Historical intake and elimination of polychlorinated biphenyls and organochlorine pesticides by the Australian population reconstructed from biomonitoring data.

Quantifying the competing rates of intake and elimination of persistent organic pollutants (POPs) in the human body is necessary to understand the levels and trends of POPs at a population level. In this paper we reconstruct the historical intake and elimination of ten polychlorinated biphenyls (PCBs) and five organochlorine pesticides (OCPs) from Australian biomonitoring data by fitting a population-level pharmacokinetic (PK) model. Our analysis exploits two sets of cross-sectional biomonitoring data for PCBs and OCPs in pooled blood serum samples from the Australian population that were collected in 2003 and 2009. The modeled adult reference intakes in 1975 for PCB congeners ranged from 0.89 to 24.5ng/kgbw/day, lower than the daily intakes of OCPs ranging from 73 to 970ng/kgbw/day. Modeled intake rates are declining with half-times from 1.1 to 1.3years for PCB congeners and 0.83 to 0.97years for OCPs. The shortest modeled intrinsic human elimination half-life among the compounds studied here is 6.4years for hexachlorobenzene, and the longest is 30years for PCB-74. Our results indicate that it is feasible to reconstruct intakes and to estimate intrinsic human elimination half-lives using the population-level PK model and biomonitoring data only. Our modeled intrinsic human elimination half-lives are in good agreement with values from a similar study carried out for the population of the United Kingdom, and are generally longer than reported values from other industrialized countries in the Northern Hemisphere.

Biomonitoring equivalents for hexachlorobenzene.

Recent efforts worldwide have resulted in a growing database of measured concentrations of chemicals in blood and urine samples taken from the general population. However, few tools exist to assist in the interpretation of the measured values in a health risk context. Biomonitoring equivalents (BEs) are defined as the concentration or range of concentrations of a chemical or its metabolite in a biological medium (blood, urine, or other medium) that is consistent with an existing health-based exposure guideline. This study reviews available health-based exposure guidance values for hexachlorobenzene (HCB) from Health Canada, the United States Environmental Protection Agency (US EPA), the US Agency for Toxic Substances and Disease Registry (ATSDR) and World Health Organization (WHO). HCB liver tissue concentrations in chronic rodent bioassays and information on human elimination rates and tissue distribution of HCB were extrapolated to estimate serum lipid-adjusted HCB concentrations that are consistent with the exposure guidance values for HCB. Estimated serum lipid-adjusted HCB concentrations ranging from 16 to 250 ng/g lipid were consistent with non-cancer-based exposure guidance values from various agencies. Concentrations associated with cancer risk-specific doses at target risk levels of interest were also estimated. These BE values may be used as screening tools for evaluation of population biomonitoring data for HCB in a risk assessment context and can assist in prioritization of the potential need for additional risk assessment efforts for HCB relative to other chemicals.

Effects of aging and sediment composition on hexachlorobenzene desorption resistance compared to oral bioavailability in rats.

Studies were conducted to assess the effects of black carbon, clay type and aging (1-1.5yr) on desorption and bioavailability of hexachlorobenzene (HCB) in spiked artificial sediments. Tenax (a super sorbent)-mediated desorption was used to examine the effects of these parameters on the physicochemical availability of HCB. The Tenax-mediated desorption of HCB from the four aged artificial sediments exhibited biphasic kinetics. The fast desorbing fractions ranged from 64.8% to 22.3%, showing reductions of 4.0-18.9% compared with freshly-spiked sediments. Statistical analysis on the fast desorbing fractions showed that all three treatment effects (i.e., montmorillonite clay, black carbon content, and aging) were significant. Two sediments with higher black carbon content exhibited much greater aging effects (i.e., greater reduction in fast desorbing fraction) than the other two sediments without the addition of black carbon. For both freshly-spiked and aged sediments, the desorption resistant sediment-bound HCB (i.e., slow desorbing fraction) correlated reasonably well to previously reported rat fecal elimination of HCB, which is a measure of the non-bioavailable fraction of sediment-bound HCB. A similar correlation was also observed between fast desorbing fraction and previously reported accumulation of HCB in the rat body (carcass+skin). These observations suggest that physicochemical availability, as defined by the desorption of HCB from sediments, provides a reasonable prediction of the oral bioavailability of sediment-bound HCB to rats. These results showed that montmorillonite clay, black carbon and aging reduced physicochemical availability and ultimately bioavailability of sediment-bound HCB.

Selective bioaccumulation of chlorinated pesticides and metabolites in Arctic seabirds.

