible source of germline DNA. Two methods for collection were compared in a 1992-1995 case-control study of oral cancer in Puerto Rico. One group of subjects (55 controls without oral cancer) collected oral rinse samples at home or work under the direction of a nonmedically trained interviewer ('self-collection'); the other group (94 controls) participated in a clinic-based collection, which also included blood and urine samples, conducted by a medical technician ('clinic collection'). Participation was higher for self-collection (98.2%) than for clinic collection (70.7%) (p < 0.001). DNA yields ranged from 2.0 to 204.5 microg (median, 25.9 microg) and did not differ by collection method, although yields varied by interviewer among self-collected samples (p = 0.02). Success rates for polymerase chain reaction amplification of the ADH3, NAT1, and multiplex CYP1A1/GSTT1/GSTM1 genotyping assays ranged from 76.4% (NAT1) to 98.2% (ADH3) for self-collected samples and were similar to those for clinic-collected samples (87.2-97.9%). Failure to amplify was associated with low DNA content (p = 0.015). Similar results were observed among cases (91 self-collected, 66 clinic collected), except that DNA yields did not vary by interviewer and a larger fraction (10.2%) of samples contained less than 5 microg of DNA, perhaps because of disease-related oral impairment. Self-collection of oral epithelial DNA samples appears satisfactory and efficient for many epidemiologic studies

While 1,3-butadiene is carcinogenic in rodents, cancer causation in humans is less certain. We examined a spectrum of genotoxic outcomes in 41 butadiene polymer production workers and 38 non-exposed controls, in China, to explore the role of butadiene in human carcinogenesis. Because in vitro studies suggest that genetic polymorphisms in glutathione S-transferase enzymes influence genotoxic effects of butadiene, we also related genotoxicity to genetic polymorphisms in GSTT1 and GSTM1. Among butadiene-exposed workers, median air exposure was 2 p.p.m. (6 h time-weighted average), due largely to intermittent high level exposures. Compared with unexposed subjects, butadiene-exposed workers had greater levels of hemoglobin N-(2,3,4-trihydroxybutyl)valine (THBVal) adducts (P < 0.0001) and adduct levels tended to correlate, among butadiene-exposed workers, with air measures (P = 0.03). Butadiene-exposed workers did not differ, however, from unexposed workers with respect to frequency of uninduced or diepoxybutane-induced sister chromatid exchanges, aneuploidy as measured by fluorescence in situ hybridization of chromosomes 1, 7, 8 and 12, glycophorin A variants or lymphocyte hprt somatic mutation. Also among the exposed, greater THBVal levels were not associated with increases in uninduced sister chromatid exchanges, aneuploidy, glycophorin A or hprt mutations. Butadiene-exposed workers had greater lymphocyte (P = 0.002) and platelet counts (P = 0.07) and lymphocytes as a percentage of white blood cells were moderately correlated with greater THBVal levels (Spearman's phi = 0.32, P = 0.07). Among butadiene-exposed workers, neither GSTM1 nor GSTT1 genotype status predicted urinary mercapturic acid butanediol formation, THBVal adducts, uninduced sister chromatid exchanges, aneuploidy or mutations in the glycophorin A or hprt genes. Overall, the study demonstrated exposure to butadiene in these workers, by a variety of short-term and long-term measures, but did not show specific genotoxic effects, at the chromosomal or gene levels, related to that exposure

Benzene is an established human leukemogen that increases the level of chromosome aberrations in lymphocytes of exposed workers. Numerical aberrations (aneusomy) can be observed by fluorescence in situ hybridization (FISH) in both interphase and metaphase cells. Whereas interphase FISH allows nondividing cells to be analyzed, one advantage of metaphase FISH is that it can also detect structural changes. The present study compares the abilities of metaphase and interphase FISH to detect aneusomy of chromosomes 7 and 8 in healthy benzene-exposed human subjects. Metaphase and interphase cells from the peripheral blood of 43 workers exposed to benzene (median = 31 ppm, 8-hr TWA) and 44 frequency-matched controls were analyzed by FISH. Normal diploid cells contained two hybridization signals, whereas those that were potentially monosomic contained one, trisomic 3 and tetrasomic 4. The frequency of cells with one hybridization signal for chromosome 7 in metaphase spreads rose from 2.72 +/- 0.19 (%, mean +/- SE) in controls to 3.79 +/- 0.63 in workers exposed to 31 or fewer ppm benzene and 5.9 +/- 0.85 in those exposed to more than 31 ppm (P(trend) < 0.0001). No similar dose-dependent increase in the frequency of cells with one hybridization signal was observed by interphase FISH, probably because of probe overlap artifact. Although significant dose-dependent increases in the frequency of cells with three hybridization signals for chromosome 7 were detected by both methods in the higher-exposed group, a larger, more significant difference was detected by metaphase FISH between controls and workers exposed to 31 or fewer ppm. Similar data were obtained for chromosome 8. Interphase and metaphase FISH were moderately correlated for three hybridization signals but not for one hybridization signal in chromosome 7 or 8. In general, metaphase FISH was more sensitive in detecting both monosomy and trisomy in the lymphocytes of exposed workers