Faculty Bibliography

A large cohort study of 74,828 benzene-exposed and 35,805 unexposed workers employed between 1972 and 1987 in 12 cities in China were followed to determine mortality from all causes and the incidence of lymphohematopoietic malignancies and other hematologic disorders. Benzene-exposed study subjects were employed in a variety of occupations, including painting, printing, and the manufacture of footwear, paint, and other chemicals. All-cause mortality was similar in the benzene-exposed and unexposed comparison group. Statistically significant excess deaths were noted among benzene-exposed subjects for leukemia (RR = 2.3, 95% CP 1.1-5.0), malignant lymphoma (RR = 4.5, 95% CI: 1.3-28.4), and nonneoplastic diseases of the blood (RR = 95% CP 2.5-infinity), and a marginally significant excess was noted for lung cancer (RR = 1.4, 95% CI: 1.0-2.0). Risk was significantly elevated for the incidence of all lymphohematopoietic malignancies (RR = 2.6, 95% CI: 1.5-5.0), malignant lymphoma (RR = 3.5, 95% CI: 1.2-14.9), and leukemia (RR = 2.6, 95% CI.. 1.3-5.7). Among the leukemia subtypes, only acute myelogenous leukemia (AML) incidence was significantly elevated (RR = 3.1, 95% CI: 1.2-10.7), although nonsignificant excesses were also noted for chronic myelogenous leukemia (CML) (RR = 2.6, 95% CI: 0.7-16.9) and lymphocytic leukemias (RR = 2.8, 95% CI.. 0.5-54.5). Significant excesses were found for aplastic anemia (RR = infinity, 95% CI: 2.2-co) and myelodysplastic syndrome (RR = infinity, 95% CI: 1.7-infinity). Employment in benzene-associated occupations in China is associated with a wide spectrum of myelogenous and lymphocytic malignant diseases and related disorders. Investigations continue to assess the nature of these associations

Benzene is a well-established hematotoxin. However, reports of its effects on specific blood cells have been somewhat inconsistent and the relative toxicity of benzene metabolites on peripheral blood cells in humans has not been evaluated. We compared hematologic outcomes in a cross-sectional study of 44 workers heavily exposed to benzene (median: 31 parts permillion [ppm] as an 8-hr time-weighted average [TWA] and 44 age and gender-matched unexposed controls from Shanghai, China. All hematologic parameters (total white blood cells [WBC], absolute lymphocyte count, platelets, red blood cells, and hematocrit) were decreased among exposed workers compared to controls, with the exception of the red blood cell mean corpuscular volume (MCV), which was higher among exposed subjects. In a subgroup of workers who were not exposed to more than 31 ppm benzene on any of 5 sampling days (n = 11, median 8 hr TWA = 7.6 ppm, range = 1-20 ppm), only the absolute lymphocyte count was significantly different between exposed workers (mean [sd]1.6 [0.4] x 10(3) mu L) and controls (1.9 [0.4] x l0(3) uL, p = 0.03). Among exposed subjects, a dose response relationship with various measures of current benzene exposure (i.e., personal air monitoring, benzene metabolites in urine) was present only for the total WBC count, the absolute lymphocyte count, and the MCV. Correlations between benzene metabolites and hematologic parameters were generally similar, although hydroquinone was somewhat more strongly associated with a decrease in the absolute lymphocyte count, and catechol was more strongly associated with an increase in MCV. Morphologic review of peripheral blood slides demonstrated an excess of red blood cell abnormalities (i.e., stomatocytes and target cells) only in the most heavily exposed workers, with no differences in granulocyte, lymphocyte, or platelet morphology noted. Although benzene can affect all the major peripheral blood elements, our results support the use of the absolute lymphocyte count as the most sensitive indicator of benzene-induced hematotoxicity

We report an isotope dilution mass spectrometry method using capillary gas chromatography/negative ion chemical ionization to quantitate urine concentrations of benzidine (BZ) and of its acetylated metabolites N-acetylbenzidine (ABZ) and N,N'-diacetylbenzidine (DABZ). Urine samples were purified by solid-phase extraction columns, reduced with LiAlH4/THF, and derivatized with pentafluoropropionic anhydride. The derivatives were measured by selected ion monitoring relative to deuterium-labeled internal standards. A detection limit as low as 0.5, 0.8, and 1.5 ppt for BZ, ABZ, and DABZ, respectively, can easily be achieved. Urinary concentrations of ABZ substantially exceed those of either BZ or of DABZ in workers exposed to BZ or BZ-based dyes. This method has been successfully used to measure BZ, ABZ, and DABZ in 1.0-ml urine samples collected from workers involved in manufacturing BZ and BZ-based dyes. The method should be applicable to the measurement of other aromatic amines and their acetylated metabolites

