Putative adverse outcome pathways for female reproductive disorders to improve testing and regulation of chemicals

Modern living challenges female reproductive health. We are witnessing a rise in reproductive disorders and drop in birth rates across the world. The reasons for these manifestations are multifaceted and most likely include continuous exposure to an ever-increasing number of chemicals. The cause-effect relationships between chemical exposure and female reproductive disorders, however, have proven problematic to determine. This has made it difficult to assess the risks chemical exposures pose to a woman's reproductive development and function. To address this challenge, this review uses the adverse outcome pathway (AOP) concept to summarize current knowledge about how chemical exposure can affect female reproductive health. We have a special focus on effects on the ovaries, since they are essential for lifelong reproductive health in women, being the source of both oocytes and several reproductive hormones, including sex steroids. The AOP framework is widely accepted as a new tool for toxicological safety assessment that enables better use of mechanistic knowledge for regulatory purposes. AOPs equip assessors and regulators with a pragmatic network of linear cause-effect relationships, enabling the use of a wider range of test method data in chemical risk assessment and regulation. Based on current knowledge, we propose ten putative AOPs relevant for female reproductive disorders that can be further elaborated and potentially be included in the AOPwiki. This effort is an important step towards better safeguarding the reproductive health of all girls and women.Peer reviewe

Does perinatal exposure to endocrine disruptors induce autism spectrum and attention deficit hyperactivity disorders? Review

Aim: To provide an overview of studies on perinatal exposure in humans to endocrine disrupting chemicals (EDCs) in relation to autism spectrum (ASD) and attention deficit hyperactivity (ADHD) disorders. Methods: A review of the literature (PubMed) was performed. Exposure-related keywords, including various chemicals, were matched with keywords describing outcome. Animal studies as well as publications not written in English were excluded. In total, 834 titles were retrieved. The final selection included 21 publications. Results: Positive associations were found for ASD in relation to exposure to all chemicals investigated, which included hazardous air pollutants, pesticides and bisphenol A (BPA). Increased risks of ADHD or positive associations were found for exposure to polychlorinated biphenyls (PCBs), dialkyl phosphate (DAP) and chlorpyrifos. BPA, polybrominated diphenylethers (PBDEs) and low molecular weight (LMW) phthalates were positively associated with externalizing behaviour. Five of 17 studies did not find any association between exposure and ADHD. Conclusion: Perinatal exposure to EDCs appears to be associated with the occurrence of ASD as well as ADHD. Disruption of thyroid hormone function and gamma-aminobutyric acid (GABA)ergic mechanisms may offer an explanation for the observed relations; though, conclusive evidence in humans is limited

Toddler exposure to flame retardant chemicals: Magnitude, health concern and potential risk- or protective factors of exposure: Observational studies summarized in a systematic review

Endocrine disrupting flame retardant (FR) chemicals form a human health concern, that is investigated mostly from the perspective of adult- and early life exposure. No overview of studies on toddler exposure and health effects exist. However, toddlerhood is a critical developmental period and toddlers are at increased risk for exposure because of their age-specific behavior. This systematic review encompasses toddler FR exposure studies in three countries, associated health effects and potential environmental, demographic, or behavioral risk- or protective factors for toddler exposure. A systematic literature search in four databases (PubMed, Embase.com, The Cochrane Library (via Wiley) and Web of Science Core collection) resulted in the identification of ten publications representing seven unique studies that measured brominated and/or phosphorylated FRs in toddlers' (8-24 month-old) serum, urine, hand wipes and feces. This review showed that toddlers are exposed to a range of FRs, that thyroid hormone disruption is associated with FR exposure and that factors in the indoor environment, including products such as plastic toys, might increase FR exposure. Considering the limited amount of studies, and the variety of biological matrices, FRs, and risk- and protective factors, this review did not reveal a uniform pattern of toddler exposure across the different cohorts studied. More evidence is necessary and considering the feasibility of invasive sampling in young children, we suggest to emphasize research on non-invasive matrices

Association of exposure to organophosphate flame retardants and children's behavior at a median age of 18 months

