Isomers and metabolites of the organochlorine pesticide chlordane persist in the environment and bioaccumulate in Arctic marine food webs. Rodent studies indicate that there are gender-related differences in trans-nonachlor and oxychlordane metabolism. Thus, comparative tissue depletion studies were undertaken in male and female rats exposed to trans-nonachlor, oxychlordane, or trans-chlordane at 2.5 mg/kg body weight/d by gavage for 28 d followed by two consecutive 28-d depletion periods. None of the test chemicals were overtly toxic at this dose, although increased liver weights in some groups were consistent with microsomal enzyme induction. The metabolite oxychlordane accumulated in tissues from rats exposed to trans-nonachlor and trans-chlordane. trans-Nonachlor and oxychlordane residue levels were highest in tissues from female rats at each time point; however, trans-chlordane was completely eliminated from males and females by the end of the study. Body burden calculations showed no significant clearance of oxychlordane in females over 56 d postdosing, whereas males lost approximately half their oxychlordane body burden in the same period. For the chiral contaminants oxychlordane and trans-chlordane, tissues from male and female rats were selectively depleted of the (+)-enantiomer; however, there were gender-related differences in enantiomer depletion patterns over time. In general, residue analyses confirmed that gender-related metabolic differences and contaminant structural properties, including chirality, influenced chlordane contaminant elimination from rat tissues. The study points to a need for similar knowledge of gender-related responses in humans in order to provide relevant dietary recommendations for populations exposed to chlordane-related contaminants in foods.

The chlordane constituent trans-nonachlor and its metabolite oxychlordane are among the most persistent chlordane-related contaminants and are found in tissues and milk from humans ingesting diets high in Arctic marine mammal fat. Although chlordane is no longer registered in North America, there is a need for toxicological data on chlordane-related contaminants found in food and the environment which are either structurally different or relatively more abundant than the constituents of the original chlordane mixture. Thus, a feeding study was undertaken to provide toxicological data on trans-nonachlor. Male and female Sprague-Dawley rats were exposed to 0, 5, 13 or 50 ppm trans-nonachlor in feed for 90 days and clinical, hematological and histopathological changes were assessed in each rat. Female rats were less able than males to metabolize and eliminate trans-nonachlor and, as a result, accumulated more trans-nonachlor in their adipose tissues. trans-Nonachlor, like technical chlordane and other organochlorines, induced liver microsomal enzymes in a pattern similar to phenobarbital. Endocrine effects included functional and morphological changes in the thyroid and adrenals. In male rats exposure to trans-nonachlor was associated with changes in endpoints indicative of increased oxidative stress, which may be related to both direct action on cellular targets or to secondary effects resulting from cytochrome P450 induction. The results indicate that subchronic trans-nonachlor exposure in rats induced hepatic changes with far-reaching metabolic and endocrine effects. Differences in target organ responses in male and female rats indicate that the sex-related metabolic differences affecting trans-nonachlor bioaccumulation and elimination merit further study.

Due to widespread usage of the pesticide chlordane until the 1980's, this toxic and persistent mixture has accumulated in the food chain. The Arctic acts as a global sink for these and other persistent organic pollutants, which bioaccumulate in the marine and freshwater food chains. As a result, humans consuming diets high in Arctic fish and marine mammal fat can ingest higher levels of chlordane contaminants than humans consuming "southern" diets. The most abundant constituents of the chlordane mixture are trans-chlordane, cis-chlordane, trans-nonachlor, cis-nonachlor and heptachlor; oxychlordane is the major metabolite of the chlordanes and nonachlors. In humans the predominant chlordane-related contaminants detected in breast milk and adipose tissues are trans-nonachlor and oxychlordane. The present studies were undertaken to provide toxicological data on oxychlordane for the purpose of clarifying target organ toxicity and risks to human health associated with ingesting contaminated foods. Female rats were gavaged with oxychlordane at doses ranging from 0.01 to 10 mg/kg body weight/day for up to 28 days. In terms of general toxicity oxychlordane had a steep dose-response curve: 10 mg/kg oxychlordane was acutely toxic and 1 mg/kg oxychlordane caused no measurable effects. Weight loss, reduced feed consumption and thymic atrophy were the hallmarks of acute oxychlordane toxicity. At lower doses rats showed signs of hepatic changes indicative of microsomal enzyme induction. Oxychlordane was more bioaccumulative and was toxic at levels approximately 8 times lower than trans-nonachlor and cis-nonachlor. Thus, ingestion of trans-nonachlor and related chlordane contaminants in foods results in the formation of a metabolite that is more toxic and bioaccumulative than the parent contaminants.

Tissues were obtained from three separate experiments in order to quantify the tissue distribution of organochlorine chemicals that are thought to be potential reproductive toxicants in males: 1) Sprague Dawley rats received 1 microCi of 14C-Aldrin or 14C-Dieldrin (20.6 microCi/micromole) i.p. once a week for three weeks. One week and four weeks after the last injection, tissues were harvested and stored at -80 degrees C. Tissue 14C levels were quantified by scintillation spectrometry. 2) Cis- or trans-nonachlor (0, 0.25, 2.5, 25 mg/kg body weight) were administered daily in corn oil to male rats by gavage for 28 days. Tissues were harvested and frozen at -80 degrees C on the 29th day. Organochlorine residues were extracted and quantified by gas chromatography with electron capture detection. 3) Technical grade toxaphene (0, 0.1, 0.4 or 0.8 mg/kg body weight) was ingested daily by female cynomolgus monkeys of reproductive age for 18 months prior to being mated with control males. Dosing continued during pregnancy and lactation. Their infants received toxaphene via breast milk, and upon weaning, they ingested the same dose as their mothers for 48 to 49 weeks until, at 77 to 80 weeks of age, tissues were harvested and stored at -80 degrees C. Organochlorine residues were extracted and quantified as previously stated. In all three experiments, organochlorine residues in the testis were lower than in most of the other reproductive tract and nonreproductive tract tissues we examined. For example, testicular aldrin and dieldrin levels were <5% the epididymal content; testicular cis- and trans-nonachlor were <25% the epididymal content and, testicular toxaphene levels were <15% of the epididymal content. The reasons for the low degree of accumulation by the testis in comparison with other tissues are unknown. However, the lower testicular content may afford germ cells some protection from the potentially toxic effects of these chemicals.