TCDD administered on activated carbon eliminates bioavailability and subsequent shifts to a key murine gut commensal.

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.

Anniston community health survey: Follow-up and dioxin analyses (ACHS-II)--methods.

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.

Kaolinic clay derived PCDD/Fs in the feed chain from a sorting process for potatoes.

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.

Congener profiles of PCBs and PCDD/Fs in Yucheng victims fifteen years after exposure to toxic rice-bran oils and their implications for epidemiologic studies.

In 1978-1979, a mass poisoning occurred in central Taiwan from rice-bran oil contaminated by heat-degraded PCBs was later called the Yucheng (oil disease in Chinese). Only a few studies have so far investigated the levels of specific polychlorinated biphenyl (PCB) or polychlorinated dibenzodioxin/furan (PCDD/F) congeners in the Yucheng victims. This study aimed to investigate the serum residual levels of thirty-three PCBs and seventeen 2,3,7,8-substituted PCDD/F congeners in the Yucheng victims 15 years after the exposure. Forty-one blood samples were collected from individual Yucheng victims in 1994-1995. The mean levels of total 33 PCBs and 17 PCDD/Fs were 2468 ng/g lipid (13.3 ng/g sample) and 6550 pg/g lipid (30.9 pg/g sample) respectively. The higher levels were found in PCBs #99, #138, #153, #156, #170, #179, and #180 among 33 PCB congeners, while 2,3,4,7,8-PeCDF, 1,2,3,4,7,8-HxCDF, and OCDD had the higher concentrations among 17 PCDD/F congeners. The total TEQ was contributed in decreasing order by 10 PCDFs (44%), three non-ortho-PCBs (24%), six mono-ortho-PCBs (20%), and seven PCDDs (12%). The mean total PCB levels and TEQ value of the 17 PCDD/Fs in the Yucheng victims 15 years after the toxic exposure were still 9 and 46 times higher than those in the general population in Taiwan. Principle component analysis (PCA) indicated that seven PCB congeners, PCBs #99, #138, #153, #156, #170, #179, and #180, accounted for 73% of the total variances in PCBs. On the other hand, six PCDD/F congeners, 2,3,4,7,8-PeCDF, 1,2,3,4,7,8-HxCDF, 1,2,3,6,7,8-HxCDF, 1,2,3,6,7,8-HxCDD, 1,2,3,4,6,7,8-HpCDF, and OCDD, accounted for 97% of the total variances in PCDD/Fs. In addition, PCA revealed that at least three characteristic patterns of congener profiles for PCBs were observed among the Yucheng victims. Similar trend was also observed for PCDD/Fs. These patterns may reflect distinctive exposure scenarios and/or different metabolizing capabilities among the Yucheng victims. We suggest that these patterns, in contrast to total PCB and PCDD/F levels, may be valuable for the future epidemiologic studies when linking exposure with specific health effect.

Effect of Chlorella pyrenoidosa on fecal excretion and liver accumulation of polychlorinated dibenzo-p-dioxin in mice.

The effect of Chlorella pyrenoidosa on fecal excretion and liver accumulation of polychlorinated dibenzo-p-dioxin in C57BL/6N mice administered dioxin was examined. Mice were administered 2.2 microg of 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin (H6CDD) dissolved in corn oil once after a period of acclimatization, after which they were fed either a basal diet, a 10% C. pyrenoidosa diet, or a 10% Spinach diet, for five weeks. Among mice fed the 10% C. pyrenoidosa diet, cumulative fecal excretion of H6CDD over the first week following administration was significantly greater (9.2-fold) than that observed among mice fed the basal diet. Moreover, excretion during the fifth week following administration of H6CDD was still significantly greater (3.1-fold) among mice fed the 10% C. pyrenoidosa diet than among mice fed the basal diet. Five weeks after administration of H6CDD, liver accumulation of H6CDD in mice fed the 10% C. pyrenoidosa diet was significantly less than that observed among mice fed either the basal diet and the Spinach diet (by 27.9% and 34.8%, respectively). These findings suggest that C. pyrenoidosa may be useful in inhibiting the absorption of dioxins via food and the reabsorption of dioxins stored already in the body in the intestinal tract, thus preventing accumulation of dioxins within the body.