Chlorinated pesticides and metabolites (CPs) were quantified in the seabird species: little auk (Alle alle), Brünnich's guillemot (Uria lomvia), black guillemot (Cepphus grylle) and black-legged kittiwake (Rissa tridactyla). The purpose was to evaluate avian accumulation of selected CPs based on their concentrations and relative patterns, their relation to dietary descriptors (stable isotopes of carbon and nitrogen), to enzymes involved in biotransformation, as well as CPs' accumulation potential relative to the recalcitrant polychlorinated biphenyl PCB-153. In all species, the CP pattern was dominated by p,p'-dichlorodiphenyltrichloroethane (DDE) and hexachlorbenzene (HCB). Except for HCB, concentrations were not related to trophic position. Most CPs were quantified in black guillemot, indicating a slower elimination compared to other seabird species. Brünnich's guillemot showed efficient elimination of chlordanes, whereas the opposite was found for little auk. Kittiwake showed higher accumulation of persistent CP and metabolites than auks, whereas accumulation of less recalcitrant CPs was low.

Toxicity of hexachlorobenzene and its transference from microalgae (Chlorella kessleri) to crabs (Chasmagnathus granulatus).

The aim of this work was to study the transference of hexachlorobenzene from a green alga (Chlorella kessleri) to an estuary crab (Chasmagnathus granulatus), and to analyze the toxic effects that the xenobiotic has on the latter. The effect of hexachlorobenzene uptake was evaluated measuring oxidative stress, Uroporphyrinogen decarboxylase activity and morphometric parameter alteration, and also performing a histological analysis of crab hepatopancreas. Results demonstrated that hexachlorobenzene enters the alga, is accumulated in it, and then transferred into the crab, causing a decrease in Uroporphyrinogen decarboxylase activity in both organisms. The high malondialdehyde levels detected in crab hepatopancreas after the toxic treatment suggested the existence of hexachlorobenzene-induced lipid peroxidation. Antioxidant defenses such as superoxide dismutase activity and reduced glutathione content fell below normal values on the fourth week of treatment. At the same time, the hepatosomatic index, used as a morphometric parameter, reduced 20% with respect to the control. The histological analysis revealed epithelium disorganization in hepatopancreas tubules, confirming the existence of structural damage caused by hexachlorobenzene.

An updated physiologically based pharmacokinetic model for hexachlorobenzene: incorporation of pathophysiological states following partial hepatectomy and hexachlorobenzene treatment.

Physiologically based pharmacokinetic (PBPK) modeling is generally used for describing xenobiotic disposition in animals and humans with normal physiological conditions. We describe here an updated PBPK model for hexachlorobenzene (HCB) in male F344 rats with the incorporation of pathophysiological conditions. Two more features contribute to the distinctness of this model from the earlier published versions. This model took erythrocyte binding into account, and a particular elimination process of HCB, the plasma-to-gastrointestinal (GI) lumen passive diffusion (i.e., exsorption), was incorporated. Our PBPK model was developed using data mined from multiple pharmacokinetic studies in the literature, and then modified to simulate HCB disposition under the conditions of our integrated pharmacokinetics/liver foci bioassay. This model included plasma, erythrocytes, liver, fat, rapidly and slowly perfused compartments, and GI lumen. To account for the distinct characteristics of HCB absorption, the GI lumen was split into an upper and a lower part. HCB was eliminated through liver metabolism and the exsorption process. The pathophysiological changes after partial hepatectomy, such as alterations in the liver and body weights and fat volume, were incorporated in our model. With adjustment of the transluminal diffusion-related parameters, the model adequately described the data from the literature and our bioassay. Our PBPK model simulation suggests that HCB absorption and exsorption processes depend on exposure conditions; different exposure conditions dictate different absorption and exsorption rates. This model forms a foundation for our further exploration of the quantitative relationship between HCB exposure and development of preneoplastic liver foci.

Adipose tissue concentrations of p,p'-DDE and the risk for endometrial cancer.

