Receptor-mediated toxicity

Ah-receptor-mediated toxicity is particularly associated with the highly toxic compound 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD), commonly referred to as dioxin. TCDD, and the concept of toxicity equivalency factors (TEFs) based on TCDDs, will be dealt with in Chapter 7. The main point to make at this juncture is that the toxicity of each individual coplanar congener in a mixture can be expressed in terms of a toxic equivalent calculated relative to the toxicity of dioxin. Summation of the toxic equivalents of the individual coplanar PCBs gives a measure of the toxicity of the whole mixture, as expressed through the Ah receptor mechanism. 

The toxicology of PCBs is complex and not fully understood. Coplanar PCBs interact with the Ah-receptor, with consequent induction of cytochrome P4501A1/2 and Ah-receptor-mediated toxicity. Induction of P4501A1 provides the basis of valuable biomarker assays, including bioassays such as CALUX. Certain PCBs, for example, 3,3, 4,4 -TCB, are converted to monohydroxymetabolites, which act as thyroxine antagonists. PCBs can also cause immunotoxicity (e.g., in seals). 

PCDDs and PCDEs, together with coplanar PCBs, can express Ah-receptor-mediated toxicity. TCDD (dioxin) is used as a reference compound in the determination of TEFs, which can be used to estimate TEQs (toxic equivalents) for residues of PHAHs found in wildlife samples. Biomarker assays for Ah-receptor-mediated toxicity have been based on the induction of P450 lAl. TEQs measured in field samples have sometimes been related to toxic effects upon individuals and associated ecological effects (e.g., reproductive success). 

Coplanar PCBs, PCDDs, and PCDFs express Ah-receptor-mediated toxicity (Chapter 6, Section 6.2.4). Binding to the receptor leads to induction of cytochrome P4501 and a number of associated toxic effects. Again, toxic effects are related to the extent of binding to this receptor and appear to be additive, even with complex mixtures of planar polychlorinated compounds. Induction of P4501A1/2 has been widely used as the basis of a biomarker assay. Residue data can be used to estimate TEQs for dioxin (see Chapter 7, Section 7.2.4). 

Particular attention is given to the development of new mechanistic biomarker assays and bioassays that can be used as indices of the toxicity of mixtures. These biomarker assays are typically based on toxic mechanisms such as brain acetylcholinesterase inhibition, vitamin K antagonism, thyroxin antagonism, Ah-receptor-mediated toxicity, and interaction with the estrogenic receptor. They can give integrative measures of the toxicity of mixtures of compounds where the components of the mixture share the same mode of action. They can also give evidence of potentiation as well as additive toxicity. 

Ah-receptor-mediated toxicity Toxic effects associated with the binding of polychlorinated aromatic componnds snch as coplanar PCBs and PCDDs to the Ah receptor. 

Zinc is important to the normal functioning of the central nervous system (CNS). At low concentrations, zinc protects mammalian brain neurons by blocking N-methyl-D-aspartate receptor-mediated toxicity. At high concentrations, zinc is a potent, rapidly acting neurotoxicant in the mammalian brain, as judged by zinc-induced neuronal injury of in vitro mature cortical cell cultures (Choi et al. 1988). Increased brain levels of zinc are associated with Pick s disease in certain strains of rodents with inherited epileptic seizures. Intravenous injection of zinc in rats with genetically inherited epilepsy produces seizures a similar response occurs with intracranial injection of zinc in rabbits with inherited audiogenic seizures (Choi et al. 1988). 

Villeneuve, D.L. Crunkilton, R.L. DeVita, W.M. 1997, Aryl hydrocarbon receptor-mediated toxic potency of dissolved lipophilic organic contaminants collected from Lincoln Creek, Milwaukee, Wisconsin, USA, to PLHC-1 (Poeciliopsis lucida) fish hepatoma cells. Environ. Toxicol. Chem. 16 977-984. 

The mechanism of toxic action of PBBs is not completely understood and no methods exist to block the toxic response due to exposure to PBBs. A more complete characterization of the cytosolic Ah receptor protein, to which some PBB congeners are thought to bind, and understanding of physiological effects of receptor blockage would be useful for the possible identification of blockers of Ah receptor-mediated toxic effects. Further studies aimed at elucidating the nonreceptor-mediated mechanism of action of some PBBs would also be valuable. 

TEF concept, were that TEFs may be useful for risk management (i.e., quantitative estimation of Ah receptor-mediated toxic potential) of mixtures of CDDs, CDFs and the coplanar non-ortho and monoortho PCBs, but that the TEF concept is not applicable for the various toxic responses whose mechanisms do not involve the Ah receptor (Ahlborg et al. 1992, 1994). 

The toxicity equivalent (TEQ) of TCDD is calculated by multiplying the exposure level of a particular dioxin-like compound by its toxicity equivalency factor(TEF). TEFs are based on congener-specific data and the assumption that Ah receptor-mediated toxicity of dioxin-like chemicals is additive. The TEF scheme compares the relative toxicity of individual dioxin-like compounds to that of TCDD. 

Prediction of receptor-mediated toxicity would require a training set based on other than short-term, primarily acute, standardized toxicity tests. 

Receptor-Mediated Toxicity QSARs for Estrogen Receptor Binding and Priority Setting of Potential... 

Ah-receptor mediated toxicity resulted in wide range of biological responses, including alterations in metabolic pathways, body weight loss, thymic atrophy, impaired immune responses, hepatotoxicity, chloracne and related skin lesions, developmental and reproductive effects, and neoplasia. 

TEFs are used in the risk assessment of substances with the same toxic mechanism as TCDD. By multiplying the concentration of each substance in a tissue with its TEF, the concentration of TCDD toxic equivalents (TEQ) can be estimated. It should be emphasized that the TEFs are based only on the Ah receptor mediated toxicity and the assumption that the toxic effects of TCDD-like substances are additive. Some of the toxic effects of PCNs are likely to be due to binding to the Ah receptor, but there are most probably also other independent mechanisms that influence the toxicity as well. 

Mydlineou C, Radcliffe P, Leonardi EK, Werner P, Olanow CW (1997) L-deprenyl protects mesencephalic dopamine neurons from glutamate receptor-mediated toxicity in vitro. J Neurochem 68 33-39. 

Receptor-Mediated Toxicity, Endocrine Disruption, and a Mechanistic SAR Analysis of PCB Toxicity... 

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