Comparative assessment of endocrine modulators with oestrogenic activity. II. Persistent organochlorine pollutants.

Risk assessments of synthetic chemicals with oestrogen-like activity must take into account the high dietary levels of natural endocrine modulators in food. In view of current regulations of the European Union, a hygiene-based margin of safety (HBMOS) for xeno-oestrogens was defined as a quotient of estimated human daily intakes weighted by relative rodent in vivo potencies of the compounds. Such comparisons of intakes and potencies of natural isoflavones, with short half-lives, with those of polychlorinated organic pollutants (POP) displaying significant toxicokinetic accumulation, deserves the special consideration of toxicokinetics. For slowly accumulating compounds such comparison is much more favourable when based on comparative blood and tissue levels, not on scenarios of daily exposures. Observing these principles, the present communication extends the HBMOS concept to POP, using o,p'-DDT, the oestrogenic component of DDT mixtures, as a prototype. An HBMOS of 137 is derived for o,p'-DDT indicative of a sufficient margin of safety to ensure the absence of risk to human health due to its hormonal action, under exposure conditions now prevailing in Western countries.

Uptake and excretion of organochlorine compounds in neonatal calves.

Intestinal absorption mechanisms of young calves change rapidly during the first 24 h postpartum and subsequently effect the absorption efficiencies of a wide range of compounds. This study was conducted to determine absorption efficiencies of (p,p'-dichlorodiphenyl)dichloroethylene (DDE), 2,2',4,4',5,5'-hexachlorobiphenyl (PCB-153), and 1,2,3,4,6,7,8,9-octachlorodibenzo-p-dioxin (OCDD) when administered in colostrum to neonatal calves. Four male Holstein calves were given a single oral dose containing 100 mg each of DDE, PCB-153, and OCDD either 1 h (n = 2) or 65 h (n = 2) postpartum to determine whether time of exposure influenced the rate or extent of absorption. Another male calf received 100 mg each of DDE and OCDD 1 h postpartum. One gram of chromic oxide (Cr2O3) was administered as a digestion marker to dosed calves. Two male calves, receiving only colostrum, served as controls. Serum IgG concentrations indicated that the 1-h calves absorbed 20 to 37% of the ingested IgG and 65-h calves < 2%; therefore, the gut absorption mechanisms had changed by 65 h. Plasma DDE, PCB-153, and OCDD profiles did not differ based on time of exposure, suggesting that their mechanism of absorption was not influenced by the changing gut. Trapezoidal area under the curve to the last time point values indicated that, during the trial, relative plasma organochlorine concentrations amounted to PCB-153 > DDE > OCDD. Tissue concentrations were similar across treatment groups, with DDE and PCB-153 residues concentrating in adipose tissue and OCDD in the liver. Absorption efficiencies, calculated from fecal recoveries, were >97%, >74%, and >72% for DDE, PCB-153, and OCDD, respectively. These doses of DDE, PCB-153, and OCDD (2.5 +/- 0.1 mg/kg) did not produce signs of toxicosis based on detailed clinical observations, serum clinical chemistry, and gross and histological observations at necropsy. The results of this study indicate that DDE, PCB-153, and OCDD were absorbed and distributed similarly in calves exposed 1 or 65 h postpartum and did not induce toxicosis when administered in combination at these concentrations.

A non-absorbable dietary fat substitute enhances elimination of persistent lipophilic contaminants in humans.

