Development of a neurotoxic equivalence scheme of relative potency for assessing the risk of PCB mixtures.

PCBs produce adverse effects in humans and animals by several modes of action. The first mode of action is binding of coplanar or mono-ortho-PCBs to the aryl hydrocarbon (Ah) receptor leading to effects associated with the activation of this receptor. The remaining PCB congeners do not activate this receptor and have different modes of action underlying their toxic effects. One mode of action that has been shown for di-ortho-substituted non-coplanar PCBs (PCB congeners with two or more chlorines in the ortho-positions) is the interference with intracellular signaling pathways dependent on Ca(2+) homeostasis and the resulting cellular, organ-level and organismal effects. The ortho-substituted non-coplanar congeners produce other cellular or organ-level effects including changes in protein kinase C translocation, changes in cellular dopamine (DA) uptake, formation of reactive oxygen species, and thyroid effects. Here, we propose a scheme for developing relative potency estimates (REP) for the PCB congeners not considered in the TEF scheme used to assess the toxicity of coplanar and mono-ortho-PCBs and chlorinated dioxins and furans. Because a number of the modes of action listed here for the ortho-substituted non-coplanar PCB congeners have been implicated in the neurotoxic effects of these PCBs congeners, this relative potency scheme is referred to here as the Neurotoxic Equivalent (NEQ) scheme for estimating toxicity of PCB mixtures. The Neurotoxic Equivalent (NEQ) values are developed in a way similar in concept to the derivation of the well-known TEF congener values. Although this scheme is in its infancy and the set of NEQ values are limited by the current data, there are several compelling reasons for proposing such a scheme now. First, it should open discussions as to how different modes of action can be utilized to predict congener potency differences for the effects they produce. Second, consideration and evaluation of the ability of the proposed NEQ scheme to predict the toxicity of PCB mixtures will assist in the identification of the specific modes of action relevant to the effects produced by non-coplanar PCBs. If other modes of action are suggested and subsequently identified, then other schemes of relative potency could be developed specifically for those modes of action, distinct from either the TEF scheme or the NEQ scheme. Knowing these other modes of action and the relative toxicity of the various congeners would advance our understanding of PCB toxicology and thereby ultimately improve our ability to estimate the toxic potency of PCB mixtures for each identified mode of action. Third, a quantitative scheme for assessing the toxicity of the non-coplanar PCB congeners present in a mixture has the potential to improve significantly future risk assessments of PCB mixtures.