Chemical Exposure Levels Research Articles

#1053 The exposure of phthalates and alternative plasticizers among chronic kidney disease patients during COVID-19 pandemic

Abstract Background and Aims Phthalates are widely used in many consumer products as plasticizer and well known to be detrimental to human health. Phthalates mainly disrupt the endocrine system. Recently, phthalate exposures are revealed to be associated with decreased kidney function and increased albuminuria. Risk perception levels and behavioral patterns of CKD patients have been changing with COVID-19 pandemic. However, the effect of these changes on the environmental chemical exposures has not been investigated. We aimed to investigate the environmental chemical phthalates and alternative plasticizer exposure levels during COVID-19 pandemic among CKD patients. Method We analyzed the data from a study with a prospective cohort of CKD patient, namely the Study on Kidney disease and EnviromenTal CHemicals (SKETCH, Clinical Trial No. NCT04679168). This cohort included patients with CKD who visited the participating hospitals for the first time between June and October 2020 and followed up to December 2022. Demographic data, behavioral characteristics including hygienic behavior and social distancing, and laboratory data were collected prospectively. Thirty-seven metabolites from 9 light phthalates, 12 heavy phthalates, and 16 alternative plasticizers were measured in urine samples. Results The level of light phthalates and alternative plasticizers during the COVID-19 pandemic significantly increased, and heavy phthalates concentrations decreased compared to the pre-pandemic levels. During the 1-year follow-up period, the level of risk perception for infectious disease including COVID-19 significantly decreased. During the 1-yr pandemic period, light phthalate levels decreased for the first 6-month period, and significantly increased for the second 6-month. Heavy phthalates levels were decreased steadily. However, alternative plasticizer levels were maintained during the 1-yr follow-up period. Heavy phthalates levels were significantly higher in the higher risk perception group. However, heavy phthalates levels were not different according to the behavioral patterns. In contrast, the levels of light phthalates and alternative plasticizers were not different according to either behavioral strengthening or risk perception. Conclusion COVID-19 pandemic was associated with decreased exposure of heavy phthalates and increased exposure of light phthalates and alternative plasticizers. During the COVID-19 pandemic, levels of light phthalate exposures initially decreased at first 6-month period and gradually increased. This trend of environmental chemicals exposure might be associated with the change of risk perception levels.

Using in vitro data to derive acceptable exposure levels: A case study on PBDE developmental neurotoxicity

BackgroundCurrent acceptable chemical exposure levels (e.g., tolerable daily intake) are mainly based on animal experiments, which are costly, time-consuming, considered non-ethical by many, and may poorly predict adverse outcomes in humans. ObjectiveTo evaluate a method using human in vitro data and biological modeling to calculate an acceptable exposure level through a case study on 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) developmental neurotoxicity (DNT). MethodsWe reviewed the literature on in vitro assays studying BDE-47-induced DNT. Using the most sensitive endpoint, we derived a point of departure using a mass-balance in vitro disposition model and benchmark dose modeling for a 5% response (BMC05) in cells. We subsequently used a pharmacokinetic model of gestation and lactation to estimate administered equivalent doses leading to four different metrics of child brain concentration (i.e., average prenatal, average postnatal, average overall, and maximum concentration) equal to the point of departure. The administered equivalent doses were translated into tolerable daily intakes using uncertainty factors. Finally, we calculated biomonitoring equivalents for maternal serum and compared them to published epidemiological studies of DNT. ResultsWe calculated a BMC05 of 164 μg/kg of cells for BDE-47 induced alteration of differentiation in neural progenitor cells. We estimated administered equivalent doses of 0.925–3.767 μg/kg/day in mothers, and tolerable daily intakes of 0.009–0.038 μg/kg/day (composite uncertainty factor: 100). The lowest derived biomonitoring equivalent was 19.75 ng/g lipids, which was consistent with reported median (0.9–23 ng/g lipids) and geometric mean (7.02–26.9 ng/g lipids) maternal serum concentrations from epidemiological studies. ConclusionThis case study supports using in vitro data and biological modeling as a viable alternative to animal testing to derive acceptable exposure levels.

