Serum persistent organic pollutants and diminished ovarian reserve: a single-exposure and mixture exposure approach from a French case-control study.

STUDY QUESTION: Are persistent organic pollutants (POPs) associated with a diminished ovarian reserve (DOR) in women of reproductive age? SUMMARY ANSWER: Amongst 17 POPs detected in over 20% of serum samples, only p,p'-DDE was significantly associated with an increased risk of DOR, and ß-hexachlorocyclohexane (ß-HCH) was significantly associated with a decreased risk of DOR whilst mixture analyses yielded non-significant associations and did not detect any interactions between POPs. WHAT IS KNOWN ALREADY: Animal studies have shown that several POPs can alter folliculogenesis and increase follicle depletion. However, only a few studies have been conducted in humans, with small sample sizes and inconsistent results. STUDY DESIGN, SIZE, DURATION: Our study included 138 cases and 151 controls from the AROPE case-control study. Study participants were women between 18 and 40 years of age recruited amongst couples consulting for infertility in four fertility centres in western France between 2016 and 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: Cases of DOR were defined as women with anti-Müllerian hormone (AMH) levels ≤1.1 ng/ml and/or antral follicle count (AFC) <7, and controls were women with AMH levels between 1.1 and 5 ng/ml and AFC ≥ 7, without genital malformations and with a menstrual cycle length between 26 and 35 days. A total of 43 POPs (including 15 organochlorine pesticides, 17 polychlorinated biphenyls, and 9 polybromodiphenylethers) were measured in the serum at inclusion into the study. We conducted logistic regression adjusted for potential confounders using a directed acyclic graph to study the effect of each POP on DOR as single exposures, and used Bayesian kernel machine regression (BKMR) to measure the mixture effect of POPs on DOR. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 43 POPs, 17 were detected in over 20% of the serum samples. In the single-exposure multivariate logistic regressions, p,p'-DDE (median 165.0 IQR 161.0 ng/l in controls) as a continuous exposure was significantly associated with an increased risk of DOR (odds ratio (OR) 1.39, 95% CI 1.10-1.77) and non-significantly associated with an increased risk of DOR for the second and third terciles (OR 1.46, 95% CI 0.74-2.87, and OR 1.72, 95% CI 0.88-3.37, respectively). ß-HCH (median 24.2 IQR 21.5 ng/l in controls) was significantly associated with a decreased risk of DOR when ß-HCH was treated as a continuous exposure (OR 0.63, 95% CI 0.44-0.89) and for the third tercile of exposure (OR 0.43, 95% CI 0.21-0.84) and non-significantly associated with a decreased risk of DOR for the second tercile (OR 0.77, 95% CI 0.42-1.42). All sensitivity analyses confirmed our results. BKMR showed similar associations for single exposures but found no significant associations for the total mixture effect. In addition, the BKMR results did not suggest any interactions between POPs. LIMITATIONS, REASONS FOR CAUTION: Controls were recruited amongst infertile couples and thus may not be representative of all women of reproductive age. However, their POP concentrations were in the same range as in the general French population. WIDER IMPLICATIONS OF THE FINDINGS: This study is the first to examine the associations between serum POPs and DOR. The well-recognized anti-androgenic properties of p,p'-DDE and estrogenic properties of ß-HCH could explain these associations of opposite direction. If these results are replicated elsewhere, this could have an impact on fertility prevention messages and help in understanding the impact of POPs on the female reproductive system. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Fondation de France (grant numbers 2014-50537 and 00110196) and the French Biomedicine Agency (2016). None of the authors have any conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Infant neurodevelopment and behavior in Guadeloupe after lead exposure and Zika maternal infection during pregnancy.

