Biological and Toxicological Responses to Dioxins Exposures

The identification of the Aryl hydrocarbon Receptor (AhR) [Poland et al., 1982] and the finding that it mediates the toxic effects of 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD), has stimulated a large number of studies and posed several questions that, in some cases, have not yet led to a definitive conclusion. For this reason, the classification of the responses to exposure to low doses of dioxins as biological or toxicological is still arbitrary. For example, the induction of gene expression, controlled by AhR, of specific enzymes capable, in turn, to interact with other transcription factors and membrane receptors, is considered by some as an adaptive response, which is necessary to minimize the toxicity of ubiquitous environmental contaminants, and by others as a toxicological damage that can lead to a number of pathological conditions, including some extremely serious. Recently, a consistent amount of evidence indicated that some functions of the immune system might be AHR-dependent [Stevens et al., 2009]. 

Indeed, activation of the AHR signalling pathway seems to promote both differentiation of the regulatory T-cells (Treg) and proliferation of the T-helper 17 (Th17) cells, thus inducing immunosuppression and inflammation (through increased secretion of inflammatory cytokines), respectively [Kimura et al., 2008; Quintana et al., 2008; Stevens et al., 2009]. AhR is a transcriptional regulator that is highly conserved during the evolution. It is expressed in vertebrates and in invertebrates and it is linked to different functions. For example, in the nematode worm Caenorhabditis elegans AhR is involved in nervous system development, while in Drosophila it plays a role in the growth of the antennae, legs and in the colour vision [Schmidt et al., 1996]. In mammals, the physiological functions of AhR came mainly from studies in knockout mice [Schmidt et al., 1996; Fernandez-Salguero et al., 1997; Mimura et al., 1997]. These genetically modified mice, in which the expression of the AhR gene is deleted, show a reduced fertility, a lower liver volume presumably due to a vascular defect [Schmidt et al., 1996], and portal fibrosis. 

The high degree of AhR conservation along the evolutionary scale and the observations conducted on mice with mutant phenotypes suggest that this receptor has a role beyond that of mediating the toxicity of xenobiotics. Recent studies have suggested, in fact, that the toxicity mediated by dioxins may reflect the dysregulation of the endogenous function of AhR. These substances, very persistent and stable, could lead to prolonged and inappropriate stimuli, causing a sort of continuous and improper activation of the AHR-dependent signal transduction [Stockinger, 2009; Stevens et al., 2009].

 TCDD is the most studied congener of dioxins, which include both the family of polychlorinated dibenzodioxins (PCDDs) and that of polychlorinated dibenzofurans (PCDFs), and other dioxin-like environmental contaminants, such as polychlorinated biphenyls-(PCB). Because of their wide dispersal and long persistence in the environment, these substances have generated great interest not only in scientific research but also in the general population, as a consequence of environmental contamination episodes due to industrial accidents (Seveso, 1976) or food contamination (Belgian chickens, June 1999).

 Experimental studies on animals and on human cell lines, in addition to epidemiological studies conducted on populations accidentally exposed to dioxins, have revealed that the toxic responses are species-specific and are related to AhR polymorphism. In the case of human exposure to high-dose, the most commonly observed physio-pathological response is the chloracne [JECFA, 2001; Sorg et al., 2009]. This has been also confirmed by the monitoring of the Seveso population, which was exposed to high doses of dioxins in 1976 for the explosion of a reactor of the chemical industry ICMESA [Bertazzi et al., 1996].

The exposure to high doses shows an epidemiological association with other non-cancer health effects, such as an increased activity of hepatic enzymes, cardiovascular diseases, diabetes, thyroid dysfunction, effects on growth. However, most of these effects, such as chloracne, appear only at doses higher of several orders of magnitude than those to which humans are normally exposed (background of food contamination) [JECFA, 2001]. Finally, in studies focusing on high dose exposures, the pattern of exposure does not reflect that of studies accounting for low dose exposures and long term diet.