OBJECTIVE: To evaluate in a case-control study possible risk of endometrial cancer associated with environmental endocrine disruptors. METHODS: We analyzed the adipose tissue concentrations of polychlorinated biphenyls, hexachlorobenzene (HCB), p,p'-dichlorodiphenyl-dichloroethylene (p,p'-DDE), chlordanes, and polybrominated biphenyls in 76 cases with endometrial cancer and 39 controls with benign endometrial hyperplasia. RESULTS: For the different chemicals, odds ratios (ORs) and 95% confidence intervals (CI) were close to unity taking the median concentration among the controls as cutoff value. However, for p,p'-DDE OR = 1.9, 95% CI = 0.8-4.8 was obtained. Additional estrogen replacement therapy yielded in this category OR = 2.3, 95% CI = 0.6-8.6. CONCLUSION: The results suggest an interaction between p,p'-DDE and estrogen replacement drugs in the etiology of endometrial cancer, although no significant associations were found.

Organochlorine compounds in breast-fed vs. bottle-fed infants: preliminary results at six weeks of age.

BACKGROUND: Polychlorinated biphenyls (PCBs), hexachlorobenzene (HCB), and 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) are ubiquitous compounds with carcinogenic and teratogenic properties. They are chemically very stable and lipophilic and, therefore, accumulate in our food-chain. They are prenatally transmitted from mother to foetus, and mother's milk due to its high lipid content is an elimination pathway of special importance. Therefore, breast-feeding has been held responsible for elevated concentrations of these organochlorine compounds as well as for harmful effects in children later in life. METHODS: Blood samples (2.5 ml) were taken from each 10 breast-fed and bottle-fed infants at 6 weeks of age. Blood specimens were immediately centrifuged, and serum was stored in glass tubes at -20 degrees C until analysis. Three higher chlorinated PCB congeners (IUPAC nos. 138, 153 and 180), HCB, and the organic metabolite of DDT, p,p << -DDE, were analysed with capillary gas chromatography with electron capture detection. Reliability was tested with gas chromatography-mass spectrometry. RESULTS: There were no differences between the study groups of breast-fed and bottle-fed infants with regard to sex distribution, gestational age, birth-weight, age of the mothers, and smoking behaviour of the parents. In contrast, serum concentrations of all organochlorine compounds were significantly higher (P < 0.0001) in breast-fed than in bottle-fed infants (mean): PCB 138, 0.38 vs. 0.10 microg/l; PCB 153, 0.49 vs. 0.1 microg/l; PCB 180, 0.31 vs. 0.04 microg/l; SigmaPCB, 1.19 vs. 0.29 microg/l; HCB, 0.13 vs. 0.04 microg/l; p,p << -DDE, 1.05 vs. 0.18 microg/l. CONCLUSIONS: Breast-feeding significantly increases the pollution of our infants with different organochlorine compounds as early as at 6 weeks of age. The progress of the present study will show whether this pollution will further increase with longer duration of breast-feeding, and whether breast-feeding bears any health risks for our offspring.

Organochlorine pesticides and hexachlorobenzene along the central coast of New South Wales: multi-scale distributions using the territorial damselfish Parma microlepis as an indicator.

Concentrations of 10 organochlorine pesticides and hexachlorobenzene (HCB) were determined in the territorial damselfish Parma microlepis at three urban locations and three reference locations centred on the Sydney region. Dieldrin, HCB and DDE were the most frequently detected organochlorines, occurring in 70-100% of samples collected. Alpha and gamma chlordane were also reasonably common and occurred in more than 30% of the samples. Each organochlorine compound investigated had a distinct spatial pattern of distribution. Related chemicals such as alpha and gamma chlordane, and DDT, DDE and DDD tended to have similar patterns of distribution. There were clear differences in patterns of distribution in organochlorines between urban and reference locations shown using non-parametric multivariate techniques. Relative variability of samples from urban locations was higher than at reference locations in 1993, but there was no consistent pattern of differences in the dispersions of samples among urban and reference locations in 1994. Age and condition indices (K) showed no association with total concentrations of organochlorine residues in fish. Significant, but weak associations were found between organochlorine residues and size, gonad somatic and liver somatic indices.

Is there a correlation between organochlorine compounds and undescended testes?

Some pesticides and synthetic chemicals are known to act as hormonal modulators, often possessing oestrogenic activity (xenooestrogens). They are persistent and accumulate in fatty tissue. Aim of our study is to address the question, whether a selection of such compounds is to be found in the fatty tissue of children undergoing surgical procedures and whether there are differences in values obtained from patients with or without undescended testes. Fat samples of 48 patients, 18 of whom had undescended testes, were examined by high-resolution gas chromatography and mass spectrometry for DDT and metabolites, polychlorinated biphenyls (PCB), toxaphenes, hexachlorocyclohexane (HCH), chlorinated cyclodienes and chlorinated benzenes. We were able to find accumulation of all substances in every patient. Statistical analysis revealed a highly significant difference between patients from the control group and those from the undescended testes group for two compounds, namely heptachloroepoxide (HCE) and hexachlorobenzene (HCB), increased values being found in the patients with undescended testes. Since the aetiology of this entity is unknown in most of the cases, prenatal exposure to exogenous oestrogens is an attractive and plausible hypothesis. In order to confirm this, some questions will have to be answered in further studies: effect of exposure to xenooestrogens during a specific period of development, probable role of other substances with proven or suspected hormonal activity, potential synergism of such compounds and differences in individual susceptibility.

