No abstract

The European Commission asked EFSA for a scientific evaluation on the risks to human health related to the presence of perfluoroalkyl substances ( PFAS s) in food. Based on several similar effects in animals, toxicokinetics and observed concentrations in human blood, the CONTAM Panel decided to perform the assessment for the sum of four PFAS s: PFOA , PFNA , PFH xS and PFOS . These made up half of the lower bound ( LB ) exposure to those PFAS s with available occurrence data, the remaining contribution being primarily from PFAS s with short half‐lives. Equal potencies were assumed for the four PFAS s included in the assessment. The mean LB exposure in adolescents and adult age groups ranged from 3 to 22, the 95th percentile from 9 to 70 ng/kg body weight (bw) per week. Toddlers and ‘other children’ showed a twofold higher exposure. Upper bound exposure was 4‐ to 49‐fold higher than LB levels, but the latter were considered more reliable. ‘Fish meat’, ‘Fruit and fruit products’ and ‘Eggs and egg products’ contributed most to the exposure. Based on available studies in animals and humans, effects on the immune system were considered the most critical for the risk assessment. From a human study, a lowest BMDL 10 of 17.5 ng/ mL for the sum of the four PFAS s in serum was identified for 1‐year‐old children. Using PBPK modelling, this serum level of 17.5 ng/ mL in children was estimated to correspond to long‐term maternal exposure of 0.63 ng/kg bw per day. Since accumulation over time is important, a tolerable weekly intake ( TWI ) of 4.4 ng/kg bw per week was established. This TWI also protects against other potential adverse effects observed in humans. Based on the estimated LB exposure, but also reported serum levels, the CONTAM Panel concluded that parts of the European population exceed this TWI , which is of concern.

No abstract

Recent reports have shown that low birth weight infants have a higher incidence of adult hypertension. These observations have stimulated a number of studies designed to evaluate the mechanisms of this phenomenon. In this study, fetal growth retardation was induced by treating pregnant rats with dexamethasone. After birth, pups whose mothers were treated with dexamethasone had a lower body and kidney weight and a lower number of glomeruli than control pups. Immunohistochemistry on treated kidneys demonstrated a marked reduction in the number of cells undergoing mitosis in the cortical nephrogenic zone. In the treated group, body and kidney weight normalized by 60 d of age, but blood pressure was significantly higher compared with controls (130+/-4 versus 107+/-1 mm Hg). In addition, GFR was significantly lower, albuminuria was higher, urinary sodium excretion rate and fractional sodium excretion were lower, and sodium tissue content was higher. In contrast, when pregnant rats were treated with a natural glucocorticoid (hydrocortisone) which is metabolized by the placenta, fetal development and adult blood pressure were normal. In conclusion, we found that high levels of maternal glucocorticoids impair renal development and lead to arterial hypertension in offspring. Even though renal mass eventually normalizes, glomerular damage as well as sodium retention occur and these factors may contribute to the development of hypertension.

