Hepatic sequestration of chlordecone and hexafluoroacetone evaluated by pharmacokinetic modeling.

Chlordecone (CD) and mirex (M) differ by a single carbonyl group in CD in place of two chlorines in M. Although both compounds are lipophilic, their tissue distributions differ markedly: CD concentrations are highest in liver; M concentrations are highest in fat. We used tissue time course data in rats from our laboratory for CD and M and literature data from monkeys to develop PBPK models to study differences in liver and fat partitioning. The PK model for M had partitioning in tissue without specific hepatic binding. The CD model had partitioning similar to M, and also included liver binding: the maximal binding (B(max)) and binding affinity constant (Kd) required to describe the rat data were 370 nmol/g liver and 100 nM, respectively. To see if other ketones with electron withdrawing constituents at the alpha carbon were also preferentially distributed to liver, we developed a PBPK description for tissue distribution of hexafluoroacetone (HFA). Compared to acetone, HFA is known to be preferentially sequestered in liver and more slowly excreted unchanged from the body. Acetone is more equally distributed to tissues. HFA distribution was evaluated with a PBPK model that included hepatic binding. B(max) and Kd were 1.58 micromol/g liver and 301 microM. In summary, liver sequestration of CD and HFA most likely represents relatively high-affinity but reversible binding of activated carbonyls in these compounds (activated by the presence of electron withdrawing substituents on the alpha-carbons) with glutathione and glutathione transferases, that are present at much higher concentrations in liver than in other tissues. Strong, but reversible hemithioketal formation with active sulfhydryls may also be associated with the toxic responses to CD and HFA.

Nondigestible oligosaccharides do not increase accumulation of lipid soluble environmental contaminants by mice.

Supplementing diets with nondigestible fibers that are fermented by the gastrointestinal tract bacteria increases the dimension and absorptive capacities of the small intestine; we hypothesized that this would increase the accumulation of environmental contaminants. This was tested by feeding mice for 6-8 wk diets with fiber at two levels (0 and 100 g/kg) and from different sources (cellulose, lactosucrose, polydextrose, indigestible dextrin, inulin) before a 2-wk oral exposure to (14)C-labeled mirex or methylmercury in combination with (3)H-labeled retinol. Concentrations of contaminants and retinol were measured in urine and feces collected for the last 2 d of exposure and in seven tissues (small and large intestine, brain, liver, kidneys, gastrointestinal tract mesentery, gall bladder). Mice fed the same diets, but not exposed to the contaminants, were used for routine microbiology of alimentary canal contents, measurements of intestinal dimensions and in vitro rates of glucose, mirex, methylmercury and retinol absorption by the small intestine. Mice fed the diets with nondigestible oligosaccharides had higher densities of anaerobic bacteria and larger small and large intestines, but did not have greater rates of contaminant absorption or accumulation. Mice exposed to methylmercury accumulated less retinol than mice exposed to mirex. Although diets with nondigestible oligosaccharides fibers reduce accumulation of environmental contaminants, but not retinol, the specific responses vary among tissues, sources of fiber and contaminants. The mechanisms responsible for the influence of nondigestible oligosaccharides can include reduced absorption, increased fecal elimination and transformation to forms that are excreted in the urine.

ATSDR evaluation of health effects of chemicals. II. Mirex and chlordecone: health effects, toxicokinetics, human exposure, and environmental fate.

This document provides public health officials, physicians, toxicologists, and other interested individuals and groups with an overall perspective of the toxicology of mirex and chlordecone. It contains descriptions and evaluations of toxicological studies and epidemiological investigations and provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health. Additional substances will be profiled in a series of manuscripts to follow.

Minimal role of enhanced cell proliferation in skin tumor promotion by mirex: a nonphorbol ester-type promoter.

