Abstract Much progress has happened in understanding developmental vulnerability to preventable environmental hazards. Along with the improved insight, the perspective has widened, and developmental toxicity now involves latent effects that can result in delayed adverse effects in adults or at old age and additional effects that can be transgenerationally transferred to future generations. Although epidemiology and toxicology to an increasing degree are exploring the adverse effects from developmental exposures in human beings, the improved documentation has resulted in little progress in protection, and few environmental chemicals are currently regulated to protect against developmental toxicity, whether it be neurotoxicity, endocrine disruption or other adverse outcome. The desire to obtain a high degree of certainty and verification of the evidence used for decision‐making must be weighed against the costs and necessary duration of research, as well as the long‐term costs to human health because of delayed protection of vulnerable early‐life stages of human development and, possibly, future generations. Although two‐generation toxicology tests may be useful for initial test purposes, other rapidly emerging tools need to be seriously considered from computational chemistry and metabolomics to CLARITY ‐ BPA ‐type designs, big data and population record linkage approaches that will allow efficient generation of new insight; epigenetic mechanisms may necessitate a set of additional regulatory tests to reveal such effects. As reflected by the Prenatal Programming and Toxicity ( PPTOX ) VI conference, the current scientific understanding and the timescales involved require an intensified approach to protect against preventable adverse health effects that can harm the next generation and generations to come. While further research is needed, the main emphasis should be on research translation and timely public health intervention to avoid serious, irreversible and perhaps transgenerational harm.
Safety of Safety Evaluation of Pesticides: developmental neurotoxicity of chlorpyrifos and chlorpyrifos-methyl
Authorization of pesticides for market release requires toxicity testing on animals, typically performed by test laboratories on contract with the pesticide producer. The latter provides the results and summary to the regulatory authorities. For the commonly used pesticide chlorpyrifos, an industry-funded toxicity study concludes that no selective effects on neurodevelopment occur even at high exposures. In contrast, the evidence from independent studies points to adverse effects of current exposures on cognitive development in children. We reviewed the industry-funded developmental neurotoxicity test data on chlorpyrifos and the related substance chlorpyrifos-methyl. We noted treatment-related changes in a brain dimension measure for chlorpyrifos at all dose levels tested, although not been reported in the original test summary. We further found issues which inappropriately decrease the ability of the studies to reveal true effects, including a dosage regimen that resulted in too low exposure of the nursing pups for chlorpyrifos and possibly for chlorpyrifos-methyl, and a failure to detect any neurobehavioral effects of lead nitrate used as positive control in the chlorpyrifos study. Our observations thus suggest that conclusions in test reports submitted by the producer may be misleading. This discrepancy affects the ability of regulatory authorities to perform a valid and safe evaluation of these pesticides. The difference between raw data and conclusions in the test reports indicates a potential existence of bias that would require regulatory attention and possible resolution.
A Benchmark Dose Analysis for Maternal Pregnancy Urine‐Fluoride and IQ in Children
Abstract As a guide to establishing a safe exposure level for fluoride exposure in pregnancy, we applied benchmark dose modeling to data from two prospective birth cohort studies. We included mother–child pairs from the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) cohort in Mexico and the Maternal‐Infant Research on Environmental Chemicals (MIREC) cohort in Canada. Maternal urinary fluoride concentrations (U‐F, in mg/L, creatinine‐adjusted) were measured in urine samples obtained during pregnancy. Children were assessed for intelligence quotient (IQ) at age 4 ( n = 211) and between six and 12 years ( n = 287) in the ELEMENT cohort, and three to four years ( n = 407) in the MIREC cohort. We calculated covariate‐adjusted regression coefficients and their standard errors to assess the association of maternal U‐F concentrations with children's IQ measures. Assuming a benchmark response of 1 IQ point, we derived benchmark concentrations (BMCs) and benchmark concentration levels (BMCLs). No deviation from linearity was detected in the dose–response relationships, but boys showed lower BMC values than girls. Using a linear slope for the joint cohort data, the BMC for maternal U‐F associated with a 1‐point decrease in IQ scores was 0.31 mg/L (BMCL, 0.19 mg/L) for the youngest boys and girls in the two cohorts, and 0.33 mg/L (BMCL, 0.20 mg/L) for the MIREC cohort and the older ELEMENT children. Thus, the joint data show a BMCL in terms of the adjusted U‐F concentrations in the pregnant women of approximately 0.2 mg/L. These results can be used to guide decisions on preventing excess fluoride exposure in pregnant women.
