Abstract  The contamination profiles of brominated flame retardants (BFRs) such as polybrominated diphenyl ethers (PBDEs), biphenyls (PBBs), dibenzo-p-dioxins (PBDDs), and dibenzofurans (PBDFs) were determined in the liver and egg of common cormorants from Japan. PBDEs and PBBs were detected in all the samples; especially the former were detected at elevated levels. PBDDs/PBDFs were also detected in cormorants, albeit the concentrations were lower than those of the PBBs. The total concentration of PBDEs ranged from 330 to 2600 in the liver and from 600 to 3300 in the egg on a nanogram per gram of lipid basis. The concentration of PBBs was in the range from 3.0 to 33 (in the liver) and from 3.4 to 82 (in the egg) on a nanogram per gram of lipid basis. The 2,2',4,4',5,5'-hexabromobiphenyl (BB-153) was the most predominant PBB congener in either organ, which corresponds to a major constituent of the BFR FireMaster BP-6. Concentrations of PBDDs/ PBDFs in the liver (range from 21 to 470) were slightly higher than in the egg (range from 31 to 160) on a picogram per gram of lipid basis. The results of this study imply that common cormorants accumulate a high level of PBDEs and PBBs. Comparing the concentrations of brominated organic compounds with those of chlorinated analogues, good relevance between PBBs and coplanar PCBs (r2 = 0.746 [liver] and 0.715 [egg]) was elucidated. To our knowledge, the present study demonstrates the first report of PBDEs, PBBs, and PBDDs/PBDFs in the common cormorant from Japan.

Abstract  Chloronaphthalenes are dioxin-like environmental and food contaminants that for many years have undergone diffusion from dispersed emission sources of various types on a global scale. When released into ambient air like many other semivolatile organohalogen compounds, chloronaphthalenes undergo various processes and pathways including sequestering by plant vegetation and biota. Recently available data indicate that sequestering rates of chloronaphthalenes by plant biomass and including edible plants as well as concentrations in food sources of plant origin can be greater than was earlier predicted. Additionally, it become known very recently that in some highly industrialized countries such as Japan, Canada and the UK, the technical chloronaphthalene mixtures are still a subject of industrial and commercial interest, even if such activities are illegal. Recent achievements in HRGC-HRMS have enabled elucidation and quantification of the chloronaphthalene congener composition in environmental matrices, food sources and technical mixtures, their persistency, environmental fate, accumulation in biota and potential for food chain biomagnification. However, at the same time this raised questions regarding human exposure to these compounds. By the late 1990s, these developments added to the relatively rapidly growing knowledge on these compounds and especially individual congener properties such as thermodynamic and physicochemical features and toxicity. Multistage fractionation has recently enabled routine congener-specific quantification of tetra- to octachloronaphthalene in various matrices. This paper reviews the literature on chloronaphthalenes as food chain contaminants and covers their origin, physicochemical properties, toxicity, environmental concentrations and persistency, and homologue group and congener composition in various matrices. The review also covers distribution in environmental compartments and subsequent fate and migration to food sources, as well as the magnitude of dietary intake and human body concentrations. Data on chloronaphthalene residues in food, however, are still scare, an exception being seafood sources and recently available data from Spain on their concentrations in staple foods and dietary intake.

Abstract  Ah receptor properties in human liver cells were examined. Sucrose gradient analysis was conducted by incubating 500 microliters of cytosolic preparations of human liver cell Hep-G2 with 10 nanomolar tritium labeled 2,3,7,8-tetrachlorodibenzo-p-dioxin (1746016) (TCDD) for 1 hour. Competitors included TCDD, 2,3,7,8-tetrachlorodibenzofuran (51207319) (TCDF), 2,3,4,7,8-pentachlorodibenzofuran (57117314) (PCDF), 3-methylcholanthrene (56495) (MC), and dibenzo(a,h)anthracene (53703) (DBahA). Radioactivity in fractions collected from the gradient was determined by liquid scintillation counting. Nuclear translocation was assessed and aryl-hydrocarbon-hydroxylase (AHH) activity was measured with and without preincubation with benz(a)anthracene (BA) or MC. Mouse Hepa-1 cells were used for comparison. The concentration of Ah receptor binding sites for TCDD in Hep-G2 cells was 112 femtomoles per milligram (fmol/mg). The concentration in Hepa-1 cells was 422fmol/mg. In Hep-G2 cells, the TCDDh receptor complex sedimented at 9S on sucrose density gradients. TCDD/Ah receptor binding was completely inhibited by TCDF, PCDF, MC, and DBahA. Phenobarbital (50066), dexamethasone (50022), and estradiol (50282) had no effect. The dissociation constant for the TCDD/Ah receptor complex was 9 nanomolar by Wolf plot analysis; this value was about an order of magnitude weaker than that seen using Hepa-1 cells. Cytosolic and nuclear TCDD/Ah receptor complexes that sedimented at 9S and 6S, respectively, were detected after incubation of whole Hep-G2 cells. 3MC and BA induced AHH activity in Hep-G2 cells in a dose dependent manner. The concentrations causing half maximal induction (EC50s) were 1.3 and 5.3 micromolar (microM), respectively. The EC50 for induction of AHH activity by BAin Hepa-1 cells was 0.3microM. The authors conclude that Hep-G2 cells possess a drug metabolizing activity that is associated with cytochrome-P-450IA1 and at least part of the receptor mechanism needed to regulate it.