For individuals contaminated with persistent lipophilic pollutants, there is an urgent need for a therapy to enhance contaminant elimination from the body and hence reduce long term exposure. This study investigated the possibility of enhancing the excretion of native chemical via the faeces by augmenting the lipophilic properties of the faeces with the non-absorbable lipid substitute olestra. The faecal excretion of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), polychlorinated biphenyls (PCBs), and hexachlorobenzene (HCB) was measured in 3 volunteers. The excretion while eating an olestra-free diet was compared with the excretion while eating a diet supplemented wit 25 g/d of olestra. The excretion while on the olestra diet was higher by a factor of 1.5-11, depending on the compound. This resulted from higher concentrations of the contaminants in the faeces and higher excretion of faeces dry mass due to the food additive. Using 2,3,7,8-Cl4DD as an example, it was estimated that ingestion of 25 g/d of olestra would more than double the overall rate of elimination of this compound from the body. It is concluded that regular consumption of olestra may provide a therapeutic approach for reducing the body burden of persistent lipophilic contaminants.

[Effect of protoporphyrin on digestive tract absorption of dioxins in rats].

This paper presents the fecal excretion of polychlorinated dibenzo-p-dioxin (PCDD) congeners, and polychlorinated dibenzofuran (PCDF) congeners in male rats fed a diet containing 0.5% disodiumprotoporphyrin (PPNa) or 0.5% hemin. The animals were administered 4 g of 0.5% PPNa or 0.5% hemin diet containing 0.5 ml of the causal rice-bran oil of Yusho that had occurred in the Southwest part of Japan in 1968 and kept on the same diet for five days. The fecal excretion of 2,3,7,8-T4CDD and 2,3,4,7,8-P5CDF in the group fed with 0.5% PPNa were 2.1 and 1.9 times higher, respectively, than that in the group fed with a control diet. Hemin did not show any significant effect on the inhibition of absorption of dioxins. Next, the rats were given a diet containing 0.5% PPNa or 0.5% Hemin for four weeks after a week interval from the day of the causal rice-bran oil administration. The fecal excretion of 2,3,7,8-T4CDD and 2,3,4,7,8-P5CDF in the group fed with 0.5% PPNa were stimulated 2.1 times higher, respectively, than that in the group fed with a control diet. Hemin did not show any significant effect on the inhibition of re-absorption of dioxins.

[Effect of green vegetable on digestive tract absorption of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans in rats].

The effect green vegetable on fecal excretion of polychlorinated dibenzo-p-dioxin (PCDD) congeners and polychlorinated dibenzofuran (PCDF) congeners was examined in male rats. The rats were administered 10% vegetable diets or a basal diet containing 0.2 ml of the causal rice-bran oil of Yusho that had occurred in the Southwest part of Japan in 1968 and kept on the same diet for five days. The fecal excretion of 2,3,7,8-T4CDD and 2,3,4,7,8-P5CDF in the group fed with Komatsuna, Mitsuba, Spinach and Perilla were 7.6-11.6 and 6.5-9.4 times higher, respectively, than that in the group fed with a basal diet. The fecal excretion of 2,3,7,8-T4CDD and 2,3,4,7,8-P5CDF in the group fed with Kale, Chinese chive, Shungiku, Chingentsuai, Green lettus and Sweet pepper were 3.3-4.8 and 4.3-4.5 times higher, respectively, than that in the basal group. The fecal excretion of 2,3,7,8-T4CDD and 2,3,4,7,8-P5CDF in the group fed with Chinese cabbage, Broccoli, Onion, Welsh onion, Cabbage and Celery were 1.6-3.0 and 1.2-1.3 times higher, respectively, than that in the basal group. A correlation between Chllophyll consumption and fecal excretion of PCDD and PCDF congeners was highly significant (p < 0.01). Next, we investigated the fecal excretion of PCDD and PCDF congeners from day 8 to day 35 in rats administered with 0.5 ml of the rice oil. The fecal excretion of 2,3,7,8-T4CDD and 2,3,4,7,8-P5CDF in the group fed with Perilla, Kale and Spinach were 3.1-4.9 and 3.0-3.6 times higner, respectively, than that in the basal group. The presents results suggest that the green vegetables might be useful in treatment of humans exposed to PCDD and PCDF congeners.

