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The effects of curcumin on the bioavailability of polychlorinated dibenzo-p-dioxins/furans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (DL-PCBs) were investigated in Sprague-Dawley rats. Tetra- and penta-chlorinated PCDFs had the lowest bioavailability and hexa-chlorinated PCDD/Fs had the highest, while there was no obvious change in that of DL-PCBs. Curcumin markedly reduced the toxic equivalent (TEQ) of PCDD/Fs in rats, illustrating the potential to competitively inhibit absorption of PCDD/Fs by the epithelial cells of the small intestine due to the similar chemical structure (diphenyl) between curcumin and PCDD/Fs. Moreover, curcumin lowered the TEQ of DL-PCBs in the liver of male rats, but not female rats. The significant decrease in the bioavailability of PCDD/Fs and DL-PCBs demonstrates the potential detoxification mechanisms of curcumin.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), commonly referred to simply as "dioxin", is a persistent environmental pollutant. Because of its high environmental persistence and biological accumulation, humans and animals are often exposed to TCDD. Therefore, the harmful effects on humans and animals is a major concern. Although studies have elucidated the adverse estrogenic and anti-estrogenic effects of TCDD, it is unclear in which tissues TCDD exerts these effects in vivo. To investigate the estrogen-related effects of TCDD in various tissues, we generated an improved estrogen-responsive reporter transgenic mouse in which the luciferase gene luc2 is expressed in response to estrogenic signals. Using these mice, we clarified that TCDD inhibits estrogenic signaling in liver and kidney but enhances estrogenic signaling in the pituitary gland in the same individual. Expression of aryl hydrocarbon receptor, aryl hydrocarbon receptor nuclear translocator, and estrogen receptor alpha mRNA was detected in liver, kidney, and pituitary gland, suggesting that the effects of TCDD on estrogenic signaling in these organs is independent of the expression pattern of these receptors. Thus, our results indicate that TCDD exerts both estrogenic and anti-estrogenic tissue-specific effects within the same individual., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitous, toxic, persistent and bioaccumulative organic pollutant. TCDD can potentially enter the food chain through contaminated food of animal origin as a consequence of feed contamination. Prediction of the TCDD transfer from feed into animal products is thus important for human health risk assessment. Here, we develop several physiologically based toxicokinetic (PBTK) models of TCDD transfer from contaminated feed into growing pigs (Sus scrofa) exposed to doses ranging from 24.52 to 3269.25 ng of TCDD. We test the consequences of explicit dose-dependent absorption (DDA) versus the indirect effects of a self-induced liver metabolism (SIM). The DDA and SIM models showed similar fit to experimental data, although currently it is not possible to unequivocally make statement on a mechanistic preference. The performance of both toxicokinetic models was successfully evaluated using the 1999 Belgian case of contaminated fats for feeding. In combination with toxicokinetic models of other dioxin congeners, they can be used to formulate maximum allowance levels of dioxins in feedstuffs for pigs. Additionally, the implementation of in silico-predicted partition coefficients was explored as a useful alternative to predict TCDD tissue distribution in low-dose scenarios without recurring to animal experiments.

Accumulating evidence including studies of AHR-deficient mice and TCDD toxicity suggests multiple physiologic AHR functions. Challenges to identify responsible mechanisms are due to marked species differences and dependence upon cell type and cellular context. Transient AHR modulation is often necessary for physiologic functions whereas TCDD-mediated sustained receptor activation has been demonstrated to be responsible for toxic outcomes. To stimulate studies on responsible action mechanisms the commentary is focused on human AHR target genes and crosstalk with transcription factors. Discussed AHR functions include chemical and microbial defense, organ development, modulation of immunity and inflammation, reproduction, and NAD + -dependent energy metabolism. Obviously, much more work is needed to elucidate action mechanisms. In particular, studies of pathways leading to NAD + -dependent energy metabolism may shed light on the puzzling species differences of TCDD-mediated lethality and provide options for treatment of obesity and age-related degenerative diseases., (Copyright © 2019. Published by Elsevier Inc.)

Bioaccessibilities of PCDD/PCDF congeners contributing to cancer risk were determined in twelve soil samples from the American Creosote Works Superfund site in Florida. Based upon sample locations, congener profiles (i.e., the same dominant congeners), and total (Toxic Equivalent; TEQ) concentrations, each of these samples has PCDD/PCDF contamination reasonably attributable to the site. Bioaccessibility was determined using a 2-phase in vitro extraction method that included both simulated gastric and intestinal conditions of the human GI tract. Measured congener-specific bioaccessibility values ranged from 34.3 to 62.1%. There was no apparent relationship between the extent of chlorination of PCDD/PCDF congeners and their bioaccessibility. TEQ-weighted bioaccessibility values varied among individual soil samples, which is not unexpected based upon the literature. This variability could not be explained by differences in soil pH, composition, or organic carbon content. The average TEQ-weighted bioaccessibility value of 59% for the twelve samples was accepted as representing site-specific bioavailability of PCDD/PCDFs. This value is higher than most dioxin/furan bioaccessibility values reported in the literature and at the upper end of the range of relative oral bioavailability (RBA) values reported for PCDD/PCDFs from in vivo bioavailability studies. This study used a finer fraction of soil particles (<150 microns versus the more typical <250 microns) to better represent soil that is incidentally ingested. This finer fraction would be expected to have a greater surface area available for extraction of PCDD/PCDFs per unit mass, which might account for the greater than expected bioaccessibility., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Persistent organic pollutants (POPs) are known to accumulate in adipose tissues (AT). This storage may be beneficial by diverting POPs from other sensitive tissues or detrimental because of chronic release of pollutants as indirectly suggested during weight loss. The aim is to study the biological and/or toxic effects that chronic POP release from previously contaminated grafted AT could exert in a naïve mouse., Methods: C57BL/6J male mice were exposed intraperitoneally to 2,3,7,8-tetrachlorodibenzo-p-doxin (TCDD); their epididymal fat pads were collected and grafted on the back skin of uncontaminated recipient mice whose brain, liver, and epididymal ATs were analyzed (TCDD concentration, relevant gene expression). Kinetics of release and redistribution were modeled using Physiologically Based PharmacoKinetics (PBPK)., Results: The grafts released TCDD over a period of 10 weeks with different kinetics of distribution in the three organs studied. A PBPK model was used to simulate the AT releasing process and the incorporation of TCDD into the major organs. At three weeks post-graft, we observed significant changes in gene expression in the liver and the host AT with signatures reminiscent of inflammation, gluconeogenesis and fibrosis as compared to the control., Conclusions: This study confirms that AT-stored TCDD can be released and distributed to the organs of the recipient hence leading to distinct changes in gene expression. This original model provides direct evidence of the potential toxic-relevant effects when endogenous sources of contamination are present., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Trace metal ions such as cadmium (Cd 2+ ) and trace organics typified by 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) are common co-contaminants in the environment and cause toxic effects in aquatic organisms that pose serious health risks. We studied the effects of Cd 2+ on the regulation of cytochrome P450 1A1 (cyp1a1) gene-induction by TCDD using zebrafish embryos and larvae and adult zebrafish tissues. Our results showed that TCDD induced the cyp1a1 gene in all developmental stages and tissues of zebrafish, and the induction was higher in females than males. However, for the upstream genes (ahr2 and arnt2b) that mediate cyp1a1 gene induction in the zebrafish liver cell line was not induced by TCDD similar to the pattern of cyp1a1 in all investigated groups. After co-treatment with Cd 2+ , induction of the aryl hydrocarbon receptor pathway by TCDD was inhibited in the zebrafish larvae and the livers, intestines, kidneys and gills of adult zebrafish, but not in the embryos or brains of adult zebrafish, indicating that the toxicological effects of Cd 2+ on TCDD are dependent on the developmental stages and tissue types. The present study confirms that Cd 2+ blocks the TCDD-induced cyp1a1 gene in vivo but emphasizes that the effects are specific to the developmental stage, type of tissue and sex. The combined effects of Cd 2+ and TCDD must be taken into consideration together with these parameters to accurately predict and assess cadmium and TCDD-induced toxicity in fish and carcinogenesis in animals in general., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The effects of body fat mass on the elimination of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was examined in mice. When male C57BL/6J mice are fed a high-fat, simple carbohydrate diet (HFD) for 13 weeks, they develop an obese phenotype. In contrast, A/J mice fed an HFD do not become obese. After 13 weeks on a normal diet (ND) or HFD, male C57BL/6J and A/J mice received a single dose by gavage of 0.1 or 5.0 µg of 2,3,7,8-tetrachloro[1,6-3H] dibenzo-p-dioxin per kg body weight. Using classical pharmacokinetics, the blood elimination half-life of TCDD was approximately 10 and 2 times longer in the C57BL/6J on the HFD compared with the mice on the ND at 0.1 and 5.0 μg/kg doses, respectively. The diet did not increase the blood half-life of TCDD in the A/J mice, which did not get obese. Using a physiologically based pharmacokinetic model for TCDD that incorporated experimentally derived percent body fat mass and tissue partition coefficients, as well as data on hepatic sequestration, did not provide accurate predictions to the data and could not explain the increase in half-life of TCDD in the HFD groups. This work demonstrates that obesity influences the half-life of TCDD, but other undetermined factors are involved in its elimination because the increase in body fat mass, decreases in cytochrome P4501A2, and altered partition coefficients could not completely explain the prolonged half-life.

