Comparison of the Dose Addition and Response Addition Models Assessing the Hepatotoxic Interaction Between the Water Disinfection By-Products Chloroform (CHCL3) and Bromodichloromethane (BDCM)
Creators: name: Keegan, Thomas E.
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 1996

description: CHCl3, and BDCM are the two most prevalent chlorination disinfection by-products, occurring ubiquitously in treated drinking water. The potential human health risk posed by chemical mixtures is due to the possibility of synergistic (greater than additive) interactions. The additivity assumption may be tested by either response addition (1+1=2) or dose addition (D[1]/D[x1] + D[2]/D[x2]=1 where D[x1] and D[x2] are isoeffective (equitoxic) doses and D[1] and D[2] are the concentrations in the mixture). Although response addition has been used more frequently to study noncancer health effects, the appropriateness of its use for two active chemicals has been questioned. The objective of this study was to use the dose addition and response addition models to assess and to compare interactive hepatotoxicity, and to estimate NOAELs and LOAELs for both chemicals after concurrent exposure to CHCl3 and BDCM given orally in an aqueous vehicle to Fischer-344 rats (-90 days old). Hepatotoxicity was assessed 24 hr later by serum alanine (ALT) and aspartate (AST) aminotransferase and sorbitol dehydrogenase (SDH). For dose addition assessment, rats were gavaged with various dosages of CHCl3 or BDCM alone (based on prior dose-response curves) and mixtures of CHCl3 + BDCM. At 0.50 mmol/kg, where CHCl3 and BDCM were equitoxic, a 1:1 mixture (0.25 mmol CHCl3/kg:0.25 mmol BDCM/kg) did not deviate significantly from additivity for ALT, AST ancl SDH. At 1.0 mmol/kg, where CHCl3 and BDCM were also equitoxic, a 1:1 mixture did not deviate significantly from additivity for ALT, AST and SDH. BDCM and CHCl3 were also equitoxic at 1.5 mmol/kg; a 1:1 mixture (0.75 mmol CHCl3/kg:0.75 mmol BDCM/kg did not deviate from additivity in one experiment although dosage ratios of 2:1 (1.0 mmol CHCl3/kg:0.5 mmol BDCM/kg) and 1:2 (0.5 mmol CHCl3/kg:1.0 mmol BDCM/kg) were significantly less than additive at p=0.05, but not at p=0.01, in another. At 3.0 mmol/kg, where CHCl3 and BDCM were isoeffective for AST and SDH, nonadditivity was not detected for dosage ratios of 2:1 and 1:2. In a repeat experiment, at this same dosage, where CHCl3 and BDCM were isoeffectlve for ALT and AST, dosage ratios of 1:1, 1:2 and 2:1 did not deviate significantly from additivity. For response addition assessment, rats were gavaged with dosages of either: CHCl3 alone; BDCM alone; or, a combination of CHCl3 + BDCM in the same concentrations that were administered alone. Statistical significance was not observed for the following dosage combinations: 0.25 mmol CHCl3/kg + 0.25 mmol BDCM/kg; 0.50 mmol CHCl3/kg + 0.50 mmol BDCM/kg; 0.75 mmol CHCl3/kg + 0.75 mmol BDCM/kg; and 1.00 mmol CHCl3/kg + 1.00 mmol BDCM/kg. However, for 1.50 mmol CHCl3/kg + 1.50 mmol BDCM/kg, significant deviations from additivity were detected, showing a synergistic interaction for ALT and AST. In contrast, 3.00 mmol CHCl3/kg + 3.00 mmnol BDCM/kg produced significant deviations from additivity, showing antagonistic interactions for all three hepatotoxic markers. In sum: within the dosage range examined, 0.25 mmol/kg is estimated to be the LOAEL for both CHCl3 and BDCM with the NOAEL postulated to be very close to this number; and, synergistic interactions between CHCl3 and BDCM were not found with the dose additive model, whereas both synergy and antagonism were observed with the response addition model at higher dosages.