Exposure to polybrominated diphenyl ether (PBDE) flame retardants (FRs) could have adverse effects on neurodevelopment in children. Some organophosphate (OPFRs) are used as alternatives for the phased-out decabromodiphenylether such as resorcinol bis(diphenyl phosphate (PBDPP) and bisphenol A bis(diphenyl phosphate (BPA-BDPP). This study aims to investigate the relationship between indoor OPFR exposure and neurodevelopmental behavior in children. OPFRs were measured in house dust and hand wipes from 42 children, aged 8-16 months, from the LInking maternal Nutrition to Child health (LINC) study. At the median age of 18 months, the children's behavior was assessed with the Child Behavior Checklist, using three composite behavior scales: externalizing problems, internalizing problems, and total problems. Linear regression analysis was performed, adjusting for maternal education and smoking by the partner. Children with higher BPA-BDPP, PBDPP, and tris(chloroethyl) phosphate (TCEP) house dust concentrations were found to have higher scores on the behavioral problems scales. A 10-fold increase in BPA-BDPP and PBDPP concentration was associated with a 4.1 and 2.6 point increase on the internalizing problems scale (respectively p=0.004 and p=0.042). Increased BPA-BDPP concentrations were associated with elevated scores on the externalizing problems scale and total behavioral problems scale (respectively 7.6 and 16 points increase per 10-fold BPA-BDPP concentration increase, p=0.015 and p=0.007). TCEP dust concentrations were associated with the externalizing problems scale (13 point increase per 10-fold TCEP concentration increase, p=0.043). This study showed the importance of investigating the health effects of exposure to organophosphate flame retardants. Further research on neurodevelopmental health effects of OPFR exposure is warranted

Toddler behavior, the home environment, and flame retardant exposure

Toddlers are at increased risk of dust ingestion and subsequently flame retardant (FR) exposure because they often play close to the floor and mouth hands and objects. Exposure to some FRs have been associated to endocrine disruption and neurodevelopmental disorders. Previous research has shown higher FR concentrations in toddlers’ serum and urine, but which toddler-behaviors influence exposure levels remains to be determined. We investigated how toddler-behaviors are associated to FRs in hand wipes (HWs) and saliva. Fifty 8-18 month-old children from the Linking EDCs in maternal Nutrition to Child health study, were visited at home. The child's behavior was observed and assessed using a questionnaire. Hand-to-object behavior frequency was associated with HW tris(chloroethyl) phosphate (TCEP), tris(1,3-dichloroisopropyl) phosphate (TDCIPP), tris(phenyl) phosphate, tris(methylphenyl) phosphate, and resorcinol bis(diphenyl phosphate) levels above the detection limit. Children playing with electronics multiple times per week had higher TDCIPP HW levels compared to children playing with electronics once per month or never (p = 0.032 and p = 0.046). Frequent mouth-to-object and frequent mouthing a pacifier were associated with lower TDCIPP (p = 0.019) and tris(2-chloroisopropyl) phosphate (TCIPP) HW levels, respectively (p = 0.002–0.019). Exposure estimates based on hand-to-mouth behavior did not exceed the available reference doses. This is the first study investigating toddler-behavior in relation to FR hand loadings. Although a range of behaviors was investigated, only a few showed a relation with FR HW levels, suggesting that toddler-behavior might not alone be responsible for the elevated FR levels in children. It is therefore important to explore other pathways including dermal absorption and inhalation

Electronics, interior decoration and cleaning patterns affect flame retardant levels in the dust from Dutch residences

Consumer products such as furniture foam and electronic device casings are treated with flame retardant chemicals (FRs) to prevent the spread of fire. Many FRs are able to leach out of a product and end up in house dust. FRs in house dust can be taken up by humans through inhalation, ingestion or dermal adsorption. This study aims to identify factors in the home environment that are associated with FR levels in house dust. House dust and a wide range of data on characteristics of electronics, including age and use, interior decoration, domestic house and cleaning patterns, were collected from 50 households in the Netherlands. Decabromodiphenyl ether (BDE209) and several organophosphate flame retardants were measured in dust at detection percentages ranging from 58 to 94%, with median concentrations ranging from 32 ng/g (resorcinol-bis(diphenyl)phosphate (PBDPP)) to 825 ng/g (tris(chloropropyl)phosphate (TCIPP)). For the first time, age, hours of operation and use of the standby function of electronic devices were found to affect FR levels in dust. We found that if the total number of electronic devices purchased before 2008 increased by 1 device, BDE209 levels in house dust significantly increased by 66%. In addition, house dust from homes with carpeted floors was significantly associated with a 70–80% lower concentration of several FRs compared to homes with smooth floors (e.g., laminate). Less frequent vacuum cleaning and dusting were significantly associated with 41 to 88% higher concentrations of several FRs in dust. These associations suggest that actions such as frequent vacuum cleaning and dusting as well as different FR regulations for electronic devices affect indoor exposure levels

