Biomonitoring and exposure assessment of people living near or working at an Italian waste incinerator: methodology of the SPoTT study.

Only few studies on the health effect of waste incinerators were focused on human biomonitoring (HBM). Our aim is to describe a protocol for assessing early variation of selected items in a population group living close to a waste incinerator in Turin, Italy. A cohort of 394 subjects was randomly selected, among residents near the incinerator and residents far from it. To achieve this sample size, 765 subjects were contacted. The cohort was monitored before the start-up of the plant and will be followed up 1 and 3 years after, with measurements of respiratory function, selected blood and urine parameters including 19 metals, 17 congeners of PCDDs/Fs, 12 congeners of DL-PCBs, 30 congeners of NDL-PCBs, 11 OH-PAHs, specific hormones (T3, T4, TSH, cortisol and ACTH) and common health parameters. The same protocol is applied for plant workers and breeders living near the plant. Individual exposure to urban pollution and waste incinerator fallout were assessed through the use of mathematical models. Information on individual habits was assessed using a specific questionnaire. SPoTT is the first Italian study that adopts a longitudinal design of appropriate statistical power to assess health impacts of waste incinerator plants' emission. The initial results comparing the baseline to the first follow-up are due at the end of 2016.

Integrated Exposure Assessment Survey (INES) exposure to persistent and bioaccumulative chemicals in Bavaria, Germany.

The Integrated Exposure Assessment Survey (INES) was started in the year 2005. Altogether 50 healthy adults living in Bavaria, Germany, were included into the study. Monitoring was conducted in accordance with relevant routes of human exposure (inhalation, ingestion) and integrated different pathways (indoor air, food, house dust). This approach consisted of a combination of external measurements of contaminants with the determination of these substances or their metabolites in body fluids. The target substances were phthalates, perfluorinated compounds (PFC), polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs), and polybrominated diphenylethers (PBDEs). This paper gives a brief description of the objectives and the concept of INES as well as methods of sampling and analyses of target compounds. Some preliminary results of biomonitoring data for PFC and phthalates as well as of the dietary intake of DEHP will be discussed.

Severe 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) intoxication: kinetics and trials to enhance elimination in two patients.

In spring 1998, two women were diagnosed with severe 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) intoxication. Over the following 3 years, TCDD levels were monitored under various attempts to enhance its elimination, and the half-lives were evaluated. Olestra, a non-digestible, non-absorbable dietary fat substitute, was continuously administered to the patients either as pure substance or in potato-chips. Additionally, in the more severely contaminated patient, we studied whether low-density lipoprotein (LDL)-apheresis, an extracorporeal means of blood lipid elimination, was effective in reducing the TCDD body burden. The blood concentrations initially measured in spring 1998 were 144,000 pg/g blood fat in patient 1 and 26,000 pg/g in patient 2, the highest levels ever measured in adults. In March 2001, concentrations in blood fat were 35,900 and 9,500 pg/g, corresponding to overall elimination half-lives of 560 days (1.5 years) in patient 1 and 1050 days (2.9 years) in patient 2, which are considerably shorter than median values of 7-9 years reported for background and moderate exposure levels. Calculations of the TCDD half-lives and measurements of TCDD elimination via different routes allowed the calculation of an unidentified route of elimination, representing 78 and 62% of the overall elimination in patient 1 and 2, respectively, probably due to an induced hepatic metabolism caused by the high TCDD exposure. As previously reported, administration of olestra was found to be effective in increasing the fecal excretion of TCDD. Due to the short half-lives in our patients, the effect of olestra on the overall elimination was relatively small, but is expected to be much greater for 'normal' half-lives. LDL-apheresis was shown to eliminate TCDD, corresponding to the eliminated blood fat. When employed twice a week, the amount of TCDD excreted by this method was comparable to fecal excretion. In view of costs and time involved, LDL-apheresis does not seem to be justified for enhancement of TCDD elimination.

Metabolism and disposition of 1,4,7,8-tetrachlorodibenzo-p-dioxin in rats.

Metabolism studies of 1,4,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a relatively nontoxic dioxin congener, were undertaken to gain a better understanding of mammalian metabolism of dioxins without the problems associated with the use of the most toxic congener, 2,3,7,8-TCDD. 14C-1,4,7,8-TCDD was dosed to conventional and bile-cannulated rats at a level of 8 mg/kg. The 14C was excreted almost entirely in 72 hours with the major routes of excretion feces and bile. Metabolites were identified from the feces, bile, and urine by GC-MS or negative ion FAB MS and 1H NMR. The two major fecal metabolites were hydroxylated tetra- and triCDDs. Glucuronide and sulfate conjugates of these hydroxyl metabolites were found in the urine and bile. Minor metabolites included dichlorocatechol, dihydroxylated tetra- and triCDDs, and conjugates of these compounds.