BACKGROUND: Prenatal lead exposure is known to have neurotoxic effects on the developing fetus, while some viral infections may have a tropism for the central nervous system. Our objective was to study whether the effects of prenatal lead exposure on infant development and behaviors at 18 months of age are modified by the occurrence of a maternal infection to Zika virus (ZIKV) during pregnancy. METHODS: During the ZIKV epidemic in Guadeloupe in 2016 a cohort of pregnant women was set up. Blood samples (pregnancy, childbirth and cord) (n = 297) enabled us to measure blood lead levels aimed to determine prenatal lead exposure and the likelihood of maternal infection during pregnancy (ZIKV status + vs -). The 18 months "Ages and Stages Questionnaire" (ASQ) was used to generate scores for global development, fine and gross motor skills, communication, problem solving, and personal-social skills. The questions from a longitudinal cohort study conducted in Canada (Québec) were used to generate hyperactivity, opposition, inattention and physical aggression scores. Associations were tested by multivariate linear regressions. RESULTS: Prenatal lead exposure was associated with delays in neurodevelopment at 18 months, reflected by lower scores in ASQ totals, and in the fine motor and problem-solving domains. Some of these associations appeared to be sex-specific, observed almost exclusively in boys (ASQ total, fine motor and personal-social scores). Prenatal lead exposure was not associated with behavioral scores. ZIKV infection during pregnancy was associated with a lower fine motor ASQ score, and higher scores for hyperactivity, opposition and physical aggression. Significant interaction between prenatal lead exposure and ZIKV status was observed with a lower personal-social score in ZIKV (-) only, and for hyperactivity and inattention scores, though some of these interactions (ASQ personal-social score, inattention score) were no longer significant when children with microcephaly were excluded from the analyses. DISCUSSION/CONCLUSION: Our study confirms previous findings of associations between prenatal exposure to lead at low levels and adverse neurodevelopmental outcomes during infancy and the particular vulnerability of boys. It suggests associations between ZIKV infection during pregnancy and adverse effects on a number of neurodevelopmental functions (fine motor function) and behaviors (opposition, hyperactivity), that need to be confirmed at later age. There is no strong evidence of interaction between ZIKV infection and lead exposure but both prenatal risk factors may affect fine motor function.

Pre- and post-natal exposure of children to organophosphate flame retardants: A nationwide survey in France.

The use of organophosphate flame retardants (OPFRs) has been on the rise ever since many brominated flame retardants were banned, back in the 2000 s. The objectives of this study are to describe the pre- and post-natal exposure of children to OPFRs, and to explore their possible determinants. A total of 259 children aged 3.5 years and 388 mothers from the French ELFE mother-child cohort were included. Both pre- and post-natal exposure to OPFRs were assessed, using OPFR concentrations in the hair of pregnant women (in 2011) and their 3.5-year-old children (in 2014-2015) for 15 OPFRs, of which 9 were detected in > 20 % hair samples. The highest geometric means for pre-natal exposure were 272 ng/g for tris(1-chloro-2-propyl) phosphate (TCPP), 69.7 ng/g for ng/g for triphenyl phosphate (TPP) and 54.4 ng/g for tris(1,3-dichloro-2-propyl) phosphate (TDCPP). The highest geometric means for post-natal exposure were 249.6 ng/g for TCPP, 85.3 ng/g for TDCPP and 83.8 ng/g for 2-ethylhexyl diphenyl phosphate (EHDPP). Correlations were found between both pre-natal exposures, and between pre-and post-natal exposures. No correlation was however found between pre-and post-natal exposures for any given OPFR. Pre-natal exposure to the 9 OPFRs was associated with pre-natal exposure to polybrominated diphenyl ethers 209 (BDE209), and 47 (BDE47). Maternal BMI was associated with pre-natal exposure to OPFRs other than TBEP. Home renovation work prior to birth was also associated with pre-natal exposure to OPFRs, with the exception of EHDPP, tris(2-butoxyethyl) phosphate (TBEP) and triethyl phosphate (TEP). Determinants of post-natal exposure appeared more disparate across OPFRs; although both the type of flooring in children's rooms and pre-natal exposure to polybrominated diphenyl ethers seem to be associated with post-natal exposure. Lastly, higher socioeconomic status appeared to be associated with lower exposure for several (though not all) OPFRs. The high prevalence of exposure to OPFRs suggests the need for studies to assess the health effects of OPFRs exposure, particularly on children.