Repeat Expansions of RFC1 in Refractory Chronic Cough: A Missing Piece of the Puzzle?

Over the last decade, the concept of cough hypersensitivity syndrome (CHS) has emerged in adults.1 CHS is defined as a clinical syndrome characterized by troublesome coughing, often triggered by low levels of thermal, mechanical, or chemical exposure. A neurologic dysfunction is now appreciated as the main mechanism of chronic cough and also of refractory chronic cough (RCC). Patients with RCC experience not only a reduction in quality of life but also a lack of explanation regarding the origin of their cough.

Chronic cough and cough hypersensitivity: from mechanistic insights to novel antitussives

Chronic cough has a global prevalence of 5–10% in the general adult population (≥18 years);1 however, few effective treatment options are available for patients. Irrespective of cause, many adult patients with chronic cough present with cough hypersensitivity, which is a syndrome of troublesome coughing triggered by low levels of thermal, mechanical, or chemical exposure. Recent scientific and clinical advances—encompassing the burden of chronic cough, underlying pathophysiological mechanisms, approaches to measuring cough and cough hypersensitivity, current management approaches, and the development of novel antitussive strategies (panel)—were presented at the Twelfth London International Cough Symposium (12th LICS) held at Imperial College London (London, UK) from July 13 to 14, 2022.

Risk from unintentional environmental mixtures in EU surface waters is dominated by a limited number of substances

Unintentional environmental mixtures happen when multiple chemicals co-occur in the environment. A generic mixture assessment factor (MAF), has been proposed to account for this. The MAF is a number by which safe exposure levels for single chemicals are divided to ensure protection against combined exposures to multiple chemicals. Two key elements to judge the appropriateness of a generic MAF are (1) defining the scope of mixtures that need to be addressed by a MAF (i.e.: simple mixtures vs complex mixtures), and (2) the existence of common risk drivers across large spatial scales. Simple mixtures with one to three risk drivers can easily be addressed by chemical-by-chemical regulatory action. Our work provides evidence on the prevalence and complexity of cumulative risk in EU freshwaters based on chemical monitoring data from one of the largest databases in the EU. With 334 chemicals being monitored, low complexity mixtures (one to 3 three risk drivers) dominated. After excluding metals, only 15 out of 307 chemicals (5 %) were most frequent chemical risk drivers. When these 15 chemicals were excluded from the analysis, 95 % of all monitoring site – year combinations did not pose a concern for cumulative risk. Most of these 15 chemicals are already banned or listed in various priority lists, showing that current regulatory frameworks were effective in identifying drivers of single chemical and cumulative risk. Although the monitoring data do not represent the entirety of environmental mixtures in the EU, the observed patterns of (1) limited prevalence of truly complex mixtures, and (2) limited number of overall risk drivers, argue against the need for implementing a generic MAF as a regulatory tool to address risk from unintentional mixtures in EU freshwaters.

Effects of chemical mixtures on liver function biomarkers in the Korean adult population: thresholds and molecular mechanisms for non-alcoholic fatty liver disease involved.

There is a scarcity of research on the effects of a mixture of chemicals on liver function biomarkers and non-alcoholic fatty liver disease (NAFLD) indices, including FSI, HIS, and FBI-4. Thus, we aimed to explore whether there is an association between chemical mixtures, including 26 chemicals found in blood and urine, liver function biomarkers, and non-alcoholic fatty liver disease (NAFLD) indices in Korean adults. The effects of exposure to chemical mixtures on liver function biomarkers and NAFLD indices were investigated using linear regression models, weighted quantile sum (WQS) regression, quantile g-computation (qgcomp), and Bayesian kernel machine regression (BKMR) among 3669 adults. In silico toxicogenomic data-mining, we evaluated molecular mechanisms associated with NAFLD, including pathways, diseases, genes, miRNAs, and biological processes. The linear regression models showed blood or urine Hg levels were the most important factors associated with AST, ALT, GGT, FSI, and HSI levels, and significant trends were observed for these chemical quartiles (p < 0.01). The WQS index was significantly associated with ALT, GGT, FSI, and HSI. The qgcomp index also found an association between chemicals and AST, ALT, GGT, and FSI. In the BKMR model, the overall effect of the mixture was significantly related to ALT, GGT, FSI, and HSI. In silico analysis, we found mixed chemicals interacted with the CYP1A2 gene and were associated with NAFLD. Seventy-eight percent of interactions were identified as physical interactions in the CYP1A2 gene related to NAFLD. Transcription factor regulation in adipogenesis and lipid metabolic processes are fundamental molecular mechanisms that could be influenced by NAFLD-related mixed chemicals. Cutoff thresholds for chemical exposure levels associated with liver function indicators and NAFLD indices were also reported. The strongest interactions and expression of miRNAs involved in NAFLD development were also identified.

