Faculty Bibliography

This report is part of an extensive study to verify the validity, specificity, and sensitivity of biomarkers of benzene at low exposures and assess their relationships with personal exposure and genetic damage. The study population was selected from benzene-exposed workers in Tianjin, China, based on historical exposure data. The recruitment of 130 exposed workers from glue-making or shoe-making plants and 51 unexposed subjects from nearby food factories was based on personal exposure measurements conducted for 3-4 weeks prior to collection of biological samples. In this report we investigated correlation of urinary benzene metabolites, S-phenylmercapturic acid (S-PMA) and trans,trans-muconic acid (t,t-MA) with personal exposure levels on the day of urine collection and studied the effect of dose on the biotransformation of benzene to these key metabolites. Urinary S-PMA and t,t-MA were determined simultaneously by liquid chromatography-tandem mass spectrometry analyses. Both S-PMA and t,t-MA, but specifically the former, correlated well with personal benzene exposure over a broad range of exposure (0.06-122 ppm). There was good correlation in the subgroup that had been exposed to <1 ppm benzene with both metabolites (P-trend <0.0001 for S-PMA and 0.006 for t,t-MA). Furthermore, the levels of S-PMA were significantly higher in the subgroup exposed to <0.25 ppm than that in unexposed subjects (n=17; P=0.001). There is inter-individual variation in the rate of conversion of benzene into urinary metabolites. The percentage of biotransformation of benzene to urinary S-PMA ranged from 0.005 to 0.3% and that to urinary t,t-MA ranged from 0.6 to approximately 20%. The percentage of benzene biotransformed into S-PMA and t,t-MA decreased with increasing concentration of benzene, especially conversion of benzene into t,t-MA. It appears that women excreted more metabolites than men for the same levels of benzene exposures. Our data suggest that S-PMA is superior to t,t-MA as a biomarker for low levels of benzene exposure

In this study, we validated measurements of free testosterone (fT) and free estradiol (fE(2)) concentrations calculated from total serum concentrations of testosterone (T), estradiol (E(2)), and sex hormone-binding globulin (SHBG), measured by direct, commercial radioimmunoassays, by comparison with reference measurements obtained by dialysis plus an in-house radioimmunoassay after extraction and chromatographic purification. The study was conducted in serum samples from 19 postmenopausal women who were part of an ongoing prospective cohort study. We also performed sensitivity analyses to examine the robustness of the theoretical calculations. Sensitivity analyses showed that in this population, competitive binding of dihydrotestosterone and total T could be ignored in the calculation of fE(2), and competitive binding by dihydrotestosterone does not need to be taken into account for calculation of fT. Furthermore, variations in albumin and SHBG concentrations had negligible effects on fT and fE(2) calculations. Values of fT and fE(2), calculated from total T and E(2) concentrations obtained by the same in-house radioimmunoassay used for the dialysis method, correlated highly with the measurements by dialysis (Pearson's coefficients of correlation above 0.97). When calculating fT and fE(2) using total T and total E(2) concentrations obtained by different direct radioimmunoassays, almost all kits gave good correlations with the reference method for fT (Pearson's r > 0.83), but only a few gave good correlations for fE(2) (Diagnostic System Laboratories and DiaSorin; r > 0.80). The direct radioimmunoassays giving the best correlation for fT and fE(2) with the dialysis method were those that best measured total concentrations of T and E(2). Furthermore, mean values of fT and fE(2) corresponded well to mean values by the reference method if SHBG measurements were also well calibrated. We conclude that in postmenopausal women, theoretical calculations are valid for the determination of fT and fE(2) concentrations and can give reliable estimation of cancer risk in epidemiological studies when the total concentrations of T, E(2), and SHBG are measured accurately

BACKGROUND: Depression of peripheral blood cells is a well-known indicator of benzene hematotoxicity. Previous studies of its effects on specific types of blood cells have yielded inconsistent results. We examine hematological findings and their possible relations with exposure markers validated in a recent biomarker project conducted in Tianjin, China. METHODS: Personal benzene exposures were sampled with 3-M organic vapor monitors, and analyzed by gas chromatography. The peripheral blood cells were counted by a cell counter. The WBC differential was manually counted on a total of 900 cells by a US commercial laboratory. RESULTS: A total of 130 exposed workers and 51 age- and gender-matched unexposed subjects were recruited in this study. Benzene exposure levels monitored on the day of biological sample collection for exposed workers ranged from 0.06 to 122 ppm. Their 4-week average and cumulative benzene exposure levels were 0.08-54.5 ppm and 6.1-623.2 ppm-years, respectively. Significant decreases of red blood cells (RBC), white blood cells (WBC), and neutrophils were observed and correlated with both personal benzene exposures and levels of urinary metabolites (S-phenylmercapuric acid and t,t-muconic acid) and albumin adducts of benzene oxide and 1,4-benzeoquinone. CONCLUSIONS: The depressions in RBC, WBC, and neutrophils observed in this study are not only exposure dependent, but also significantly different in the lowest exposed group (at or below 0.25 ppm) compared with unexposed subjects. The results of the present study appear to suggest that lymphocytes may not be more sensitive to chronic benzene exposure than neutrophils

