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Oral Session 25 – Biomarkers

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J. J. Collins, M. L. Carson, C. J. Burns, R. A. Budinsky, L. Lamparski, G. D. Martin.Dow Chemical, 1803 Building, Midland, MI 48674 USA

Introduction: The Dow Chemical Company chlorophenol worker studies have examined several medical outcomes including causes of death, male mediated reproductive outcomes, and several dimensions of morbidity. These studies have been described in 17 published papers from 1980 to the present. This group of 2192 chlorophenol workers represents one of the largest groups at a single location examined for health effects from dioxin exposure. These workers have been followed for mortality since 1940, making them the longest followed population for examination of dioxin health effects. The Dow industrial hygiene monitoring data are the most comprehensive of any of the studies of industrial workers with potential dioxin exposures. Approximately 11% (245 of 2192) of the workers in these studies developed chloracne, indicating high dioxin exposures. While exposure estimates have been developed based on industrial hygiene monitoring, biomonitoring data have not been previously collected. This study describes biomonitoring for serum dioxin levels among a sample of these workers with the goal of improving exposure assessment for this group of chlorophenol workers to enhance future studies of potential health effects.

Methods: We randomly selected 24 male workers in each of three groups: (a) with chloracne employed mostly in the trichlorophenol (TCP) area, (b) with chloracne employed mostly in pentachlorophenol (PCP) area, and (c) workers with potential workplace dioxin exposure who did not develop chloracne. We frequency matched these workers on age and year of hire with workers in the same plant but with no potential workplace exposure to dioxins or furans. We measured 7 dioxins, 10 furans and 4 coplanar PCBs using high resolution gas chromatography/mass spectrometry.

Results: Collection of blood is currently ongoing for the 99 subjects and will be completed on 14 May 2004. Final results will be available in July of 2004.

Conclusions: These data will allow us to estimate the range of serum dioxin levels in the chlorophenol workers, determine if the chlorophenol workers have levels of dioxins or furans greater than background and if TCP workers have different congener profiles than PCP workers, and ultimately improve exposure estimates for future studies.


R. Vermeulen1, Q. Lan1, L. Gunn2, D. McCarthy3, G. Li4, L. Zhang2, N. Rothman1, M. T. Smith2.1Division of Cancer Epidemiology and Genetics, NCI, Rockville; 2School of Public Health, University of California, Berkeley, CA; 3Ciphergen Biosystems, Inc., Fremont, CA; 4National Institute of Occupational Health and Disease Control, CDC, Beijing, China

Introduction: Although benzene is an established human haematotoxin and leukaemogen, the health risk posed by occupational exposure to <10 ppm is uncertain. To better understand the risk benzene poses and to produce mechanistic insight in benzene’s toxicologic effects we examined the impact of benzene on the human plasma proteome in a study of healthy shoe factory workers with well characterised occupational exposure to benzene and unexposed controls.

Methods: Two sequential studies were performed, each using sera from 10 workers exposed to benzene (overall mean benzene air level >20ppm) and 10 controls. Samples were subjected to anion exchange fractionation and protein expression patterns were detected by SELDI-TOF-MS.

Results: In the first study, univariate statistical analysis yielded 18 protein peaks that presented a statistically significant difference in the average peak intensity between the exposed and non-exposed subjects (p <0.01). Three peaks with masses of 7.7, 9.3, and 4.1 kDa, identified as having the most significant p values in the first study, were also statistically significant in the second study (p values from 0.005 to 0.02). The 7.7 and 9.3 kDa proteins were identified as a truncated form of β-thromboglobulin and connective tissue activating peptide III, respectively.

Conclusions: Both proteins are N-terminal cleavage products of the platelet basic protein (PBP) and might indicate a decrease in PBP due to benzene exposure, which would be consistent with our previous observation that platelet and other peripheral blood cell counts were decreased among benzene exposed individuals compared with controls in the overall study of 390 subjects.



Y. E. Xibiao1, F. U. Hua1, N. I. Weimin2.1School of Public Health, Fudan University Shanghai, China; 2Central Hosptial of Yangpu District, Shanghai, China

Instruction: Lead has been a known toxicant for thousands of years, and it remains a persistent environmental health threat. Several groups have studied the effects of ALAD and VDR gene polymorphisms on blood lead levels and related toxicity; however, the study results were inconsistent. None of the former studies assessed the subjects’ cumulative exposure doses (external doses), and thus failed to present effects of gene polymorphisms on dose–response of lead toxicity.

