Persistent organic pollutant residues in human fetal liver and placenta from Greater Montreal, Quebec: a longitudinal study from 1998 through 2006.

BACKGROUND: There is general concern that persistent organic pollutants (POPs) found in the environment, wildlife, food, water, house dust, human tissues, and fluids may alter normal human physiologic activities (e.g., fetal development, immune and endocrine systems). Although the levels of some POPs [polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCs)] in these matrices have decreased after their ban, others [polybrominated diphenyl ethers (PBDEs)] have increased in recent years. OBJECTIVE: To determine the longitudinal trend of specific POPs in human fetal tissues for risk assessment purposes. METHODS: We analyzed early to mid-gestation fetal liver (n = 52) and placental (n = 60) tissues, obtained after elective abortions during 1998-2006, for selected PBDEs, PCBs, and OCs using gas chromatography-mass spectroscopy. RESULTS: Total PBDEs in fetal liver increased over time (mean +/- SE: 1998, 284.4 +/- 229.8 ng/g lipid; 2006, 1,607.7 +/- 605.9; p < 0.03), whereas placental levels were generally lower, with no clear trend. Low levels of PCBs and OCs varied yearly, with no evident trend. The major analytes in 1998 were OCs (liver, 49%; placenta, 71%), whereas the major analytes in 2006 were PBDEs (liver, 89%; placenta, 98%). The 1998-2006 tissue PBDE congener profile is similar to that of DE-71, a commercial primarily pentabrominated diphenyl ether mixture manufactured in North America. CONCLUSIONS: Although commercial production of penta- and octa-brominated diphenyl ethers in North America was halted in 2004, their concentrations in fetal liver and placenta are now greater than the tissue burdens for the analyzed OCs and PCBs. Our findings also demonstrate that PBDEs accumulate within the fetal compartment at a very early stage in gestation.

Enantioselective and gender-dependent depletion of chlordane compounds from rat tissues.

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.

Toxicity of trans-nonachlor to Sprague-Dawley rats in a 90-day feeding study.

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.

Assessing human polychlorinated biphenyl contamination for epidemiologic studies: lessons from patterns of congener concentrations in Canadians in 1992.

Humans are always exposed to mixtures of polychlorinated biphenyls (PCBs), so assessment of their health effects is complicated. Because the original sources are relatively standard mixtures that change in predictable ways while traversing the environment, there is substantial uniformity in the congener mixtures people carry. To the extent that concentrations are highly correlated, measuring multiple congeners within correlated groups would be unnecessary and estimation of separate biologic effects would be impossible. We examined correlation patterns in previously collected data on 38 congeners (and 14 other organochlorines) from 497 human milk samples from Canada from 1992. Congeners 138, 153, 156, 157, 170, 183, 187, 194, 199, and 203 were highly intercorrelated; 180 had slightly lower correlations with this group. Congeners 74, 105, and 118 were highly intercorrelated and moderately to highly correlated with the first group. Congener 99 had moderate correlations with both these groups, and congener 66 had lesser correlations with the primary group. In contrast, congeners 28, 44, 49, 60, 90/101, 128, 137, and 193 showed little correlation with any other congeners. The remaining 14 congeners were uninformative; they were quantified in fewer than 30% of samples, and varying lipid concentrations meant that those quantified were not necessarily at higher concentrations than those not quantified. In study of human health effects of PCBs, the congener pattern present in the population under study should be examined when deciding which congeners to measure; instead of solely redundant or uninformative congeners, attention should be given to other congeners that may be more useful in addressing the question of interest.

Gestational exposure to persistent organic pollutants: maternal liver residues, pregnancy outcome, and effects on hepatic gene expression profiles in the dam and fetus.

Dietary exposure of Inuit people to a mixture of pesticides and polychlorinated biphenyls, or persistent organic pollutants (POPs), during pregnancy is a public health concern. We examined the consequences of administering the mixture of 28 POPs found in the Inuit diet (at doses representing 10-1000 times dietary levels) by gavage to pregnant Sprague-Dawley rats either during gestation days 0-19 or 8-19. The levels of individual components of the POPs mixture in the maternal liver were measured by high-resolution mass spectrometry. On gestation day 20, dams were sacrificed and pregnancy outcome determined. RNA isolated from maternal and fetal livers was 32P-labeled for gene expression profiling. The concentrations of individual POPs were increased in maternal livers of dams gavaged with the 1000x POPs mixture by 10- to 500-fold. While exposure to POPs had no significant effects on pregnancy outcome, dramatic changes were observed in the gene expression profiles of both the maternal and fetal livers. The gene expression profiles of maternal and fetal female and male liver were distinct with respect to the numbers of transcripts detected, the genes expressed exclusively in control or POPs-exposed livers, and those for which expression was up- or downregulated. While different genes were affected in each group, the overall consequence of POPs exposure on hepatic gene expression profiles was to decrease both the numbers of genes expressed and the relative intensity of expression. Thus, in utero exposure to POPs alters hepatic gene expression in the dam and the fetus; these changes may have functional implications.

Toxicity of the chlordane metabolite oxychlordane in female rats: clinical and histopathological changes.

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.