Prenatal and early postnatal exposure to perfluoroalkyl substances and bone mineral content and density in the Odense child cohort.

INTRODUCTION: Exposure to perfluoroalkyl substances (PFAS) has been associated with lower bone mineral density (BMD) in animal and human studies, but prospective data from children are limited. OBJECTIVES: To determine associations between prenatal and early postnatal PFAS exposure and BMD at age 7 years. METHODS: In the Odense Child Cohort, Denmark, pregnant women were recruited in 2010-2012, and their children were invited for subsequent health examinations. At 12 weeks of gestation the pregnant women delivered a serum sample, and at age 18 months serum was obtained from the child to measure perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA) by LC-MS/MS. At age 7 years DXA scans were performed to measure bone mineral content (BMC) and BMD Z-score. PFAS in pregnancy (n = 924) and/or at age 18 months (n = 511) were regressed against DXA measurements, adjusted for maternal education, child height Z-score, sex (for BMC) and for postnatal exposure, additionally duration of total breastfeeding. We additionally performed structural equation models determining combined effects of pre-and postnatal PFAS exposures. RESULTS: Higher prenatal and early postnatal serum concentrations of all measured PFAS were associated with lower BMC and BMD Z-scores at age 7 years, all estimates were negative although not all significant. For each doubling of prenatal or 18-month exposure to PFDA, BMD Z-scores were lowered by -0.07 (95 % CI -0.10; -0.03) and -0.14 (-0.25; -0.03), respectively after adjustment. Pre- and postnatal PFAS were correlated, but structural equation models suggested that associations with BMD were stronger for 18-month than prenatal PFAS exposure. DISCUSSION: Bone density is established in childhood, and a reduction in BMD during early childhood may have long-term implication for peak bone mass and lifelong bone health. Future studies of the impact of PFAS exposure on fracture incidence will help elucidate the clinical relevance.

Severity of COVID-19 at elevated exposure to perfluorinated alkylates.

Background: The course of coronavirus disease 2019 (COVID-19) seems to be aggravated by air pollution, and some industrial chemicals, such as the perfluorinated alkylate substances (PFASs), are immunotoxic and may contribute as well. Methods: From Danish biobanks, we obtained plasma samples from 323 subjects aged 30-70 years with known SARS-CoV-2 infection. The PFAS concentrations measured at the background exposures included five PFASs known to be immunotoxic. Register data was obtained to classify disease status, other health information, and demographic variables. We used ordinal and ordered logistic regression analyses to determine associations between PFAS concentrations and disease outcome. Results: Plasma-PFAS concentrations were higher in males, in subjects with Western European background, and tended to increase with age, but were not associated with the presence of chronic disease. Of the study population, 108 (33%) had not been hospitalized, and of those hospitalized, 53 (16%) had been in intensive care or were deceased. Among the five PFASs considered, perfluorobutanoic acid (PFBA) showed an odds ratio (OR) of 2.19 (95% confidence interval, CI, 1.39-3.46) for increasing severities of the disease, although the OR decreased to 1.77 (95% CI, 1.09, 2.87) after adjustment for age, sex, sampling site and interval between blood sampling and diagnosis. Conclusions: Measures of individual exposures to immunotoxic PFASs included PFBA that accumulates in the lungs. Elevated plasma-PFBA concentrations were associated with an increased risk of more severe course of CIVID-19. Given the low background exposure levels in this study, the role of PFAS exposure in COVID-19 needs to be ascertained in populations with elevated exposures.

Epigenetics as a mechanism linking developmental exposures to long-term toxicity.

A variety of experimental and epidemiological studies lend support to the Developmental Origin of Health and Disease (DOHaD) concept. Yet, the actual mechanisms accounting for mid- and long-term effects of early-life exposures remain unclear. Epigenetic alterations such as changes in DNA methylation, histone modifications and the expression of certain RNAs have been suggested as possible mediators of long-term health effects of environmental stressors. This report captures discussions and conclusions debated during the last Prenatal Programming and Toxicity meeting held in Japan. Its first aim is to propose a number of criteria that are critical to support the primary contribution of epigenetics in DOHaD and intergenerational transmission of environmental stressors effects. The main criteria are the full characterization of the stressors, the actual window of exposure, the target tissue and function, the specificity of the epigenetic changes and the biological plausibility of the linkage between those changes and health outcomes. The second aim is to discuss long-term effects of a number of stressors such as smoking, air pollution and endocrine disruptors in order to identify the arguments supporting the involvement of an epigenetic mechanism. Based on the developed criteria, missing evidence and suggestions for future research will be identified. The third aim is to critically analyze the evidence supporting the involvement of epigenetic mechanisms in intergenerational and transgenerational effects of environmental exposure and to particularly discuss the role of placenta and sperm. While the article is not a systematic review and is not meant to be exhaustive, it critically assesses the contribution of epigenetics in the long-term effects of environmental exposures as well as provides insight for future research.