Abstract  The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that can be activated by a structurally diverse range of synthetic and natural chemicals, and it mediates the toxic and biological effects of environmental contaminants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The spectrum of chemicals that bind to and activate the AhR signal transduction pathway and the identity of materials containing AhR active chemicals is only now being defined. Utilizing AhRdependent gel retardation and reporter gene bioassays, the screening of extracts of 22 dietary herbal supplements and 21 food products (vegetables and fruits) was performed to identify those containing AhR agonists. Several herbal extracts (ginseng, Fo-Ti, white oak bark, licorice, ginkgo biloba, and black cohosh) stimulated AhR DNA binding and gene expression to levels between 20 and 60% of that produced by TCDD. Although some food extracts (corn, jalapen˜o pepper, green bell pepper, apple, Brussels sprout, and potato) were relatively potent activators of AhR DNA binding (30-50% of TCDD), only corn and jalapen˜o pepper extracts induced AhR-dependent luciferase reporter gene expression. However, dilution of corn, jalapen˜o pepper, bell pepper, and potato extracts dramatically increased their ability to induce luciferase activity, suggesting that these extracts contained AhR antagonists whose effectiveness was overcome by dilution. Overall, these results demonstrate that dietary products can be a major source of naturally occurring AhR ligands to which animals and humans are chronically exposed.

Abstract  There are large inter- and intraspecies differences in susceptibility to dioxin-induced toxicities. A critical question in risk assessment of dioxin and related compounds is whether humans are sensitive or resistant to their toxicities. The diverse responses of mammals to dioxin are strongly influenced by functional polymorphisms of the arylhydrocarbon receptor (AHR). To characterize responses mediated by the human AHR (hAHR), we generated a mouse possessing hAHR instead of mouse AHR. Responses of these mice to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 3-methylcholanthrene were compared with the responses of naturally sensitive (C57BL6J) and resistant (DBA2) mice. Mice homozygous for hAHR exhibited weaker induction of AHR target genes such as cyp1a1 and cyp1a2 than did C57BL6J (Ahr(b-1/b-1)) mice. DBA2 (Ahr(d/d)) mice were less responsive to induction of cyp genes than C57BL6J mice. hAHR and DBA2 AHR exhibit similar ligand-binding affinities and homozygous hAHR and Ahr(d/d) mice displayed comparable induction of AHR target genes by 3-methylcholanthrene. However, when TCDD was administered, a greatly diminished response was observed in homozygous hAHR mice compared with Ahr(d/d) mice, indicating that hAHR expressed in mice is functionally less responsive to TCDD than DBA2 AHR. After maternal exposure to TCDD, homozygous hAHR fetuses developed embryonic hydronephrosis, but not cleft palate, whereas fetuses possessing Ahr(b-1) or Ahr(d) developed both anomalies. These results suggest that hAHR may define the specificity of the responses to various AHR ligands. Thus, the hAHR knock-in mouse is a humanized model mouse that may better predict the biological effects of bioaccumulative environmental toxicants like TCDD in humans.