A population-based, case-control study of pancreatic cancer based on direct interviews with 307 white and 179 black incident cases and 1164 white and 945 black population controls was conducted in three areas of the United States to determine the role alcohol drinking plays as a risk factor for pancreatic cancer and to estimate the extent to which it may explain the higher incidence of pancreatic cancer in blacks compared to whites. Our findings indicate that alcohol drinking at the levels typically consumed by the general population of the United States is probably not a risk factor for pancreatic cancer. Our data suggest, however, that heavy alcohol drinking may be related to pancreatic cancer risk. Among men, blacks and white who drank at least 57 drinks/week had odds ratios (ORs) of 2.2 [95% confidence interval (CI) = 0.9-5.6] and 1.4 (95% CI = 0.6-3.2), respectively. Among women, blacks who drank 8 to < 21 drinks/week had an OR of 1.8 (95% CI = 0.8-4.0), and those who drank at least 21 drinks/week had an OR of 2.5 (95% CI = 1.02-5.9), but whites with the same levels of alcohol intake experienced no increased risk. Compared to whites, blacks had significantly higher ORs associated with heavy alcohol drinking (> or = 57 drinks/week) in men (P = 0.04) and with moderate-to-heavy drinking (> or = 8 drinks/week) in women (P = 0.03). Additional research is needed to determine whether heavy alcohol drinking is causally related to pancreatic cancer and whether the risk of alcohol-related pancreatic cancer is greater in blacks than in whites

There has been increasing interest in the interaction of genetic susceptibility and xenobiotic exposures in cancer etiology. Study of gene-environment interactions may increase our ability to characterize relatively low population risks if a substantial proportion of the population cancer burden is attributed to high risk among a smaller group of genetically susceptible members. Further, these studies may provide insight into the mechanism of carcinogenesis, which can help establish the biologic plausibility of an exposure-cancer relationship. Biologic processes important in tumorigenesis that exhibit substantial interindividual differences may function as susceptibility factors. Potential examples include polymorphic enzymes, which activate and detoxify procarcinogens and carcinogens (e.g., certain P450 enzymes, N-acetyltransferase [NAT2], glutathione S-transferase M1), and variation in the capacity to repair DNA. Biologic assays are now available to evaluate many of these functions at the DNA and phenotype level and can be readily incorporated into studies of cancer etiology

PIP: Prostate cancer is the most commonly diagnosed malignancy among US males. Its incidence, however, varies markedly from 2 per 100,000 per year in Shanghai, China, to 62 and 82, respectively, for US Whites and Blacks. Mortality due to prostate cancer is twice as high among US Blacks than among US Whites. A familial component is important in determining prostate cancer risk, but does not appear to explain the variation in rates between US Blacks and Whites. Dietary fat, the consumption of which varies on a national basis in parallel with prostate cancer rates, may be a major risk factor for the disease. A study by Whittemore et al. involved more than 1500 cases and controls including Whites, Blacks, Chinese-Americans, and Japanese-Americans in five cities in the US and Canada. On the basis of detailed dietary interviews, Whittemore shows that prostate cancer risk increases with higher intake of saturated fat. The effect holds true for both younger and older men. The risk was significantly elevated for Asian-Americans, and less pronounced for Blacks and Whites, yet nonetheless consistent with an overall excess. Risk was unrelated to the intake of other macronutrients, intake of vitamin A, intake of fruits and vegetables, body mass, or physical activity. Among Asian-Americans, long-term residents in the US were at greatest risk of prostate cancer independent of dietary fat intake. A study by John et al. has found vasectomy to not be related to the development of prostate cancer. Reasons why the finding of this study is opposite from the general body of evidence supporting an increased risk of prostate cancer following vasectomy are not apparent

This review describes statistical models for the biological interaction of susceptibility genes and environmental exposures, as observed in epidemiologic studies. The importance of metabolic transformation of industrial carcinogens and the potential role of genetic polymorphisms in metabolic enzyme activity are outlined. Several genetic polymorphisms have been associated with cancer risk, but the link with the relevant exposures has only infrequently been specified. For example, studies show that slow N-acetylation increased bladder cancer risk among workers exposed to some arylamines, as found among dye workers in England, but that this effect does not hold for benzidine exposure. This link of a genetic susceptibility factor with cancer risk due to some aromatic amines, but not to others, illustrated the specific nature of metabolic environment/gene interactions. Epidemiologic studies to investigate the role of genetic susceptibility in cancer development promise to further the identification of human carcinogens by focusing on susceptible individuals and, in turn, to enhance understanding of human cancer by relating cancer risk in populations to underlying biologic processes. Occupational studies are key to this effort

