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Background: The filaggrin protein is important for skin barrier structure and function. Loss-of-function (null) mutations in the filaggrin gene FLG may increase dermal absorption of chemicals. Objective: The objective of the study was to clarify if dermal absorption of chemicals differs depending on FLG genotype. Method: We performed a quantitative real-time polymerase chain reaction (qPCR)-based genetic screen for loss-of-function mutations (FLG null) in 432 volunteers from the general population in southern Sweden and identified 28 FLG null carriers. In a dermal exposure experiment, we exposed 23 FLG null and 31 wild-type (wt) carriers to three organic compounds common in the environment: the polycyclic aromatic hydrocarbon pyrene, the pesticide pyrimethanil, and the ultraviolet-light absorber oxybenzone. We then used liquid-chromatography mass-spectrometry to measure the concentrations of these chemicals or their metabolites in the subjects’ urine over 48 h following exposure. Furthermore, we used long-range PCR to measure FLG repeat copy number variants (CNV), and we performed population toxicokinetic analysis. Results: Lag times for the uptake and dermal absorption rate of the chemicals differed significantly between FLG null and wt carriers with low (20–22 repeats) and high FLG CNV (23–24 repeats). We found a dose-dependent effect on chemical absorption with increasing lag times by increasing CNV for both pyrimethanil and pyrene, and decreasing area under the urinary excretion rate curve (AUC(0–40h)) with increasing CNV for pyrimethanil. FLG null carriers excreted 18% and 110% more metabolite (estimated by AUC(0–40h)) for pyrimethanil than wt carriers with low and high CNV, respectively. Conclusion: We conclude that FLG genotype influences the dermal absorption of some common chemicals. Overall, FLG null carriers were the most susceptible, with the shortest lag time and highest rate constants for skin absorption, and higher fractions of the applied dose excreted. Furthermore, our results indicate that low FLG CNV resulted in increased dermal absorption of chemicals. https://doi.org/10.1289/EHP7310

Firefighting foam-contaminated ground water, which contains high levels of perfluoroalkyl substances (PFAS), is frequently found around airports. In 2018 it was detected that employees at a municipal airport in northern Sweden had been exposed to high levels of short-chain PFAS along with legacy PFAS (i.e., PFOA, PFHxS, and PFOS) through drinking water.In this study, we aimed to describe the PFAS profile in drinking water and biological samples (paired serum and urine) and to estimate serum half-lives of the short-chain PFAS together with legacy PFAS.Within 2 weeks after provision of clean water, blood sampling was performed in all 26 airport employees. Seventeen of them were then followed up monthly for 5 months. PFHxA, PFHpA, PFBS, PFPeS, and PFHpS together with legacy PFAS in water and biological samples were quantified using LC/MS/MS. Half-lives were estimated by assuming one compartment, first-order elimination kinetics.The proportions of PFHxA, PFHpA, and PFBS were higher in drinking water than in serum. The opposite was found for PFHxS and PFOS. The legacy PFAS accounted for about 50% of total PFAS in drinking water and 90% in serum. Urinary PFAS levels were very low compared with serum. PFBS showed the shortest half-life {average 44 d [95% confidence interval (CI): 37, 55 d]}, followed by PFHpA [62 d (95% CI: 51, 80 d)]. PFPeS and PFHpS showed average half-lives as 0.63 and 1.46 y, respectively. Branched PFOS isomers had average half-lives ranging from 1.05 to 1.26 y for different isomers. PFOA, PFHxS, and linear PFOS isomers showed average half-lives of 1.77, 2.87, and 2.93 y, respectively.A general pattern of increasing half-lives with increasing chain length was observed. Branched PFOS isomers had shorter half-lives than linear PFOS isomers. https://doi.org/10.1289/EHP6785.