Semi-volatile organic compounds (SVOCs) present in indoor environments are known to cause adverse health effects through multiple routes of exposure. To assess the aggregate exposure, the bioaccessibility and bioavailability of SVOCs need to be determined. In this review, we discussed measurements of the bioaccessibility and bioavailability of SVOCs after inhalation. Published literature related to this issue is available for 2,3,7,8-tetrachlorodibenzo-p-dioxin and a few polycyclic aromatic hydrocarbons, such as benzo[a]pyrene and phenanthrene. Then, we reviewed common modeling approaches for the characterization of the gas- and particle-phase partitioning of SVOCs during inhalation. The models are based on mass transfer mechanisms as well as the structure of the respiratory system, using common computational techniques, such as computational fluid dynamics. However, the existing models are restricted to special conditions and cannot predict SVOC bioaccessibility and bioavailability in the whole respiratory system. The present review notes two main challenges for the estimation of SVOC bioaccessibility and bioavailability via inhalation in humans. First, in vitro and in vivo methods need to be developed and validated for a wide range of SVOCs. The in vitro methods should be validated with in vivo tests to evaluate human exposures to SVOCs in airborne particles. Second, modeling approaches for SVOCs need to consider the whole respiratory system. Alterations of the respiratory cycle period and human biological variability may be considered in future studies., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Activated carbon (AC) is an increasingly attractive remediation alternative for the sequestration of dioxins at contaminated sites globally. However, the potential for AC to reduce the bioavailability of dioxins in mammals and the residing gut microbiota has received less attention. This question was partially answered in a recent study examining 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced hallmark toxic responses in mice administered with TCDD sequestered by AC or freely available in corn oil by oral gavage. Results from that study support the use of AC to significantly reduce the bioavailability of TCDD to the host. Herein, we examined the bioavailability of TCDD sequestered to AC on a key murine gut commensal and the influence of AC on the community structure of the gut microbiota. The analysis included qPCR to quantify the expression of segmented filamentous bacteria (SFB) in the mouse ileum, which has responded to TCDD-induced host toxicity in previous studies and community structure via sequencing the 16S ribosomal RNA (rRNA) gene. The expression of SFB 16S rRNA gene and functional genes significantly increased with TCDD administered with corn oil vehicle. Such a response was absent when TCDD was sequestered by AC. In addition, AC appeared to have a minimal influence on murine gut community structure and diversity, affecting only the relative abundance of Lactobacillaceae and two other groups. Results of this study further support the remedial use of AC for eliminating bioavailability of TCDD to host and subsequent influence on the gut microbiome.

Differentiated human bronchial epithelial cells in air liquid interface cultures (ALI-PBEC) represent a promising alternative for inhalation studies with rodents as these 3D airway epithelial tissue cultures recapitulate the human airway in multiple aspects, including morphology, cell type composition, gene expression and xenobiotic metabolism. We performed a detailed longitudinal gene expression analysis during the differentiation of submerged primary human bronchial epithelial cells into ALI-PBEC to assess the reproducibility and inter-individual variability of changes in transcriptional activity during this process. We generated ALI-PBEC cultures from four donors and focussed our analysis on the expression levels of 362 genes involved in biotransformation, which are of primary importance for toxicological studies. Expression of various of these genes (e.g., GSTA1, ADH1C, ALDH1A1, CYP2B6, CYP2F1, CYP4B1, CYP4X1 and CYP4Z1) was elevated following the mucociliary differentiation of airway epithelial cells into a pseudo-stratified epithelial layer. Although a substantial number of genes were differentially expressed between donors, the differences in fold changes were generally small. Metabolic activity measurements applying a variety of different cytochrome p450 substrates indicated that epithelial cultures at the early stages of differentiation are incapable of biotransformation. In contrast, mature ALI-PBEC cultures were proficient in the metabolic conversion of a variety of substrates albeit with considerable variation between donors. In summary, our data indicate a distinct increase in biotransformation capacity during differentiation of PBECs at the air-liquid interface and that the generation of biotransformation competent ALI-PBEC cultures is a reproducible process with little variability between cultures derived from four different donors.

A number of studies have found an association between the concentrations of persistent organic pollutants (POP) and type 2 diabetes. Causality has remained uncertain. This study describes the pharmacokinetic behavior of PCDD/Fs (polychlorinated dibenzo-p-dioxins and dibenzofurans) both in a theoretical model based on elimination rate constants, and in a group of 409 adult surgical patients with known PCDD/F concentrations and dietary information. A model assuming 10% annual decrease in past PCDD/F intake, predicted the measured profile of TEQ (toxic equivalents) in the patient population fairly well. The dominant determinant of PCDD/F level was age, and the level in patients was also associated with consumption of animal source products. Predicted daily intakes correlated with diet, but also with body mass index (BMI), indicating that high BMI was preceded by high consumption of foods containing PCDD/Fs. The results suggest that a third factor, e.g. high intake of animal source foods, could explain both higher levels of POPs in the body and higher incidence of type 2 diabetes, and BMI is not sufficient in describing the confounding caused by diet. Thus, to fully address the causality between POPs and type 2 diabetes, careful studies considering the pharmacokinetics of the studied compounds, and including the analysis of food consumption, are needed., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Persistent organic pollutants (POPs), including polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), polychlorinated biphenyls (PCBs), polybrominated dibenzo-p-dioxins and dibenzofurans (PBDD/Fs), polybrominated biphenyls (PBBs), and polybrominated diphenyl ethers (PBDEs), have been identified in penguins, lichens, soils, and ornithogenic soils in the Antarctic coastal environment in this study. To the best of our knowledge, no previous study has reported PBDD/F and PBB data from Antarctica. The POP mass contents in penguins were in the following order: PCBs >> PBDEs >> PCDD/Fs; PCBs were the dominant pollutants (6310-144,000 pg/g-lipid), with World Health Organization toxic equivalency values being 2-14 times higher than those of PCDD/Fs. Long-range atmospheric transport is the most primary route by which POPs travel to Antarctica; however, local sources, such as research activities and penguin colonies, also influence POP distribution in the local Antarctic environment. In penguins, the biomagnification factor (BMF) of PCBs was 61.3-3760, considerably higher than that for other POPs. According to BMF data in Adélie penguins, hydrophobic PBDE congeners were more biomagnified at log Kow > 6, and levels decreased at log Kow > 7.5 because larger molecular sizes inhibited transfer across cell membranes., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