The mercapturic acid biotransformation pathway of hexachlorobenzene is not involved in the induction of splenomegaly, or skin and lung lesions in the Brown Norway rat.

Involvement of the mercapturic acid pathway in the induction of splenomegaly and skin and lung pathology by hexachlorobenzene (HCB) in the rat was investigated by seeking to determine whether pentachloronitrobenzene (PCNB) has the same inflammatory effects as HCB, since both compounds are directly conjugated to glutathione, and further processed into the same mercapturic acid metabolites which are excreted via the urine. Female Brown Norway (BN/SsNO1aHsd) rats at 3 to 4 weeks of age were orally exposed to diets with or without supplementation with 450 mg HCB or equimolar (467 mg) or higher (934 mg) amounts of PCNB per kilogram of diet over 4 weeks. Gross skin lesion development and body weight gains were assessed during exposure and spleen and liver weights as well as histopathologic changes in skin and lung were assessed after exposure. After 3 weeks of exposure, urinary metabolites of the mercapturic acid and oxidative biotransformation pathways were identified using high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS). Oral exposure of the rats to 450 mg/kg HCB resulted in an increase in relative spleen and liver weights as well as in the development of skin and lung pathology in the absence of overall liver toxicity. Equimolar or higher concentrations of PCNB caused none of these effects. Urinary levels of the mercapturic acid N-acetyl-S-(pentachlorophenyl)-cysteine (PCP-NAC), were comparable in HCB- and PCNB-treated rats. Levels of closely related methylsulfide derivatives of PCP-NAC, also generated via the same mercapturic acid pathway, appeared to be significantly higher in PCNB- than in HCB-treated rats, whereas the reverse was true for the urinary levels of the oxidative metabolite pentachlorophenol (PCP). Thus, results indicate that metabolites of the mercapturic acid pathway are not involved in the induction of splenomegaly and skin and lung pathology caused by HCB exposure in BN rats and that the main urinary metabolite of HCB in these BN rats is PCP. Since PCP itself, as well as other cytochrome P450-derived metabolites from HCB, are not likely to be involved in the induction of splenomegaly and skin and lung pathology, it is suggested that either the parent compound HCB or as-yet-unidentified non-P450-generated metabolites are involved in these inflammatory effects of HCB.

Feeding fish oil to rats accelerates the metabolism of hexachlorobenzene.

This study was conducted to examine the influence of dietary fat on the metabolism and excretion of hexachlorobenzene (HCB), a ubiquitous food contaminant which is metabolized at a low rate. Three groups of rats were fed semi-purified diets containing 10 g/100 g of either soybean oil, lard or fish oil for 2 wk and then given a single dose of HCB by intragastric gavage. The concentrations of HCB and pentachlorophenol (PCP), a major metabolite of HCB, were monitored in the blood for 5 d. Fecal excretion of HCB did not differ among the three groups, indicating no difference in HCB retained in the body among the groups. Concentrations of HCB in blood, liver and brain samples from the lard and fish oil groups, the members of which had a low fat tissue mass, were consistently higher as compared with those in samples from the soybean oil group. The concentration of PCP and the PCP/HCB ratio in the blood were higher in the fish oil group than in the other groups. In addition, the amount of PCP excreted in urine was highest in the fish oil group. The hepatic cytochrome P-450 content in the fish oil group was higher than that in the other groups. These findings indicate that feeding fish oil to rats accelerated HCB metabolism. An increase in hepatic HCB concentration due to a small fat tissue mass and high hepatic cytochrome P-450 content may have played a role in accelerating HCB metabolism in the fish oil group.

Influence of iron on the induction of hepatic tumors and porphyria by octachlorostyrene in C57BL/10ScSn mice.

