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

Exposure to environmental pollution is rarely limited to a single comp ound or even a single class of compounds. The Superfund site located i n Massena, NY, is contaminated by both halogenated aromatic hydrocarbo ns (HAHs) and polycyclic aromatic hydrocarbons (PAHs). Since represent atives of both HAHs and PAHs are capable of binding to the aromatic hy drocarbon receptor (AhR), two well-documented AhR-mediated effects, im munosuppression and induction of hepatic aryl hydrocarbon hydroxylase (AHH) activity, were used to evaluate the individual and interactive t oxicity of these compounds. Fifteen PAHs were first screened for their ability to suppress the antibody response in C57BL/6 (Ah(+/+)) mice i mmunized 12 h after a single oral dose of 0.1, 1, 10, or 100 mg/kg. Ac enaphthene, anthracene, benzo[g,h,i]perylene, fluoranthene, fluorene, naphthalene, phenanthrene, and pyrene had little or no effect. Seven P AHs caused > 50% suppression at 100 mg/kg. Listed in order of decreasi ng potency they were benzo[k]fluoranthene, benzo[b]fluoranthene, inden o[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 furth er evaluated to determine the dependence of these effects on the Ah ph enotype by comparing responses of C57BL/6 and congenic B6.D2 (Ah(-/-)) mouse strains. Chrysene immunosuppression was maximal at 0.1 mg/kg an d was Ah phenotype-independent whereas chrysene AHH induction was Ah p henotype-dependent, but a 100-fold less sensitive indicator of exposur e. In contrast, B[a]P immunosuppression and AHH induction were coincid ent in B6 mice and Ah phenotype-dependent. In the final phase, a new a pproach was used to evaluate toxic interactions. This approach conside rs 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 cur ve 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 ED(20) of B[a]P with the difference betwee n the ED(20) and ED(40) of TCDD, and vice versa, to produce 40% suppre ssion. The results of the combination were consistent with additivity regardless of the composite arrangement or phenotype although some ant agonism could not be excluded with certainty.