Toxicity and Mechanisms of Toxicity of HHCs

HHCs exert specific or broad-spectrum effects on living organisms. They can be acutely lethal or exert subchronic and chronic toxic effects, such as developmental (terato-genic), hormonal (endocrine disruptors), carcinogenic, neurotoxic, immunotoxic, and neurobehavioral effects.

Haloethylenes undergo epoxidation by P4502E1 and form oxiranes depending on halogen substituents, which are highly reactive and bind covalently to DNA. Compared to ethylene oxide, vinyl chloride and vinyli-dene chloride, with increasing chlorination, show an increase in bond strength of the chlorinated carbon to the oxygen and a decrease in the bond strength to non-chlorinated carbon. The asymmetric chloroethylenes are more carcinogenic than symmetrical ones because the bond breakage potentiates covalent bonding to DNA. There are limits to the effectiveness of highly reactive species, for example, weak carcinogenic activity of vinyl chloride may be due to instability of its putative metabolite (1,1-dichloroxirane), which is likely to be degraded rapidly. The less reactive oxiranes are more DNA binding.

Glutathione conjugates of several haloalkanes in liver are converted to cysteine conjugates in kidney, where their episulfonium ions bind covalently to DNA and proteins leading to nephrotoxicity and carcinogenicity. Vinyl chloride and bromide are genotoxic and carcinogenic. Trichloroethylene is not carcinogenic in liver while vinylidene chloride is. Dichloromethane is a central nervous system (CNS) depressant and may even suppress normal inspiration via this route. It is metabolized to CO, which forms COHb and HCHO (which can react with DNA). Chloroform affects liver and causes renal epithelial tumors. Its metabolite phosgene covalently binds to liver proteins and depletes hepatocyte GSH. Carbon tetrachloride forms trichloromethyl, trichloromethylperoxy, and chlorine-free radicals, which can attack unsaturated bonds of fatty acids in the endoplasmic reticulum leading to lipid peroxidation and membrane damage. It causes centrilobular necrosis and fatty liver.

In experimental mammals, HHCs that cause fatty liver without necrosis include chlorobromomethane, dichloro-methane, «'/-1,2-dichloroethylene, tetrachloroethylene, and 2-chloroethylene. Those HHCs which cause fatty liver and necrosis include carbon tetrachloride, carbon tetraiodide, carbon tetrabromide, bromotrichloromethane, chloroform, iodoform, bromoform, 1,1,2,2-tetrachloroethane, 1,2-dichloroethane, 1,2-dichloromethane, 1,1,1-trichlor-oethane, 1,1,2-trichloroethylene, 2-chloro-»-propane, and 1,2-dichloro-p-propane. Those HHCs which cause no liver hypertrophy but only necrosis are methylene chloride, methyl bromide, methyl iodide, dichlorodifluoromethane, tra»s-1,2-dichloroethylene, ethylene chloride, ethyl bromide, ethyl iodide, and »-butylchloride.

Aliphatic HHC insecticides can be neurotoxic (which inhibit GABA-A1 chloride ion channels in brain and ATP-ases in axons), respiratory poisons, endocrine dis-ruptors, teratogens, carcinogens, etc. Some ofthese HHCs can cause liver enlargment and induction of cytochrome P-450 isozymic forms, mostly P4502B.

Aromatic halogens and polyaromatic HHCs also cause hepatic hypertrophy and induction of P450 isozymes, both P4501A and 2B. This induction of P4501A is mediated via transport of these HHCs by cytosolic Ah receptor (AHR, a member of the basic-helix-loop-helix/ per, ARNT/AHR, SIM homology (bHLH/PAS) protein) inside the nucleus where heterodimer ARNT (Ah-recep-tor nuclear translocator) binds to specific nucleotide recognition sequence on regulatory region of the target gene DNA (dioxin response element, DRE). This leads to altered gene expression and results in hepatotoxicity, carcinogenicity, teratogenicity, etc. These and other responses are highly tissue, sex, age, and species specific. Differences in ARNT domain may be responsible for differential gene expression and altered sensitivities of strains and species, as well as to differences in genomic sequence at promoter and enhancer region. The gene expression of AHR and ARNT during embryonic development is stage and tissue specific. AHR mRNA appears in fetal mouse tissue between gestation days (GDs) 10 and 16. In DRE-lacZ mouse model, AHR is present in several developing tissues including genital tubercle, palate, and paws. In a transgenic mice model, the TCDD exposure i» utero at GD 14.5 induced lacZ expression in the mesench-ymal epithelium of developing paws and alteration in gene expression profile were observed after 24 h.

In liver cells of rats exposed subchronically for 13 weeks to AHR agonists TCDD (toxicity equivalent factor, TEF = 1), pentachlorobenzofuran (TEF = 0.5), 3,3',4,4',5-pentachlorobiphenyl (TEF = 0.1) several genes exhibited altered expression. Out of these genes, Serpia 7 (27-fold),

Cyp3a13 (1000-fold), and Ces3 (fivefold) were downregu-lated. PCB126 and -153 had no effects but their mixture mimicked TCDD downregulation of 11 genes. Gender-and species-specific repression occurred within this subset of genes. In AHR knockout mice, seven of the 11 genes were downregulated. This early downregulation is followed by upregulation and liver carcinogenesis. 1» utero exposure of mice to TCDD upregulates amphiregulin (one of the epidermal growth factor signaling ligand) gene expression in fetal ureter. In mice, disruption of AHR signaling by TCDD decreases body weight and fecundity, and causes liver defects and disruption of cardiac and vascular development.

The a-, ¿3/7-, and 6-isoforms of the nuclear hormone receptor superfamily of ligand-activated transcription factors (peroxisome proliferator activated receptors) respond to perfluorooctanoic acid and perfluorooctane sulfonate (in vivo and i» utero) and alter gene expression in various tissues during development and in adults leading to developmental toxicity and other adverse effects.

Tetrachloroazo- and tetrachloroazoxybenzenes inhibit adrenocorticotropic hormone release and affect thymus and other lymphatic systems. Toxic potency of congeners of polychlorinated aromatics is usually compared with that of TCDD and expressed as 'dioxin equivalent factor'. DEF depends on the coplanarity and chlorination in para-and meta-positions. The net toxicity of the PCB mixtures depends on these coplanar congeners, whose concentration in most commercial mixtures is very low. The DEF is reflective of the affinity of the congener for the cytosolic AHR causing its activation. The increased synthesis of the CYPIA1 gene product P4501A1 increases the catalysis (hydroxylation) of coplanar HHCs. The interaction of HHCs with AHR initiates a constellation of effects, such as thymic atrophy, hypo- and/or hypertrophy of liver, chloracne, wasting, teratogenesis, etc. TCDD is 40-400 times more potent than other halogenated aromatics in binding with AHR. The non-AHR-type effects include hepatomegaly, induction of Phase II enzymes, and por-phyria. However, the acute lethality of TCDD and other halogenated aromatics is dependent on species. In the case of PCBs, the confromational restrictions and hydro-xylations are important in their estrogenic activity. Porpyhria-related diseases are species specific and frequently slow to develop. These polyhalogenated aromatics and their metabolites are, also, potent inducers of 6-aminolevolunic acid synthase, the rate-limiting enzyme of porphyrin synthesis.

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