Comparison of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) disposition following pulmonary, oral, dermal, and parenteral exposures to rats.

In evaluating human health risks posed by dioxins, it is necessary to accurately predict systematic dosimetry or the fate of these chemicals. Pharmacokinetic parameters pertaining to inhalation, ingestion, and dermal absorption may be estimated using animal models. The present study was designed to assess absorption, tissue distribution, and elimination of TCDD following intratracheal instillation (itr.), oral gavage (p.o.), or intravenous administration (i.v.) of 1 nmol [3H]TCDD/kg to male rats; experimental conditions were chosen to permit comparison to a previous dermal disposition study (Banks and Birnbaum, Toxicol. Appl. Pharmacol. 107, 302-310, 1991). After treatment, rats were housed in individual metabolism cages for 3 days with daily excreta collection. Following termination, radioactivity was quantified in tissues and excreta. By 3 days postexposure, fecal excretion accounted for 22 (i.v.), 26 (itr.), and 32% (p.o.) of dose, while urinary excretion was only 2.2 (i.v.), 1.3 (itr), and 1.4% (p.o.). Pulmonary absorption was calculated as 95% of administered dose, while oral absorption was 88%. Dermal absorption of an equivalent administered dose was 40% (Banks and Birnbaum, 1991). For all exposure routes by 3 days, major tissue depots for absorbed dose were liver and fat. Distribution of absorbed dose was 37% (i.v.) and 35% (itr.) to liver and 21% (i.v.) and 16% (itr.) to fat. Oral gavage-treated rats had similar dosimetry (28-30% absorbed dose) in both liver and fat. In contrast following dermal exposure, distribution to liver and fat was 52 and 22%, respectively (Banks and Birnbaum, 1991). Results suggest that inhalation can be an important route for systemic absorption of dioxins. Moreover, all environmentally relevant routes of exposure (oral, dermal, and respiration) must be uniquely considered as important routes of systemic exposure for TCDD and related compounds.

Reference range data for assessing exposure to selected environmental toxicants.

We analyzed blood and urine specimens from 32 charter boat captains, anglers, and spouses from both groups, who reportedly ate fish from Lakes Michigan, Huron, or Erie, for selected environmental toxicants. The toxicants measured in serum were polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), coplanar polychlorinated biphenyls, other polychlorinated biphenyls (PCBs), and persistent pesticides. Nonpersistent pesticides and elements were measured in urine; and elements were measured in blood. Internal dose levels of these toxicants will be compared to reference range data that we have compiled. These reference range data will be used to ascertain the exposure status of individuals or groups within this study.

Absorption of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) after low dose dermal exposure.

Human dermal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) occurs through contact with soil and paper products. In a previous study, relative percutaneous absorption of TCDD increased as the dose decreased (Brewster et al., 1989). To determine the rate of absorption of a low dose of TCDD, absorption, distribution, and elimination were examined at 1, 4, 8, 12, 24, 48, 72, and 120 hr after dermal application of 200 pmol (111 pmol/cm2) [3H]TCDD to 10-week-old male Fischer 344 rats. The compound was applied over a 1.8 cm2 area of the interscapular region of the back in 60 microliters acetone and covered with a perforated cap; animals were held in individual metabolism cages. Within 120 hr after dosing, 82 pmol (26 ng) of TCDD was absorbed. Absorption kinetics appeared to be first-order; the absorption rate constant was 0.005 hr-1. At each time point, greater than 70% of the radioactivity detected in the application site could be removed by swabbing with acetone. The time-related increase in the amount of TCDD in liver and fat closely paralleled the amount absorbed, while the percentage of the administered dose detected in the blood was never greater than 0.3%. Thus, absorption of a low dose of TCDD through the skin is extremely slow and appears to be a first-order process.

Age-related changes in dermal absorption of 2,3,7, 8-tetrachlorodibenzo-p-dioxin and 2,3,4,7,8-pentachlorodibenzofuran.