On July 10, 1976, an explosion at a chemical plant in Seveso, Italy, released up to 30kg of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-the most potent dioxin congener. Twenty years later, the Seveso Women's Health Study (SWHS) initiated a follow-up assessment of a cohort of female Seveso residents. Researchers collected serial blood, measured for TCDD levels, and recorded information about the women's medical history after the explosion. The study's aims were to: 1) modify the human PBPK model for TCDD (Emond et al. 2004; Emond et al. 2005; NCEA-USEPA, 2010) to include repetitive gestation and lactation; 2) simulate TCDD blood concentrations during different life stages including pregnancy and lactation, under different exposure scenarios; and 3) use this PBPK model to compare the influence of gestation and lactation on elimination of TCDD. After optimization of the model, it was assessed using data from the SWHS cohort. The 23 women in Subcohort A, were 4-39years old and in Subcohort B, the 18 women were 3-17years old when the explosion occurred. The model accurately predicted the blood concentrations during the 20years post-exposure, including periods of pregnancy and lactation. The model was also used to analyze the contribution of gestation and lactation to the mother's elimination of TCDD. The results suggest that gestation and lactation do not significantly impact TCDD blood elimination. Future efforts will focus on using additional data to evaluate the PBPK model and improving the mathematical descriptions of lactation and multiple gestations., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Benign prostatic hyperplasia, prostate cancer, and changes in the ratio of circulating testosterone and estradiol often occur concurrently in aging men and can lead to lower urinary tract (LUT) dysfunction. To explore the possibility of a fetal basis for the development of LUT dysfunction in adulthood, Tg(CMV-cre);Nkx3-1(+/-);Pten(fl/+) mice, which are genetically predisposed to prostate neoplasia, were exposedin uteroand during lactation to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, 1 μg/kg po) or corn oil vehicle (5 ml/kg) after a single maternal dose on 13 days post coitus, and subsequently were aged without further manipulation, or at 8 weeks of age were exposed to exogenous 17 β-estradiol (2.5 mg) and testosterone (25 mg) (T+E2) via slow release subcutaneous implants.In uteroand lactational (IUL) TCDD exposure in the absence of exogenous hormone treatment reduced voiding pressure in adult mice, but otherwise had little effect on mouse LUT anatomy or function. By comparison, IUL TCDD exposure followed by exogenous hormone treatment increased relative kidney, bladder, dorsolateral prostate, and seminal vesicle weights, hydronephrosis incidence, and prostate epithelial cell proliferation, thickened prostate periductal smooth muscle, and altered prostate and bladder collagen fiber distribution. We propose a 2-hit model whereby IUL TCDD exposure sensitizes mice to exogenous-hormone-induced urinary tract dysfunction later in life., (© The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

While the U.S. EPA has issued a draft report with a 1% TCDD effective dose (ED01) of 87.9pg/kg/day based on continuous integration of key scientific evidence, a detailed and comprehensive uncertainty analysis has not been well documented. In this study, a new estimate for ED01 was derived based on uncertainty analysis by quantitatively assessing the potential bias arising from the selection of kinetic models, dose-response models and cohorts. The cumulative serum lipid concentration (CSLC) and cumulative body burden (CBB) were reconstructed as dose metrics using a concentration- and age-dependent pharmacokinetic model (CADM), physiologically based pharmacokinetic model (PBPK), and age-dependent half-life model (FV), and the reconstructed dose metrics based on CADM and PBPK were generally higher than those based on the FV model. Three dose-response curves (linear, multiplicative and power) were used to link dose metrics and cancer risk to estimate ED01, and the linear model resulted in the lowest ED01, followed by the power model and multiplicative model, for the same cohort. Meanwhile, ED01 based on the CADM model was the highest, followed by those based on the PBPK model and first-order model. Finally, the ED01 was estimated to be 17.03±7.83pg/kg/day by statistically analyzing the distribution of ED01 values based on various kinetic models, cohorts and dose-response models. The study presented here strengthens the scientific basis for understanding the potential health implications of TCDD exposure., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

High serum concentrations of polychlorinated biphenyls (PCBs) have been reported previously among residents of Anniston, Alabama, where a PCB production facility was located in the past. As the second of two cross-sectional studies of these Anniston residents, the Anniston Community Health Survey: Follow-Up and Dioxin Analyses (ACHS-II) will yield repeated measurements to be used to evaluate changes over time in ortho-PCB concentrations and selected health indicators in study participants. Dioxins, non-ortho PCBs, other chemicals, heavy metals, and a variety of additional clinical tests not previously measured in the original ACHS cohort will be examined in ACHS-II. The follow-up study also incorporates a questionnaire with extended sections on diet and occupational history for a more comprehensive assessment of possible exposure sources. Data collection for ACHS-II from 359 eligible participants took place in 2014, 7 to 9 years after ACHS.

Polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (dl-PCBs) were measured in plankton samples from the Atlantic, Pacific, and Indian Oceans collected during the Malaspina circumnavigation cruise. The concentrations of PCDD/Fs and dl-PCBs in plankton averaged 14 and 240 pg gdw(-1), respectively, but concentrations were highly variable. The global distribution of PCDD/Fs and dl-PCBs was not driven by proximity to continents but significantly correlated with plankton biomass, with higher plankton phase PCDD/F and dl-PCB concentrations at lower biomass. These trends are consistent with the interactions between atmospheric deposition, biomass dilution, and settling fluxes of organic matter in the water column (biological pump), as key processes driving POPs plankton phase concentrations in the global oceans. The application of a model of the air-water-plankton diffusive exchange reproduces in part the influence of biomass on plankton phase concentrations and suggests future modeling priorities. The estimated oceanic sink (Atlantic, Pacific, and Indian Oceans) due to settling fluxes of organic matter bound PCDD/Fs and dl-PCBs is of 400 and 10,500 kg y(-1), respectively. The atmospheric inputs due to gross diffusive absorption and dry deposition are nearly 3 and 10 times larger for PCDD/Fs and dl-PCBs, respectively, than the oceanic sink. These observations suggest that the coupling of atmospheric deposition with water column cycling supports and drives the accumulation of dl-PCBs and PCDD/Fs in plankton from the global oligotrophic oceans.

In a previous study of female Han/Wistar (H/W) and Long-Evans (L-E) rats, we found that adult exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was associated with size decreases in the cranium and especially the face. In this study we compared these crania to those from male and female Sprague-Dawley (S-D) rats with in utero/lactational exposure to TCDD, using morphometric variables of size, shape, and fluctuating asymmetry to quantify the effects of dose on craniofacial development and growth. At the highest levels of exposure, in utero/lactational and adult TCDD exposures both resulted in small but significant reductions in facial size parameters (i.e., 3-5%) in only females and minor effects on facial shape in both sexes. The shape effects of in utero/lactational exposure were most significant at the sutural intersections, whereas adult exposure to TCDD corresponded to dose-dependent changes of decreasing facial length and vault breadth. Fluctuating asymmetry in general explained a relatively small amount of shape variation compared with other effects, and only increased significantly in female L-E rats with high levels of adult exposure to TCDD. These results indicate that TCDD-related changes in cranial development and growth in rats can vary with the timing and duration of exposure, and with sex. Further investigations of other dioxin-like compounds and animal species will broaden our understanding of how chemicals exposure can influence the development and growth of the mammalian skeleton., (Published by Elsevier Ireland Ltd.)