Associating Increased Chemical Exposure to Hurricane Harvey in a Longitudinal Panel Using Silicone Wristbands.

Hurricane Harvey was associated with flood-related damage to chemical plants and oil refineries, and the flooding of hazardous waste sites, including 13 Superfund sites. As clean-up efforts began, concerns were raised regarding the human health impact of possible increased chemical exposure resulting from the hurricane and subsequent flooding. Personal sampling devices in the form of silicone wristbands were deployed to a longitudinal panel of individuals (n = 99) within 45 days of the hurricane and again one year later in the Houston metropolitan area. Using gas chromatography–mass spectroscopy, each wristband was screened for 1500 chemicals and analyzed for 63 polycyclic aromatic hydrocarbons (PAHs). Chemical exposure levels found on the wristbands were generally higher post-Hurricane Harvey. In the 1500 screen, 188 chemicals were detected, 29 were detected in at least 30% of the study population, and of those, 79% (n = 23) were found in significantly higher concentrations (p < 0.05) post-Hurricane Harvey. Similarly, in PAH analysis, 51 chemicals were detected, 31 were detected in at least 30% of the study population, and 39% (n = 12) were found at statistically higher concentrations (p < 0.05) post-Hurricane Harvey. This study indicates that there were increased levels of chemical exposure after Hurricane Harvey in the Houston metropolitan area.

Impact of Ergonomic Posture on the Chemical Exposure of Workers in the Petroleum and Chemical Industry.

Despite a rise in automation, workers in the petroleum refining and petrochemical manufacturing industry are potentially exposed to various chemicals through inhalation while performing routine job duties. Many factors contribute to the degree of exposure experienced in this setting. The study objective was to characterize the impact of workplace conditions, anthropometric variability, and task orientation on exposure for a simulated routine operations task. A chemical exposure laboratory simulation study was designed to evaluate the dependent variable of chemical exposure level in the breathing zone for methane and sulfur hexafluoride. The independent variables were (i) posture of the worker, (ii) worker anthropometry, (iii) process configuration, and (iv) gas density. Pipe height was a significant predictor of gas concentration measured in the breathing zone when located in a position that encouraged the gas to enter the breathing zone of the worker. Worker anthropometry had a major impact; tall worker's (male) chemical concentrations exceeded those of the short worker (female) for methane simulations but the opposite resulted for sulfur hexafluoride. Also, worker posture had a significant impact on gas exposure where nonneutral postures were found to have higher levels of chemical concentration. The study findings indicate that the breathing zone location is altered by posture and worker height, which changes the exposures relative to the emission source depending on the gas density of the chemicals that are present. As a result, qualitative risk assessment cannot be performed accurately without accounting for these factors. Practically, controls may need to account for worker size differences and posture adaptations.

The effects of chemical mixtures on lipid profiles in the Korean adult population: threshold and molecular mechanisms for dyslipidemia involved.