Recently, a number of prospective studies showed evidence that the growth hormone/insulin-like growth factor I (IGF-I) axis may be important in the development of colorectal cancer. However, only a few studies have reported on the possible relationship of colorectal cancer risk with circulating levels of IGF-II, which are not growth hormone dependent and which do not vary with alterations in energy balance. In a case-control study of 102 cases and 200 matched controls nested within a cohort of 14,275 women in New York, we examined the relationship between colorectal cancer risk and prediagnostic serum levels of IGF-II. Conditional logistic regression analysis showed an odds ratio (OR) for colorectal cancer of 2.02 (95% confidence interval (CI): 0.83-4.93), comparing the upper to lower quintile of IGF-II. This association was slightly attenuated after excluding IGF-II measurements in serum samples taken within 1 year before case diagnosis (OR of 1.81; 95% CI: 0.71-4.64) and moderately attenuated after excluding IGF-II measurements in serum samples taken within 2 years before case diagnosis (OR of 1.47; 95% CI: 0.56-3.91). Adjustment for IGF-1, IGF binding protein (BP)-1, IGFBP-3, smoking, or body mass index did not substantially alter the association, whereas adjustment for IGFBP-2 moderately attenuated the relationship. Our results confirm those of three recent case-control studies, and collectively these results suggest a possible increase in colorectal cancer risk among subjects with comparatively elevated serum IGF-II. Mechanisms that might cause the increase in IGF-II levels are unknown but may include loss of parental imprinting of the IGF-II gene

Breast cancer incidence rates after radiation exposure in eight large cohorts are described and compared. The nature of the exposures varies appreciably, ranging from a single or a small number of high-dose-rate exposures (Japanese atomic bomb survivors, U.S. acute post-partum mastitis patients, Swedish benign breast disease patients, and U.S. infants with thymic enlargement) to highly fractionated high-dose-rate exposures (two U.S. tuberculosis cohorts) and protracted low-dose-rate exposure (two Swedish skin hemangioma cohorts). There were 1,502 breast cancers among 77,527 women (about 35,000 of whom were exposed) with 1.8 million woman-years of follow-up. The excess risk depends linearly on dose with a downturn at high doses. No simple unified summary model adequately describes the excess risks in all groups. Excess risks for the thymus, tuberculosis, and atomic bomb survivor cohorts have similar temporal patterns, depending on attained age for relative risk models and on both attained age and age at exposure for excess rate models. Excess rates were similar in these cohorts, whereas, related in part to the low breast cancer background rates for Japanese women, the excess relative risk per unit dose in the bomb survivors was four times that in the tuberculosis or thymus cohorts. Excess rates were higher for the mastitis and benign breast disease cohorts. The hemangioma cohorts showed lower excess risks suggesting ameliorating dose-rate effects for protracted low-dose-rate exposures. For comparable ages at exposure (approximately 0.5 years), the excess risk in the hemangioma cohorts was about one-seventh that in the thymus cohort, whose members received acute high-dose-rate exposures. The results support the linearity of the radiation dose response for breast cancer, highlight the importance of age and age at exposure on the risks, and suggest a similarity in risks for acute and fractionated high-dose-rate exposures with much smaller effects from low-dose-rate protracted exposures. There is also a suggestion that women with some benign breast conditions may be at elevated risk of radiation-associated breast cancer

The association between aspirin use and lung cancer risk in women was examined in a case-control study nested in the New York University Women's Health Study, a large cohort in New York. Case subjects were all the 81 incident lung cancer cases who had provided information about aspirin use at enrollment and during the 1994-1996 follow up. Ten controls per case were randomly selected from among study participants who matched a case by age, menopausal status, and dates of enrollment and follow-up. Relative to no aspirin use, the odds ratio for lung cancer (all histological sub-types combined) among subjects who reported aspirin use three or more times per week for at least 6 months was 0.66 (95% confidence interval 0.34-1.28), after adjustment for smoking and education. A stronger inverse association was observed in analyses restricted to non-small cell lung cancer (adjusted odds ratio 0.39, 95% confidence interval 0.16-0.96). These results suggest that regular aspirin use might be inversely associated with risk of lung cancer in women, particularly the non-small cell sub-type

The hypothesis that intracranial energy deposition from handheld cellular telephones causes acoustic neuroma was tested in an epidemiologic study of 90 patients and 86 control subjects. The relative risk was 0.9 (p = 0.07) and did not vary significantly by the frequency, duration, and lifetime hours of use. In patients who used cellular telephones, the tumor occurred more often on the contralateral than ipsilateral side of the head. Further efforts should focus on potentially longer induction periods