The Bien Hoa airbase (south of Vietnam) is known as one of the Agent Orange hotspots which have been seriously contaminated by Agent Orange/dioxin during the Vietnam War. Hundreds of samples including soil, sediment and fish were collected at the Bien Hoa Agent Orange hotspot for assessment of the environmental contamination caused by dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs). The toxicity equivalency quotient (TEQ) concentration of PCDD/Fs in soil and sediment varied from 7.6 to 962,000 and 17 to 4860 pg/g dry wt, respectively, implying very high contamination of PCDD/Fs in several areas. PCDD/F levels in fish ranged between 1.8 and 288 pg/g TEQ wet wt and was generally higher than advisory guidelines for food consumption. 2,3,7,8-Tetrachlorinated dibenzo-p-dioxins (2,3,7,8-TCDD) contributed 66-99 % of TEQ for most of the samples, suggesting 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) from Agent Orange as the major source of the contamination. The vertical transport of PCDD/Fs was observed in soil column with high TEQ levels above 1000 pg/g dry wt (Vietnamese limit for necessary remediation activities- TCVN 8183:2009 (2009)) even at a depth of 1.8 m. The vertical transport of PCDD/Fs has probably mainly taken place during the "Ranch Hand" defoliant spray activities due to the leaks and spills of phenoxy herbicides and solvents. The congener patterns suggest that transports of PCDD/Fs by weathering processes have led to their redistribution in the low-land areas. Also, an estimate for the total volume of contaminated soil requiring remediation to meet Vietnamese regulatory limits is provided.

Agent Orange was sprayed in parts of southern Vietnam during the U.S.-Vietnam war and was a mixture of two chlorophenoxy herbicides. The mixture was contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD and other dioxins and furans are measurable in the milk of Vietnamese women. We explored whether the TCDD in milk from these women was from Agent Orange and whether lactational exposure can be a mode of transgenerational effects of TCDD from Agent Orange. A review of the world's literature on milk concentrations of polychlorinated compounds showed the presence of TCDD and other dioxins and furans in all countries that have been assessed. The congener profile of these chemicals, that is, the proportion of different congeners in the sample, can be used to assess the source of milk contamination. Measurements in most countries, including contemporary measurements in Vietnam, are consistent with non-Agent Orange exposure sources, including industrial activities and incineration of waste. Models and supporting human data suggest that TCDD from breastfeeding does not persist in a child past adolescence and that the adult body burden of TCDD is independent of whether the individual was breast- or bottle-fed as a child. These findings suggest that exposure to Agent Orange in Vietnam did not result in persistent transgenerational exposure through human milk., (© 2015 Wiley Periodicals, Inc.)

Ponds at the former US airbase at Ben Hoa, Vietnam are contaminated with Agent Orange. The ponds had been used for aquaculture, and in all likelihood, fish from those ponds have been sold to the public. We assessed human exposure to 2,3,7,8-tetrachloro-dibenzo-dioxin (2,3,7,8-TCDD) in fish samples from the ponds. For on-base tilapia, muscle concentrations 2,3,7,8-TCDD ranged from 1.4 to 32.7 pg/g. Fat concentrations ranged from 73.3 to 3990 pg/g. Estimated human exposure doses exceed international guidelines and exceed 2,3,7,8-TCDD's lowest adverse effect levels. The Bien Hoa fishponds are a completed human pathway for TCDD exposure.

A physiologically-based pharmacokinetic model was developed for the disposition of 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) in 2 fish species--fathead minnow and medaka. The model was developed based on the empirical data on disposition of dioxins in fish tissues, as well as existing knowledge on the mechanisms of uptake, distribution, storage, and elimination of dioxins in various species (other than fish). The present study examined the applicability of mechanisms known to occur in other species for fish and concluded that the same mechanisms defined for disposition of 2,3,7,8-TCDD in (mostly) rodents can be applicable for the 2 fish species examined as well. Parameter values for the model were selected and/or calibrated using available databases. Model compartments included the gill, kidney, liver, and other richly-perfused tissues, as well as fat and other slowly-perfused tissues. The model was calibrated using 2 independent datasets for exposure of fathead minnow and medaka to 2,3,7,8-TCDD in water. The initial values of the model parameters were selected from several sources, and calibrated to represent the 2 exposure datasets. With very few exceptions, the estimated parameter values for the 2 species were comparable, and the final predictions were in strong agreement with the observations. The model developed in the present study can therefore be used in the prediction of the body burden of 2,3,7,8-TCDD in fathead minnow and medaka. Uncertainty in the model prediction as a result of variability in input parameters is discussed for the parameters with the highest impacts on the model outcome., (© 2013 SETAC.)

Objectives: Recent findings demonstrate that nuclear receptor - aryl hydrocarbon receptor (AhR) may play an important role in the pathogenesis of Sjögren's syndrome (SS) via involvement in Epstein-Barr virus reactivation. In that study a reporter system was used. Therefore, it was decided to define AhR expression in human salivary cell line (HSY) and its functional regulators., Design: The expression and functional regulation of AhR was studied in HSY cells. The cells were incubated with dioxin (TCDD) - AhR model inducer, IL-1 and TNF-α. qRT-PCR was applied to assess the expression of AHR, AHRR (AhR repressor), ARNT (AhR nuclear translocator) as well as AhR dependent genes: CYP1A1 and CYP1B1. Enzymatic activity of CYP1A1 and CYP1B1 was evaluated using luciferin-labelled CYPs substrate., Results: In general, dioxin did not significantly influence the expression of AHR and ARNT, but reduced AHRR level. AhR dependent gene expression, i.e. CYP1A1 and CYP1B1 increased gradually with TCDD incubation time. TNF-α significantly induced AHR along with CYP1A1 and CYP1B1 expression. IL-1β did not affect AHR expression, and had minimal effects on CYP1 mRNA levels. Exposure of HSY cells to TCDD resulted in time-dependent induction of CYP1A1 and CYP1B1 enzymatic activity., Conclusions: This study documents functional expression of AhR in HSY as well as induction of AhR and its dependent genes by TNF-α., (Copyright © 2014. Published by Elsevier Ltd.)

Risk assessment for mixtures of dioxin-like compounds uses the toxic equivalency factor (TEF) approach. Although current WHO-TEFs are mostly based on oral administration, they are commonly used to determine toxicity equivalencies (TEQs) in human blood or tissues. However, the use of "intake" TEFs to calculate systemic TEQs in for example human blood, has never been validated. In this study, intake and systemic relative effect potencies (REPs) for 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD), 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF), 3,3',4,4',5-pentachlorobiphenyl (PCB-126), 2,3',4,4',5-pentachlorobiphenyl (PCB-118) and 2,3,3',4,4',5-hexachlorobiphenyl (PCB-156) were compared in rats. The effect potencies were calculated based on administered dose and liver, adipose or plasma concentrations in female Sprague-Dawley rats 3 days after a single oral dose, relative to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Hepatic ethoxyresorufin-O-deethylase activity and gene expression of Cyp1a1, 1a2, 1b1 and aryl hydrocarbon receptor repressor in liver and peripheral blood lymphocytes were used as endpoints. Results show that plasma-based systemic REPs were generally within a half log range around the intake REPs for all congeners tested, except for 4-PeCDF. Together with our previously reported systemic REPs from a mouse study, these data do not warrant the use of systemic REPs as systemic TEFs for human risk assessment. However, further investigation for plasma-based systemic REPs for 4-PeCDF is desirable.

Immune modulation by the aryl hydrocarbon receptor (AhR) has been primarily studied using 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD). Recent reports suggest another AhR ligand, 6-formylindolo[3,2-b]carbazole (FICZ), exhibits distinct immunomodulatory properties, but side-by-side comparisons of these 2 structurally distinct, high-affinity ligands are limited. In this study, the effects of in vivo AhR activation with TCDD and FICZ were directly compared in a mouse model of influenza virus infection using 3 key measures of the host response to infection: pulmonary neutrophilia, inducible nitric oxide synthase (iNOS) levels, and the virus-specific CD8(+) T-cell response. By this approach, the consequences of AhR activation on innate and adaptive immune responses to the same antigenic challenge were compared. A single dose of TCDD elicited AhR activation that is sustained for the duration of the host's response to infection and modulated all 3 responses to infection. In contrast, a single dose of FICZ induced transient AhR activation and had no effect on the immune response to infection. Micro-osmotic pumps and Cyp1a1-deficient mice were utilized to augment FICZ-mediated AhR activation in vivo, in order to assess the effect of transient versus prolonged AhR activation. Prolonged AhR activation with FICZ did not affect neutrophil recruitment or pulmonary iNOS levels. However, FICZ-mediated AhR activation diminished the CD8(+) T-cell response in Cyp1a1-deficient mice in a similar manner to TCDD. These results demonstrate that immunomodulatory differences in the action of these 2 ligands are likely due to not only the duration of AhR activation but also the cell types in which the receptor is activated.

Polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans, and mono- and non-ortho polychlorinated biphenyls (dioxin-like PCBs) are identified as a family or group of organic compounds known as 'dioxins' or dioxin-like chemicals (DLCs). The most toxic member of this group is 2,3,7,8-tetrachlorodibenzo-(p)-dioxin (TCDD). Historically, DLCs have caused a variety of negative human health effects, but a disfiguring skin condition known as chloracne is the only health effect reported consistently. As part of translational research to make computerized models accessible to health risk assessors, the Concentration- and Age-Dependent Model (CADM) for TCDD was recoded in the Berkeley Madonna simulation language. The US Agency for Toxic Substances and Disease Registry's computational toxicology laboratory used the recoded model to predict TCDD tissue concentrations at different exposure levels. The model simulations successfully reproduced the National Health and Nutrition Examination Survey (NHANES) 2001-2002 TCDD data in age groups from 6 to 60 years and older, as well as in other human datasets. The model also enabled the estimation of lipid-normalized serum TCDD concentrations in breastfed infants. The model performed best for low background exposures over time compared with a high acute poisoning case that could due to the large dose and associated liver toxicity. Hence, this model may be useful for interpreting human biomonitoring data as a part of an overall DLC risk assessment.

Background: Using methods of molecular toxicology to study dioxin intoxication consequences the contribution was accessed of pathologic alterations induced and manifested by specific biomarkers and ecogenetic effects among Vietnamese population living on contaminated territories. The causes of variability in individual sensitivity to toxic activity were also evaluated., Materials and Methods: Individual biomedical indices were compared between those living in contaminated with dioxins (n = 8142) and control (n = 4421) regions. Dioxin concentrations were measured by high resolution chromato-mass spectrometry (84 samples). The characteristics of cytochrome P-450 system state (94 persons) and cytogenetic parameters (368 persons, 331 450 cells) reflected the molecular and genetic effects. Variable sensitivity to dioxins was demonstrated by associations of genetic polymorphism (CYP1A1, GSTM1, GSTT1, n = 195) and congenital morphogenetic variants among children (n = 1734)., Results: Numerous consequences were demonstrated among the exposed individuals: noticeable absobtion of dioxins from environmental objects; direct effects of P-450 system's induction; systemic alterations in nucleus and genetic stability; changes in cellular generation's rate. The associations were revealed of genetic polymorphism in xenobiotic biotransformation/detoxification system and the peculiarities of development and morphogenesis among exposed children., Conclusion: Characteristics of population chronicle intoxication with dioxins permitted to describe its numerous preclinical and clinical manifestations, to show the key elements in pathogenesis of revealed alterations. Future investigations are to create the groundwork for developing a method for prevention of dioxin pathology induction and realization based on revealing preclinical signs and effects of intoxication.

The construction of the first and, until now, only hazardous waste incinerator (HWI) in Spain finished in 1998. To assess its potential impact on the population living in the vicinity, a surveillance program was established. It includes the periodical biomonitoring of PCDD/Fs body burden. On the basis of this program, in 2012 we determined the levels of PCDD/Fs in plasma of nonoccupationally exposed individuals living near the HWI. The results were compared with those of the baseline study, and with those of two previous surveys (2002 and 2007). A multicompartment, physiologically based pharmacokinetic (PBPK) model was also applied to estimate the levels of PCDD/Fs in plasma. The model was validated by comparing the results with our experimental data (baseline, 2002, 2007, and 2012). The current mean concentration was 6.18 pg I-TEQ/g lipid, with a range between 2.03 and 18.8 pg I-TEQ/g lipid. In 1998 (baseline), the mean concentration of PCDD/Fs in plasma was 27.0 pg I-TEQ/g lipid (reduction of 77%, p < 0.001). Significant reductions were also noted in our previous 2002 and 2007 surveys, with mean concentrations of 15.7 and 9.36 pg I-TEQ/g lipid, respectively. However, the comparison between simulated (using the PBPK model) and experimental results was very successful, as PCDD/F values in plasma were very similar (7.95 vs 6.18 pg I-TEQ/g lipid). The levels of PCDD/Fs in plasma of nonoccupationally exposed individuals living near the HWI here assessed are comparatively lower than most recently reported values.

We present here an initial characterization of ATP binding cassette (ABC) transporter function and regulation at the blood-spinal cord barrier. We isolated capillaries from rat spinal cords and studied transport function using a confocal microscopy-based assay and protein expression using western blots. These capillaries exhibited transport function and protein expression of P-glycoprotein (Abcb1), multidrug resistance protein 2 (Mrp2, Abcc2), and breast cancer-related protein (Bcrp, Abcg2). Exposing isolated capillaries to dioxin (activates aryl hydrocarbon receptor) increased transport mediated by all three transporters. Brain and spinal cord capillaries from dioxin-dosed rats exhibited increased P-glycoprotein-mediated transport and increased protein expression for all three ABC transporters. These findings indicate similar ABC transporter expression, function, and regulation at the blood-spinal cord and blood-brain barriers.

Concentrations of polychlorinated dibenzofurans (PCDFs) and other dioxin-like compounds in soils and sediments of the Tittabawassee River and associated floodplains downstream of Midland, Michigan, USA, are greater than upstream sites. As a result of these concentrations, which are some of the greatest ever reported, a site-specific exposure assessment of belted kingfisher breeding in the assessment area was conducted. To reduce the uncertainty associated with predicting exposure from abiotic matrices, concentrations of residues were quantified in site-specific prey items and in eggs and nestlings of belted kingfisher. Dietary exposure, expressed as the potential average daily dose, based on site-specific concentrations of PCDFs, polychlorinated dibenzo-p-dioxins (PCDDs), and 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents (TEQ(WHO-Avian)) in prey items was consistently greater along the Tittabawassee River than in associated reference areas and further downstream sites in the Saginaw River. Concentrations of PCDD/DFs in eggs and nestlings of belted kingfisher varied among sampling areas, being greater in both eggs and nestlings nesting along the Tittabawassee River compared to those of belted kingfisher from upstream reference areas. Geometric mean concentrations of PCDD/DFs were 130 and 200 ng/kg wet weight in eggs and nestlings of belted kingfisher, respectively. These concentrations are the equivalent of 84 and 95 ng TEQ(WHO-Avian)/kg. Site-specific biomagnification factors for select PCDD/DF congeners ranged from <1.0 to 1.8 in belted kingfisher., (Copyright © 2012 SETAC.)

Several million people are exposed to dioxin and dioxin-like compounds, primarily through food consumption. Skin lesions historically called "chloracne" are the most specific sign of abnormal dioxin exposure and classically used as a key marker in humans. We followed for 5 years a man who had been exposed to the most toxic dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), at a single oral dose of 5 million-fold more than the accepted daily exposure in the general population. We adopted a molecular medicine approach, aimed at identifying appropriate therapy. Skin lesions, which progressively covered up to 40% of the body surface, were found to be hamartomas, which developed parallel to a complete and sustained involution of sebaceous glands, with concurrent transcriptomic alterations pointing to the inhibition of lipid metabolism and the involvement of bone morphogenetic proteins signaling. Hamartomas created a new compartment that concentrated TCDD up to 10-fold compared with serum and strongly expressed the TCDD-metabolizing enzyme cytochrome P450 1A1, thus representing a potentially significant source of enzymatic activity, which may add to the xenobiotic metabolism potential of the classical organs such as the liver. This historical case provides a unique set of data on the human tissue response to dioxin for the identification of new markers of exposure in human populations. The herein discovered adaptive cutaneous response to TCDD also points to the potential role of the skin in the metabolism of food xenobiotics.