Children's white blood cell counts in relation to developmental exposures to methylmercury and persistent organic pollutants.

BACKGROUND: To explore possible markers of developmental immunotoxicity, we prospectively examined 56 children to determine associations between exposures to methylmercury and persistent organic pollutants since birth and the comprehensive differential counts of white blood cells (WBC) at age 5 years. MATERIALS AND METHODS: Extended differential count included: neutrophils, eosinophils, basophils, lymphocytes (includingT cells, NK cells, and B cells), and monocytes. Organochlorine compounds (OCs) including polychlorinated biphenyls (PCBs) and pesticides, five perfluoroalkyl substances (PFASs), and total mercury (Hg) were measured in maternal (n=56) and children's blood at 18 months (n=42) and 5 years (n=54). We constructed latent functions for exposures at three different ages using factor analyses and applied structural equation models adjusted for covariates. RESULTS: Prenatal mercury exposure was associated with depleted total WBC, especially for lymphocytes, where a one standard deviation (SD) increase in the exposure was associated with a decrease by 23% SD (95% CI: -43, -4) in the cell count. Prenatal exposure to OCs was marginally associated with decreases in neutrophil counts. In contrast, the 5-year PFASs concentrations were associated with higher basophil counts (B=46% SD, 95% CI: 13, 79). Significantly reduced subpopulations of lymphocytes such as B cells, CD4-positive T helper cells and CD4 positive recent thymic emigrants may suggest cellular immunity effects and dysregulation of T-cell mediated immunity. CONCLUSION: Developmental exposure to environmental immunotoxicants appears to have different impacts on WBC counts in childhood.

Prenatal pesticide exposure and PON1 genotype associated with adolescent body fat distribution evaluated by dual X-ray absorptiometry (DXA).

Many modern pesticides have endocrine disrupting abilities and early-life exposure may affect growth and disease risk later in life. Previously, we reported associations between prenatal pesticide exposure and higher childhood body fat content measured by anthropometry. The associations were affected by child PON1 Q192R genotype. We aimed to study whether prenatal pesticide exposure was still associated with body fat content and distribution in the children at puberty and the potential impact of both maternal and child PON1 Q192R genotype. In this prospective cohort study of 247 children born by occupationally exposed or unexposed women (greenhouse workers and controls) two follow-up examinations (age 10-15 and 11-16 years) including simple anthropometry, skinfold measurements, pubertal staging and blood sampling were performed. Total and regional fat% was determined by dual X-ray absorptiometry (DXA) at age 10-15. Prenatal pesticide exposure was associated with increased total, android, and gynoid fat percentage (DXA) at age 10-15 years after adjustment for sex, socioeconomic status, and puberty (all ß = 0.5 standard deviation score (SDS) p < 0.05). Stratified by sex, the associations were significant in girls (total fat: ß = 0.7 SDS, android-gynoid ratio: ß = 0.1, both p < 0.05), but not in boys. Carrying the R-allele (child or mother, separately, or both) augmented the differences between exposed and unexposed children (total fat: ß = 1.0 SDS, ß = 0.8 SDS, p < 0.05, respectively, and ß = 1.2 SDS, p < 0.01). No exposure-related differences were found if either the child or mother had the QQ wild-type. At age 11-16, exposed children tended to have a higher total fat% estimated by skinfolds than unexposed children (p = 0.06). No significant associations between prenatal exposure and body mass index or waist circumference were found. Prenatal pesticide exposure was associated with higher adolescent body fat content, including android fat deposition, independent of puberty. Girls appeared more susceptible than boys. Furthermore, the association depended on maternal and child PON1 Q192R genotype.

Burden of disease and costs of exposure to endocrine disrupting chemicals in the European Union: an updated analysis.