Objective: To explore effects of ALAD and VDR gene polymorphisms on dose–response of lead toxicity.

Methods: All published papers have been reviewed and a meta-analysis has been conducted, focusing on blood lead level. In the present study, 216 lead exposed workers were included. A volume of 5 mL of venous blood was collected from each subject for blood lead measurement and genomic DNA isolation and serum analysis. Blood lead (BPb) levels were measured by flameless atomic absorption spectrophotometry. Urinary concentrations of lead (UPb),y α-aminolaevulinic acid (UALA),,N-acetyl-β-glucosaminidase (UNAG), and albumin (UALB) were adjusted by urine creatine. Biomarkers of reproductive toxicity (serum levels of luteinising hormone, testosterone, and follicle stimulating hormone) were measured. PCR-RFLP was used for genotyping. Blood was measured three times, with 5 minute intervals. Dose–response patterns were compared for subgroups with different genotypes.

Results: Meta-analysis showed that ALAD gene polymorphism could play a role in elevation of BPb level for a population with BPb level >25 ug/dl. In our study, BPb levels were 26.94 and 40.29 ug/dl (p>0.05) for ALAD11 and ALAD12 groups respectively, and 26.64 and 37.94 ug/dl (p>0.05) for VDRbb and VDRBb/BB groups respectively. Compared with the ALAD11 group, the ALAD12 group had larger elevations in kidney damage with increasing BPb level. Workers with the VDRB allele had larger elevations in systolic blood pressures with increasing BPb level than VDRbb genotypes. The ALAD12 group had a higher level of LH than ALAD11 (p = 0.05): 15.55 mIU/ml and 8.19 mIU/ml respectively. However,workers with VDRB allele had lower levels of luteinising hormone than VDRbb genotypes (3.26 mIU/ml and 9.38 mIU/ml) respectively (p<0.05). No differences were found for indicators of testosterone and follicle stimulating hormone.

Conclusions: Our analysis and study suggested that ALAD and VDR polymorphisms may change the pharmacokinetics and lead toxicity of kidney, blood pressure, and the reproductive system.


D. Echeverria1,2, J. S. Woods1,2, N. J. Heyer1, A. C. Bittner Jr1,2, F. M. Farin2.1Battelle CPHRE, Seattle, WA USA.; 2Dept. of Environmental Health, U of Washington, Seattle, WA USA

Introduction: Associations between BDNF and CPOX4 polymorphisms, mercury exposure, and reduced performance on behavioural performance were hypothesised.

Methods: Exposed subjects comprised 215 male dentists and 242 female dental assistants. Subjects provided buccal cell and spot urinary samples, and the Behavioral Evaluation for Epidemiologic Studies (BEES) Test Battery was administered. We evaluated DNA samples for the presence of BDNF and CPOX4 polymorphisms, and urinary samples for mercury concentration. Our analytical approach involved independent male and female multiple regression analyses to simultaneously evaluate associations between polymorphism status, mercury exposure, and performance on a battery of behavioural tests, controlling for age, alcohol and caffeine consumption, visual acuity, and vocabulary.

Results: Associations between mercury concentrations and performance were significant (p<0.05) for digit span, spatial span, symbol digit, finger tapping, and adaptive tracking among dentists, and for digit span, symbol digit, finger tapping and Trails B among dental assistants. Significant associations with BDNF included pattern memory and finger tapping among dentists and symbol digit among dental assistants. Significant associations with CPOX4 included pattern discrimination and finger tapping, Trails B, switching and vigilance among dentists and symbol digit among dental assistants. Virtually all effects were additive (no interactions between mercury exposure and polymorphisms).

Conclusions: Our observations support the hypothesis that BDNF and CPOX4 may be useful biological markers of susceptibility for behavioural outcomes. However, effects were predominantly observed among male dental assistants. This may be due to the greater uniformity of baseline performance among dentists.

Acknowledgement: Supported by ES04696 and ES07033.