Changes in the structure and function of aged skin may alter percutaneous absorption of environmental compounds such as the halogenated aromatic hydrocarbons. TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) and 2,3,4,7,8-penta-chlorodibenzofuran (4PeCDF) were previously found to be poorly absorbed in 3 months male Fischer 344 rats within 3 days after dermal administration. In order to examine age-related changes in dermal absorption and changes in potential for systemic exposure, the absorption, distribution, and elimination of TCDD and 4PeCDF were examined in male Fischer 344 rats of various ages (TCDD: 10, 36, and 96 week; 4PeCDF: 10, 36, 64, 96, and 120 week). Each compound was applied at a dose of 0.1 mumol/kg and/or 0.04 mumol in 60 microliters acetone to a preclipped region of the back and covered with a stainless-steel perforated cap. Rats were housed in individual metabolism cages for 3 days. Dermal absorption of both compounds was decreased in older age groups compared to 10 week rats. The major tissue depots for both compounds were liver, adipose, skin, and muscle and in comparable age groups, the liver:fat ratio was greater in 4PeCDF-treated animals. Age-related changes in the distribution of the administered dose and the absorbed dose varied with the compound as well as the depot. Elimination of TCDD and 4PeCDF was limited at all ages. Results indicate that percutaneous absorption of these compounds is decreased in older animals, suggesting that systemic bioavailability may be decreased in older organisms following dermal exposure to TCDD or 4PeCDF.

Influence of phenobarbital and TCDD on the hepatic metabolism of TCDD in the dog.

The influence of phenobarbital and TCDD pretreatment on the formation and biliary excretion of TCDD-metabolites following single doses of 3H-TCDD was investigated. Without pretreatment, 24.5% of the absorbed 3H-TCDD dose was excreted in the bile within 110 h. Phenobarbital did not influence this rate, whereas a single dose of 10 micrograms of unlabeled TCDD/kg b.wt nine days earlier resulted in a doubling of the amount of radioactive material eliminated in the bile (47.4%).

Studies on the metabolic fate of [14C]2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the mouse.

Studies on the Metabolic Fate of [14C]2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) in the Mouse. KOSHAKJI, R. P., HARBISON, R. D., and BUSH, M. T. (1984). Toxicol. Appl. Pharmacol. 73, 69-77. After a single po dose (135 micrograms/kg; 62 microCi/kg) of 14C-labeled 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in male ICR/Ha Swiss mice, 67 to 76% of the administered dose was eliminated via the feces and 1 to 2% in the urine during the first 24 hr following treatment. It seems likely that most of this material was simply not absorbed. Much of the remaining chemical was then excreted slowly in the urine (2%) and feces (7%) during the next 10 days, partly as the unchanged compound and partly as metabolites. One of the metabolites (Fraction II) appears to be a single polar, acidic metabolite characterized in urine (0.4 +/- 0.1%) and feces (2.2 +/- 0.2%), and is also likely excreted as a glucuronide conjugate. The rest of the radioactivity was in the form of unchanged TCDD in the animal body (17 +/- 2%). Steady rates of decline in the concentrations of the 14C as well as of the unchanged TCDD were reached in the feces and urine after the fifth day following the administration of the chemical. Based on this steady rate, the half-life of the radioactivity in the body was approximately 20 days. Urine, feces, and whole body were analyzed by solvent extraction, 14C counting, thin-layer chromatography, and countercurrent distribution.

Fate of 2,3,7,8-tetrachlorodibenzo-p-dioxin metabolites from dogs in rats.

1. Metabolites of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were extracted from the bile of TCDD-treated dogs and administered by gavage to bile-duct-cannulated rats and also to an intact rat. 2. Radioactivity of the TCDD metabolites was rapidly cleared from the body of the rats, indicating that bioaccumulation of these compounds does not occur. 3. Biliary excretion was the most important route of elimination in the cannulated rats and amounted to greater than 30% of the administered dose within 24h. TCDD metabolites were also eliminated to a minor extent by the kidneys. The combined recovery of radioactivity in faeces, bile and urine after 24h accounted for greater than 85% of the dose. 4. The intact animal exhibited a somewhat different kinetic behaviour in that only 13% dose was excreted in faeces and urine after 24h, which indicates enterohepatic circulation. The administered radioactivity was completely recovered after 72h. 5. Results from the present experiments indicate that metabolism of TCDD is the rate-limiting step in elimination of TCDD from the liver. Interspecies variability in the toxicity of TCDD may in part be attributable to different rates at which the species metabolize and excrete TCDD.