A previous report documented that endocrine disrupting chemicals contribute substantially to certain forms of disease and disability. In the present analysis, our main objective was to update a range of health and economic costs that can be reasonably attributed to endocrine disrupting chemical exposures in the European Union, leveraging new burden and disease cost estimates of female reproductive conditions from accompanying report. Expert panels evaluated the epidemiologic evidence, using adapted criteria from the WHO Grading of Recommendations Assessment, Development and Evaluation Working Group, and evaluated laboratory and animal evidence of endocrine disruption using definitions recently promulgated by the Danish Environmental Protection Agency. The Delphi method was used to make decisions on the strength of the data. Expert panels consensus was achieved for probable (>20%) endocrine disrupting chemical causation for IQ loss and associated intellectual disability; autism; attention deficit hyperactivity disorder; endometriosis; fibroids; childhood obesity; adult obesity; adult diabetes; cryptorchidism; male infertility, and mortality associated with reduced testosterone. Accounting for probability of causation, and using the midpoint of each range for probability of causation, Monte Carlo simulations produced a median annual cost of €163 billion (1.28% of EU Gross Domestic Product) across 1000 simulations. We conclude that endocrine disrupting chemical exposures in the EU are likely to contribute substantially to disease and dysfunction across the life course with costs in the hundreds of billions of Euros per year. These estimates represent only those endocrine disrupting chemicals with the highest probability of causation; a broader analysis would have produced greater estimates of burden of disease and costs.

Toxicology research for precautionary decision-making and the role of Human & Experimental Toxicology.

A key aim of toxicology is the prevention of adverse effects due to toxic hazards. Therefore, the dissemination of toxicology research findings must confront two important challenges: one being the lack of information on the vast majority of potentially toxic industrial chemicals and the other being the strict criteria for scientific proof usually required for decision-making in regard to prevention. The present study ascertains the coverage of environmental chemicals in four volumes of Human & Experimental Toxicology and the presentation and interpretation of research findings in published articles. Links in SciFinder showed that the 530 articles published in four selected volumes between 1984 and 2014 primarily dealt with metals (126 links) and other toxicants that have received substantial attention in the past. Thirteen compounds identified by US authorities in 2006 as high-priority substances, for which toxicology documentation is badly needed, were not covered in the journal issues at all. When reviewing published articles, reliance on p values was standard, and non-significant findings were often called 'negative.' This tradition may contribute to the perceived need to extend existing research on toxic hazards that have already been well characterized. Several sources of bias towards the null hypothesis can affect toxicology research, but are generally not considered, thus adding to the current inclination to avoid false positive findings. In this regard, toxicology is particularly prone to bias because of the known paucity of false positives and, in particular, the existence of a vast number of toxic hazards which by default are considered innocuous due to lack of documentation. The Precautionary Principle could inspire decision-making on the basis of incomplete documentation and should stimulate a change in toxicology traditions and in toxicology research publication.

Spermatogenic capacity in fertile men with elevated exposure to polychlorinated biphenyls.

BACKGROUND: Endocrine disrupting industrial chemicals, such as polychlorinated biphenyls (PCBs), are suspected to adversely affect male reproductive functions. OBJECTIVES: The Faroe Islands community exhibits an unusually wide range of exposures to dietary contaminants, and in this setting we examined the possible association between PCB exposure and semen quality and reproductive hormones in fertile Faroese men. METHODS: Participants in this cross-sectional study include 266 proven fertile men residing in the Faroe Islands. PCB levels and hormone profiles were measured in serum samples taken at the clinical examination that included semen quality parameters. RESULTS: A significant positive association was seen between serum-PCB and the testosterone/estradiol ratio (p=0.04). In the unadjusted analyses, elevated PCB exposure was associated with increased serum concentrations of SHBG (p=0.01) and FSH (p=0.05). We found no association between the serum PCB concentration and the semen quality variables. CONCLUSION: In this population of highly exposed fertile men, the current serum-PCB concentration was associated with higher androgen/estrogen ratio. Further studies are needed to establish the findings and further document PCB-associated hormonal effects, any time windows of increased susceptibility, and the role of PCB in sub-fecundity.

Exposure to persistent organic pollutants and sperm sex chromosome ratio in men from the Faroe Islands.