Background: Extensive exposure to per- and polyfluoroalkyl substances (PFAS) have been observed in many countries. Current deterministic frameworks for risk assessment lack the ability to predict the likelihood of effects and to assess uncertainty. When exposure exceeds tolerable intake levels, these shortcomings hamper risk management and communication. Objective: The integrated probabilistic risk assessment (IPRA) combines dose-response and exposure data to estimate the likelihood of adverse effects. We evaluated the usefulness of the IPRA for risk characterization related to decreased levels of total triiodothyronine (T3) in humans following a real case of high exposure to PFAS via drinking water. Methods: PFAS exposure was defined as serum levels from residents of a contaminated area in Ronneby, Sweden. Median levels were 270 ng/mL [perfluorooctane sulfonic acid (PFOS)] and 229 ng/mL [perfluorohexane sulfonic acid (PFHxS)] for individuals who resided in Ronneby 1 y before the exposure termination. This data was integrated with data from a subchronic toxicity study in monkeys exposed daily to PFOS. Benchmark dose modeling was employed to describe separate dose–effect relationship for males and females, and extrapolation factor distributions were used to estimate the corresponding human benchmark dose. The critical effect level was defined as a 10% decrease in total T3. Results: The median probability of critical exposure, following a combined exposure to PFOS and PFHxS, was estimated to be [2.1% (90% CI: 0.4%–13.1%)]. Gender-based analysis showed that this risk was almost entirely distributed among women, namely [3.9% (90% CI: 0.8%–21.6%)]. Discussion: The IPRA was compared with the traditional deterministic Margin of Exposure (MoE) approach. We conclude that probabilistic risk characterization represents an important step forward in the ability to adequately analyze group-specific health risks. Moreover, quantifying the sources of uncertainty is desirable, as it improves the awareness among stakeholders and will guide future efforts to improve accuracy. https://doi.org/10.1289/EHP6654

Programa Infantes y Salud Ambiental Programa ISA Infant´s Environmental Health Study Infant´s Environmental Health Program BACKGROUND: Although growing evidence suggests that early-life excess manganese (Mn) impairs neurodevelopment, data on the neurodevelopmental effects of mancozeb, a fungicide containing Mn, and its main metabolite ethylenethiourea (ETU) are limited. OBJECTIVE: We examined whether prenatal mancozeb exposure and excess Mn were associated with neurodevelopment in 355 1-y-old infants living near banana plantations with frequent aerial mancozeb spraying in Costa Rica. METHODS: We measured urinary ETU, hair Mn, and blood Mn concentrations in samples collected 1–3 times during pregnancy from mothers enrolled in the Infants’ Environmental Health (ISA) study. We then assessed neurodevelopment in their 1-y-old infants using the Bayley Scales of Infant and Toddler Development, 3rd edition (BSID-III). We estimated exposure–outcome associations using linear regression models adjusted for maternal education, parity, gestational age at birth, child age, Home Observation for Measurement of the Environment score, and location of neurodevelopmental assessment. RESULTS: Median (P25–P75) urinary ETU, hair Mn, and blood Mn measured during pregnancy were 3:3 lg=L (2.4–4.9; specific gravity–corrected), 1:7 lg=g (0.9–4.1), and 24:0 lg=L (20.3–28.0), respectively. Among girls, higher ETU was associated with lower social-emotional scores [b per 10-fold increase= −7:4 points (95% CI: −15:2, 0.4)], whereas higher hair Mn was associated with lower cognitive scores [−3:0 (−6:1, 0.1)]. Among boys, higher hair Mn was associated with lower social-emotional scores [−4:6 (−8:5, −0:8)]. We observed null associations for blood Mn, language, and motor outcomes. CONCLUSIONS: Our findings indicate that maternal exposure to mancozeb and excess Mn during pregnancy may have adverse and sex-specific effects on infant neurodevelopment. ANTECEDENTES: Aunque la evidencia creciente sugiere que el exceso de manganeso (Mn) en las primeras etapas de la vida afecta el desarrollo neurológico, los datos sobre los efectos del desarrollo neurológico de mancozeb, un fungicida que contiene Mn, y su principal metabolito etilentiourea (ETU) son limitados. OBJETIVO: Examinamos si la exposición prenatal a mancozeb y el exceso de Mn estaban asociados con el desarrollo neurológico en 355 bebés de 1 año que vivían cerca de plantaciones de banano con fumigación aérea frecuente de mancozeb en Costa Rica. MÉTODOS: Medimos las concentraciones de ETU urinaria, Mn en el cabello y Mn en sangre en muestras recolectadas de 1 a 3 veces durante el embarazo de madres inscritas en el estudio Infants ’Environmental Health (ISA). Luego evaluamos el desarrollo neurológico en sus bebés de 1 año utilizando las Escalas de Bayley para bebés y niños pequeños Desarrollo, 3ª edición (BSID-III). Estimamos las asociaciones exposición-resultado utilizando modelos de regresión lineal ajustados por educación