A scarcity of research assesses the effects of exposure to a combination of chemicals on lipid profiles as well as molecular mechanisms related to dyslipidemia. A cross-sectional study of 3692 adults aims to identify the association between chemical mixtures, including blood and urine 26 chemicals, and lipid profiles among Korean adults (aged ≥ 18) using linear regression models, weighted quantile sum (WQS) regression, quantile g-computation (qgcomp), and Bayesian kernel machine regression (BKMR). In silico toxicogenomic data-mining, we assessed molecular mechanisms linked with dyslipidemia, including genes, miRNAs, pathways, biological processes, and diseases. In the linear regression models, heavy metals, volatile organic compound metabolites, and phthalate metabolites were found to be related to HDL-C, triglycerides, LDL-C, total lipids, and total cholesterol, and significant trends were observed for these chemical quartiles (p < 0.01). The WQS index was significantly linked with HDL-C, triglycerides, LDL-C, total cholesterol, and total lipids. The qgcomp index also found a significant association between chemicals and HDL-C, triglycerides, and total lipids. In BKMR analysis, the overall effect of the chemical mixture was significantly associated with HDL-C, triglycerides, total cholesterol, and total lipids. We found that mixed chemicals interacted with the PPARA gene and were linked with dyslipidemia. Several pathways ("SREBF and miR33 in cholesterol," "estrogen receptor pathway and lipid homeostasis," and "regulation of PGC-1α"), "negative regulation of hepatocyte apoptotic process," "negative regulation of sequestering of triglycerides," "regulation of hepatocyte apoptotic process," and "negative regulation of cholesterol storage," and "abdominal obesity metabolic syndrome" were identified as key molecular mechanisms that may be affected by mixed chemicals and implicated in the development of dyslipidemia. The highest interaction and expression of miRNAs involved in the process of dyslipidemia were also described. Especially, the cutoff levels for chemical exposure levels related to lipid profiles were also provided.

Hazardous Exposures of Prosthetic and Orthotic Workshop

Background Prosthetic and orthotic PampO professionals are exposed to noise and chemicals in amounts greater than statutorily allowed and this can have adverse effect on their health. This cross-sectional project work was based on a number of difficulties faced by PampO professionals and effects on their health along with the causes.Objectives 1. To analyse the effects of hazardous exposures due to continuous noise of machines and chemical used in PampO workshop. 2. To check the frequency of noise produced due to the use of machinery and to determine the level of noise emission from the machines. 3. To propose solution within the limits of the PampO workshop of Mobility India MI.Methods Fifty prosthetic and orthotic PampO professionals were included in the study. Data was collected through personal and telephonic interviews using a questionnaire survey. Sound levels of the individual machines and all the machines operated together were measured using a sound level meter.Results The exposure to noise level was found to be higher indicating an urgent need for attention of the management and supervisor. One of the problems observed was the lack of awareness among participants about noise pollution and safety procedures or devices to prevent these hazards in the work environment.Conclusion This study found increased exposure levels of sound and chemicals thus affecting the well-being of the participants.

Before and After Study to Reduce Chemical Exposure and Noise Level Exposure through CASHE (Change Agents for Safety, Health & Environment) Program at large Scale Petrochemical Industry

Before and After Study to Reduce Chemical Exposure and Noise Level Exposure through CASHE (Change Agents for Safety, Health & Environment) Program at large Scale Petrochemical Industry

Machine Learning Prediction of the Three Main Input Parameters of a Simplified Physiologically Based Pharmacokinetic Model Subsequently Used to Generate Time-Dependent Plasma Concentration Data in Humans after Oral Doses of 212 Disparate Chemicals.

Physiologically based pharmacokinetic (PBPK) modeling has the potential to play significant roles in estimating internal chemical exposures. The three major PBPK model input parameters (i.e., absorption rate constants, volumes of the systemic circulation, and hepatic intrinsic clearances) were generated in silico for 212 chemicals using machine learning algorithms. These input parameters were calculated based on sets of between 17 and 65 chemical properties that were generated by in silico prediction tools before being processed by machine learning algorithms. The resulting simplified PBPK models were used to estimate plasma concentrations after virtual oral administrations in humans. The estimated absorption rate constants, volumes of the systemic circulation, and hepatic intrinsic clearance values for the 212 test compounds determined traditionally (i.e., based on fitting to measured concentration profiles) and newly estimated had correlation coefficients of 0.65, 0.68, and 0.77 (p < 0.01, n = 212), respectively. When human plasma concentrations were modeled using traditionally determined input parameters and again using in silico estimated input parameters, the two sets of maximum plasma concentrations (r = 0.85, p < 0.01, n = 212) and areas under the curve (r = 0.80, p < 0.01, n = 212) were correlated. Virtual chemical exposure levels in liver and kidney were also estimated using these simplified PBPK models along with human plasma levels. These results indicate that the PBPK model input parameters for humans of a diverse set of compounds can be reliability estimated using chemical descriptors calculated using in silico tools.