People in the Arctic as well as fishermen on the polluted Swedish east coast are highly exposed to persistent organic pollutants (POPs). These compounds have been shown to affect the sperm Y:X chromosome ratio. In present study, the aim was to investigate whether polychlorinated biphenyl (PCB) congeners and 1,1,-dichloro-2,2,-bis(p-chlorophenyl)ethane (p,p'-DDE) influence sperm sex chromosome ratio in Faroese men, and whether these men differ regarding Y:X ratio compared to Greenland Inuit and Swedish fishermen. The study population (n=449) consisted of young men from the general population (n=276) as well as proven fertile men (n=173). The Y:X ratio was assessed by fluorescent in situ hybridization. Serum concentrations of POPs were measured using gas chromatography. Associations between POP concentrations and Y:X ratio were calculated using linear and non-linear regression models as well as trend analysis and pairwise comparison of exposure data categorized into quartiles. The selected POPs were associated with Y:X ratio in fertile Faroese men, but not in the total population; p,p'-DDE (95% CI for B=-0.005 to -0.001, p=0.005) and ΣPCB (95% CI for B=-0.005 to -0.001, p=0.012). Since p,p'-DDE and ΣPCB correlated significantly (r=0.927, p<0.001), the results involving the exposure variables can be regarded as a single finding. The Y:X ratio for the total Faroese population was 0.500±0.018, which was statistically significantly lower than in both Inuit and Swedish fishermen (0.512 for both). In conclusion, Faroese men presented with lower Y:X ratio than Greenland Inuit and Swedish fishermen. Although no direct health effects are expected due to the lower Faroese Y:X ratio, it could be indicative of adverse effects on the reproductive system.

[The use of intrauterine device in nulliparous over 18 years: a Belgian consensus]. / La contraception intra-utérine chez la nultlipare de plus de 18 ans: vers un consensus belge.

Under the presidency of prof. H. Depypere (UZ Ghent) and Prof. P. Simon (ULB Erasme) a Belgian panel of thirteen experts (gynecologists, representatives of universities and scientific associations for gynecology-obstetrics) reached a consensus on the use of intrauterine systems, both copper IUDs as hormone IUDs, in nultiparous women.

Early breast development in girls after prenatal exposure to non-persistent pesticides.

Contemporary American and European girls experience breast development at earlier ages compared with 15-20 years ago. Alterations in BMI alone cannot account for these changes. Several currently used pesticides possess endocrine disrupting properties and may interfere with reproductive development, but human data are sparse. We examined girls whose mothers worked in greenhouses in the first trimester of pregnancy to assess the long-term effects of prenatal pesticide exposure on puberty. Mothers were prenatally categorized as exposed or unexposed to pesticides. We studied the offspring of these greenhouse workers, and evaluated the anthropometry, pubertal staging in the girls, and blood samples were drawn at 3 months of age (n = 90) and again once at school age (6-11 years, n = 83). No clinical and biochemical differences were found between the exposed and unexposed girls at 3 months of age. Mean onset of B2+ was 8.9 years (95% CI: 8.2; 9.7) in prenatally exposed girls, compared with 10.4 years (9.2; 17.6) in the unexposed (p = 0.05), and 10.0 (9.7-10.3) years in a Danish reference population (p = 0.001). Exposed girls had higher serum androstenedione levels (geometric means: 0.58 vs. 0.79 nmol/L, p = 0.046) and lower Anti-Müllerian Hormone (AMH) compared with the unexposed (geometric means: 16.4 vs. 21.3 pmol/L, p > 0.05) and the reference group (20.2 pmol/L, p = 0.012). Levels of testosterone, estradiol, prolactin, FSH, LH, SHBG, DHEAS, DHT, Inhibin A and Inhibin B did not differ between the groups. In conclusion, our findings suggest that prenatal exposure to currently approved pesticides may cause earlier breast development in girls. This association appeared not to be because of changes in gonadotropins, but rather to higher androgen levels, which indirectly may increase oestrogens through aromatization. In addition, lower serum AMH levels indicated a reduced pool of antral ovarian follicles. The long-term consequences of our findings with regard to establishment of future reproductive function still remain unknown.

Smaller genitals at school age in boys whose mothers were exposed to non-persistent pesticides in early pregnancy.

Endocrine disrupting chemicals are believed to play a role in the development of the testicular dysgenesis syndrome. Many pesticides are known to have endocrine disrupting abilities. In a previous study, sons of women who were occupationally exposed to non-persistent pesticides in early pregnancy showed signs of impaired reproductive function (reduced genital size and altered serum hormone concentrations) at three months of age. To assess the possible long-term effects of prenatal pesticide exposure, the boys were re-examined at 6-11 years. The 94 boys (59 exposed, 35 unexposed) underwent genital examinations including ultrasound of testicular volumes, puberty staging (Tanner), anthropometry, and blood sampling. Only a few of the boys had reached puberty (n = 3). Among prepubescent boys, testicular volume and penile length (age- and weight-adjusted) were reduced if mothers were exposed to pesticides. The effects were associated with the maternal exposure levels, so that high-exposed boys had smaller genitals than medium-exposed boys, who had smaller genitals than those who were unexposed. Boys of mothers in the high exposure group (n = 23) had 24.7% smaller testes (95% CI: -62.2; -10.1) and 9.4% shorter penile length (95% CI: -16.8; -1.1) compared with the unexposed. The testicular volume and penile length at school age could be tracked to measures from the same boys made at 3 months, e.g. those that had small testes at school age also had small testes at 3 months. Pituitary and testicular hormone serum concentrations did not differ between exposed and unexposed boys. Eight prenatally exposed boys had genital malformations (no unexposed). These boys had smaller testis, shorter penile length and lower inhibin B concentrations than prepubertal boys without genital malformations. The findings support the results obtained at three months of age and indicate that prenatal pesticide exposure has long-term effects on reproductive function in boys.

