INTERACTIVE EFFECTS OF 3 STRUCTURALLY DIFFERENT POLYCHLORINATED-BIPHENYLS IN A RAT-LIVER TUMOR PROMOTION BIOASSAY

Interactive effects between the non-ortho-substituted 3,3', 4,4',5-pen tachlorobiphenyl (PCB126), the mono-ortho-substituted 2,3,3',4,4'-pent achlorobiphenyl (PCB105), and the di-ortho-substituted 2,2',4,4',5,5'- hexachlorobiphenyl (PCB153) were studied in an initiation/promotion bi oassay. Female Sprague-Dawley rats were injected with 30 mg/kg ip of N -nitroso-diethylamine 24 h after partial hepatectomy. Five weeks later , weekly sc administrations of the three PCBs in 15 systematically sel ected dose combinations started. After 20 weeks of administration, the animals were killed and the livers were analyzed for areas expressing placental glutathione-S-transferase as a marker of preneoplastic foci . In addition, concentration of liver and kidney retinoids and plasma retinol was analyzed, as well as body and organ weights, plasma transa minases, and induction of hepatic cytochrome P450 1A1/2 (CYP1A1/2) and CYP2B1/2 activities. Data were analyzed with a multivariate method. A t the doses applied in this study, weak antagonism was observed betwee n PCB126 and PCB153 for effects on volume fraction of foci, number of foci/cm(3), concentration of plasma retinol and liver retinoids, relat ive liver weight, and induction of CYP2B1/2 activity. Weak antagonism was also observed between PCB126 and PCB105 for effects on volume frac tion of foci, number of foci/cm(3), and plasma retinol concentration. No interactions other than pure additivity were observed between PCB10 5 and PCB153. Synergism was not observed within the dose ranges invest igated in this study. Knowledge of interactive effects is important fo r risk assessment of environmental mixtures of dioxin-like compounds. Antagonism between congeners generally results in risk assessments tha t overestimate human risk. The significance to human risk assessment o f the relatively weak antagonism observed in this study is however unc lear, considering many other uncertainties involved in the toxic equiv alency factor (TEF) concept. A change of the TEF concept for risk asse ssments of dioxin-like substances is not motivated based on the result s of this study. (C) 1998 Academic Press.