The effect of intracerebroventricular injection of the mitosis inhibitor colchicine and of immobilization stress, subcutaneous injection of capsaicin, and intraperitoneal injection of hypertonic salt solution on expression of c-Fos-like immunoreactivity was studied in the rat brain with immunohistochemistry. All the procedures induced c-Fos immunoreactivity in parvocellular neurons of the paraventricular nucleus, and many of these neurons also contained corticotropinreleasing factor immunoreactivity. c-Fos immunoreactivity was also observed, for example, in subpopulations of neurons in the locus coeruleus, the ventrolateral medulla oblongata, and the nucleus tractus solitarii. Many of these cells also expressed catecholamine-synthesizing enzymes. The results suggest that intraventricular injection of colchicine is a stressful stimulus and support the view that several catecholamine cell groups in the lower brainstem are part of the brain circuitry mediating stress reactions, as are the hypothalamic neurons that contain corticotropin-releasing factor.The c-fos gene (1, 2) is expressed in many tissues in response to growth factor stimulation (3-9). It has been suggested that induction of protooncogenes such as c-fos may be important in the establishment of prolonged functional changes in neurons (10). It has been demonstrated by immunohistochemical methods that various types of stimulation induce a c-Fos protein-like immunoreactivity in specific neuron populations in various brain regions (11)(12)(13). Thus, immunohistochemical analysis of expression of c-Fos protein in nervous tissue may represent a new tool in neurobiology for metabolic mapping at the cellular level (14). In fact, numerous papers based on this methodology have appeared during the last 2 years.In the present study we have used immunohistochemistry to analyze to what extent various stressors may induce expression of c-Fos-like immunoreactivity in certain brain regions. In addition, antisera to neuropeptides and transmitter-synthesizing enzymes were used to further characterize c-Fos-activated neurons. Of particular interest to us has been the question whether or not intracerebroventricular (i.c.v.) injections of the mitosis inhibitor colchicine (15) may affect stress-related systems. Ever since colchicine was shown to inhibit axonal transport (16,17) and to cause marked accumulation of amine storage granules in cell bodies (18), this drug has been used to improve histochemical visualization of transmitters, peptides, and related substances in neuronal cell bodies (19,20). Our results demonstrate that several stress-inducing procedures as well as i.c.v. colchicine treatment, including the i.c.v. injection procedure per se, cause expression of c-Fos protein in restricted neuronal cell populations both in the hypothalamus, including the corticotropin-releasing factor (CRF)-positive neurons in the paraventricular nucleus (PVN), and in the lower brainstem, particularly in catecholamine neurons. MATERIALS AND METHODSMale Sprague-Dawley rats (250...

The European Commission asked EFSA for a scientific evaluation on the risks to human health related to the presence of perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) in food. Regarding PFOS and PFOA occurrence, the final data set available for dietary exposure assessment contained a total of 20,019 analytical results (PFOS n = 10,191 and PFOA n = 9,828). There were large differences between upper and lower bound exposure due to analytical methods with insufficient sensitivity. The CONTAM Panel considered the lower bound estimates to be closer to true exposure levels. Important contributors to the lower bound mean chronic exposure were 'Fish and other seafood', 'Meat and meat products' and 'Eggs and egg products', for PFOS, and 'Milk and dairy products', 'Drinking water' and 'Fish and other seafood' for PFOA. PFOS and PFOA are readily absorbed in the gastrointestinal tract, excreted in urine and faeces, and do not undergo metabolism. Estimated human half-lives for PFOS and PFOA are about 5 years and 2-4 years, respectively. The derivation of a health-based guidance value was based on human epidemiological studies. For PFOS, the increase in serum total cholesterol in adults, and the decrease in antibody response at vaccination in children were identified as the critical effects. For PFOA, the increase in serum total cholesterol was the critical effect. Also reduced birth weight (for both compounds) and increased prevalence of high serum levels of the liver enzyme alanine aminotransferase (ALT) (for PFOA) were considered. After benchmark modelling of serum levels of PFOS and PFOA, and estimating the corresponding daily intakes, the CONTAM Panel established a tolerable weekly intake (TWI) of 13 ng/kg body weight (bw) per week for PFOS and 6 ng/kg bw per week for PFOA. For both compounds, exposure of a considerable proportion of the population exceeds the proposed TWIs.

No abstract

Substantial evidence indicates that predisposition to diseases can be acquired during early stages of development and interactions between environmental and genetic factors may be implicated in the onset of many pathological conditions. Data collected over several decades have shown that chemicals are among the relevant factors that can endanger CNS. We previously showed that perinatal exposure to methylmercury (MeHg) causes persistent changes in learning and motivational behavior in mice. In this study, we report that the depression‐like behavior in MeHg‐exposed male mice is reversed by chronic treatment with the antidepressant fluoxetine. Behavioral alterations are associated with a decrease in brain‐derived neurotrophic factor (BDNF) mRNA in the hippocampal dentate gyrus and fluoxetine treatment restores BDNF mRNA expression. We also show that MeHg‐exposure induces long‐lasting repressive state of the chromatin structure at the BDNF promoter region, in particular DNA hypermethylation, an increase in histone H3‐K27 tri‐methylation and a decrease in H3 acetylation at the promoter IV. While fluoxetine treatment does not alter hypermethylation of H3‐K27, it significantly up‐regulates H3 acetylation at the BDNF promoter IV in MeHg‐exposed mice. Our study shows that developmental exposure to low levels of MeHg predisposes mice to depression and induces epigenetic suppression of BDNF gene expression in the hippocampus.