Contribution of exposure and genetics to the development of beryllium sensitization and chronic beryllium disease

Beryllium is a low-density metal with unique properties used in a number of industries including automotive, electronics, communications, medical, defense, and aerospace. Workers exposed to aerosols generated by the fabrication of beryllium-containing materials are at risk for developing beryllium sensitization (BeS) and chronic beryllium disease (CBD). Several studies have identified at least one genetic host factor, a glutamic acid at position 69 (E69) of the HLA-DPB1 gene, that increases individual susceptibility to BeS and CBD. This dissertation research was designed to evaluate the relationship between beryllium exposure and E69 in the risk of BeS and CBD.;In Chapter 2, the combined risk of BeS and CBD was evaluated as a function of beryllium exposure and carriage of any E69 genotype in a case-control study of current and former workers from a U.S. nuclear weapons production facility, the Y-12 National Security Complex (Oak Ridge, TN). Those with both risk factors had additive odds for BeS/CBD (OR 38.0, 95% CI: 6.02--240). The study demonstrated that HLA-DPB1 E69 carriage and high exposure to beryllium appeared to be additive risk factors for the development of BeS and CBD. In addition, from this study, it appeared that the magnitude of risk associated with either elevated beryllium exposure or carriage of E69 was similar.;In Chapter 3, the risk of BeS and CBD was evaluated separately as a function of beryllium exposure and specific E69 genotype in a case-control study of former workers from a decommissioned U.S. nuclear weapons production facility, Rocky Flats Environmental Technology Site (RFETS, Arvada, CO). Study participants included 70 individuals with BeS, 61 with CBD, and 255 controls with potential beryllium exposure. For this study, beryllium exposures were assessed through a combination of worker interviews and assessment of task exposures based on facility-specific and industry-wide industrial hygiene exposure measurements. This study showed that different HLA-DPB1 E69 alleles or more than one copy of an E69 allele may confer differential risk of BeS and CBD. Lifetime weighted beryllium exposure conferred an approximate two-fold increased odds of CBD (OR: 2.22, 95% CI: 1.21--4.07) regardless of E69 genotype again suggesting an additive relationship between E69 and exposure. Beryllium exposure was not a significant predictor of BeS.;The study in Chapter 4 compared three different, but related, retrospective exposure assessment methods applied to the participants of the case-control study in Chapter 3. Beryllium exposures for each participant were assessed using three different methods: (1) a traditional job exposure matrix (JEM method) that assigned beryllium exposures at the job title level based on interviews with a few workers in each job title and assessment of available industrial hygiene exposure measurements for this job title; (2) individual worker interviews evaluating the tasks each worker performed followed by "expert" assessment of task exposures by two industrial hygienists based solely on professional judgment (IH rating method) as was used in Chapter 2 of this dissertation, and; (3) individual worker interviews as described in ;Taken together, the three studies confirm the importance of both beryllium exposure and E69 genotype in the risk of CBD suggesting an additive relationship between the two. Furthermore, it appears that BeS and CBD risk is differentially distributed among E69 genotypes with carriers of rarer non-*02 E69 alleles at higher risk. These studies also provide additional evidence on the importance of extremely low beryllium exposures in the risk of BeS even after adjusting for genetic susceptibility. Finally, the studies provide evidence to validate a more efficient exposure assessment method based on task exposures assessed using "expert" industrial hygiene assessment rather than resource-intensive compilation and analysis of thousands of exposure measurements. (Abstract shortened by UMI.)...