Approach to risk assessment of chlorinated dioxins from Yusho PCB poisoning.

A Japanese was estimated to ingest 3 and 11 pg/kg/day of TEQ from PCDD/PCDFs and coplanar PCBs respectively through foods. A Japanese baby was calculated to consume 100-530 pg/kg/day level of TEQ through breast milk feeding, more than 60% being attributed to TEQ of coplanar PCBs. These intakes of TEQ were compared to the average (154 ng/kg/day) and minimum (28 ng/kg/day) intakes of Yusho, a PCB posioning occurred in Japan in 1968. There are three or four orders of magnitude difference between the daily TEQ intakes of general population and Yusho patients. However, the TEQ intakes by breast milk-fed babies of general population are at least 53 times less than the minimum intake of Yusho patients.

Subchronic dose-response study of 2,3,7,8-tetrachlorodibenzo-p-dioxin in female Sprague-Dawley rats.

Toxic and biochemical potencies of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were studied in a 13-week feeding study in female Sprague-Dawley rats. The diets were supplemented with 0, 0.2, 0.4, 0.7, 5, or 20 micrograms TCDD/kg diet. The estimated daily intakes were calculated to be 0, 14, 26, 47, 320, or 1024 ng TCDD/kg body wt/day. At the end of the study, TCDD concentrations were measured in liver and adipose tissue. The lowest estimated daily intake that caused an increase in liver weight was 320 ng TCDD/kg/day, while an intake of 47 ng TCDD/kg/day resulted in a decrease in plasma thyroid hormone concentrations and a decrease in body weight gain. Decreases in relative thymus weights, loss of hepatic retinoids, and induction of CYP1A1 and CYP1A2 activities were already found at 14 ng/kg/day, the lowest dose used. Therefore, 95% confidence limits for the no-effect levels (CNELs) were calculated from the corresponding dose-response relationships by using sigmoidal curve fittings (Hill, Weibull, and a Logistic model) and a probability level of p < 0.05. For increases in CYP1A1 and CYP1A2 activities, the right critical values for the CNELs ranged from 0.7 to 4 ng TCDD/kg/day (Hill and Weibull). Based on hepatic TCDD residue levels, these right critical values for the CNELs ranged from 0.06 to 0.4 ng TCDD/g liver (wet weight) (Hill and Weibull). The CNELs in this study agree very well with the no-observed-adverse-effects levels as reported before in chronic, carcinogenicity, and reproductive studies with rats and TCDD, i.e., 1 ng/kg/day.

Toxic potency of 3,3',4,4',5-pentachlorobiphenyl relative to and in combination with 2,3,7,8-tetrachlorodibenzo-p-dioxin in a subchronic feeding study in the rat.

Toxic and biochemical potencies of 3,3',4,4',5-pentachlorobiphenyl (PCB 126) were studied relative to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in a 13-week feeding study in female Sprague-Dawley rats. To study possible interactive effects the combinations of both compounds were administered. The diets were supplemented with PCB 126 (7, 50, or 180 micrograms/kg diet), with TCDD (0.4 or 5 micrograms/kg diet), or with combinations of both compounds. An estimated daily intake of 0.47 micrograms PCB 126/kg body weight/day caused thymic atrophy, a dramatic loss in hepatic retinoids, and a marked induction in CYP1A1 and CYP1A2 activities. At a daily intake of 3.18 micrograms PCB 126/kg body weight/day a decrease in body weight gain, liver enlargement, and plasma thyroid hormone concentrations occurred. Based on a simultaneous subchronic feeding study with TCDD, a toxic equivalency factor range between 0.01 and 0.1 was estimated for PCB 126 for the mentioned effects. Antagonism was found between TCDD and PCB 126 for hepatic retinol levels and CYP1A2 activity. At the same time, TCDD and PCB 126 liver residue levels were slightly decreased by coadministration. However, these antagonistic effects occurred at maximum induction levels of CYP1A1 and CYP1A2, which are not likely to occur at levels relevant for humans.

