Evaluation of three beryllium sequestering agents by isothermal titration calorimetry

Occupational exposure to beryllium may cause Chronic Beryllium Disease (CBD), a granulomatous interstitial pneumonitis. Molecular epidemiological studies indicate charge interaction between beryllium and a specific MHC class II human leukocyte antigen as a factor in disease susceptibility. Therefore, increased research efforts are focusing on the development of a CBD treatment by chelation therapy. In this work, we use direct and competitive isothermal titration calorimetry methods to evaluate the chelation potential of three organic chelators: nitrilotriacetic acid (NTA), nitrilotripropionic acid (NTP) and 4,5-dihydroxy-1,3-benzene disulphonate (Tiron). We first validate the use of competitive ITC to measure association constants <= 10(3) M-1 using a Be2+-Ca2+-EDTA(4-) system. Data of direct and competitive titrations were analyzed using the Origin (R) scientific plotting software. We obtained an intrinsic association constant of 3.2 (+/- 1.6) x 10(12) M-1 for the beryllium-Tiron complex, 9.4 (+/- 1.2) x 10(13) M-1 for beryllium-NTP and 1.1 (+/- 1.1) x 10(7) M-1 for beryllium-NTA. NTP and Tiron form more stable complexes with beryllium than NTA.