Derivation of a biological limit value (BLV) for inorganic lead based on lead-induced genotoxicity in workers using the benchmark dose approach (BMD)

BackgroundSafe exposure levels for industrial chemicals are a prerequisite to the safety of workers in occupational settings. MethodsThe application areas of the benchmark dose (BMD) approach have tremendously increased in recent years. Quantitative analyzes of dose-response relationships of genotoxic chemicals are among these application areas too. This study investigates the applicability of sister chromatid exchange (SCE) frequencies in lymphocytes of lead-exposed workers to derive a biological limit value (BLV) for inorganic lead. To this end, our previously published occupational lead exposure data were pooled and re-examined by using the BMD approach. Subsequently, we determined the point of departure (POD) value for lead-induced SCE frequencies in lymphocytes. Accordingly, the blood lead concentrations and SCE frequencies in lymphocytes of 26 control and 108 lead-exposed male voluntary workers employed in a battery manufacturing plant were subjected to BMD modeling to determine the BMD confidence interval (BMD-CI). ResultsAccording to our data set, benchmark dose lower bound (BMDL) of 6.55 μg Pb/dL blood for the SCE frequencies in lymphocytes of lead-exposed workers has been obtained. ConclusionThe blood lead concentration of 6.55 μg/dL might be proposed as the BLV for lead and its inorganic lead compounds based on our dataset.

Threshold of Toxicological Concern: Extending the chemical space by inclusion of a highly curated dataset for organosilicon compounds

The Threshold of Toxicological Concern (TTC) for non-genotoxic substances, a risk assessment tool to establish safe exposure levels for chemicals with insufficient toxicological data, is based on the 5th percentile of cumulated distributions of Point of Departures in a high amount of repeat-dose, developmental and reproductive toxicity studies, grouped by Cramer Classes. The lack of organosilicon compounds in this dataset has resulted in regulatory concerns over the applicability of the TTC concept for this chemistry. We collected publicly available, scientifically robust oral repeat-dose and DART studies for 71 organosilicon substances for inclusion in the existing TTC dataset, using criteria for evaluation of studies and derivation of points of departure analogous to the Munro and COSMOS TTC publications. The resulting 5th percentile of this dataset was 13-fold higher than the 5th percentile for Cramer Class III compounds reported by Munro (which is the default for silicon-containing substances). Both the existing TTC for Cramer Class III compounds from Munro (1.5 μg/kg bw/day) and the COSMOS TTC (2.3 μg/kg bw/day), recommended by the SCCS for cosmetics-related substances, provide a conservative and sufficiently protective approach for this class of chemistry.

Application of Meta-Analysis to Derivation of Points-of-Departure for Short-Term Inhalation Exposure Levels of Hazardous Chemicals

