Interactive effects of three structurally different polychlorinated biphenyls in a rat liver tumor promotion bioassay.
Interactive effects between the non-ortho-substituted 3,3', 4,4', 5-pentachlorobiphenyl (PCB126), the mono-ortho-substituted 2,3,3',4, 4'-pentachlorobiphenyl (PCB105), and the di-ortho-substituted 2,2',4, 4',5,5'-hexachlorobiphenyl (PCB153) were studied in an initiation/promotion bioassay. Female Sprague-Dawley rats were injected with 30 mg/kg ip of N-nitrosodiethylamine 24 h after partial hepatectomy. Five weeks later, weekly sc administrations of the three PCBs in 15 systematically selected 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 transaminases, and induction of hepatic cytochrome P450 1A1/2 (CYP1A1/2) and CYP2B1/2 activities. Data were analyzed with a multivariate method. At the doses applied in this study, weak antagonism was observed between PCB126 and PCB153 for effects on volume fraction of foci, number of foci/cm3, concentration of plasma retinol and liver retinoids, relative liver weight, and induction of CYP2B1/2 activity. Weak antagonism was also observed between PCB126 and PCB105 for effects on volume fraction of foci, number of foci/cm3, and plasma retinol concentration. No interactions other than pure additivity were observed between PCB105 and PCB153. Synergism was not observed within the dose ranges investigated in this study. Knowledge of interactive effects is important for risk assessment of environmental mixtures of dioxin-like compounds. Antagonism between congeners generally results in risk assessments that overestimate human risk. The significance to human risk assessment of the relatively weak antagonism observed in this study is however unclear, considering many other uncertainties involved in the toxic equivalency factor (TEF) concept. A change of the TEF concept for risk assessments of dioxin-like substances is not motivated based on the results of this study.
Haag-Grönlund
M
M
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, S-171 77, Sweden. Marie.Haag.Gronlund@imm.ki.se
Johansson
N
N
Fransson-Steen
R
R
Hâkansson
H
H
Scheu
G
G
Wärngård
L
L
D000818:Animals; D001835:Body Weight; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D019362:Cytochrome P-450 CYP2B1 / Q000096:biosynthesis; D004052:Diethylnitrosamine / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D005982:Glutathione Transferase / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D009929:Organ Size; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012176:Retinoids / Q000097:blood
D012176:Retinoids; C067940:2,3,3',4,4'-pentachlorobiphenyl; D004052:Diethylnitrosamine; D011078:Polychlorinated Biphenyls; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D005982:Glutathione Transferase; C023035:3,4,5,3',4'-pentachlorobiphenyl; C014024:2,4,5,2',4',5'-hexachlorobiphenyl