Abstract  Recently, several countries agreed to adopt the Stockholm convention on persistent organic pollutants (POPs). One future obligation will be to add other POPs as new evidence becomes available. In vitro cell-based bioassays offer a rapid, sensitive, and relatively inexpensive solution to screen possible POP candidates. In the present study, we investigated the aryl hydrocarbon (Ah)-receptor activity of several dioxin-like POPs by using the Micro-EROD (Ethoxy-Resorufin-O-Deethylase) and DR-CALUX (Dioxin-Responsive-Chemical Activated Luciferase gene eXpression) bioassays, which are two state-of-the-art methods. The Micro-EROD system used in our study utilizes a wild-type rat liver cell line (rat liver H4IIEC3/T cells), while the DR-CALUX bioassay consists of a genetically modified rat hepatoma H4IIE cell line that incorporates the firefly luciferase gene coupled to dioxin-responsive elements (DREs) as a reporter gene. In the case of the DR-CALUX bioassay, we used an exposure time of 24 h, whereas we used a 72-h exposure time in the Micro-EROD bioassay. The aim of this study was to compare conventional dioxin-like POPs (such as polychlorinated dibenzodioxins and -furans, PCDD/Fs and coplanar polychlorinated biphenyls, PCBs) with several other classes of possible candidates to be added to the current toxicity equivalent factor (TEF) model in the future. Therefore, this study compares in vitro CYP1A1 (Micro-EROD bioassay) and firefly luciferase induction (DR-CALUX bioassay) in several mixed polyhalogenated dibenzodioxins and -furans (PXDD/Fs; X=Br, Cl, or F), alkyl-substituted polyhalogenated dibenzodioxins and -furans (PMCDD/Fs; M=methyl), polyhalogenated biphenyls (PXBs, X=Br, Cl ), polybrominated diphenyl ethers (PBDEs), pentabromophenols (PBPs), and tetrabromobisphenol-A (TBBP-A). We also evaluate congener-specific relative potencies (REPs) and efficacies (% of TCDD(max)) and discuss the dose-response curves of these compounds, as well as the dioxin-like potency of several other Ah-receptor agonists, such as those of the polyaromatic hydrocarbons (PAHs) and polychlorinated naphthalenes (PCNs). The highest REP values were found for several PXDD/F congeners, followed by some coplanar PXBs, trichlorinated PCDD/Fs, PAHs, PBDE-126, 1-6-HxCN, and some brominated flame retardants (TBBP-A). These in vitro investigations indicate that further research is necessary to evaluate more Ah-receptor agonists for dioxin-like potency.

Abstract  Hexabrominated naphthalenes (HBNs) have been identified as contaminants in the commercial PBB mixture, Firemaster. Similarities between polyhalogenated naphthalenes and polyhalogenated biphenyls, dibenzofurans, and dibenzo-p-dioxins with regards to structure and capacity to elicit certain toxicological responses in laboratory animals have previously been evaluated. In this study, teratogenicity and embryo/fetal toxicity, which have been associated with maternal exposure to other toxic polyhalogenated aromatics, was characterized for a synthetic mixture of HBNs in C57BL/6N mice. Pregnant adult mice were treated on gestation Days 6 through 15 with 0.5, 1.0, 2.5, 5.0, 7.5, and 10.0 mg HBN/kg body wt/day and sacrificed on gestation Day 18. Maternal toxicity as evidenced by decreased body weight gain or actual weight loss was observed at 7.5 and 10.0 mg/kg/day. Maternal liver-to-body weight ratios were increased relative to controls at all exposure levels. Dose-related increases were recorded in fetal mortality at 5.0, 7.5, and 10.0 mg/kg/day, and in the incidence of various teratogenic effects at all dose levels. Kidney lesions, best described as apparent hydronephrosis, were the most sensitive fetal abnormality observed, followed by a reduction in the size of lymphatic organs (thymus and spleen), cleft palate, subcutaneous edema, sternebral anomalies, and delayed cranial ossification. HBNs are concluded to be potent fetotoxic and teratogenic agents producing similar effects to TCDD and other toxic polyhalogenated aromatic hydrocarbons.

Abstract  Groups of 6 male and 6 female rats were maintained for 13 weeks on diets containing 12378-PeCDF (2, 20 and 200 μg/kg), 12348-PeCDF (600 and 6000 μg/kg), 123678-HxCDF (2, 20 and 200 μg/kg) and 2,3,7,8-TCDD (2 μg/kg). In addition, a mixture of 23478-PeCDF, 12378-PeCDD, 123678-HxCDF and 2378-TCDD was administered in the diet (20, 10, 10 and 2 μg/kg, respectively, and tenfold diluted). The parameters investigated included body weight development, food consumption, terminal organ weights, hematology and blood chemistry. Tissues were also examined microscopically. The expected toxic syndrome was observed with the toxic isomers, but dosage required to produce the same degree of lesions was quite different. The toxic potency of the isomers relative to TCDD was estimated as follows: (TCDD: 1); 12378-PeCDF: 0.01; 123678-HxCDF: 0.1; 12348-PeCDF: <0.0003. The response of the animals towards the mixture was in accord with additive toxicity of the individual isomers.