Effect of dose, time, and pretreatment on the biliary excretion and tissue distribution of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the rat.

Previous studies of the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) pretreatment on the biliary excretion and hepatic disposition indicated that TCDD did not induce its own metabolic elimination. Pretreatment with TCDD did enhance its hepatic uptake. The present work was designed to further examine the effects of dose, time, and pretreatment on the tissue distribution and biliary elimination of [3H]TCDD. Adult male F-344 rats were administered 0 or 100 nmol [14C]TCDD or [3H]-TCDD/kg body weight po 3 days prior to bile duct cannulation and iv injection of 0 or 1 nmol [3H]TCDD or 1, 10, or 100 nmol [14C]TCDD/kg. Bile was collected for up to 8 hr while rats were maintained under pentobarbital anesthesia. Biliary TCDD and TCDD metabolites were quantified by liquid scintillation spectrometry. In naive animals which received no pretreatment, similar rates of excretion (% dose) were observed following iv administration of 1 nmol [3H]TCDD/kg or 10 or 100 nmol [14C]-TCDD/kg. Metabolic elimination of highly purified [3H]TCDD (> 99%) appeared to be linear with respect to time with approximately 0.8% of the dose being excreted in the bile over a 5- to 8-hr collection period 0 or 24 hr after iv dosing (1, 10, or 100 nmol/kg) and 72 hr after oral dosing (100 nmol/kg). In all groups, higher concentrations of TCDD were found in liver versus fat, and perirenal fat concentrations were elevated relative to epididymal fat concentrations, probably reflective of the enhanced blood perfusion of the former tissue. Pretreatment enhanced hepatic concentrations and decreased fat concentrations of the challenge dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of [125I]-2-iodo-3,7,8-trichlorodibenzo-p-dioxin in mice: analysis with a physiological modeling approach.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent inducer of hepatic microsomal enzymes. The influence of an inducing dose of TCDD on tissue distribution and other pharmacokinetic behavior of a TCDD analog in the mice was examined by employing a high specific activity radioligand. [125I]-2-iodo-3,7,8-trichlorodibenzo-p-dioxin (ITCDD). Female C57BL/6J mice were pretreated with 0.1 mumol/kg of TCDD or the vehicle only, followed by 0.1 nmol ITCDD/kg 3 days later. The control animals had the highest concentration of ITCDD-derived radioactivity in the fat, but the TCDD-pretreated animals had the highest concentration in their livers. Whole-body elimination of ITCDD approximated first-order behavior, and induction by pretreatment with the inducing dose of TCDD almost doubled the rate of excretion (control mice, t1/2 = 14.2 days; pretreated mice, t1/2 = 8.0 days). All disposition results in naive and pretreated mice were satisfactorily described by a consistent physiologically based pharmacokinetic model (Leung et al., 1988a) in which induction increased the amount of microsomal ITCDD-binding protein from 1.75 to 20 nmol/liver and increased the rate constant for metabolism of free ITCDD from 1 to 3/hr/kg liver. The binding affinity of the microsomal ITCDD-binding protein was the same (20 nM) in both induced and noninduced mice. Model simulations indicated a time delay in the elimination of nonparent ITCDD metabolites from the body and a more rapid absorption of the parent ligand in the pretreated mice. Consistent with previous physiological modeling with TCDD in different mouse strains, the primary factor influencing the liver/fat concentration ratio appears to be the affinity and capacity of the microsomal TCDD-binding proteins, which are altered by induction. These dose-dependent pharmacokinetic differences with ITCDD are important considerations for TCDD risk assessment in which data from high dose rodent experiments are extrapolated to predict behavior at much lower environmental concentrations in exposed humans.