Secondary retroperitoneal teratoma.

Retroperitonal teratomas are rare. We report on a case of a retroperitoneal secondary localisation of a gonadal teratoma in a patient who had developed primary testicular teratoma 12 years previously. The retroperitoneal mass was detected with an abdominal CT requested for the management of a non-specific abdominal pain. CT and MRI examinations showed cystic retroperitoneal masses combined with calcifications and peripheral enhancement. Review of the literature is presented, including the common differential diagnoses to be considered.

Individual radiation therapy patient whole-body phantoms for peripheral dose evaluations: method and specific software.

This study presents a method aimed at creating radiotherapy (RT) patient-adjustable whole-body phantoms to permit retrospective and prospective peripheral dose evaluations for enhanced patient radioprotection. Our strategy involves virtual whole-body patient models (WBPM) in different RT treatment positions for both genders and for different age groups. It includes a software tool designed to match the anatomy of the phantoms with the anatomy of the actual patients, based on the quality of patient data available. The procedure for adjusting a WBPM to patient morphology includes typical dimensions available in basic auxological tables for the French population. Adjustment is semi-automatic. Because of the complexity of the human anatomy, skilled personnel are required to validate changes made in the phantom anatomy. This research is part of a global project aimed at proposing appropriate methods and software tools capable of reconstituting the anatomy and dose evaluations in the entire body of RT patients in an adapted treatment planning system (TPS). The graphic user interface is that of a TPS adapted to obtain a comfortable working process. Such WBPM have been used to supplement patient therapy planning images, usually restricted to regions involved in treatment. Here we report, as an example, the case of a patient treated for prostate cancer whose therapy planning images were complemented by an anatomy model. Although present results are preliminary and our research is ongoing, they appear encouraging, since such patient-adjusted phantoms are crucial in the optimization of radiation protection of patients and for follow-up studies.

Prevalence and incidence of Parkinson's disease in The Faroe Islands.

OBJECTIVE: A study in The Faroe Islands in 1995 suggested a high prevalence of idiopathic Parkinson's disease (IPD) and total parkinsonism of 187.6 and 233.4 per 100,000 inhabitants respectively. METHODS: Detailed case-finding methods 10 years later were used and a neurologist has verified the diagnosis. RESULTS: The crude prevalence of IPD and total parkinsonism was 206.7 per 100,000 and 227.4 per 100,000 respectively. The age-adjusted prevalence is twice as high as data from Norway and Denmark. Age at initiation of treatment and the fatality rate did not explain the increased prevalence. During 1995-2005, the average annual incidence was 21.1 per 100,000 persons for Parkinson's disease, and 22.9 per 100,000 persons, if including atypical parkinsonism. CONCLUSION: The high prevalence was verified and linked to a high incidence. The cause of the high prevalence is unknown, but neurotoxic contaminants in traditional food may play a role in the pathogenesis in this population, perhaps jointly with genetic predisposition.

Indicadores biológicos para la valoración de la exposición humana a compuestos químicos industriales : Níquel

Traducción de la obra en inglés \"Biological indicators for the assessment of human exposure to industrial chemicals\" publicada por la Oficina para las Publicaciones Oficiales de las Comunidades Europeas. Contiene: propiedades químicas y físicas del níquel, metabolismo, indicadores biológicos, níquel en sangre, orina, heces y tejidos...

Indicadores biológicos para la valoración de la exposición humana a compuestos químicos industriales : Monóxido de Carbono, Etilbenceno, Metilestireno, Isopropilbenceno, Selenio

Traducción de la obra en inglés \"Biological indicators for the assessment of human exposure to industrial chemicals\" (EUR 12174 EN) publicada por la Oficina para las Publicaciones Oficiales de las Comunidades Europeas. Contiene: propiedades físicas y químicas, efectos en humanos, metabolismo, efectos en los humanos, indicadores biológicos, indicadores de efectos...