title: Immunosuppressive potential of several polycyclic aromatic hydrocarbons (PAHs) found at a Superfund site: new model used to evaluate additive interactions between benzo[a]pyrene and TCDD.
abstract: Exposure to environmental pollution is rarely limited to a single compound or even a single class of compounds. The Superfund site located in Massena, NY, is contaminated by both halogenated aromatic hydrocarbons (HAHs) and polycyclic aromatic hydrocarbons (PAHs). Since representatives of both HAHs and PAHs are capable of binding to the aromatic hydrocarbon receptor (AhR), two well-documented AhR-mediated effects, immunosuppression and induction of hepatic aryl hydrocarbon hydroxylase (AHH) activity, were used to evaluate the individual and interactive toxicity of these compounds. Fifteen PAHs were first screened for their ability to suppress the antibody response in C57BL/6 (Ah+/+) mice immunized 12 h after a single oral dose of 0.1, 1, 10, or 100 mg/kg. Acenaphthene, anthracene, benzo[g,h,i]perylene, fluoranthene, fluorene, naphthalene, phenanthrene, and pyrene had little or no effect. Seven PAHs caused > 50% suppression at 100 mg/kg. Listed in order of decreasing potency they were benzo[k]fluoranthene, benzo[b]fluoranthene, indeno[1,2,3,c,d]pyrene, benzo[a]pyrene, chrysene, dibenzo[a,h]anthracene, and benz[a]anthracene. Chrysene and benzo[a]pyrene (B[a]P), were further evaluated to determine the dependence of these effects on the Ah phenotype by comparing responses of C57BL/6 and congenic B6.D2 (Ah-/-) mouse strains. Chrysene immunosuppression was maximal at 0.1 mg/kg and was Ah phenotype-independent whereas chrysene AHH induction was Ah phenotype-dependent, but a 100-fold less sensitive indicator of exposure. In contrast, B[a]P immunosuppression and AHH induction were coincident in B6 mice and Ah phenotype-dependent. In the final phase, a new approach was used to evaluate toxic interactions. This approach considers the mechanism of action of each compound and accounts for the fact that the extent of increase in toxic response caused by an incremental change of dose is determined by its position on the dose-response curve rather than on the absolute amount of dose administered. Thus, the immunotoxic effects of combined exposure to B[a]P and the AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a representative HAH, were evaluated by combining the ED20 of B[a]P with the difference between the ED20 and ED40 of TCDD, and vice versa, to produce 40% suppression. The results of the combination were consistent with additivity regardless of the composite arrangement or phenotype although some antagonism could not be excluded with certainty.
authors.affiliation: Wadsworth Center for Laboratories and Research, New York State Department of Health, Albany 12201-0509, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Silkworth
authors.forename: T
authors.initials: T
authors.lastname: Lipinskas
authors.forename: C R
authors.initials: CR
authors.lastname: Stoner
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis; D001564:Benzo(a)pyrene / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004781:Environmental Exposure; D004790:Enzyme Induction; D006256:Hazardous Waste / Q000009:adverse effects*; D007108:Immune Tolerance / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000633:toxicity*; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011084:Polycyclic Aromatic Hydrocarbons / Q000633:toxicity*
chemical_list: D006256:Hazardous Waste; D007166:Immunosuppressive Agents; D000072317:Polychlorinated Dibenzodioxins; D011084:Polycyclic Aromatic Hydrocarbons; D001564:Benzo(a)pyrene; D001189:Aryl Hydrocarbon Hydroxylases