BACKGROUND AND AIM: For short-term chemical inhalation exposures to hazardous chemicals, the incidence of a health effect usually conforms to a generalized linear model with a bivariate probit link function dependent on inhalant concentration ({C}) and the duration of exposure ({t}). The National Academy’s Acute Exposure Guideline Levels (AEGLs) Committee relies on this model when deriving AEGLs. Threshold concentrations at AEGL durations are established by the toxic load equation, {C}^{n} x {t} = {constant}, which Toxic Load Exponent {n} (TLE or {n}-value) directly follows from the probit model. When multiple probit datasets are available, often they cannot be directly pooled together because of disparities in experimental design. METHODS: Recently, we reported both a meta-analytical framework for multiple studies and an application of the new methodology to dimethyl sulfide. The new methodology allows accurate TLE estimation even if multiple datasets are heterogenous. The utilized techniques include categorical regression, common-effect and random-effects models. The proposed framework was applied to multiple-study datasets from AEGL technical support documents. RESULTS:Using the framework, both new TLEs and confidence intervals on them were derived. The recalculated TLEs and points-of-departure include ammonia ({n} = 2.13, 95% CI: 1.98–2.27), allyl alcohol ({n} = 0.95, 95% CI: 0.76–1.15), 1,1,1-trichloroethane ({n} = 3.46, 95% CI: 2.85–4.07 ), carbon tetrachloride ({n} = 2.51, 95% CI: 2.27–2.76), and oxygen difluoride ({n} = 1.29, 95% CI: 0.26–2.32). CONCLUSIONS:The new TLEs and their confidence intervals were applied in calculations of short-term inhalation points of departure at five reference AEGL durations. Disclaimer: The findings and conclusions in this presentation have not been formally disseminated by the Centers for Disease Control and Prevention/the Agency for Toxic Substances and Disease Registry and should not be construed to represent any agency determination or policy. KEYWORDS: Risk Assessment, Meta-analysis, Toxic Load Exponent (TLE), n-value, Probit, Categorical Regression

First nationwide exposure profile of major persistent organic pollutants among Korean adults and their determinants: Korean National Environmental Health Survey Cycle 3 (2015-2017).

Since 2009, Korea has measured the exposure levels of major environmental chemicals and heavy metals among representative adult populations through the Korean National Environmental Health Survey (KoNEHS). However, exposure to persistent organic pollutants (POPs) has never been assessed. This study reports the serum concentrations of twenty-four POPs and their influencing factors for Korean adults (n=1295) who participated in the KoNEHS Cycle 3 (2015-2017). The POPs included seven organochlorine pesticides (OCPs), eleven polychlorinated biphenyls (PCBs), and six polybrominated diphenyl ethers (PBDEs). Among them, three OCPs (i.e., hexachlorobenzene (HCB), p,p'-dichlorodiphenyltrichloroethane (p,p'-DDT), and p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE)) and five PCBs (i.e., PCB52, PCB118, PCB138, PCB153, and PCB180) were detected in over 60% of the samples. PBDEs were not detected at a detection frequency of 60% or above. The most frequently detected POPs were p,p'-DDE (99.8%, geometric mean of 128.47ng/g lipid), followed by PCB180 (98.8%, 8.49ng/g lipid), PCB153 (98.8%, 13.14ng/g lipid), HCB (96.2%, 67.08ng/g lipid), PCB138 (95.2%, 8.84ng/g lipid), PCB118 (89.6%, 2.66ng/g lipid), p,p'-DDT (80.5%, 6.68ng/g lipid), and PCB52 (71.2%, 1.57ng/g lipid). The concentrations of most POPs were lower than or similar to concentrations reported in national-scale biomonitoring surveys. The only exception was HCB, whose concentration was up to seven-fold higher than the concentration reported by the Canadian Health Measures Survey. Excluding HCB and PCB52, most POPs showed increasing serum levels among older adults, adults with higher body mass index, adults living in coastal areas, and more frequent fish consumption. Relatively higher POP concentrations were observed in menopausal women. This study provides the first data on POP exposure levels among the representative adult population in Korea, and the results highlight the need to integrate POPs in the national biomonitoring program.

Network Analysis to Identify Communities Among Multiple Exposure Biomarkers Measured at Birth in Three Flemish General Population Samples.