Pigs accidentally given feed contaminated by dioxin-like pollutants are a serious public health issue. We have examined whether pigs with limited exposure during early periods of fattening would be categorized as non-compliant with the EU limit at slaughtering when growth-dilution, excretion and metabolism effects are considered. Sixteen female and sixteen castrated male weaned pigs were divided into four groups (e.g. DG0, DG1, DG2 and DG3) in week 2 after birth. From weeks 3 to 13, groups DG1, DG2, and DG3 pigs were fed with a polychlorinated dibenzo-p-dioxin/dibenzofuran (PCDD/F) and polychlorinated biphenyl (PCB) mixture at dosages of 1, 10 and 100ng-toxic equivalent (TEQ) per kg dry mass feed in capsules, respectively. From weeks 13 to 23, the animals were nourished with clear feed. Control group DG0 was always fed with clear feed. Subcutaneous fat samples were collected at weeks 13, 18 and 23 by biopsies. The pollutant residues were analyzed by high resolution gas chromatography-high resolution mass spectrometry and quantified by a (13)C-isotope dilution method. The results showed the following: (1) when slaughtered at week 23, the TEQ for DG1 pigs (0.66±0.21pg/g fat) was under the EU limit of 1pg PCDD/F-TEQ/g fat; (2) PCDD/F congener-specific first-order elimination rates were linearly correlated with their toxicity equivalency factors (TEFs), and the rates were significantly dose-dependent for the more toxic congeners (TEF≥0.1). Therefore, the pigs' exposure above the EU limit during the early fattening stage did not necessarily lead to their categorization as non-compliant pork; and the residual TEQ for pork can be predicted from early exposure concentrations based on the models established here., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The Ah receptor (AhR) is a ligand-dependent transcription factor that mediates a wide range of biological and toxicological effects that result from exposure to a structurally diverse variety of synthetic and naturally occurring chemicals. Although the overall mechanism of action of the AhR has been extensively studied and involves a classical nuclear receptor mechanism of action (i.e., ligand-dependent nuclear localization, protein heterodimerization, binding of liganded receptor as a protein complex to its specific DNA recognition sequence and activation of gene expression), details of the exact molecular events that result in most AhR-dependent biochemical, physiological, and toxicological effects are generally lacking. Ongoing research efforts continue to describe an ever-expanding list of ligand-, species-, and tissue-specific spectrum of AhR-dependent biological and toxicological effects that seemingly add even more complexity to the mechanism. However, at the same time, these studies are also identifying and characterizing new pathways and molecular mechanisms by which the AhR exerts its actions and plays key modulatory roles in both endogenous developmental and physiological pathways and response to exogenous chemicals. Here we provide an overview of the classical and nonclassical mechanisms that can contribute to the differential sensitivity and diversity in responses observed in humans and other species following ligand-dependent activation of the AhR signal transduction pathway.

The fish early life-stage (FELS) test guideline (OECD 210 or OCSPP 850.1400) is the most frequently used bioassay for predicting chronic fish toxicity and supporting aquatic ecological risk assessments around the world. For each chemical, the FELS test requires a minimum of 360 fish and 1 to 3 months from test initiation to termination. Although valuable for predicting fish full life-cycle toxicity, FELS tests are labor and resource intensive and, due to an emphasis on apical endpoints, provide little to no information about chemical mode of action. Therefore, the development and implementation of alternative testing strategies for screening and prioritizing chemicals has the potential to reduce the cost and number of animals required for estimating FELS toxicity and, at the same time, provides insights into mechanisms of toxicity. Using three reference chemicals with well-established yet distinct adverse outcome pathways (AOPs) in early life stages of fish, we proposed FELS-specific AOPs as conceptual frameworks for identifying useful chemical screening and prioritization strategies. The reference chemicals selected as case studies were a cardiotoxic aryl hydrocarbon receptor agonist (2,3,7,8-tetrachlorodibenzo-p-dioxin), neurotoxic acetylcholinesterase inhibitor (chlorpyrifos), and narcotic surfactant (linear alkylbenzene sulfonate). Using qualitative descriptions for each chemical during early fish development, we developed generalized AOPs and, based on these examples, proposed a three-tiered testing strategy for screening and prioritizing chemicals for FELS testing. Linked with biologically based concentration-response models, a tiered testing strategy may help reduce the reliance on long-term and costly FELS tests required for assessing the hazard of thousands of chemicals currently in commerce.

In vitro assays are needed in order to assess the effects on environmental contaminants in animals. In farmed fish, fatty fish species such as the Atlantic salmon are known to accumulate relatively high levels of persistent organic pollutants. Primary cultures consisting of cells isolated directly from a tissue or organ have traditionally been used in toxicological assessments; however, environmentally unrealistic high doses are often required in order to get a response using fish primary cells. It has been suggested that that the sensitivity of in vitro systems can be significantly improved by adding other cell types to the culture. The aim of this study was therefore to develop and test an in vitro co-culture system consisting of Atlantic salmon hepatocytes and monocytes as a potentially more sensitive model than the mono-cultures of hepatocytes used today. Monocytes isolated from blood were cultured together with primary hepatocytes. Dioxins (2,3,7,8,-TCDD and 1,2,3,7,8-PCDD) were selected as model toxicants and RT-qPCR was used to examine if the co-culture system offered improved sensitivity studying the transcription of important biotransformation and xenobiotic genes. Co-cultivating salmon hepatocytes with monocytes altered the response at the gene transcription level for CYP1a, UGT and bcl-x compared to the conventional hepatocyte mono-culture, indicating that co-culture models are promising models that should be evaluated closer for future in vitro toxicological assessments in fishes., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), the prototypical aryl hydrocarbon receptor (AhR) ligand, exhibits immune suppression in vivo and in vitro. Suppression of primary humoral immune responses in particular has been well characterized as one of the most sensitive functional immune endpoints in animals treated with TCDD. Previous studies have used purified TCDD to elucidate the mechanisms by which TCDD and dioxin-like compounds (DLC) impair IgM production by B cells, but did not represent the route by which animals and humans are likely to be exposed environmentally. In the studies reported here, mice were treated with TCDD adsorbed onto a well-defined synthetic silica phase of known purity and physical properties, followed by sensitization with sheep erythrocytes to initiate a humoral immune response. We found that surfactant-templated mesoporous forms of amorphous silica provided an ideal combination of purity, dispersibility and textural properties for immobilizing TCDD. TCDD-adsorbed silica distributed to the spleen and liver after oral administration as assessed by induction of cyp1a1 gene expression. Most notably, TCDD delivered in the adsorbed state on amorphous silica and as a solute in corn oil (CO) produced similar suppression of the anti-sheep red blood cell immunoglobulin M antibody forming cell (sRBC IgM AFC) response at equivalent doses of TCDD. These results suggest that TCDD immobilized on silicate particles found in soils distributes to the spleen and suppresses humoral immunity., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Tissue distribution provides important information regarding the pharmacokinetic behavior of pollutants and is invaluable when analyzing the risk posed to avian species by the exposure to such kind of pollutants. In this study, concentrations of polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) were determined in muscle, liver, spleen, kidney, stomach, gall bladder, skin, heart, pancreas, intestine and lung tissue extracts of cormorants collected from Dongting Lake, China. Tissue distribution results showed preferential accumulation of PCDD/Fs in both liver and skin. The total concentration of PCDD/Fs ranged from 421 to 5696 pg/g lipid weight. Octachlorinated dibenzo-p-dioxin (OCDD) was the predominant congener in all tissues and contributed between 31% and 82% to all 17 PCDD/Fs in different tissues. The liver/muscle ratios progressively increased with the degree of chlorination of PCDDs, except for OCDD. The relative toxic potential of PCDDs and PCDFs in tissues were calculated using the World Health Organization (WHO) Toxic Equivalency Factors (TEFs) for birds. The concentrations of WHO-toxic equivalent in different tissues ranged between 14.8 and 2021 pg/g lipid weight. These results indicated PCDD/Fs may have been bio-accumulated in cormorant via food-web. Furthermore, when compared with studies reported in the literatures, the PCDD/Fs levels in the cormorant collected from Dongting Lake were still relatively high.