Occupational exposure to benzene is known to cause leukemia, but the mechanism remains unclear. Unlike most other carcinogens, benzene and its metabolites are weakly or nonmutagenic in most simple gene mutation assays. Benzene and its metabolites do, however, produce chromosomal damage in a variety of systems. Here, we have used the glycophorin A (GPA) gene loss mutation assay to evaluate the nature of DNA damage produced by benzene in 24 workers heavily exposed to benzene and 23 matched control individuals in Shanghai, China. The GPA assay identifies stem cell or precursor erythroid cell mutations expressed in peripheral erythrocytes of MN-heterozygous subjects, distinguishing the NN and N phi mutant variants. A significant increase in the NN GPA variant cell frequency (Vf) was found in benzene-exposed workers as compared with unexposed control individuals (mean +/- SEM, 13.9 +/- 1.7 per million cells vs. 7.4 +/- 1.1 per million cells in control individuals; P = 0.0002). In contrast, no significant difference existed between the two groups for the N phi Vf (9.1 +/- 0.9 vs. 8.8 +/- 1.8 per million cells; P = 0.21). Further, lifetime cumulative occupational exposure to benzene was associated with the NN Vf (P = 0.005) but not with the N phi Vf (P = 0.31), suggesting that NN mutations occur in longer-lived bone marrow stem cells. NN variants result from loss of the GPA M allele and duplication of the N allele, presumably through recombination mechanisms, whereas NO variants arise from gene inactivation, presumably due to point mutations and deletions. Thus, these results suggest that benzene produces gene-duplicating mutations but does not produce gene-inactivating mutations at the GPA locus in bone marrow cells of humans exposed to high benzene levels. This finding is consistent with data on the genetic toxicology of benzene and its metabolites and adds further weight to the hypothesis that chromosome damage and mitotic recombination are important in benzene-induced leukemia

Mutational inactivation of the p53 tumor suppressor gene is an infrequent event in human nasopharyngeal carcinoma (NPC), a malignancy showing a high incidence in southern China and southeast Asia. To examine the possible involvement of an activated p53 pathway in nasopharynx carcinogenesis, we have screened primary NPC biopsies for possible point mutations in WAF-1/CIP-1/p21, an effector gene transcriptionally regulated by and functioning as a mediator of the p53 tumor suppressor gene. Mutations in WAF-1/CIP-1/p21 might mimic p53 mutations in tumors having wild-type p53 such as most NPCs. The mutational analysis of WAF/CIP/p21 by PCR-single strand conformational polymorphism-direct sequencing revealed no point mutation in 41 primary NPC biopsies. A codon 31ser-->arg polymorphism was, however, detected. A striking difference in the distribution of the serine (WAF-ser) and arginine (WAF-arg) forms of WAF-1/CIP-1/p21 was observed when normal healthy Caucasians and Chinese were compared (P < 0.0001). The majority of Caucasians examined were found to be homozygous for WAF-ser (89%, n = 65), while Chinese living in areas of high NPC incidence show a greater than 86% homozygous or heterozygous WAF-arg (Taiwan, n = 66; Hunan, n = 32). The two forms of WAF-1/CIP-1/p21 were examined for potential functional differences in their ability to inhibit cyclin-dependent kinases and tumor cell growth. No significant differences were detected. Furthermore, no association between WAF-1/CIP-1/p21 genotype and NPC risk was observed in a case-control study of 76 NPC cases and 66 normal controls conducted in Taiwan.(ABSTRACT TRUNCATED AT 250 WORDS)

The feasibility of using dentine from surgically extracted human teeth as in vivo dosimeters was investigated. The organic fraction of human dentine was removed by Soxhlet extraction with diethylenetriamine. The specimens were then crushed and 75 to 250 microns granules were given doses of gamma radiation ranging from 50 mGy to 8 Gy. Following irradiation, electron paramagnetic resonance spectra were collected. Signals were detected with Lande factors of g = 2.0018, line width = 0.903 mT; and g = 1.9961, line width = 0.444 mT. These signals have both been reported for hydroxyapatite of bone and enamel. Several other signals were also seen but not characterized. It was concluded that doses of 500 mGy or less may be resolved with prior removal of the organic component of dentine