High lead level in the Alps in XIXth century, learning from the analysis of 138 historical hair stands.

Analysis of hair is known to provide useful information about environmental and toxic exposures. Very little historical use has been made of this type of investigation. Here we study 138 human hair samples from 19th century in France. In order to examine the potential association between contamination and historical health impacts, we characterized contamination by 33 elements in a set of hair strands sampled during the last quarter of the 19th century in the Savoy region of France. After a selected washing step on 138 hair strands conserved at the Museum National d'Histoire Naturelle in Paris (France), we assessed the presence of inorganics by ICP/MS, and lead level was higher than values reported in literature. We then compared concentrations and distributions between women and men, sampling locations and crossing gender and geographical origin. Hair lead level was high throughout Savoy at the end of the 19th century: significantly higher for people living in towns or industrial valleys, and lower for those of countryside and mountains areas. Environmental and economic changes (industrialization and urbanization with water adduction and leaded paints), living habits (kitchenware, cosmetics, wine, and tobacco), and local features (mines exploitation, railroad development, and industrialized narrow valleys) could be envisaged for explaining the level of lead contamination. In the same period, the two main industrial valleys of Savoy (Maurienne and Tarentaise) had high rates of endemic goiter and cretinism and among the highest hair lead levels. Other lines of evidence will need to be explore to investigate a possible link between historical Pb exposure and goiter in the study area.

Veterinary pharmaceutical contamination in mixed land use watersheds: from agricultural headwater to water monitoring watershed.

Veterinary pharmaceuticals, widely used in intensive livestock production, may contaminate surface waters. Identifying their sources and pathways in watersheds is difficult because i) most veterinary pharmaceuticals are used in human medicine as well and ii) septic or sewer wastewater treatment plants (WWTP) can release pharmaceuticals into surface water, even in agricultural headwater watersheds. This study aimed to analyze the spatiotemporal variability of animal-specific, mixed-use, and human-specific pharmaceuticals, from agricultural headwaters with intensive livestock production and a WWTP to a watershed used for Water Framework Directive monitoring. Grab sampling was performed during one hydrological year upstream and downstream from a WWTP and at three dates in seven nested watersheds with areas of 1.9-84.1km2. Twenty pharmaceuticals were analyzed. Animal-specific pharmaceuticals were detected at all sampling dates upstream and downstream from the WWTP and at concentrations higher than those of human-specific pharmaceuticals. The predominance of animal-specific and mixed-use pharmaceuticals vs. human-specific pharmaceuticals observed at these sampling points was confirmed at the other sampling points. Animal-specific pharmaceuticals were detected mainly during runoff events and periods of manure spreading. A large percentage of mixed-use pharmaceuticals could come from animal sources, but it was difficult to determine. Mixed-use and human-specific pharmaceuticals predominated in the largest watersheds when runoff decreased. In areas of intensive livestock production, mitigation actions should focus on agricultural headwater watersheds to decrease the number of pathways and the transfer volume of veterinary pharmaceuticals, which can be the main contaminants.

Semi-volatile organic compounds in the air and dust of 30 French schools: a pilot study.

The contamination of indoor environments with chemical compounds released by materials and furniture, such as semi-volatile organic compounds (SVOCs), is less documented in schools than in dwellings-yet children spend 16% of their time in schools, where they can also be exposed. This study is one of the first to describe the contamination of the air and dust of 90 classrooms from 30 nursery and primary schools by 55 SVOCs, including pesticides, phosphoric esters, musks, polycyclic aromatic hydrocarbons (PAHs), polychlorobiphenyls (PCBs), phthalates, and polybromodiphenylethers (PBDEs). Air samples were collected using an active sampling method, and dust samples were collected via two sampling methods (wiping and vacuum cleaning). In air, the highest concentrations (median >100 ng/m3 ) were measured for diisobutyl phthalate (DiBP), dibutyl phthalate (DBP), diethyl phthalate (DEP), bis(2-ethylhexyl) phthalate (DEHP), and galaxolide. In dust, the highest concentrations (median >30 µg/g) were found for DEHP, diisononyl phthalate (DiNP), DiBP, and DBP. An attempt to compare two floor dust sampling methods using a single unit (ng/m²) was carried out. SVOC concentrations were higher in wiped dust, but frequencies of quantification were greater in vacuumed dust.