Octachlorostyrene (OCS) is an environmental contaminant, present in fish of Northern European waters and the Great Lakes of America. It has many distribution and toxic similarities to hexachlorobenzene (HCB). Administration of OCS at 0.01% of the diet to C57BL/10ScSn mice within iron overload for 18 months gave only a low incidence of hepatic nodular hyperplasia (2/10 survivors) and no hepatocellular adenomas or carcinomas. In contrast, with a similar regime, HCB causes severe liver cancer or nodules in all exposed mice. Whole body autoradiography of mice given [14C]OCS or [14C]HCB showed no gross variations in distribution or covalent binding of the radiolabelled compound to account for the difference between the chemicals in the development of tumours. In 12-week studies, the CYP1A subfamily was induced to a greater degree by HCB than OCS and iron-enhanced uroporphyria was significantly greater with HCB. The findings are consistent with the proposal that uroporphyria and liver cancer induced in mice by HCB are associated through related mechanisms, but occur to a significantly lesser extent with OCS.

Comparison of the urinary metabolite profiles of hexachlorobenzene and pentachlorobenzene in the rat.

The urinary metabolite profile of hexachlorobenzene (HCB) and pentachlorobenzene (PCBz) in the rat is compared after dietary exposure for 13 weeks. Both HCB and PCBz are oxidized to pentachlorophenol (PCP) and tetrachlorohydroquinone (TCHQ), which were the only two mutual metabolites formed. Additional urinary metabolites of HCB are N-acetyl-S(pentachlorophenyl)cysteine (PCTP-NAC), which appeared to be quantitatively the most important product, and mercaptotetrachlorothioanisole (MTCTA), which was excreted as a glucuronide. PCBz is more extensively metabolized to the major metabolites 2,3,4,5-tetrachlorophenol (TCP), mercaptotetrachlorophenol (MTCP) and the glucuronide of pentachlorothiophenol (PCTP), and the minor metabolites methylthiotetrachlorophenol (MeTTCP), hydroxytetrachlorophenyl sulphoxide (HTCPS), and bis(methylthio)-trichlorophenol (bis-MeTTriCP). The biotransformation of HCB and PCBz was modulated by selective inhibition of cytochrome P450IIIA in rats which received combined treatment of HCB or PCBz with triacetyloleandomycin (TAO). Rats receiving this diet had a strongly diminished excretion of both PCP and TCHQ, as compared to rats fed HCB or PCBz alone, indicating the involvement of P450IIIA in the oxidation of both compounds. However, the excretion of 2,3,4,5-TCP was not diminished by co-treatment of rats with PCBz and TAO, indicating that: (i) the oxidation of PCBz to PCP and 2,3,4,5-TCP does not proceed via a common intermediate; and (ii) oxidation of PCBz to 2,3,4,5-TCP is not mediated by P450IIIA. Co-treatment of rats with PCBz and TAO had a differential effect on the excretion of sulphur-containing metabolites, resulting in a decrease in the excretion of PCTP glucuronide, whereas no change was observed in the excretion of MTCP, as compared to rats receiving PCBz alone. The observed differences in HCB and PCBz metabolites clearly deserve further in vitro studies to elucidate their origin.

Body distribution and endocrine toxicity of hexachlorobenzene (HCB) in the female rat.

Hexachlorobenzene (HCB) residue levels in dosed rats (50.0 mg kg-1 body wt.day-1, n = 9) were significantly (P < 0.05) greater in the periovarian fat compared to the thyroid gland. Hexachlorobenzene residue levels were significantly (P < 0.05) greater in the thyroid versus the adrenal and ovary. Ovarian HCB residue levels were greater than those found in the thymus, liver and lung. Serum thyroxin (T4) and the free T4 index (FTI) were significantly (P < 0.05) suppressed in HCB-treated rats compared to the control group (n = 8). In contrast, no significant differences in serum concentrations of oestradiol (E2), progesterone (P4) or percentage triiodothyronine uptake (%T3) were observed, thus suggesting an HCB-induced hypothyroid-like state. In a second experiment, adult female Sprague Dawley rats (n = 16) were dosed as above and superovulated with pregnant mare serum gonadotrophin (PMSG, 10 IU s.c.) and human chorionic gonadotrophin (hCG, 20 IU s.c.). Circulating levels of P4 were significantly (P < 0.05) elevated compared to the control group (n = 8). The %T3 uptake and serum T4 levels were significantly (P = 0.05) suppressed compared to controls. Hexachlorobenzene treatment had no effect on circulating levels of E2 or on the FTI. These results suggest that HCB-induced changes found in the spontaneously cycling rat are augmented by ovulation induction strategies. We also conclude that HCB concentrates in the endocrine tissues in addition to the fat.