LInking EDCs in maternal Nutrition to Child health (LINC study) - protocol for prospective cohort to study early life exposure to environmental chemicals and child health

Abstract Background The presence of chemicals in the environment is ubiquitous. Human biomonitoring studies have shown that various chemicals can be detected in the majority of the population, including pregnant women. These compounds may pass the placenta, and reach the fetus. This early life exposure in particular may be detrimental as some chemicals may disrupt the endocrine system, which is involved in various processes during development. The LINC study is a prospective birth cohort designed to study associations between early life environmental exposures and child health, including growth and neurodevelopment. The purpose of this paper is to give an overview of this cohort. Methods and design Recruitment for this cohort has started in 2011 in three Dutch areas and is still ongoing. To date over 300 mother-child pairs have been included. Women are preferably included during the first trimester of pregnancy. Major congenital anomalies and twin births are reasons for exclusion. To assess exposure to environmental chemicals, cord blood, placenta, meconium and vernix are collected. Parents collect urine of the child shortly after birth and breast milk in the second month of life. Exposure to a broad range of environmental chemicals are determined in cord plasma and breast milk. Furthermore various hormones, including leptin and cortisone, are determined in cord plasma, and in heel prick blood spots (thyroxine). Data on anthropometry of the child is collected through midwives and youth health care centres on various time points until the child is 18 months of age. Furthermore cognitive development is monitored by means of the van Wiechen scheme, and information on behavioral development is collected by means of the infant behavior questionnaire and the child behavior checklist. When the child is 12 months of age, a house visit is scheduled to assess various housing characteristics, as well as hand-to-mouth behavior of the child. At this visit exposure of the child to flame retardants (with endocrine disrupting properties) in house dust is determined by means of body wipes. They are furthermore also measured in a saliva sample of the child. Next to these measurements, women receive questionnaires each trimester regarding amongst others lifestyle of the parents, general health of the parents and the child, and mental state of the mother. Discussion This study was approved by the medical ethics committee of the VU University Medical Centre. Consent for the infant is given by the mother, who is specifically required to give consent for both herself as well as her child. Results will be published regardless of the findings of this study, and will be widely disseminated among related medical stakeholders (e.g. midwives and pediatricians), policy makers, and the general public

An effective clean-up technique for GC/EI-HRMS determination of developmental neurotoxicants in human breast milk

The increasing number of children suffering from developmental disorders has raised questions regarding their association with the presence of environmental contaminants in mothers and children. We therefore developed a new method for the determination of 78 proven and potential developmental neurotoxicants, including polychlorinated biphenyls, legacy pesticides, pyrethroids, and old and new halogenated flame retardants in breast milk. The essential part of sample preparation was dialysis as a non-destructive clean-up step which was newly used at 10 °C and showed more efficient lipid removal (up to 96%) than the conventional methods such as gel permeation chromatography or freezing-lipid filtration and thus ensured low limits of detection (LOD) by reducing the sample volume prior to injection. Next advantages were significant solvent reduction and no risk of sample cross-contamination. Gas chromatography coupled with high resolution mass spectrometry (GC-HRMS) was subsequently used for the separation and compound quantification. The method was validated using breast milk samples fortified with the analyzed compounds. Recoveries for most of the compounds ranged from 63 to 121% with a relative standard deviation of 2-25%, and LODs ranged between 0.001 and 0.87 ng g(-1) lipid weight. The method was applied to breast milk samples from a Dutch birth cohort where 35 out of the 78 compounds were quantified in more than 60% of the samples. For novel flame retardants, the method provides unique results regarding their occurrence in human matrices in Europe. Overall, the analysis of a complex mixture of developmental neurotoxicants could be useful for the assessment of the influence of the studied compounds to child health and development. Graphical abstract Flow diagram of the method and levels of the developmental neurotoxicants in Dutch human milk samples