Benchmark dose calculations for PFAS exposure based on two data sets on immunotoxic effects
Exposure to perfluorinated alkylate substances (PFAS) is associated with harmful effects on human health, including developmental immunotoxicity. This outcome was chosen as the critical effect by the European Food Safety Authority (EFSA), which calculated a new joint reference dose for four PFAS using a Benchmark Dose (BMD) analysis of a study of 1-year old children. However, the U.S. Environmental Protection Agency (EPA) recently proposed much lower exposure limits.
Arsenic exposure at birth, socioeconomic status, and epigenetic aging among adults in northern Chile
Background Arsenic exposure remains a major global health concern, and early-life exposure has been linked to cancer, cardiovascular disease, and diabetes. Epigenetic biomarkers of aging may capture long-term effects of arsenic, yet whether exposure during sensitive developmental windows leaves detectable epigenetic signatures decades later remains unclear. Socioeconomic status (SES) may modify these relationships, yet its role as a modifier has not been examined. Methods We leveraged a natural experiment in northern Chile, where municipal drinking-water arsenic concentrations were extremely high from 1958 to 1972. Decades later, leukocyte DNA methylation was measured among 358 adults (mean age = 65.7 years) using the Illumina EPIC v2 array. Arsenic concentration at birth (0-860 μg/L) was assigned from historical water records. Current exposure was measured in urine (2-646 μg/g creatinine). We evaluated associations of birth and current arsenic exposure with epigenome-wide methylation and epigenetic aging, incorporating multiplicative interaction and stratification by SES. Results No CpGs were linked to birth arsenic exposure, whereas nine CpGs passed the Bonferroni threshold for current urinary arsenic (pBonferroni
Arsenic exposure at birth, socioeconomic status, and epigenetic aging among adults in northern Chile
Background Arsenic exposure remains a major global health concern, and early-life exposure has been linked to cancer, cardiovascular disease, and diabetes. Epigenetic biomarkers of aging may capture long-term effects of arsenic, yet whether exposure during sensitive developmental windows leaves detectable epigenetic signatures decades later remains unclear. Socioeconomic status (SES) may modify these relationships, yet its role as a modifier has not been examined. Methods We leveraged a natural experiment in northern Chile, where municipal drinking-water arsenic concentrations were extremely high from 1958 to 1972. Decades later, leukocyte DNA methylation was measured among 358 adults (mean age = 65.7 years) using the Illumina EPIC v2 array. Arsenic concentration at birth (0-860 μg/L) was assigned from historical water records. Current exposure was measured in urine (2-646 μg/g creatinine). We evaluated associations of birth and current arsenic exposure with epigenome-wide methylation and epigenetic aging, incorporating multiplicative interaction and stratification by SES. Results No CpGs were linked to birth arsenic exposure, whereas nine CpGs passed the Bonferroni threshold for current urinary arsenic (pBonferroni
Emerging contaminants: A One Health perspective
Environmental pollution is escalating due to rapid global development that often prioritizes human needs over planetary health. Despite global efforts to mitigate legacy pollutants, the continuous introduction of new substances remains a major threat to both people and the planet. In response, global initiatives are focusing on risk assessment and regulation of emerging contaminants, as demonstrated by the ongoing efforts to establish the UN’s Intergovernmental Science-Policy Panel on Chemicals, Waste, and Pollution Prevention.
Delayed discovery, dissemination, and decisions on intervention in environmental health: a case study on immunotoxicity of perfluorinated alkylate substances
Identification and characterization of environmental hazards that impact human health must rely on the best possible science to inform and inspire appropriate public health intervention. The perfluorinated alkylate substances (PFASs) are persistent emerging pollutants that are now being recognized as important human health hazards. Although the PFASs have been produced for over 60 years, academic research on environmental health aspects has appeared only in the most recent 10 years or so. In the meantime, these persistent chemicals accumulated in the global environment. Some early studies e.g., on population exposures and toxicity, were not released to the public until after year 2000. Still, the first PFAS risk assessments ignored these reports and relied on scant journal publications. The first guidelines and legal limits for PFAS exposure, e.g., from drinking water, were proposed 10 years ago. They have decreased substantially since then, but remain higher than suggested by data on human adverse effects, especially on the immune system, that occur at background exposure levels. By now, the best-known PFASs are being phased out, and related PFASs are being introduced as substitutes. Given the substantial delays in discovery of PFAS toxicity, in dissemination of findings, and in regulatory decisions, PFAS substitutes and other persistent industrial chemicals should be subjected to prior scrutiny before widespread usage.