Volatile and semi-volatile organic compounds of respiratory health relevance in French dwellings.

Over the last decades, the prevalence of childhood respiratory conditions has dramatically increased worldwide. Considering the time spent in enclosed spaces, indoor air pollutants are of major interest to explain part of this increase. This study aimed to measure the concentrations of pollutants known or suspected to affect respiratory health that are present in dwellings in order to assess children's exposure. Measurements were taken in 150 homes with at least one child, in Brittany (western France), to assess the concentrations of 18 volatile organic compounds (among which four aldehydes and four trihalomethanes) and nine semi-volatile organic compounds (seven phthalates and two synthetic musks). In addition to descriptive statistics, a principal component analysis (PCA) was used to investigate grouping of contaminants. Formaldehyde was highly present and above 30 µg/m(3) in 40% of the homes. Diethyl phthalate, diisobutyl phthalate, and dimethylphthalate were quantified in all dwellings, as well as Galaxolide and Tonalide. For each chemical family, the groups appearing in the PCA could be interpreted in term of sources. The high prevalence and the levels of these compounds, with known or suspected respiratory toxicity, should question regulatory agencies to trigger prevention and mitigation actions.

Measurements of semi-volatile organic compounds in settled dust: influence of storage temperature and duration.

Indoor dust samples cannot always be analyzed immediately after collection. However, little information is currently available on how storage conditions may affect measurements. This study was designed to determine how sample storage conditions may affect the concentration of semi-volatile organic compounds (SVOCs) in the dust. A composite dust was prepared using a Standard Reference Material (SRM 2585) with real indoor dust samples. The composite dust was stored in various types of packaging, at different temperatures (-18°C, 5°C, 20°C, and 35°C), and in different light conditions. The concentration of SVOCs was measured after various storage durations. No effect on SVOC concentrations was observed for the composite dust stored in an amber glass vial at -18°C for 36 months. At 5°C, 20°C, and 35°C, losses occurred for the more volatile compounds. The experimental storage conditions clearly showed that temperature and duration affected the concentrations of SVOCs in the composite dust. The type of packaging material (polyethylene zip bag or polyethylene garbage bag) did not seem to have a systematic effect on the preservation of SVOCs in the composite dust. Maximum storage duration times are proposed for each compound at various temperatures. For most compounds, samples can be stored for 2 months at 20°C. For samples that cannot be analyzed immediately, we recommend to store them in the dark at -18°C to ensure a good recovery of all tested compounds.

Storage of natural water samples and preservation techniques for pharmaceutical quantification.

In order to perform a human and ecological risk assessment of pharmaceutical products (PPs) in natural waters, it is necessary to accurately quantify a broad variety of PPs at low concentrations. Although numerous currently implemented analytical methodologies, less is known about the preservation of PPs in natural water samples within the period before analysis (holding time, storage conditions). This paper is the first literature review about the stability of PPs in natural waters (surface and groundwaters) during sample storage. The current work focuses on a comparison of the performances of the available preservation techniques (filtration, container materials, storage temperature, preservative agents, etc.) for PPs in samples. All 58 reviewed PPs may be successfully stabilized during 7 days in surface waters by at least one appropriate methodology regarding temperature, acidic and non-acidic preservatives. When temperature is not a sufficient preservation parameter for some PPs (hormones and fluoxetine) its combination with the addition of chemical agents into the samples may prolong the integrity of the PPs during storage in surface water. There is a strong need to use standard protocols to assess and compare the stability of PPs in environmental water matrices during storage as well as during analytical preparation or analysis (European criteria 2002/657/EC). Since the stability of PPs during sample storage is a critical parameter that could call into question the quality of the data provided for the concentrations, the design of stability studies should rigorously take into account all critical parameters that could impact the concentrations of the PPs with time.