Introduction: Humans are exposed to multiple environmental chemicals via different sources resulting in complex real-life exposure patterns. Insight into these patterns is important for applications such as linkage to health effects and (mixture) risk assessment. By providing internal exposure levels of (metabolites of) chemicals, biomonitoring studies can provide snapshots of exposure patterns and factors that drive them. Presentation of biomonitoring data in networks facilitates the detection of such exposure patterns and allows for the systematic comparison of observed exposure patterns between datasets and strata within datasets.Methods: We demonstrate the use of network techniques in human biomonitoring data from cord blood samples collected in three campaigns of the Flemish Environment and Health Studies (FLEHS) (sampling years resp. 2002–2004, 2008–2009, and 2013–2014). Measured biomarkers were multiple organochlorine compounds, PFAS and metals. Comparative network analysis (CNA) was conducted to systematically compare networks between sampling campaigns, smoking status during pregnancy, and maternal pre-pregnancy BMI.Results: Network techniques offered an intuitive approach to visualize complex correlation structures within human biomonitoring data. The identification of groups of highly connected biomarkers, “communities,” within these networks highlighted which biomarkers should be considered collectively in the analysis and interpretation of epidemiological studies or in the design of toxicological mixture studies. Network analyses demonstrated in our example to which extent biomarker networks and its communities changed across the sampling campaigns, smoking status during pregnancy, and maternal pre-pregnancy BMI.Conclusion: Network analysis is a data-driven and intuitive screening method when dealing with multiple exposure biomarkers, which can easily be upscaled to high dimensional HBM datasets, and can inform mixture risk assessment approaches.

A novel method for combining outcomes with different severities or gene-level classifications.

Chemical risk assessment is currently based on consideration of health effects individually. The present work discusses a method for combining data by characterizing the dose-related sequence of the development of lower- to higher-order toxicological effects or the range of bioactivity observed at genomic level caused by a chemical/mixture. A reference point profile (RPP) is defined as the relation between benchmark doses for considered effects (or bioactivity measures) and a standardized severity or rank score determined for these effects. For a given dose of a chemical/mixture, the probability for exceeding the RPP can be assessed. An overall toxicological response can also be derived at the same dose by integrating contributions across all effects, with a rational for severity weighing. Conversely, dose equivalents corresponding to specified responses can be estimated. The variation in RPPs across chemicals suggests that joint consideration of effects under the proposed concept differentiates the consequence of chemical exposure, both at genomic and apical levels, to a higher extent compared to using a specific effect as a basis. This may help to refine the development of points of departure or sets of such values describing a range of health concerns. Analysis and comparison of apical and genomic RPPs, as well as consideration of functional relations between gene sets within such analyses, may aid in the transition towards a new approach method-based risk assessment paradigm that to a higher degree may require methods for combination of effect data compared to relying on specific outcomes.

Assessing the cognitive and behavioral development of 3-year-old children born from fathers with severe male infertility

