Relative potency based on hepatic enzyme induction predicts immunosuppressive effects of a mixture of PCDDS/PCDFS and PCBS

• Published in: Toxicology and applied pharmacology 2008-03, Vol.227 (3), p.477-484
• Main Authors: Smialowicz, R.J., DeVito, M.J., Williams, W.C., Birnbaum, L.S.
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; ANIMAL TISSUES; Animals; ANTIBODIES; Antibody Formation - drug effects; Antibody response; Benzofurans - toxicity; Biological and medical sciences; Body Weight - drug effects; Cytochrome P-450 CYP1A1 - analysis; Cytochrome P-450 CYP1A1 - metabolism; Cytochrome P-450 CYP1A2 - analysis; Cytochrome P-450 CYP1A2 - metabolism; Dibenzofurans, Polychlorinated; DIOXIN; Dose-Response Relationship, Drug; DOSE-RESPONSE RELATIONSHIPS; ENZYME ACTIVITY; ENZYME INDUCTION; ERYTHROCYTES; Erythrocytes - immunology; Female; FURANS; Immune Tolerance - drug effects; Immunotoxicity; LIVER; Liver - drug effects; Liver - enzymology; LUNGS; Medical sciences; MICE; Mice, Inbred Strains; Mouse; Organ Size - drug effects; PCB; PCDF; PFC; POLYCHLORINATED BIPHENYLS; Polychlorinated Biphenyls - toxicity; Polychlorinated Dibenzodioxins - analogs & derivatives; Polychlorinated Dibenzodioxins - toxicity; Relative potency; SHEEP; SKIN; SPLEEN; TCDD; THYMUS; TOXICITY; Toxicology
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2007.11.018

The toxic equivalency factor (TEF) approach was employed to compare immunotoxic potency of mixtures containing polychlorinated dibenzo- p-dioxins, polychlorinated dibenzofurans and polychlorinated biphenyls relative to 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD), using the antibody response to sheep erythrocytes (SRBC). Mixture-1 (MIX-1) contained TCDD, 1,2,3,7,8-pentachlorodibenzo- p-dioxin (PeCDD), 2,3,7,8-tetrachlorodibenzofuran (TCDF), 1,2,3,7,8-pentachlorodibenzofuran (1-PeCDF), 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF), and 1,2,3,4,6,7,8,9-octachlorodibenzofuran (OCDF). Mixture-2 (MIX-2) contained MIX-1 and the following PCBs, 3,3′,4,4′-tetrachlorobiphenyl (IUPAC No. 77), 3,3′,4,4′,5-pentachlorobiphenyl (126), 3,3′,4,4′,5,5 N-hexachlorobiphenyl (169), 2,3,3′,4,4′-pentachlorobiphenyl (105), 2,3′,4,4′,5-pentachlorobiphenyl (118), and 2,3,3′,4,4′,5-hexachlorobiphenyl (156). The mixture compositions were based on relative chemical concentrations in food and human tissues. TCDD equivalents (TEQ) of the mixture were estimated using relative potency factors from hepatic enzyme induction in mice [DeVito, M.J., Diliberto, J.J., Ross, D.G., Menache, M.G., Birnbaum, L.S., 1997. Dose–response relationships for polyhalogenated dioxins and dibenzofurans following subchronic treatment in mice. I .CYP1A1 and CYP1A2 enzyme activity in liver, lung and skin. Toxicol. Appl. Pharmacol. 130, 197–208; DeVito, M.J., Menache, G., Diliberto, J.J., Ross, D.G., Birnbaum L.S., 2000. Dose–response relationships for induction of CYP1A1 and CYP1A2 enzyme activity in liver, lung, and skin in female mice following subchronic exposure to polychlorinated biphenyls. Toxicol. Appl. Pharmacol. 167, 157–172] Female mice received 0, 1.5, 15, 150 or 450 ng TCDD/kg/day or approximately 0, 1.5, 15, 150 or 450 ng TEQ/kg/day of MIX-1 or MIX-2 by gavage 5 days per week for 13 weeks. Mice were immunized 3 days after the last exposure and 4 days later, body, spleen, thymus, and liver weights were measured, and antibody response to SRBCs was observed. Exposure to TCDD, MIX-1, and MIX-2 suppressed the antibody response in a dose-dependent manner. Two-way ANOVA indicated no differences in the response between TCDD and the mixtures for body weight, spleen/body weight and decreased antibody responses. The results support the use of the TEF methodology and suggest that immune suppression by dioxin-like chemicals may be of concern at or near background human exposures.