The mechanism of dioxin toxicity: relationship to risk assessment.

Abstract

Risk characterization involves hazard identification, determination of dose-response relationships, and exposure assessment. Improvement of the risk assessment process requires inclusion of the best available science. Recent findings in the area of dioxin toxicity have led to a major effort to reassess its risk. 2,3,7,, commonly referred to as "dioxin," is the most toxic member of a class of related chemicals including the polyhalogenated dibenzo-p-dioxins, dibenzofurans, biphenyls, naphthalenes, azo-and azoxy-benzenes, whose toxicities can be expressed as fractional equivalencies of TCDD. These chemicals exert their effects through interaction with a specific intracellular protein, the Ah receptor. While binding to the receptor is necessary, it is not sufficient to bring about a chain of events leading to various responses including enzyme induction, immunotoxicity, reproductive and endocrine effects, developmental toxicity, chloracne, tumor promotion, etc. Some of these responses appear to be linear at low doses. Immunotoxicity and effects on the reproductive system appear to be among the most sensitive responses. The Ah receptor functions as a transcriptional enhancer, interacting with a number of other regulatory proteins (heat shock proteins, kinases, translocases, DNA binding species). Interaction with specific base sequences in the DNA appear to be modulated by the presence of other growth factors, hormones, and their receptors as well as other regulatory proteins. Thus, dioxin appears to function as a hormone, initiating a cascade of events that is dependent upon the environment of each cell and tissue. While Ah receptor variants exist, all vertebrates examined have demonstrated such a protein with similar numbers of receptors and binding affinity for TCDD. Most species respond similarly to dioxin and related compounds. While a given species may be an outlier for a given response, it will behave like other animals for other responses. For both in vivo and in vitro end points where animal and human data exist, such as enzyme induction, chloracne, immunotoxicity, developmental toxicity, and cancer, the sensitivity of humans appears similar to that of experimental animals. Current levels of environmental exposure to this class of chemicals may be resulting in subtle responses in populations at special risk such as subsistence fisherman and the developing infant, as well as in the general population. Increased understanding of the mechanism of dioxin's effects as well as elucidation of exposure-dose relationships is leading to the development of a biologically based dose-response model in the ongoing process of incorporating the best science into the risk assessment of TCDD and related compounds.-Environ Health Perspect 102(Suppl 9) 157-167(1994)

2,3,7,8-Tetrachlorodibenzo-p-dioxin induces apoptotic cell death and cytochrome P4501A expression in developing Fundulus heteroclitus embryos

“…TCDD is a teratogen and developmental toxicant in many species but is especially potent at inducing hydronephrosis and cleft palate in mouse embryos (Birnbaum, 1994). TCDD can also affect the endocrine and reproductive systems (Peterson et al, 1993;Birnbaum, 1994;Heimler et al, 1998), as well as the development of other organ systems (Sakamoto et al, 1995;Henshel, 1998;MacLusky et al, 1998).…”

Aryl Hydrocarbon Receptor Activation Impairs the Priming but Not the Recall of Influenza Virus-Specific CD8+ T Cells in the Lung

“…The pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin) is used as a model AhR agonist because of all the AhR agonists identified to date, it has the highest binding affinity, and has been used for the majority of studies characterizing the consequences of AhR activation (6,(11)(12)(13)(14). Although very little is known about the endogenous function of the AhR in the immune system, TCDD has a very profound effect on immune function.…”

Long-Term Toxic Impact of 2,3,7,8-Tetrachlorodibenzo-p-dioxin on the Reproduction, Sexual Differentiation, and Development of Different Life Stages of Gobiocypris rarus and Daphnia magna

“…There is no mechanistic explanation for the sex ratio change with TCDD. The observation, however, may support the hypothesis that dioxin modi"es hormonal balance (Birnbaum, 1994;Mocarelli et al, 1996). It has been reported that 4-tert-pentylphenol caused feminization and intersex in genetically all-male carp, with oocytes embodied in testis (Gimeno et al, 1996).…”