Contamination levels of human pharmaceutical compounds in French surface and drinking water.

The occurrence of 20 human pharmaceutical compounds and metabolites from 10 representative therapeutic classes was analysed from resource and drinking water in two catchment basins located in north-west France. 98 samples were analysed from 63 stations (surface water and drinking water produced from surface water). Of the 20 human pharmaceutical compounds selected, 16 were quantified in both the surface water and drinking water, with 22% of the values above the limit of quantification for surface water and 14% for drinking water). Psychostimulants, non-steroidal anti-inflammatory drugs, iodinated contrast media and anxiolytic drugs were the main therapeutic classes of human pharmaceutical compounds detected in the surface water and drinking water. The results for surface water were close to results from previous studies in spite of differences in prescription rates of human pharmaceutical compounds in different countries. The removal rate of human pharmaceutical compounds at 11 water treatment units was also determined. Only caffeine proved to be resistant to drinking water treatment processes (with a minimum rate of 5%). Other human pharmaceutical compounds seemed to be removed more efficiently (average elimination rate of over 50%) by adsorption onto activated carbon and oxidation/disinfection with ozone or chlorine (not taking account of the disinfection by-products). These results add to the increasing evidence of the occurrence of human pharmaceutical compounds in drinking water that may represent a threat to human beings exposed to a cocktail of human pharmaceutical compounds and related metabolites and by-products in drinking water.

Health ranking of ingested semi-volatile organic compounds in house dust: an application to France.

UNLABELLED: People spend most of their time indoors. Dust settled in the home may be contaminated by semi-volatile organic compounds (SVOCs). Exposure to these compounds is of great concern, in particular for infants. Their number is large so arose the question of which ones should be selected for dust ingestion exposure assessment. This work proposes a health ranking of SVOCs ingested through settled dust. This ranking is based on the toxicity and contamination of SVOCs in dust. Data on compounds and contamination was retrieved from a bibliographic review. Where possible, toxicity data was retrieved from databases, otherwise it was calculated from raw data. One hundred and fifty-six SVOCs were selected, 66 of which were prioritized. Forty-two could not be prioritized because contamination data was below the limit of detection, and 48 could not be prioritized because there was no contamination or toxicity data. The top-ranked compounds were phthalates, pesticides, short-chain chlorinated paraffins, PBDEs, PFCs, organotins, PCBs, and PAHs. As most of these have reprotoxic and neurotoxic properties, an integrated multi-pollutants approach to exposure is required and simultaneous measurement methods should be developed. PRACTICAL IMPLICATIONS: The large number of compounds identified in settled dust in recent years should be considered for the assessment of exposure to dust ingestion. This work provides a health ranking of SVOCs ingested through settled dust. Most of the top-ranked compounds have reprotoxic and neurotoxic properties, and particular attention should, therefore, be paid to them in future studies.

Identifying sources of lead exposure for children, with lead concentrations and isotope ratios.

Despite a dramatic decrease in children's blood lead levels (BLL), lead exposure remains a public health concern because increasing evidence shows effects at very low doses. Lowering BLL still further requires the identification of lead sources and, therefore, new tools to investigate and thus prevent exposure. We describe a procedure that uses both lead concentrations and isotope ratios (IRs) to identify sources of overexposure in homes. Water, dust, and paint chips were sampled from the homes of 21 children with elevated BLL from Aubervilliers (Paris metropolitan area). Lead concentrations of concern were calculated from reverse physiologically based pharmacokinetic modeling for water and dust. Isotope ratio matching of blood and environmental samples (with a lead content above the concentration of concern) was performed by computation of the distance between their IRs. When the IR of the source did not match that of the blood, the source was eliminated as a source of lead intoxication. The number of sources eliminated (per child) due to lead concentration ranged from 14% to 86% (mean 66%) for dust, and 100% for water samples. The number of remaining potential sources eliminated by IR interpretation varied from 0% to 100% for both dust and paint chips (mean 63% and 58%, respectively). IRs made it possible to eliminate at least one source in 20 of 21 cases and identified a single source in 11 of 21. The number of dust and paint sources not eliminated by concentration or IR varied from 8% to 45% (median 18%). The pilot study supports the usefulness of these procedures and the added value of IRs for identifying sources of lead poisoning. However, systematic use should be supported by cost-effectiveness analysis on a larger and more representative population of elevated BLL.