Background: Reproductive and hormonal factors are involved in the etiology of breast cancer, but there are only a few prospective studies on endogenous sex hormone levels and breast cancer risk. We reanalyzed the worldwide data from prospective studies to examine the relationship between the levels of endogenous sex hormones and breast cancer risk in postmenopausal women. Methods: We analyzed the individual data from nine prospective studies on 663 women who developed breast cancer and 1765 women who did not. None of the women was taking exogenous sex hormones when their blood was collected to determine hormone levels. The relative risks (RRs) for breast cancer associated with increasing hormone concentrations were estimated by conditional logistic regression on case-control sets matched within each study. Linear trends and heterogeneity of RRs were assessed by two-sided tests or chi-square tests, as appropriate. Results: The risk for breast cancer increased statistically significantly with increasing concentrations of all sex hormones examined: total estradiol, free estradiol, non-sex hormone-binding globulin (SHBG)-bound estradiol (which comprises free and albumin-bound estradiol), estrone, estrone sulfate, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone. The RRs for women with increasing quintiles of estradiol concentrations, relative to the lowest quintile, were 1.42 (95% confidence interval [CI] = 1.04 to 1.95), 1.21 (95% CI = 0.89 to 1.66), 1.80 (95% CI = 1.33 to 2.43), and 2.00 (95% CI = 1.47 to 2.71; Ptrend<.001); the RRs for women with increasing quintiles of free estradiol were 1.38 (95% CI = 0.94 to 2.03), 1.84 (95% CI = 1.24 to 2.74), 2.24 (95% CI = 1.53 to 3.27), and 2.58 (95% CI = 1.76 to 3.78; Ptrend<.001). The magnitudes of risk associated with the other estrogens and with the androgens were similar. SHBG was associated with a decrease in breast cancer risk (Ptrend = .041). The increases in risk associated with increased levels of all sex hormones remained after subjects who were diagnosed with breast cancer within 2 years of blood collection were excluded from the analysis. Conclusion: Levels of endogenous sex hormones are strongly associated with breast cancer risk in postmenopausal women

Some 2,224 children given X-ray therapy for tinea capitis (ringworm of the scalp) have been followed for up to 50 years to determine cancer incidence, along with a control group of 1,380 tinea capitis patients given only topical medications. The study found a relative risk (RR) of 3.6 (95% confidence interval, 2.3-5.9) for basal cell skin cancer (BCC) of the head and neck among irradiated Caucasians (124 irradiated cases and 21 control cases), in response to a scalp dose of about 4.8 Gy. No melanomas of the head and neck have been seen, and only a few squamous cell carcinomas. About 40% of irradiated cases have had multiple BCCs, for a total of 328 BCCs. Although 25% of both the irradiated and control groups are African-American, only 3 skin cancers have been seen among them, all in the irradiated group, indicating the importance of susceptibility to UV radiation as a cofactor. Light complexion, severe sunburning and North European ancestry were predictive of BCC risk in the irradiated group, but chronic sun exposure was not. Children irradiated at young ages had the highest BCC risk. The RR for BCC risk is approximately constant with time since exposure, suggesting that risk will probably last for a lifetime

Albumin adducts of benzene oxide (BO-Alb) and 1,4-benzoquinone (1,4-BQ-Alb) were investigated among 134 workers exposed to benzene and 51 unexposed controls in Tianjin, China. Concentrations of both adducts increased with benzene exposure [range = 0.07-46.6 parts/million (ppm); median = 3.55 ppm] and with urinary cotinine. Adduct levels were less than proportional to benzene exposure, suggesting saturable CYP 2E1 metabolism of benzene. Because the transition from linear to saturable metabolism began at approximately 1 ppm, the common assumption of linear kinetics at much higher benzene exposures could lead to substantial underestimation of leukemia risks. Adduct levels were generally lower in older workers, indicating that CYP 2E1 metabolism diminished with age, at approximately 2%/year of life. The ratio of 1,4-BQ-Alb:BO-Alb decreased with age and coexposure to toluene, and increased with alcohol consumption. This indicates that factors affecting CYP 2E1 metabolism exerted a greater role on production of 1,4-BQ than BO, presumably because of the second oxidation step from phenol to hydroquinone. The adduct ratio was also positively associated with urinary cotinine, suggesting that both benzene and hydroquinone from cigarette smoke affected adduct levels. Results of a limited time course study of 11 subjects indicated moderate chemical instability of 1,4-BQ-Alb (half life = 13.5 days compared with 21 days for normal Alb turnover), whereas no evidence of instability of BO-Alb was observed. This study illustrates that Alb adducts can be used to investigate the dispositions of reactive metabolites of procarcinogens in humans, provided that exposures are adequately characterized in the month preceding blood collection