materna, paridad, edad gestacional al nacer, edad del niño, observación en el hogar para medir el puntaje ambiental y ubicación de la evaluación del desarrollo neurológico. RESULTADOS: La ETU urinaria mediana (P25-P75), el Mn del cabello y el Mn en sangre medidos durante el embarazo fueron 3: 3 lg = L (2.4-4.9; gravedad específica corregida), 1: 7 lg = g (0.9-4.1), y 24: 0 lg = L (20,3-28,0), respectivamente. Entre las niñas, una ETU más alta se asoció con puntuaciones socioemocionales más bajas [b por aumento de 10 veces = −7: 4 puntos (IC del 95%: −15: 2, 0,4)], mientras que una mayor Mn de cabello se asoció con puntuaciones cognitivas más bajas [−3: 0 (−6: 1, 0,1)]. Entre los niños, una mayor cantidad de cabello Mn se asoció con puntuaciones socioemocionales más bajas [−4: 6 (−8: 5, −0: 8)]. Observamos asociaciones nulas para Mn en sangre, lenguaje y resultados motores. CONCLUSIONES: Nuestros hallazgos indican que la exposición materna al mancozeb y el exceso de Mn durante el embarazo pueden tener efectos adversos y específicos del sexo en el desarrollo neurológico infantil. Universidad Nacional, Costa Rica Ministerio de Ciencia, Tecnología y Telecomunicaciones (MICITT), Costa Rica International Development Research Centre (IDRC), Canadá Health Canada, Canadá Swedish Research Council Formas, Suecia National Institutes of Health(NIH)/National Institute of Environmental Health Sciences (NIEHS), EE.UU Instituto Regional en Estudios en Sustancias Tóxicas

IRET, CERCH Background: Mancozeb and its main metabolite ethylene thiourea (ETU) may alter thyroid function; thyroid hormones are essential for fetal brain development. In Costa Rica, mancozeb is aerially sprayed at large-scale banana plantations on a weekly basis. Objectives: Our goals were to evaluate urinary ETU concentrations in pregnant women living near large-scale banana plantations, compare their estimated daily intake (EDI) with established reference doses (RfDs), and identify factors that predict their urinary ETU concentrations. Methods: We enrolled 451 pregnant women from Matina County, Costa Rica, which has large-scale banana production. We visited 445 women up to three times during pregnancy to obtain urine samples (n = 872) and information on factors that possibly influence exposure. We determined urinary ETU concentrations using liquid chromatography mass spectrometry. Results: Pregnant women’s median urinary ETU concentrations were more than five times higher than those reported for other general populations. Seventy-two percent of the women had EDIs above the RfD. Women who lived closest (1st quartile, < 48m) to banana plantations on average had a 45% (95% CI: 23, 72%) higher urinary ETU compared with women who lived farthest away (4th quartile, ≥ 565m). Compared with the other women, ETU was also higher in women who washed agricultural work clothes on the day before sampling (11%; 95% CI: 4.9, 17%), women who worked in agriculture during pregnancy (19%; 95% CI: 9.3, 29%), and immigrant women (6.2%; 95% CI: 1.0, 13%). Conclusions: The pregnant women’s urinary ETU concentrations are of concern, and the principal source of exposure is likely to be aerial spraying of mancozeb. The factors predicting ETU provide insight into possibilities for exposure reduction. Antecedentes: el mancozeb y su principal metabolito etilen tiourea (ETU) pueden alterar la función tiroidea; Las hormonas tiroideas son esenciales para el desarrollo del cerebro fetal. En Costa Rica, mancozeb se fumiga por vía aérea en plantaciones de banano a gran escala semanalmente. Objetivos: Nuestros objetivos fueron evaluar las concentraciones urinarias de ETU en mujeres embarazadas que viven cerca de grandes plantaciones de banano, comparar su ingesta diaria estimada (EDI) con las dosis de referencia establecidas (RfD) e identificar factores que predicen sus concentraciones urinarias de ETU. Métodos: Inscribimos a 451 mujeres embarazadas del condado de Matina, Costa Rica, que tiene una producción bananera a gran escala. Visitamos a 445 mujeres hasta tres veces durante el embarazo para obtener muestras de orina (n = 872) e información sobre los factores que posiblemente influyen en la exposición. Determinamos las concentraciones urinarias de ETU mediante cromatografía líquida y espectrometría de masas. Resultados: Las concentraciones medias de ETU en orina de las mujeres embarazadas fueron más de cinco veces más altas que las informadas para otras poblaciones generales. Setenta y dos por ciento de las mujeres tenían EDI por encima de la RfD. Las mujeres que vivían más cerca (1er cuartil

