Age- and Concentration-Dependent Elimination Half-Life of 2,3,7,8-Tetrachlorodibenzo-p-dioxin in Seveso Children

OBJECTIVE: Pharmacokinetic and statistical analyses are reported to elucidate key variables affecting 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) elimination in children and adolescents. DESIGN: We used blood concentrations to calculate TCDD elimination half-life. Variables examined by statistical analysis include age, latency from exposure, sex, TCDD concentration and quantity in the body, severity of chloracne response, body mass index, and body fat mass. PARTICIPANTS: Blood was collected from 1976 to 1993 from residents of Seveso, Italy, who were < 18 years of age at the time of a nearby trichlorophenol reactor explosion in July 1976. RESULTS: TCDD half-life in persons < 18 years of age averaged 1.6 years while those ≥18 years of age averaged 3.2 years. Half-life is strongly associated with age, showing a cohort average increase of 0.12 year half-life per year of age or time since exposure. A significant concentration-dependency is also identified, showing shorter half-lives for TCDD concentrations > 400 ppt for children < 12 years of age and 700 ppt when including adults. Moderate correlations are also observed between half-life and body mass index, body fat mass, TCDD mass, and chloracne response. CONCLUSIONS: Children and adolescents have shorter TCDD half-lives and a slower rate of increase in half-life than adults, and this effect is augmented at higher body burdens. RELEVANCE: Modeling of TCDD blood concentrations or body burden in humans should take into account the markedly shorter elimination half-life observed in children and adolescents and concentration-dependent effects observed in persons > 400–700 ppt

Cancer incidence in the population exposed to dioxin after the "Seveso accident": twenty years of follow-up

<p>Abstract</p> <p>Background</p> <p>The Seveso, Italy accident in 1976 caused the contamination of a large population by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Possible long-term effects have been examined through mortality and cancer incidence studies. We have updated the cancer incidence study which now covers the period 1977-96.</p> <p>Methods</p> <p>The study population includes subjects resident at the time of the accident in three contaminated zones with decreasing TCDD soil levels (zone A, very high; zone B, high; zone R, low) and in a surrounding non-contaminated reference territory. Gender-, age-, and period-adjusted rate ratios (RR) and 95% confidence intervals (95% CI) were calculated by using Poisson regression for subjects aged 0-74 years.</p> <p>Results</p> <p>All cancer incidence did not differ from expectations in any of the contaminated zones. An excess of lymphatic and hematopoietic tissue neoplasms was observed in zones A (four cases; RR, 1.39; 95% CI, 0.52-3.71) and B (29 cases; RR, 1.56; 95% CI, 1.07-2.27) consistent with the findings of the concurrent mortality study. An increased risk of breast cancer was detected in zone A females after 15 years since the accident (five cases, RR, 2.57; 95% CI, 1.07-6.20). No cases of soft tissue sarcomas occurred in the most exposed zones (A and B, 1.17 expected). No cancer cases were observed among subjects diagnosed with chloracne early after the accident.</p> <p>Conclusion</p> <p>The extension of the Seveso cancer incidence study confirmed an excess risk of lymphatic and hematopoietic tissue neoplasms in the most exposed zones. No clear pattern by time since the accident and zones was evident partly because of the low number of cases. The elevated risk of breast cancer in zone A females after 15 years since the accident deserves further and thorough investigation. The follow-up is continuing in order to cover the long time period (even decades) usually elapsing from exposure to carcinogenic chemicals and disease occurrence.</p

The influence of semantic and phonological factors on syntactic decisions: An event-related brain potential study

During language production and comprehension, information about a word's syntactic properties is sometimes needed. While the decision about the grammatical gender of a word requires access to syntactic knowledge, it has also been hypothesized that semantic (i.e., biological gender) or phonological information (i.e., sound regularities) may influence this decision. Event-related potentials (ERPs) were measured while native speakers of German processed written words that were or were not semantically and/or phonologically marked for gender. Behavioral and ERP results showed that participants were faster in making a gender decision when words were semantically and/or phonologically gender marked than when this was not the case, although the phonological effects were less clear. In conclusion, our data provide evidence that even though participants performed a grammatical gender decision, this task can be influenced by semantic and phonological factors

In Vivo Dioxin Favors Interleukin-22 Production by Human CD4+ T Cells in an Aryl Hydrocarbon Receptor (AhR)-Dependent Manner

The transcription factor aryl hydrocarbon receptor (AhR) mediates the effects of a group of chemicals known as dioxins, ubiquitously present in our environment. However, it is poorly known how the in vivo exposure to these chemicals affects in humans the adaptive immune response. We therefore assessed the functional phenotype of T cells from an individual who developed a severe cutaneous and systemic syndrome after having been exposed to an extremely high dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).T cells of the TCDD-exposed individual were studied for their capacity to produce cytokines in response to polyclonal and superantigenic stimulation, and for the expression of chemokine receptors involved in skin homing. The supernatants from T cells of the exposed individual contained a substantially increased amount of interleukin (IL)-22 but not of IL-17A, interferon (IFN)-γ or IL-10 when compared to nine healthy controls. In vitro experiments confirmed a direct, AhR-dependent, enhancing effect of TCDD on IL-22 production by CD4+ T cells. The increased production of IL-22 was not dependent on AhR occupancy by residual TCDD molecules, as demonstrated in competition experiments with the specific AhR antagonist CH-223191. In contrast, it was due to an increased frequency of IL-22 single producing cells accompanied by an increased percentage of cells expressing the skin-homing chemokine receptors CCR6 and CCR4, identified through a multiparameter flow cytometry approach. Of interest, the frequency of CD4+CD25(hi)FoxP3+ T regulatory cells was similar in the TCDD-exposed and healthy individuals.This case strongly supports the contention that human exposure to persistent AhR ligands in vivo induce a long-lasting effect on the human adaptive immune system and specifically polarizes CD4+ T cells to produce IL-22 and not other T cell cytokines with no effect on T regulatory cells