Despite the large number of babies born worldwide following intracytoplasmic sperm injection, concerns about the procedure's safety still exist owing to the use of suboptimal spermatozoa. Thus, follow-up of children conceived via intracytoplasmic sperm injection is highly recommended. We propose the use of parent-administered questionnaires to monitor the development of offspring conceived via intracytoplasmic sperm injection. This study aimed to determine whether male infertility treatment affects offspring development. We compared obstetrical and neonatal outcomes andphysical and psychological development of toddlers conceived viainvitro fertilization and intracytoplasmic sperm injection. Once newborns reached 3 years of age, participating patients were sent a set of parent-administered questionnaires, including the Ages and Stages Questionnaires; Prescreening Developmental Questionnaire 2; Peabody Developmental Motor Scales, Second Edition; Social Skills Rating System; Parenting Stress Index, Third Edition; and Child Behavior Checklist for Ages 2-3. Child development was measured by the Ages and Stages Questionnaires; Prescreening Developmental Questionnaire 2; and Peabody Developmental Motor Scales, Second Edition, questionnaires, whereas Social Skills Rating System; Parenting Stress Index, Third Edition; and Child Behavior Checklist for Ages 2-3 questionnaires were used to measure child behavior. The child's developmental or behavioral outcome was considered "abnormal" when he or she scored below average in ≥2 questionnaires from the respective category. We also conducted subanalyses to assess the effects of male genomic integrity, DNA fragmentation, chemical exposure, utilization of surgically retrieved spermatozoa, and extended embryo culture to determine the development of a child conceived via intracytoplasmic sperm injection. A total of 12,306 couples met the inclusion criteria for this study; 1914 of 7433 patients (25.8%) who underwent intracytoplasmic sperm injection and 451 of 4873 patients (9.3%) who underwent invitro fertilization returned the questionnaires. Our comparison of obstetrical outcomes between the 2 groups did not reveal any significant differences in the mode of delivery distribution, with most mothers having uncomplicated vaginal deliveries. Furthermore, gender distribution, gestational ages, and birthweights were also comparable between children conceived via intracytoplasmic sperm injection and invitro fertilization. However, children conceived via invitro fertilization displayed impaired developmental characteristics compared with the intracytoplasmic sperm injection-conceived cohort (adjusted odds ratio, 0.72; 95% confidence interval, 0.5-0.9; P=.0004). There was no difference in child behavior. Furthermore, 3 cases of autism were reported, 1 case from the invitro fertilization group and 2 from the intracytoplasmic sperm injection group, all conceived from couples with an older male partner. Ages and Stages Questionnaires outcomes were also compared for the offspring conceived via invitro fertilization and intracytoplasmic sperm injection by gender; however, no significant differences were observed. In addition, 5 separate subanalyses were then conducted exclusively for the intracytoplasmic sperm injection-conceived group. Levels of spermatogenic failure, DNA fragmentation, and chemical exposure did not significantly affect offspring development. Interestingly, although the length of embryo culture did not seem to influence child development, the abnormal behavior rate was significantly higher in children from the day 3 embryo transfer cohort (adjusted odds ratio, 0.4; 95% confidence interval, 0.05-0.34; P=.04). Children conceived via intracytoplasmic sperm injection from ejaculated spermatozoa displayed impaired developmental and behavioral characteristics compared with toddlers conceived from surgically retrieved specimens (adjusted odds ratio, 4.9; 95% confidence interval, 1.2-20.7; P=.05). Most children conceived via intracytoplasmic sperm injection and invitro fertilization are developing well without significant delays. Although the development of a child conceived via intracytoplasmic sperm injection was not affected by most of the variables assessed, those conceived from surgically retrieved spermatozoa were at a considerably lower risk of abnormal developmental and abnormal behavioral characteristics than offspring conceived from ejaculated specimens. However, given the small numbers of respondents available for many subgroups of interest, further studies of outcomes of children born from fathers with severe male factor infertility are warranted.

1H-NMR metabolomics profiling of zebra mussel (Dreissena polymorpha): A field-scale monitoring tool in ecotoxicological studies.

Biomonitoring of aquatic environments requires new tools to characterize the effects of pollutants on living organisms. Zebra mussels (Dreissena polymorpha) from the same site in north-eastern France were caged for two months, upstream and downstream of three wastewater treatment plants (WWTPs) in the international watershed of the Meuse (Charleville-Mézières "CM" in France, Namur "Nam" and Charleroi "Cr" in Belgium). The aim was to test 1H-NMR metabolomics for the assessment of water bodies' quality. The metabolomic approach was combined with a more "classical" one, i.e., the measurement of a range of energy biomarkers: lactate dehydrogenase (LDH), lipase, acid phosphatase (ACP) and amylase activities, condition index (CI), total reserves, electron transport system (ETS) activity and cellular energy allocation (CEA). Five of the eight energy biomarkers were significantly impacted (LDH, ACP, lipase, total reserves and ETS), without a clear pattern between sites (Up and Down) and stations (CM, Nam and Cr). The metabolomic approach revealed variations among the three stations, and also between the upstream and downstream of Nam and CM WWTPs. A total of 28 known metabolites was detected, among which four (lactate, glycine, maltose and glutamate) explained the observed metabolome variations between sites and stations, in accordance with chemical exposure levels. Metabolome changes suggest that zebra mussel exposure to field contamination could alter their osmoregulation and anaerobic metabolism capacities. This study reveals that lactate is a potential biomarker of interest, and 1H-NMR metabolomics can be an efficient approach to assess the health status of zebra mussels in the biomonitoring of aquatic environments.