Abstract  Several classes of brominated flame retardants (BFRs), namely polybrominated biphenyls (PBBs), polybrominated diphenyl ethers (PBDEs), tetrabromobisphenol A (TBBPA), hexabromocyclododecane (HBCCD), bis(2,4,6-tribromophenoxy)ethane (BTBPE), and tris(2,3-dibromopropyl)phosphate (Tris), have been identified as environmental contaminants. PBDEs, TBBPA, and HBCCD are of particular concern due to increasing environmental concentrations and their ubiquitous presence in the tissues of humans and wildlife from Europe, Japan, and North America. Regardless, the toxicokinetics, in particular metabolism, of BFRs has received little attention. The present review summarizes the current state of knowledge of BFR metabolism, which is an important factor in determining the bioaccumulation, fate, toxicokinetics, and potential toxicity of BFRs in exposed organisms. Of the minimal metabolism research done, BFRs have been shown to be susceptible to several metabolic processes including oxidative debromination, reductive debromination, oxidative CYP enzyme-mediated biotransformation, and/or Phase II conjugation (glucuronidation and sulfation).However, substantially more research on metabolism is necessary to fully assess BFR fate, uptake and elimination kinetics, metabolic pathways, inter-species differences, the influence of congener structure, and the potential health risks to exposed organisms.

Abstract  A considerable body of research over the past fifteen years establishes that in laboratory animals the Ah (aromatic hydrocarbon) receptor (AhR) mediates most, if not all, toxic effects of halogenated aromatic hydrocarbons such as polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans, and polyhalogenated biphenyls. More recently the AhR has been shown to also exist in a wide variety of human tissues and human cell lines. In general the AhR in humans appears to function very much like the AhR in rodents. However, the affinity with which toxic HAHs such as 2,3,7,8-tetrachlorodibenzo-p-dioxin bind to the AhR from human sources generally is lower than the affinity with which these HAHs bind to the Ah receptors from rodent tissues. This lower affinity may explain, in part, why the human species seems less sensitive than many laboratory animals to the effects of HAHs. The AhR enhances transcription of genes encoding cytochrome P450 enzymes in the CYP1A subfamily, but most of the toxic effects of HAHs do not seem to require P450 induction per se. Recent molecular approaches to the mechanism of HAH toxicity indicate that the AhR also may mediate expression of several other genes, including genes that regulate cell growth and differentiation. Despite the expanding repertoire of cellular responses known to be altered by HAHs (potentially through the AhR) it is not yet clear which AhR-mediated actions are the key events in HAH toxicity. Within the past year two subunits of the AhR have been cloned; this cloning, along with other molecular investigations, should greatly expand our opportunity to understand the specific mechanisms and pathways by which HAHs cause toxicity.

Abstract  This article reviews the state of the science regarding the health effects of polybrominated dibenzo-p-dioxins (PBDDs) and dibenzofurans (PBDFs). While thousands of articles have been published on the health effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related polychlorinated dibenzodioxins (PCDDs) and dibenzofurans (PCDFs), little is know about the brominated and mixed chloro/bromo homologs. Available literature suggests that brominated compounds have similar toxicity profiles to their chlorinated homologs. However, further research investigating health effects will only be useful if exposure scenarios truly exist. Current exposure data is extremely limited, posing a major data gap in assessing potential risk of these chemicals. The rapid increase in the use of brominated flame retardants has raised the level of environmental concern regarding PBDDs/PBDFs as it is likely that human, as well as wildlife, exposure to brominated dioxins and furans will increase with their use.

Abstract  The Caspian seal Pusa caspica is the only endemic mammalian species throughout the Caspian Sea. This is the first report on risk assessment of persistent organic pollutants (POPs) in Caspian seals by age-sex and tissue-specific uptake, and their surrounding environment (seawater, surface sediments, and suspended particulate matters, SPMs) in the Gorgan Bay (Caspian Sea, Iran). Among the quantified 70 POPs (∑35PCBs, ∑3HCHs, ∑6CHLs, ∑6DDTs, ∑17PCDD/Fs, HCB, dieldrin, and aldrin), ∑35PCBs were dominant in abiotic matrices (48.80% of ∑70POPs), followed by HCHs > CHLs > DDTs > PCDD/Fs > other POPs in surface sediments > SPMs > seawater, while the toxic equivalent quantity (TEQWHO) exceeded the safe value (possible risk in this area). In biota, the highest levels of ∑70POPs were found in males (756.3 ng g-1 dw, p < 0.05), followed by females (419.0 ng g-1 dw) and pups (191.6 ng g-1 dw) in liver > kidney > muscle > blubber > intestine > fur > heart > spleen > brain. The positive age-related POPs declining correlation between mother-pup pairs suggested the possible maternal transfer of POPs to offspring. The cocktail toxicity assessment revealed that Caspian seals can pose a low risk based on their mixed-TEQ values. Self-organizing map (SOM) indicated the non-coplanar PCB-93 as the most over-represented functional congener in tissue-specific POPs bioaccumulation. Quantitative toxicant tissue-profiling is valuable for predicting the state of mixture toxicity in pinniped species.