Background: Animal studies indicate that some phthalate metabolites may harm female reproductive function. Objectives: We assessed the associations between exposure to phthalate metabolites and pregnancy loss. Methods: Using a previously established cohort of couples planning their first pregnancy, we analyzed four primary and two oxidized secondary phthalate metabolites in urine samples collected on day 10 after the first day of the last menstrual period before conception occurred (n = 128) and during the previous cycle (if any, n = 111). Subclinical embryonal loss was identified by repeated measurement of urinary human chorionic gonadotropin, and information on clinical spontaneous abortions was obtained by telephone interview with the mother. Results: Pregnancy loss (n = 48) was increased among women with urinary concentration of monoethylhexyl phthalate (MEHP) in the upper tertile in the conception sample compared with women in the lowest tertile [adjusted odds ratio (OR) = 2.9; 95% confidence interval (CI): 1.1, 7.6]. The corresponding OR for subclinical embryonal loss (n = 32) was 40.7 (95% CI: 4.5, 369.5). Conclusions: The phthalate metabolite MEHP was associated with higher occurrence of pregnancy loss. Because this is the first human study to show this association and the sample size is small, the findings need to be corroborated in independent studies.

During recent years, it has been widely discussed whether environmental chemicals mimicking or inhibiting the action of endogenous hormones, the so-called endocrine disruptors (EDs), have an adverse effect on male reproductive function (Skakkebaek et al. 2001; Toppari et al. 1996). This debate followed reports indicating negative secular trends in sperm counts and concomitant increases in the incidence of testicular cancer as well as congenital abnormalities of male genitalia, such as cryptorchidism and hypospadias (Giwercman et al. 1993). These abnormalities, together with some forms of male infertility, constitute the so-called testicular dysgenesis syndrome (TDS). Furthermore, it has been suggested that TDS is due to a hormonal imbalance in the male reproductive system caused by fetal exposure to EDs (Skakkebaek et al. 2001). Compounds with potential ED effects, including persistent organohalogen pollutants (POPs), such as polychlorinated dibenzo-furans, polychlorinated dibenzo-p-dioxins, polychlorinated biphenyls (PCBs), dichloro-diphenyltrichloroethane (DDT), and dichloro-diphenyldichloroethene (p,p′-DDE; the most stable daughter compound of DDT), are ubiquitous environmental contaminants. These compounds are highly persistent, which results in bioaccumulation and biomagnification in the food chain. Measurable levels of PCBs and p,p′-DDE are found in a large proportion of the general population (Longnecker et al. 1997). Some of these chemicals can disrupt multiple endocrine pathways and induce a wide range of toxic responses (Toppari et al. 1996). A variety of studies have demonstrated their estrogenic, antiestrogenic, and androgen-interfering properties (Danzo 1997; Kelce et al. 1995). Furthermore, some of the PCBs have dioxin-like activity and therefore, through binding to the aryl hydrocarbon receptor (AhR) (Pocar et al. 2005), indirectly modify sex steroid action. Provided that POPs can act as EDs, one should expect these compounds to interfere with the normal hypothalamo–pituitary–gonadal axis. However, the data regarding such associations are relatively limited, and the overall picture of the effect of exposure on hormone levels is not uniform. It is not feasible to analyze all of the several hundred POP compounds that might be detected in human serum. Therefore, reliable proxy markers of exposure need to be used. The PCB congener 2,2′,4,4′5,5′-hexachloro-biphenyl (CB-153), found in relatively high concentrations in human serum, has been selected as a biomarker for POP exposure because of its very high correlation with the total PCB concentration (Glynn et al. 2000; Grimvall et al. 1997), the 2,3,7,8-tetra-chlorodibenzo-p-dioxin (TCDD) equivalent (TEQ) from PCBs, and the total POP-derived TEQ (Gladen et al. 1999a) in Swedish and North American populations. Likewise, the major DDT metabolite p,p′-DDE, an anti-androgenic compound, is another good indicator of POP exposure. Previous studies from Greenland, Sweden, Poland, and Ukraine indicate that the exposure for p,p′-DDE is still considerable (Czaja et al. 1997; Deutch and Hansen 2000; Gladen et al. 1999b; Sjodin et al. 2002). As a part of a European Union–supported action, the impact of POP exposure on different aspects of male reproductive function was investigated in three European populations and among Greenland Inuit (Biopersistent Organochlorines in Diet and Human Fertility: Epidemiologic Studies of Time to Pregnancy and Semen Quality in Inuit and European Populations; INUENDO 2006). The aim of the present study was to assess the possible association between levels of CB-153 and p,p′-DDE in serum and reproductive hormones in males. Our hypothesis was that, provided that POPs act as EDs, the levels of the two exposure markers should to some degree correlate with concentrations of markers of testicular [testosterone, estradiol (E2), inhibin B] and/or pituitary [follicle-stimulating hormone (FSH) and luteinizing hormone (LH)] function. The action of POPs on the hypothalamo–pituitary–gonadal axis might be primarily exerted through the testis or via the hypothalamus/hypophysis. Because these chemicals can possess a multitude of endocrine effects, we did not, a priori, hypothesize which type of hormonal changes would be expected.