The soil of a residential area in Tokyo was found to contain dioxins, namely polychlorinated dioxins, furans, and dioxin-like biphenyls, the levels of which exceeded the environmental guideline [1,000 pg toxic equivalent (TEQ)/g] by up to 6.8 times. To assess the exposure levels of people living in this area and to study the possible relationship of blood dioxin concentrations of children with breast milk and/or formula feeding, a health survey was carried out in 2006, involving a total of 138 people, including 66 children aged 3-15 years, and blood dioxin concentrations and the characteristics and lifestyles of these people were analyzed. Mean ± standard error of the mean (SEM) of blood dioxin concentrations (pg/g-lipid) of group 1 (3-6 years old), group 2 (7-15 years old), and group 3 (≥16 years old) were 13 ± 1.9, 6.6 ± 0.65, and 10 ± 0.54, respectively. The congener/isomer profile of dioxins in blood samples differed markedly from that of the contaminated soil samples. According to the feeding mode of children, blood dioxin concentrations (pg/g-lipid) were 17 ± 2.9 for breast milk only, 7.4 ± 0.82 for both breast milk and formula, and 4.7 ± 1.1 for formula only, with a significant difference from one another. We conclude that people living in the dioxin-contaminated area are less likely to be exposed to excessive amounts of dioxins, and that blood dioxin concentrations of children aged 3-15 years seem to be strongly affected by breast feeding duration.

The University of Michigan Dioxin Exposure Study was undertaken to address concerns that the industrial discharge of dioxin-like compounds in the Midland, Michigan, USA area had resulted in the contamination of soil and vegetation in the Tittabawassee River floodplain and downwind of the incinerator in the City of Midland. The study included the analysis of 597 vegetation samples, predominantly grass and weeds, from residential properties selected through a multistage probabilistic sample design in the Midland area, and in Jackson and Calhoun Counties (Michigan), as a background comparison, for 29 polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs). The mean toxic equivalent (TEQ) of the house perimeter vegetation samples ranged from 4.2 to 377 pg/g. The ratio of TEQs (vegetation to soil) was about 0.3, with a maximum of 3.5. Based on a calculation of the similarity of the congener patterns between the soil and the vegetation, it appeared that the source of the contamination on the vegetation was the surrounding soil. This conclusion was supported by linear regression analysis, which showed that the largest contributor to the R(2) for the outcome variable of log(10) of the vegetation concentration was log(10) of the surrounding soil concentration. Models of vegetation contamination usually focus on atmospheric deposition and partitioning. The results obtained here suggest that the deposition of soil particles onto vegetation is a significant route of contamination for residential herbage. Thus, the inclusion of deposition of soil particles onto vegetation is critical to the accurate modeling of contamination residential herbage in communities impacted by historic industrial discharges of persistent organic compounds., (Copyright © 2010 SETAC.)

National Health and Nutrition Examination Survey data show an association between hypertension and exposure to dioxin-like halogenated aromatic hydrocarbons (HAHs). Furthermore, chronic exposure of mice to the prototypical HAH, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), induces reactive oxygen species (ROS), endothelial dysfunction, and hypertension. Because TCDD induces cytochrome P4501A1 (CYP1A1) and CYP1A1 can increase ROS, we tested the hypothesis that TCDD-induced endothelial dysfunction and hypertension are mediated by CYP1A1. CYP1A1 wild-type (WT) and knockout (KO) mice were fed one control or TCDD-containing pill (180 ng TCDD/kg, 5 days/week) for 35 days (n = 10-14/genotype/treatment). Blood pressure was monitored by radiotelemetry, and liver TCDD concentration, CYP1A1 induction, ROS, and aortic reactivity were measured at 35 days. TCDD accumulated to similar levels in livers of both genotypes. TCDD induced CYP1A1 in endothelium of aorta and mesentery without detectable expression in the vessel wall. TCDD also induced superoxide anion production, measured by NADPH-dependent lucigenin luminescence, in aorta, heart, and kidney of CYP1A1 WT mice but not KO mice. In contrast, TCDD induced hydrogen peroxide, measured by amplex red assay, to similar levels in aorta of CYP1A1 WT and KO mice but not in heart or kidney. TCDD reduced acetylcholine-dependent vasorelaxation in aortic rings of CYP1A1 WT mice but not in KO mice. Finally, TCDD steadily increased blood pressure after 15 days, which plateaued after 25 days (+20 mmHg) in CYP1A1 WT mice but failed to alter blood pressure in KO mice. These results demonstrate that CYP1A1 is required for TCDD-induced cardiovascular superoxide anion production, endothelial dysfunction, and hypertension.

Physiologically based pharmacokinetic (PBPK) models have proven to be successful in integrating and evaluating the influence of age- or gender-dependent changes with respect to the pharmacokinetics of xenobiotics throughout entire lifetimes. Nevertheless, for an effective application of toxicokinetic modelling to chemical risk assessment, a PBPK model has to be detailed enough to include all the multiple tissues that could be targeted by the various xenobiotics present in the environment. For this reason, we developed a PBPK model based on a detailed compartmentalization of the human body and parameterized with new relationships describing the time evolution of physiological and anatomical parameters. To take into account the impact of human variability on the predicted toxicokinetics, we defined probability distributions for key parameters related to the xenobiotics absorption, distribution, metabolism and excretion. The model predictability was evaluated by a direct comparison between computational predictions and experimental data for the internal concentrations of two chemicals (1,3-butadiene and 2,3,7,8-tetrachlorodibenzo-p-dioxin). A good agreement between predictions and observed data was achieved for different scenarios of exposure (e.g., acute or chronic exposure and different populations). Our results support that the general stochastic PBPK model can be a valuable computational support in the area of chemical risk analysis., ((c)2010 Elsevier Inc. All rights reserved.)

There have been several studies on the maternal administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and effects in the reproductive tract of male offspring, subsequent to risk assessments undertaken in 2001. This review compares the methodology and results to examine key methodological features, and consistency in reported outcomes. Maternal dosing at >0.8 microg TCDD/kg causes lethality and weight loss, and it is difficult to distinguish between direct and indirect effects of TCDD at these dose levels. Statistically significant effects of maternal doses of <1 microg TCDD/kg (i.e. the dose levels relevant for risk assessment) on prostate weight or epididymal sperm counts in offspring were reported in the minority of studies. The pharmacokinetics of TCDD differs considerably between acute and chronic dosing, and with dose level of TCDD. On the basis of body burden, TCDD had different potency at inducing adverse effects in the only comparison study between acute and chronic dosing. Understanding of the pharmacokinetics of TCDD and relationship to adverse effects in offspring is required. These analyses identify key features of TCDD developmental toxicity in male offspring, and identify data needs for future risk assessment., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Trace amounts of polychlorinated dibenzo-p-dioxins/furans (PCDD/Fs) and polychlorinated biphenyls (PCBs) are ubiquitous in the environment. Because of industrial activity, other human activities, and accidents, higher concentrations of these chemicals may be present in soil, in residential and recreational areas. Human uptake of these chemicals from such soils has been assumed by regulators, and people contacting such soils may be concerned about potential adverse health effects. Accordingly, clean up levels have been set by state and federal agencies. Whether and to what extent humans actually take up these chemicals from soil is the focus of this review. Since humans are also exposed to PCDD/Fs and PCBs in food and air, their concentrations in these media are presented. We find that their presence in soils is unlikely to increase human body burdens., ((c) 2009 Elsevier Inc. All rights reserved.)

