Toxicity of mixtures of polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls determined by dose-response curve analysis.

Abstract

Polyhalogenated aromatic hydrocarbons (PHAH) such as polychlorinat ed dibenzop-dioxins (PCDD), dibenzofurans (PCDF), and biphenyls (PCB) are persistent environmental pollutants, that bioaccumulate throughout the food chain and may pose a health risk to humans and animals (Safe 1994). The most toxic and most studied PHAH is 2,3,7,8-TCDD. PCDD, PCDF, and PCB elicit a number of common biologic and toxic effects in laboratory animals and mammalian cells in culture. The induction of hepatoma microsomal EROD or the associated cytochrome P450 isoenzymes is one of the most characteristic and sensitive response. The toxic mechanism is mediated through combining with the arylhydrocarbon (Ah) receptor (Poland and Knutson 1982; Safe 1990; Whitlock 1993). Since biota in the environment is exposed to mixtures of these compounds rather than to a single congener, simultaneous or sequential exposure of organism to two or more of these compounds may alter quantitative and qualitative biological responses. Therefore, studies with mixtures could provide more information about the possible interactive effects between these compounds and the fundamental mechanisms behind these interactive effects. The concept of independent action, which is sometimes termed effect multiplication, is based on agents acting on different molecular target sites only. An evaluation of tendency and degree of over or under estimation of mixture toxicity can be done by comparative analysis of dose-additive and independent action. The new approach is the use of doseresponse curves (DRC) for evaluating observed combined effects with respect to additive as well as to independence (Poch 1993; Poch et al. 1995). This model and analysis method occasionally are applied in pharmacologic al studies. In general, the simplest cost and time saving approach is to do a dose-response study with a substance A alone and in the presence of a fixed dose of a “similarly” acting substance B. This method is proved can provide a rather simple procedure for obtaining evidence of magnitude and mechanism of action. The aim of the present study was to evaluate the combined effects of 2,3,7,8