Abstract  Dioxins and related compounds are chlorinated aromatic hydrocarbons that are persistent in both environmental and biological samples. Many members of this class of compounds produce a similar spectrum of toxicity which is mediated by interaction with the Ah receptor. The toxic effects of these chemicals can best be described by their actions as growth dysregulators. Dioxins disrupt normal homeostatic processes that tightly regulate cellular growth and differentiation. Disruption in these processes produce a variety of toxicities and pathologies. The available data indicate that humans are sensitive to the toxic effects of these chemicals. Clearer definition of human responses and the body burdens associated with such effects requires more research. Comprehensive risk assessments of dioxins should include all Ah receptor ligands such as the halogenated dibenzofurans and biphenyls.

Abstract  An expert meeting was organized by the World Health Organization (WHO) and held in Stockholm on 15-18 June 1997. The objective of this meeting was to derive consensus toxic equivalency factors (TEFs) for polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) and dioxinlike polychlorinated biphenyls (PCBs) for both human, fish, and wildlife risk assessment. Based on existing literature data, TEFs were (re)evaluated and either revised (mammals) or established (fish and birds). A few mammalian WHO-TEFs were revised, including 1,2,3,7,8-pentachlorinated DD, octachlorinated DD, octachlorinated DF, and PCB 77. These mammalian TEFs are also considered applicable for humans and wild mammalian species. Furthermore, it was concluded that there was insufficient in vivo evidence to continue the use of TEFs for some di-ortho PCBs, as suggested earlier by Ahlborg et al. [Chemosphere 28:1049-1067 (1994)]. In addition, TEFs for fish and birds were determined. The WHO working group attempted to harmonize TEFs across different taxa to the extent possible. However, total synchronization of TEFs was not feasible, as there were orders of a magnitude difference in TEFs between taxa for some compounds. In this respect, the absent or very low response of fish to mono-ortho PCBs is most noticeable compared to mammals and birds. Uncertainties that could compromise the TEF concept were also reviewed, including nonadditive interactions, differences in shape of the dose-response curve, and species responsiveness. In spite of these uncertainties, it was concluded that the TEF concept is still the most plausible and feasible approach for risk assessment of halogenated aromatic hydrocarbons with dioxinlike properties.

Abstract  Treatment of pregnant female Sprague-Dawley rats on Gestational Day 15 with a single oral dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (0.5, 1.0, or 2.0 micrograms/kg) or indole-3-carbinol (I3C, 1.0 or 100 mg/kg), an aryl hydrocarbon (Ah) receptor agonist which is found in cruciferous vegetables, resulted in reproductive abnormalities in the male offspring (three to five litters in each treatment group). Anogenital distance and crown to rump length were altered by both compounds; however, the timing of the effects (Day 1 or 5) was variable and the responses were not necessarily dose-dependent. In 62-day-old offspring, seminal vesicle (24 to 26%), prostate (32 to 44%), testicular parenchymal (14%), and epididymal weight (19%) were decreased by one or more doses of TCDD. In contrast, I3C at one or more doses decreased daily sperm production/g testicular parenchyma (13 to 20%) and daily sperm production/testis (22%). Total number of sperum in the epididymis was significantly decreased (30 to 33%) in rats perinatally exposed to TCDD and this was due to a decreased (49 to 51%) number of sperm in the tail of the epididymis. Perinatal exposure to I3C did not affect any of these parameters. TCDD did not affect epididymal transit time of sperm through the complete epididymis at any of the doses (0.5 to 2.0 micrograms/kg). However, at the two highest doses (1.0 and 2.0 micrograms/kg), TCDD increased epididymal transit rate of sperm through the tail of the epididymis by 33 and 37%, respectively. In contrast, primarily due to decreased transit rate (39%) of sperm through the head plus body of the epididymis. I3C (1 mg/kg) significantly increased total epididymal transit time by 31%. In conclusion, perinatal exposure of pregnant rats to I3C, an Ah receptor agonist similar to TCDD, causes reproductive abnormalities in male rat offspring; however, I3C and TCDD elicited both common and different responses.