House wren (Troglodytes aedon), tree swallow (Tachycineta bicolor), and eastern bluebird (Sialia sialis) tissues collected in study areas (SAs) downstream of Midland, Michigan (USA) contained concentrations of polychlorinated dibenzofurans (PCDFs) and polychlorinated dibenzo-p-dioxins (PCDDs) greater than in upstream reference areas (RAs) in the region. The sum of concentrations of PCDD/DFs (SigmaPCDD/DFs) in eggs of house wrens and eastern bluebirds from SAs were 4- to 22-fold greater compared to those from RAs, whereas concentrations in tree swallow eggs were similar among areas. Mean concentrations of SigmaPCDD/DFs and sum 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents (SigmaTEQs(WHO-Avian)), based on 1998 WHO avian toxic equivalency factors, in house wren and eastern bluebird eggs ranged from 860 (430) to 1500 (910) ng/kg wet weight (ww) and 470 (150) to 1100 (510) ng/kg ww, respectively, at the most contaminated study areas along the Tittabawassee River, whereas mean concentrations in tree swallow eggs ranged from 280 (100) to 760 (280) ng/kg ww among all locations. Concentrations of SigmaPCDD/DFs in nestlings of all studied species at SAs were 3- to 50-fold greater compared to RAs. Mean house wren, tree swallow, and eastern bluebird nestling concentrations of SigmaPCDD/DFs and SigmaTEQs(WHO-Avian) ranged from 350 (140) to 610 (300) ng/kg ww, 360 (240) to 1100 (860) ng/kg ww, and 330 (100) to 1200 (690) ng/kg ww, respectively, at SAs along the Tittabawassee River. Concentrations of SigmaTEQs(WHO-Avian) were positively correlated with SigmaPCDD/DF concentrations in both eggs and nestlings of all species studied. Profiles of relative concentrations of individual congeners were dominated by furan congeners (69-84%), primarily 2,3,7,8-tetrachlorodibenzofuran and 2,3,4,7,8-pentachlorodibenzofuran, for all species at SAs on the Tittabawassee and Saginaw rivers but were dominated by dioxin congeners at upstream RAs.

At the end of 2004, during a routine monitoring project, high levels of PCDDs in milk from two farms were found. Using a bioassay and the congener patterns obtained by HRGC/HRMS, the source was traced back to the use of kaolinic clay for sorting potatoes in a production process of French fries. Rest products, especially peelings after scrubbing, were used as feed for dairy cows. Levels of PCCD/Fs in this product amounted to 44 ng WHO(1998)-TEQ kg(-1) (88% dw). The maximum level observed in milk was 20 pg WHO(1998)-TEQ g(-1) fat. A Physiologically Based PharmacoKinetic (PB-PK) model was used to model three data obtained before eliminating the source in order to estimate the starting time of the contamination of the cows, the steady-state level after prolonged contamination and the kinetics of the decrease in the levels after removal of the source. Samples of milk were continuously collected for several months showing a decrease to levels below the product limit of 3 pg WHO(1998)-TEQ g(-1) fat within 2 months, in excellent agreement with the decrease predicted by the PB-PK model. Different batches of clay were sampled and analysed, showing varying levels of especially PCDDs. All clays were confirmed to be kaolinic clay using X-ray analysis. Other by-products used for animal feed were also contaminated and led to precautionary measures at a few hundred farms, especially pig farms. However, levels in other animal derived products like pig meat did not exceed the product limits.

Linear and nonlinear toxicity criteria were derived for 2,3,7,8-tetrachlorodibenzo(p)dioxin (TCDD) using the recent National Toxicology Program rat cancer bioassay. Dose-response relationships were assessed for combined liver tumors based on lifetime average liver concentrations (LALCs) estimated with a toxicokinetic model. Rat LALC estimates at the 1% point of departure (POD) were obtained with benchmark dose (BMD) modeling to yield the BMD(01) in terms of LALC. The same toxicokinetic model was used to back-extrapolate the human-equivalent external dose (HED). A linear cancer slope factor (CSF) with a value of 1 x 10(-4) per pg/kg/day was calculated as the ratio between the benchmark response rate and the HED at the lower confidence limit of the benchmark dose (BMDL)(01). A nonlinear reference dose (RfD) with a value of 100 pg/kg/day was developed from the BMD(01) value by applying uncertainty factors to rat internal and human external doses. The RfD was 100 times higher than the 10(-4) risk-specific dose (RSD) based on the linear CSF. For comparison, BMD(01) and BMDL(01) values were developed for key events in the tumor promotion mode of action (MOA) of TCDD. This MOA involves dysregulation of the normal function of the aryl hydrocarbon receptor and its associated biological processes and results in pathologies that drive tumor promotion and progression. The BMD(01) values for key events were consistent with the timing of the key events within the MOA and provided support for the choices of the 1% tumor rate as a POD and dichotomous Hill model for representing receptor-mediated carcinogenicity. Because a threshold toxicity criterion most accurately reflects the MOA, the RfD for TCDD with a value of 100 pg/kg/day is considered appropriate for regulatory purposes, consistent with a 2006 NRC panel's recommendation to develop a threshold-based cancer potency factor for TCDD and with the methodology in U.S. Environmental Protection Agency's Cancer Guidelines.

Numerous metabolism studies have demonstrated that the toxic contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is poorly metabolized. A hallmark feature of TCDD exposure is induction of hepatic CYP1A2 and subsequent sequestration leading to high liver-to-fat concentration ratios. This study was initiated to determine whether TCDD was inherently poorly metabolized or unavailable for metabolism because of sequestration to CYP1A2. [(3)H]TCDD was administered as a single, oral dose (0.1 and 10 microg/kg) to 12 male C57BL/6N mice or 12 CYP1A2 (-/-) mice. At 96 h, less than 5% of the dose was eliminated in the urine of all groups, and TCDD detected in urine was bound to mouse major urinary protein (mMUP). Feces were the major elimination pathway (24-31% of dose), and fecal extracts and non-extractables were quantitated by HPLC for metabolites. No great differences in urinary or fecal elimination (% dose) were observed between the high and low dose treatments. TCDD concentrations were the highest in adipose tissue for CYP1A2 knockout mice but in liver for C57BL/6N mice supporting the role of hepatic CYP1A2 in the sequestration of TCDD. Overall metabolism between parental and knockout strains showed no statistical differences at either the high or low doses. The data suggested that metabolism of TCDD is inherently slow, due principally to CYP1A1, and that hepatic CYP1A2 is not an active participant in the metabolism of TCDD in male mice. Rather, CYP1A2 governs the pharmacokinetics of TCDD by making it unavailable for hepatic CYP1A1 through sequestration and attenuating extrahepatic tissue disposition.

The mink (Mustela vison) is one of the most sensitive mammals to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-like chemicals. By literature review we established that a histological lesion of the jaw bone of mink, evidenced by squamous epithelial hyperplasia in the gingival tissue that forms nests or cords that infiltrate the periodontal ligament and alveolar bone causing osteolysis of the mandible and maxilla that could lead to squamous cell carcinoma, is the most sensitive known biomarker of effect following exposure of mink to TCDD-like chemicals. Lesions have been observed when total TCDD toxic equivalents (TEQ: dioxins, furans, coplanar polychlorinated biphenyls or PCBs) in liver exceed 40 ng/kg wet weight (ww) or when total PCB exceeds 1698 ng/g ww. This is the second report of histological evidence of this lesion in wild-caught mink, and it is the first report of the lesion being grossly detectable in naturally exposed mink. Some mink living near the south shore of Lake Ontario (exposed to the lake's food web), but not inland mink (not exposed to the lake's food web), accumulate more than 40 ng total TEQ/kg or 1698 ng total PCB/kg in liver. Because of its sensitivity, the jaw lesion biomarker is very useful for assessing the health of wildlife populations exposed to TCDD-like chemicals.