Mirex, a chlorinated hydrocarbon previously used as a systemic insecticide and flame retardant, is a nongenotoxic hepatocarcinogen in both rats and mice. In liver, mirex induced biochemical responses and hyperplasia characteristic of increased cell proliferation, which is consistent with its role as a liver tumor promoter. We have recently shown that mirex is a potent nonphorbol ester-type skin tumor promoter in 7, 12-dimethylbenz[a]anthracene (DMBA)-initiated mice. However, unlike its effect in liver, a single topical application of mirex to skin does not induce the acute biochemical responses, such as increased epidermal DNA synthesis and ornithine decarboxylase activity, indicative of increased cell proliferation. Multiple topical applications of mirex over a 1 month period induced only a minimal increase in the number of epidermal nucleated cell layers, which contrasts with definitive hyperplasia induced by a comparable tumor-promoting dose of 12-O-tetradecanoylphorbol-13-acetate (TPA). Collectively, these data indicated that mirex is promoting through a novel mechanism. Further evidence that mirex promotes tumors through a mechanism distinct from that of the prototypical skin tumor promoter, TPA, was obtained by examining the effect of their simultaneous co-treatment. The co-application of mirex and TPA yielded a tumor multiplicity greater than the sum of the responses of each promoter individually. In summary, our results demonstrate that mirex, a carcinogenic and hyperplastic agent in liver, is also a very effective tumor promoter in mouse skin, but suggest that mirex operates via a novel mechanism in skin that may involve only a minimal role for enhanced cell proliferation.

Acute hepatotoxicity and lethality of CCl4 in chlordecone-pretreated rats.

In a subchronic dietary pretreatment protocol chlordecone (CD) is a powerful potentiator of CCl4 hepatotoxicity, as indicated by biochemical, hepatofunctional, histopathological, and lethality parameters. The purpose of this investigation is to further explore the CD + CCl4 interaction in an acute CD pretreatment protocol and to compare the two pretreatment protocols in terms of their effect upon quantitative histopathology, serum enzymes, and lethality. Groups of four male rats received one of the following four pretreatments: chlordecone (10 mg/kg; single po), mirex (10 mg/kg; single po), phenobarbital (PB) (80 mg/kg/day for 2 successive days; ip in 0.9% saline), or corn oil vehicle (1 ml/kg; single po). Twenty-four hours later, the rats were given a single ip injection of CCl4 (0.1 ml/kg). Twenty-four hours after CCl4 administration, serum enzymes (SGPT, SGOT, and ICD) were measured and the livers removed and fixed in 10% buffered formalin for histological evaluation. The LD50 were determined by the method of moving averages. CD + CCl4 was the most hepatotoxic combination, in terms of serum enzyme elevations and lethality followed by PB + CCl4. The PB + CCl4 combination caused a greater degree of hepatocyte necrosis. These findings indicate that the acute pretreatment with CD enhances hepatotoxicity and the lethality of CCl4 in a fashion qualitatively similar to the subchronic pretreatment protocol.

Liver protein synthesis and catabolism in mirex-pretreated rats with enlarging livers.

Incorporation and retention of [14C]amino acids in protein were studied in rats with enlarging livers. Rats were injected (i.v.) with 20 mg of mirex per kg b. wt. to stimulate liver enlargement with a concomitant and proportional increase in liver total protein. Eighteen hours later, mirex-pretreated and control rats received an i.p. dose of a L-[14C]amino acid mixture and were killed at predetermination intervals up to 48 hr. Mirex-pretreated rats incorporated [14C]amino acids into liver protein at the same rate as controls, but retained more of the radiolabeled amino acids in liver protein for a longer time. In a second experiment, (14C]bicarbonate was substituted for the amino acid mixture to determine whether differences in [14C]amino acid retention were due to reutilization or mobilization. The change in protein metabolism, which leads to an almost 2-fold increase in liver total protein within 66 hr, appears to be due to a decrease in the quantity of protein catabolized per unit time rather than an increase in the rate of protein synthesized.