Abstract  At doses as high as 750 to 1000 mumol/kg, 2,2',4,4',5,5'-hexachlorobiphenyl (HCBP) did not cause fetal cleft palate, suppress the splenic plaque-forming cell response to sheep red blood cells, or induce hepatic microsomal ethoxyresorufin O-deethylase (EROD) in C57BL/6J mice. Despite the lack of activity of HCBP in eliciting any of these aryl hydrocarbon (Ah) receptor-mediated responses, competitive binding studies indicated that HCBP competitively displaced 2,3,7,8-[3H]tetrachlorodibenzo-p-dioxin (TCDD) from the murine hepatic cytosolic receptor. Cotreatment of C57BL/6J mice with TCDD (3.7 nmol/kg) and HCBP or 4,4'-diiodo-2,2',5,5'-tetrachlorobiphenyl (I2-TCBP) (400 or 1000 mumol/kg) showed that both compounds partially antagonized TCDD-mediated cleft palate and immunotoxicity (i.e., suppression of the splenic plaque-forming cell response to sheep red blood cells), and HCBP antagonized TCDD-mediated hepatic microsomal EROD induction. Thus, HCBP and I2-TCBP, like the commercial polychlorinated biphenyl mixture Aroclor 1254, were partial antagonists of TCDD action in C57BL/6J mice; however, it was also apparent from the results that Aroclor 1254 was the more effective antagonist at lower doses. Using [3H]TCDD, it was also shown that some of the effects of HCBP on TCDD-mediated cleft palate may be due to the decreased levels of TCDD found in the fetal palates after cotreatment with TCDD and HCBP. 4,4'-[125I2]diiodo-2,2',5,5'-tetrachlorobiphenyl ([125I2]TCBP) of high specific activity (3350 Ci/mmol) was synthesized and used to investigate the direct binding of this compound to the murine hepatic Ah receptor or other cytosolic proteins. No direct specific binding was observed between 125I2-TCBP and any cytosolic proteins using a sucrose density gradient assay procedure. These results contrasted with previous studies with Aroclor 1254 that suggested that this mixture acted as a competitive Ah receptor antagonist.

Abstract  Chemoprotective phytochemicals exhibit multiple activities and interact with several cellular receptors, including the aryl hydrocarbon (Ah) receptor (AhR). In this study we investigated the AhR agonist/antagonist activities of the following flavonoids: chrysin, phloretin, kaempferol, galangin, naringenin, genistein, quercetin, myricetin, luteolin, baicalein, daidzein, apigenin, and diosmin. We also investigated the AhR-dependent activities of cantharidin and emodin (in herbal extracts) in Ah-responsive MCF-7 human breast cells, HepG2 human liver cancer cells, and mouse Hepa-1 cells transiently or stably transfected with plasmids expressing a luciferase reporter gene linked to multiple copies of a consensus dioxin-responsive element. The AhR agonist activities of the compounds (1 and 10 micro M) were as high as 25% of the maximal response induced by 5 nM 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and their potencies were dependent on cell context. Galangin, genistein, daidzein, and diosmin were active only in Hepa-1 cells, and cantharidin induced activity only in human HepG2 and MCF-7 cells. Western blot analysis confirmed that baicalein and emodin also induced CYP1A1 protein in the human cancer cell lines. The AhR antagonist activities of four compounds inactive as agonists in MCF-7 and HepG2 cells (kaempferol, quercetin, myricetin, and luteolin) were also investigated. Luteolin was an AhR antagonist in both cell lines, and the inhibitory effects of the other compound were dependent on cell context. These data suggest that dietary phytochemicals exhibit substantial cell context-dependent AhR agonist as well as antagonist activities. Moreover, because phytochemicals and other AhR-active compounds in food are present in the diet at relatively high concentrations, risk assessment of dietary toxic equivalents of TCDD and related compounds should also take into account AhR agonist/antagonist activities of phytochemicals.