Persistent organochlorine pollutants (POPs) such as polychlorinated biphenyls (PCBs) and dichlorodiphenyldichloroethylene (p,p'-DDE), the major metabolite of dichlorodiphenyltrichloroethane (DDT), are stable lipophilic compounds widely found in the environment and in the general population. They can enter the food chain, and their negative impact on male reproduction is currently under active scrutiny. To explore the hypothesis that environmental exposure to these compounds is associated with altered sperm chromatin structure integrity in human sperm, we conducted a study of 176 Swedish fishermen (with low and high consumption of fatty fish, a very important exposure source of POPs). We determined serum levels of 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) and p,p'-DDE, and we used the sperm chromatin structure assay (SCSA) to assess sperm DNA/chromatin integrity. When CB-153 serum levels (individual dose range, 39-1,460 ng/g lipid) were categorized into equally sized quintiles, we found an association with the DNA fragmentation index (%DFI). A significantly lower %DFI was found in the lowest CB-153 quintile (< 113 ng/g lipid) compared with the other quintiles; there was a similar tendency, although not statistically significant, between %DFI and p,p'-DDE. These results suggest that POP exposure may have a slight negative impact on human sperm chromatin integrity.

Background: Phthalates are used as plasticizers in soft polyvinyl chloride (PVC) and in a large number of consumer products. Because of reported health risks, diisononyl phthalate (DiNP) has been introduced as a replacement for di(2-ethylhexyl) phthalate (DEHP) in soft PVC. This raises concerns because animal data suggest that DiNP may have antiandrogenic properties similar to those of DEHP. The anogenital distance (AGD)—the distance from the anus to the genitals—has been used to assess reproductive toxicity. Objective: The objective of this study was to examine the associations between prenatal phthalate exposure and AGD in Swedish infants. Methods: AGD was measured in 196 boys at 21 months of age, and first-trimester urine was analyzed for 10 phthalate metabolites of DEP (diethyl phthalate), DBP (dibutyl phthalate), DEHP, BBzP (benzylbutyl phthalate), as well as DiNP and creatinine. Data on covariates were collected by questionnaires. Results: The most significant associations were found between the shorter of two AGD measures (anoscrotal distance; AGDas) and DiNP metabolites and strongest for oh-MMeOP [mono-(4-methyl-7-hydroxyloctyl) phthalate] and oxo-MMeOP [mono-(2-ethyl-5-oxohexyl) phthalate]. However, the AGDas reduction was small (4%) in relation to more than an interquartile range increase in DiNP exposure. Conclusions: These findings call into question the safety of substituting DiNP for DEHP in soft PVC, particularly because a shorter male AGD has been shown to relate to male genital birth defects in children and impaired reproductive function in adult males and the fact that human levels of DiNP are increasing globally. Citation: Bornehag CG, Carlstedt F, Jönsson BA, Lindh CH, Jensen TK, Bodin A, Jonsson C, Janson S, Swan SH. 2015. Prenatal phthalate exposures and anogenital distance in Swedish boys. Environ Health Perspect 123:101–107; http://dx.doi.org/10.1289/ehp.1408163