Exposure to inhaled THM: comparison of continuous and event-specific exposure assessment for epidemiologic purposes.

Trihalomethanes (THMs) (chloroform, bromoform, dibromochloromethane, and bromodichloromethane) are the most abundant by-products of chlorination. People are exposed to THMs through ingestion, dermal contact and inhalation. The objective of this study was to compare two methods for assessing THM inhalation: a direct method with personal monitors assessing continuous exposure and an indirect one with microenvironmental sampling and collection of time-activity data during the main event exposures: bathing, showering and swimming. This comparison was conducted to help plan a future epidemiologic study of the effects of THMs on the upper airways of children. 30 children aged from 4 to 10 years were included. They wore a 3M 3520 organic vapor monitor for 7 days. We sampled air in their bathrooms (during baths or showers) and in the indoor swimming pools they visited and recorded their time-activity patterns. We used stainless steel tubes full of Tenax to collect air samples. All analyses were performed with Gas Chromatography and Mass Spectrometry (GC-MS). Chloroform was the THM with the highest concentrations in the air of both bathrooms and indoor swimming pools. Its continuous and event exposure measurements were significantly correlated (r(s)=0.69 p<0.001). Continuous exposures were higher than event exposures, suggesting that the event exposure method does not take into account some influential microenvironments. In an epidemiologic study, this might lead to random exposure misclassification, thus underestimation of the risk, and reduced statistical power. The continuous exposure method was difficult to implement because of its poor acceptability and the fragility of the personal monitors. These two points may also reduce the statistical power of an epidemiologic study. It would be useful to test the advantages and disadvantages of a second sample in the home or of modeling the baseline concentration of THM in the home to improve the event exposure method.

Occurrence and fate of pharmaceutical products and by-products, from resource to drinking water.

Among all emerging substances in water, pharmaceutical products (PPs) and residues are a lot of concern. These last two years, the number of studies has increased drastically, however much less for water resources and drinking water than for wastewater. This literature review based on recent works, deals with water resources (surface or groundwater), focusing on characteristics, occurrence and fate of numerous PPs studied, and drinking water including water quality. Through this review, it appears that the pharmaceutical risk must be considered even in drinking water where concentrations are very low. Moreover, there is a lack of research for by-products (metabolites and transformation products) characterization, occurrence and fate in all water types and especially in drinking water.

Adsorption/thermal desorption-GC/MS for the analysis of pesticides in the atmosphere.

An analytical methodology using Automatic Thermal Desorption (ATD) and GC/MS was developed for the determination of the pesticides alachlor, atrazine, captan, formothion, lindane and phosalone in atmospheric samples. This methodology was developed to evaluate the atmospheric contamination by pesticides during treatments and by post-application. Atmospheric samples were collected by using (4 i.d. x 89 mm) stainless steel sampling tubes containing 125 mg of adsorbents at a flow rate of 80 ml min-1. Different types of adsorbents were tested for their ability to efficiently trap pesticides under study: Tenax TA, Carbopack Y, Carbopack B, Carbotrap, Carboxen, Chromosorb 106 and XAD-4. Results of experiment show that Tenax gives the better results for all the pesticides used but the use of the thermal-desorption method, especially for pesticides with low volatility and/or poor thermal stability presents some difficulties. This method was validated by the analysis of the contamination of atmosphere, through volatilization by post-application processes, of atrazine in a parcel of 1 ha.