Abstract  This article reviews the present state of the art regarding the toxicokinetics and metabolism of polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs). The absorption, body distribution, and metabolism can vary greatly between species and also may depend on the congener and dose. In biota, the 2,3,7,8-substituted PCDDs and PCDFs are almost exclusively retained in all tissue types, preferably liver and fat. This selective tissue retention and bioaccumulation are caused by a reduced rate of biotransformation and subsequent elimination of congeners with chlorine substitution at the 2,3,7, and 8 positions. 2,3,7,8-Substituted PCDDs and PCDFs also have the greatest toxic and biological activity and affinity for the cytosolic arylhydrocarbon (Ah)-receptor protein. The parent compound is the causal agent for Ah-receptor-mediated toxic and biological effects, with metabolism and subsequent elimination of 2,3,7,8- substituted congeners representing a detoxification process. Congener-specific affinity of PCDDs and PCDFs for the Ah-receptor, the genetic events following receptor binding, and toxicokinetics are factors that contribute to the relative in vivo potency of an individual PCDD or PCDF in a given species. Limited human data indicate that marked species differences exist in the toxicokinetics of these compounds. Thus, human risk assessment for PCDDs and PCDFs needs to consider species-, congener-, and dose-specific toxicokinetic data. In addition, exposure to complex mixtures, including PCBs, has the potential to alter the toxicokinetics of individual compounds. These alterations in toxicokinetics may be involved in some of the nonadditive toxic or biological effects that are observed after exposure to mixtures of PCDDs or PCDFs with PCBs.

Abstract  The present study was carried out to investigate the effect on tissue vitamin A levels in rats exposed to 3,3',4,4'-tetraCB (CB-77), 2,3',4,4',5-pentaCB (CB-118), 3,3',4,4',5-pentaCB (CB-126), and 2,2',4,4',5,5'-hexaCB (CB-153). The obtained results show that hepatic vitamin A levels are reduced both in male and female rats following dietary exposure to individual PCB congeners for 13 weeks. However, there are pronounced potency differences between congeners. Compared to TCDD, the hepatic vitamin A reducing potencies of CB-126, CB-77 and CB-153, are 0.05, 0.0001 and 0.00001, respectively, in male rats. Compared to male rats, female rats are equally sensitive to hepatic vitamin A reduction both by TCDD and dioxinlike CBs. Effects on renal and pulmonary vitamin A levels vary between CBs and between sexes.

Abstract  The concentrations of PCDD/Fs and 18 PCBs (DL- and NDL-) were analyzed in 16 fish and seafood species widely consumed in Catalonia (Spain). The exposure of these pollutants was subsequently estimated according to various groups of population. The concentrations of PCDD/Fs and PCBs showed an important decrease in relation to the baseline study (2000) and our last survey (2008). Sardine and red mullet were the species showing the highest pollutant concentrations, while canned tuna and cuttlefish presented the lowest levels. Sardine was the main contributor to the exposure of PCDD/Fs and PCBs. In contrast, swordfish was the species with the lowest contribution to the exposure of PCDD/Fs, DL-PCBs, and PCDD/Fs+DL-PCBs, while clam was the minor contributor for NDL-PCBs and total PCBs. For all groups of population, the current intakes of PCDD/Fs and PCBs were lower than the TDI (1-4 pg WHO-TEQ/kg body weight/day), being children the group with the highest exposure. However, this exposure should not mean a health risk for this group of population. The current intake of PCDD/Fs and PCBs through fish and seafood consumption was similar or even lower than most values reported in recent studies all over the world.

Abstract  Consensus toxicity factors (CTFs) were developed as a novel approach to establish toxicity factors for risk assessment of dioxin-like compounds (DLCs). Eighteen polychlorinated dibenzo-p-dioxins, dibenzofurans (PCDD/Fs), and biphenyls (PCBs) with assigned World Health Organization toxic equivalency factors (WHO-TEFs) and two additional PCBs were screened in 17 human and rodent bioassays to assess their induction of aryl hydrocarbon receptor-related responses. For each bioassay and compound, relative effect potency values (REPs) compared to 2,3,7,8-tetrachlorodibenzo-p-dioxin were calculated and analyzed. The responses in the human and rodent cell bioassays generally differed. Most notably, the human cell models responded only weakly to PCBs, with 3,3',4,4',5-pentachlorobiphenyl (PCB126) being the only PCB that frequently evoked sufficiently strong responses in human cells to permit us to calculate REP values. Calculated REPs for PCB126 were more than 30 times lower than the WHO-TEF value for PCB126. CTFs were calculated using score and loading vectors from a principal component analysis to establish the ranking of the compounds and, by rescaling, also to provide numerical differences between the different congeners corresponding to the TEF scheme. The CTFs were based on rat and human bioassay data and indicated a significant deviation for PCBs but also for certain PCDD/Fs from the WHO-TEF values. The human CTFs for 2,3,4,7,8-pentachlorodibenzofuran, 1,2,3,4,7,8-hexachlorodibenzofuran, 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin, and 1,2,3,4,7,8,9-heptachlorodibenzofuran were up to 10 times greater than their WHO-TEF values. Quantitative structure-activity relationship models were used to predict CTFs for untested WHO-TEF compounds, suggesting that the WHO-TEF value for 1,2,3,7,8-pentachlorodibenzofuran could be underestimated by an order of magnitude for both human and rodent models. Our results indicate that the CTF approach provides a powerful tool for condensing data from batteries of screening tests using compounds with similar mechanisms of action, which can be used to improve risk assessment of DLCs.