Predictors of serum dioxin levels among adolescent boys in Chapaevsk, Russia: A cross-sectional pilot study

BACKGROUND: Toxicological studies and limited human studies have demonstrated associations between exposure to polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and polychlorinated biphenyls (PCBs) and adverse developmental and reproductive health effects. Given that children may be particularly susceptible to reproductive and developmental effects of organochlorines, and the paucity of information available regarding childhood exposures to dioxins in particular, we undertook a pilot study to describe the distribution of, and identify potential predictors of exposure to, dioxin-like compounds and dioxins among adolescent boys in Chapaevsk, Russia. The pilot study was also designed to guide the development of a large prospective cohort study on the relationship of exposure to PCDDs, PCDFs, and PCBs with growth and pubertal development in peri-pubertal Chapaevsk boys. METHODS: 221 boys age 14 to 17 participated in the pilot study. Each of the boys, with his mother, was asked to complete a nurse-administered detailed questionnaire on medical history, diet, and lifestyle. The diet questions were used to measure the current and lifetime consumption of locally grown or raised foods. Blood samples from 30 of these boys were sent to the Centers for Disease Control and Prevention (CDC) for analysis of dioxins, furans and PCBs. RESULTS: The median (25(th), 75(th )percentile) concentrations for total PCDDs, PCDFs and coplanar PCBs were 95.8 pg/g lipids (40.9, 144), 33.9 pg/g lipids (20.4, 61.8), and 120 pg/g lipids (77.6, 157), respectively. For WHO-TEQs, the median (25(th), 75(th )percentile) for total PCDDs, PCDFs, and coplanar PCBs were 0.29 (0.1, 9.14), 7.98 (5.27, 12.3), and 7.39 (4.51, 11.9), respectively. Although TCDD was largely non-detectable, two boys had high TCDD levels (17.9 and 21.7 pg/g lipid). Higher serum levels of sum of dioxin-like compounds and sum of dioxin TEQs were positively associated with increased age, consumption of fish, local meats other than chicken, PCB 118, and inversely with weeks of gestation. CONCLUSION: The total TEQs among Chapaevsk adolescents were higher than most values previously reported in non-occupationally exposed populations of comparable or even older ages. Dietary consumption of local foods, as well as age and weeks of gestation, predicted dioxin exposure in this population

Teasing apart the heterogeneity of autism: Same behavior, different brains in toddlers with fragile X syndrome and autism

To examine brain volumes in substructures associated with the behavioral features of children with FXS compared to children with idiopathic autism and controls. A cross-sectional study of brain substructures was conducted at the first time-point as part of an ongoing longitudinal MRI study of brain development in FXS. The study included 52 boys between 18–42 months of age with FXS and 118 comparison children (boys with autism-non FXS, developmental-delay, and typical development). Children with FXS and autistic disorder had substantially enlarged caudate volume and smaller amygdala volume; whereas those children with autistic disorder without FXS (i.e., idiopathic autism) had only modest enlargement in their caudate nucleus volumes but more robust enlargement of their amygdala volumes. Although we observed this double dissociation among selected brain volumes, no significant differences in severity of autistic behavior between these groups were observed. This study offers a unique examination of early brain development in two disorders, FXS and idiopathic autism, with overlapping behavioral features, but two distinct patterns of brain morphology. We observed that despite almost a third of our FXS sample meeting criteria for autism, the profile of brain volume differences for children with FXS and autism differed from those with idiopathic autism. These findings underscore the importance of addressing heterogeneity in studies of autistic behavior

Characterization of PTZ-Induced Seizure Susceptibility in a Down Syndrome Mouse Model That Overexpresses CSTB

Down syndrome (DS) is a complex genetic syndrome characterized by intellectual disability, dysmorphism and variable additional physiological traits. Current research progress has begun to decipher the neural mechanisms underlying cognitive impairment, leading to new therapeutic perspectives. Pentylenetetrazol (PTZ) has recently been found to have positive effects on learning and memory capacities of a DS mouse model and is foreseen to treat DS patients. But PTZ is also known to be a convulsant drug at higher dose and DS persons are more prone to epileptic seizures than the general population. This raises concerns over what long-term effects of treatment might be in the DS population. The cause of increased propensity for epilepsy in the DS population and which Hsa21 gene(s) are implicated remain unknown. Among Hsa21 candidate genes in epilepsy, CSTB, coding for the cystein protease inhibitor cystatin B, is involved in progressive myoclonus epilepsy and ataxia in both mice and human. Thus we aim to evaluate the effect of an increase in Cstb gene dosage on spontaneous epileptic activity and susceptibility to PTZ-induced seizure. To this end we generated a new mouse model trisomic for Cstb by homologous recombination. We verified that increasing copy number of Cstb from Trisomy (Ts) to Tetrasomy (Tt) was driving overexpression of the gene in the brain, we checked transgenic animals for presence of locomotor activity and electroencephalogram (EEG) abnormalities characteristic of myoclonic epilepsy and we tested if those animals were prone to PTZ-induced seizure. Overall, the results of the analysis shows that an increase in Cstb does not induce any spontaneous epileptic activity and neither increase or decrease the propensity of Ts and Tt mice to myoclonic seizures suggesting that Ctsb dosage should not interfere with PTZ-treatment