In this review, we have examined the biochemical and toxic responses produced by halogenated aromatic hydrocarbons and have tried to develop a model for their mechanism of action. These compounds bind to a cellular receptor and evoke a sustained pleiotropic response. In many tissues this response consists of the expression of a battery of enzymes which are, for the most part, involved in drug metabolism, but in other tissues, those which develop toxicity, an additional set of genes is expressed which effects cellular involution, division, and/or differentiation. The toxicity of these compounds appears to be due to the sustained expression of a normal cellular regulatory system, of which we were previously unaware. In future investigations it is hoped that we will learn the nature and physiologic role of this regulatory system. Only then can we hope to understand the mechanism of toxicity of these compounds.

2,3,7,8-Tetrachlorodibenzo-p-Dioxin and Related Halogenated Aromatic Hydrocarbons: Examination of the Mechanism of Toxicity

Polycyclic aromatic hydrocarbon (PAH) biodegradation was investigated in contaminated soils from two different industrial sites under simulated land treatment conditions. Soil samples from a former impregnation plant (soil A) showed high degradation rates of PAHs by the autochthonous microorganisms, whereas PAHs in material of a closed-down coking plant (soil B) were not degraded even after inoculation with bacteria known to effectively degrade PAHs. As rapid PAH biodegradation in soil B was observed after PAHs were extracted and restored into the extracted soil material, the kind of PAH binding in soil B appears to completely prevent biodegradation. Sorption of PAHs onto extracted material of soil B follows a two-phase process (fast and slow); the latter is discussed in terms of migration of PAHs into soil organic matter, representing less accessible sites within the soil matrix. Such sorbed PAHs are suggested to be non-bioavailable and thus non-biodegradable. By eluting soil B with water, no biotoxicity, assayed as inhibition of bioluminescence, was detected in the aqueous phase. When treating soil A analogously, a distinct toxicity was observed, which was reduced relative to the amount of activated carbon added to the soil material. The data suggest that sorption of organic pollutants onto soil organic matter significantly affects biodegradability as well as biotoxicity.

Adsorption of polycyclic aromatic hydrocarbons (PAHs) by soil particles: influence on biodegradability and biotoxicity

This article reviews the present state of the art regarding the toxicokinetics and metabolism of polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs). The absorption, body distribution, and metabolism can vary greatly between species and also may depend on the congener and dose. In biota, the 2,3,7,8-substituted PCDDs and PCDFs are almost exclusively retained in all tissue types, preferably liver and fat. This selective tissue retention and bioaccumulation are caused by a reduced rate of biotransformation and subsequent elimination of congeners with chlorine substitution at the 2,3,7, and 8 positions. 2,3,7,8-Substituted PCDDs and PCDFs also have the greatest toxic and biological activity and affinity for the cytosolic arylhydrocarbon (Ah)-receptor protein. The parent compound is the causal agent for Ah-receptor-mediated toxic and biological effects, with metabolism and subsequent elimination of 2,3,7,8- substituted congeners representing a detoxification process. Congener-specific affinity of PCDDs and PCDFs for the Ah-receptor, the genetic events following receptor binding, and toxicokinetics are factors that contribute to the relative in vivo potency of an individual PCDD or PCDF in a given species. Limited human data indicate that marked species differences exist in the toxicokinetics of these compounds. Thus, human risk assessment for PCDDs and PCDFs needs to consider species-, congener-, and dose-specific toxicokinetic data. In addition, exposure to complex mixtures, including PCBs, has the potential to alter the toxicokinetics of individual compounds. These alterations in toxicokinetics may be involved in some of the nonadditive toxic or biological effects that are observed after exposure to mixtures of PCDDs or PCDFs with PCBs.

The toxicokinetics and metabolism of polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) and their relevance for toxicity.

Health effects of polybrominated dibenzo-p-dioxins (PBDDs) and dibenzofurans (PBDFs)

The risk to human health posed by contaminated soil in a residential area depends on the potential extent of exposure to soil and on the toxic properties of the contaminants. A detailed soil exposure analysis is presented for young children, older children, and adults living in a house surrounded by contaminated soil. From this analysis, a lifetime exposure model is derived and used to assess chronic health risks.

Assessment of health risk from exposure to contaminated soil

Influence of solvents and adsorbents on dermal and intestinal absorption of TCDD

Biotransformation products of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) excreted in dog and rat bile were isolated and examined by combined gas chromatography-mass spectrometry (GC-MS). In the dog, hydroxylation of the TCDD molecule at the lateral position with shift of a chlorine atom to the peri-position and chlorine displacement were found to be the main routes of metabolism. The major metabolite formed was 2-hydroxy-l,3,7,8-tetrachlorodibenzo- p-dioxin. Dihydroxy-trichlorodibenzo-p-dioxins were also identified as well as metabolites formed via cleavage of one or both ether bonds. In the rat, only one metabolite has been characterized so far. It was tentatively identified as a tetrachlorodihydroxy-diphenyl ether. At least one additional metabolite was present which has not yet been investigated. A preliminary metabolic breakdown scheme of TCDD is presented.

Structure elucidation of mammalian TCDD-metabolites.

Apart from its high toxicity, the chemical stability and persistence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the environment bring about additional hazards. However, until now there has been no evidence for degradation of this dioxin in biological systems, and it is considered unusual that a compound which is insusceptible to biological attack should be so extremely toxic. In in vitro studies with microsomal preparation from mouse, rat and rabbit liver, as well as in vivo, no metabolite of TCDD has been detected by several workers. Recent data, showing a lower toxicity of TCDD in rats after stimulation of the hepatic mixed-function oxidase, suggested possible metabolic transformation of this compound. In the present study, we used tritiated TCDD to search for metabolites in the bile of rats and found marked changes in lipophilicity and mobility in TLC of the excreted radioactivity. Treatment with diazomethane yielded at least two new compounds. These observations hinted at the formation of phenolic hydroxyl groups in the dioxin molecule.

Biological degradation of TCDD in rats.

1. Three pentachlorodibenzofurans (23478-, 12378- and 12348-penta-CDF) were prepared by isomer-specific syntheses and administered to bile duct-cannulated rats in single oral doses. All three compounds were metabolized and metabolites excreted in the bile.2. Metabolites were identified by g.l.c.-mass spectrometry after clean-up and methyl-ation of bile samples. Phenolic metabolites (identified as methyl ether derivatives) were formed from all three penta-CDFs by aromatic hydroxylation or by hydrolytic dechlorination. Cleavage of the ether bond with formation of a biphenyl derivative was observed with 23478-penta-CDF; from this compound small amounts of a sulphur-containing metabolite were also formed.3. All three penta-CDFs followed a common metabolic pathway but differed in the distribution of the metabolites. 12348-CDF was biotransformed more efficiently than the two other isomers. Unmetabolized penta-CDFs were also excreted in the bile.

H. Poiger

Papers

Influence of solvents and adsorbents on dermal and intestinal absorption of TCDD

Structure elucidation of mammalian TCDD-metabolites.

Biological degradation of TCDD in rats.

The metabolism of some pentachlorodibenzofurans in the rat.

Acute oral toxicity of TCDD-metabolites in male guinea pigs.