Abstract  BIOSIS COPYRIGHT: BIOL ABS. RRM GUINEA-PIG RAT MOUSE HAMSTER ENVIRONMENTAL POLLUTION SOLUBLE RECEPTOR PROTEINS EPIDERMAL TOXICITY

Abstract  Human biomonitoring (HBM) monitors levels of environmental pollutants in human samples, which often is a topic of concern for residents near industrially contaminated sites (ICSs). Around an ICS area in Menen (Belgium), including a (former) municipal waste incinerator and a metal recovery plant, increasing environmental concentrations of dioxins and polychlorinated biphenyls (PCBs) were observed, causing growing concern among residents and authorities. The local community succeeded in convincing the responsible authorities to investigate the problem and offer research funding. Persistent organic pollutants (POPs) were measured in two consecutive HBM studies (2002-2006 and 2010-2011), in the context of the Flemish Environment and Health Study (FLEHS), as well as in soil and locally produced food. Meanwhile, local authorities discouraged consumption of locally produced food in a delineated area of higher exposure risk. Ultimately, HBM and environmental data enabled tailored dietary recommendations. This article demonstrates the usefulness of HBM in documenting the body burdens of residents near the ICS, identifying exposure routes, evaluating remediating actions and providing information for tailored policy strategies aiding to further exposure reduction. It also highlights the role of the local stakeholders as an example of community-based participatory research and how such an approach can create societal support for research and policy.

Abstract  The aryl hydrocarbon receptor (AhR) was first identified as the intracellular protein that bound and mediated the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) and dioxin-like compounds (DLCs). Subsequent studies show that the AhR plays an important role in maintaining cellular homeostasis and in pathophysiology, and there is increasing evidence that the AhR is an important drug target. The AhR binds structurally diverse compounds, including pharmaceuticals, phytochemicals and endogenous biochemicals, some of which may serve as endogenous ligands. Classification of DLCs and non-DLCs based on their persistence (metabolism), toxicities, binding to wild-type/mutant AhR and structural similarities have been reported. This review provides data suggesting that ligands for the AhR are selective AhR modulators (SAhRMs) that exhibit tissue/cell-specific AhR agonist and antagonist activities, and that their functional diversity is similar to selective receptor modulators that target steroid hormone and other nuclear receptors.

Abstract  Flotation sludge from the meat processing industry can be applied as biofuel in already existing plant-scale boilers. This biosolid is rich in oil and grease and has higher energetic content on a dry ash-free basis (22.74 and 27.71 MJ kg−1) than the wood-based fuel (16.62 and 16.16 MJ kg−1). Co-combustion trials were performed at a pilot-scale cyclonic combustor (100 kg h−1) and at an industrial flamotubular rotatory grate-fired system (6000 kg h−1), co-firing pre-dried and centrifuged flotation sludges (respectively) and wood at a mass ratio of 1:3. At a moisture content of 60.13 wt%, the lower heating value of the centrifuged sludge was 10.24% lower compared to wood, thus reducing it to at least 40 wt% would be advisable to obtain energy gains in the industrial plant when operating the co-combustion. The emissions were evaluated and compared to emission standards, including the characterization of polycyclic aromatic hydrocarbons and polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (given as Toxicity Equivalent Factors at O2ref = 7%), which have not yet been reported. The 16 target polycyclic aromatic hydrocarbons were identified at pilot and plant scales (0.582 ± 0.143 μg Nm−3 and 0.602 ± 0.506 μg Nm−3, respectively) being lower than the Danish reference standard (5.0 μg Nm−3). The polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans concentrations were 0.0004 ± 0.0001 ng Nm−3 at pilot scale and 0.3617 ± 0.1310 ng Nm−3 at plant scale, both below the Brazilian and American standards but differed greatly between the scales, requiring further investigation since their formation can occur due to combustion and postcombustion conditions. © 2021 American Institute of Chemical Engineers.