Dose dependence of prenatal fluoride exposure associations with cognitive performance at school age in three prospective studies
Abstract Background Fluoride may be a developmental neurotoxicant at elevated exposures. We merged new data from a prospective Odense Child Cohort (OCC) with results from two previous birth cohort studies from Mexico and Canada to characterize the dose–effect relationship in greater detail. Methods The OCC contributed 837 mother–child pairs to the total of >1500. We measured creatinine-adjusted urine-fluoride concentrations in maternal urine samples obtained during late pregnancy. Child IQ was determined at age 7 years using an abbreviated version of the Wechsler Intelligence Scales for Children. Findings from the three cohorts were used to calculate the joint benchmark concentration (BMC) and the lower confidence limit (BMCL) after adjustment for covariables. Results In the OCC, urine-fluoride concentrations varied between 0.08 and 3.04 mg/l (median 0.52 mg/l) but were not significantly associated with full-scale IQ at age 7 years (β = 0.08; 95% confidence interval −1.14 to 1.30 for a doubling in exposure). No difference was apparent between boys and girls. In the OCC, the BMC was 0.92 mg/l, with a BMCL of 0.30 mg/l. The joint analysis of all three cohorts showed a statistically significant association between urine-fluoride and IQ, with a BMC of 0.45 mg/l (BMCL, 0.28 mg/l), slightly higher than the BMC previously reported for the two North American cohorts alone. Conclusions As the BMCL reflects an approximate threshold for developmental neurotoxicity, the results suggest that pregnant women and children may need protection against fluoride toxicity.
Application of benchmark analysis for mixed contaminant exposures: Mutual adjustment of perfluoroalkylate substances associated with immunotoxicity
Background Developmental exposure to perfluorinated alkylate substances (PFASs) is associated with deficient IgG antibody responses to childhood vaccines. As this immunotoxicity outcome may represent a critical effect, calculation of benchmark dose (BMD) results would be useful for defining protective limits of exposure. However, exposures to the major PFASs that are associated with this adverse effect are interrelated, and mutually adjusted BMD results would be desirable. Methods We carried out BMD calculations on prospective data from two prospective birth cohort studies from the Faroe Islands with a total of 1,146 children. Exposure data included serum concentrations of five major PFASs at birth and at age 5 years and, as outcome parameters, the serum concentrations of specific IgG antibodies against tetanus and diphtheria at ages 5 and 7. We calculated the BMDs and their lower confidence bounds (BMDLs) and included mutual adjustment for five major PFASs. BMD and BMDL were expressed in terms of the serum concentration of the PFASs. Results The BMDLs for the immunotoxicants were of similar magnitude before and after adjustment. As compared to linear dose-response models, the PFASs showed lower results for a piecewise linear model, which also provided a slightly better fit. Weaker associations with the antibody outcomes were observed after adjustments due to the correlation between the PFASs. However, while the adjustments resulted in elevated BMD results and p values, the BMDL values were not materially changed. Conclusions Adjustment for co-exposure to a related immunotoxicant increased both the BMD values and their standard errors, though affected the BMDL values only to a negligible extent. Thus, when correlated toxicants appear to affect the same outcome and none of them is known a priori to be solely responsible, all exposures may be considered responsible in BMD calculations. Our BMDL results, both before and after adjustment are generally below current exposure levels and therefore suggest that all five perfluorinated substances should attract regulatory attention, at least until additional evidence shows otherwise.
Emerging questions in exposure, regulation, and remediation of PFAS
My research is highly interdisciplinary and includes exposure and risk analysis. Many of our colleagues have diverse backgrounds and work together to address the interdisciplinary challenges associated with PFAS contamination …I think one of the largest gaps right now is understanding the importance of different exposure pathways for the general population.Given the tremendous physical and mental toll affected communities have experienced due to their exposure to PFAS, there is an unusually strong connection between citizens and scientists, and I hope that bond will strengthen over time.
Shifting Global Exposures to Poly- and Perfluoroalkyl Substances (PFASs) Evident in Longitudinal Birth Cohorts from a Seafood-Consuming Population
Abstract. Rapid declines in legacy poly- and perfluoroalkyl substances (PFASs) have been reported in human populations globally following changes in produc
Chronic methylphenidate abuse: Effects on behaviour, redox homeostasis, and cholinergic system
Methylphenidate (MPH) (metil 2-fenil-2-(piperidin-2-il) acetato) is used as a drug of abuse as well as a cognitive enhancer owing to its amphetaminic structure. The objective of this study was to evaluate whether chronic exposure to an abusive context and dose of MPH (80 mg/L for 15 min/day for 7 days) in adult life causes behavioural changes related to anxiety, fear, sociability, locomotion, and memory as well as altered levels of biochemical markers, cortisol, and the cholinergic system. Here we used the zebrafish (Danio rerio) as a translatio Nnal model. We showed that fish exposed to MPH showed marked hypolocomotion and anxiogenic patterns, fear behaviour, and memory delay. MPH exposure also increased the levels of antioxidant enzymes, non-protein thiols, and reactive oxygen species compared with those in the control group, and the redox status was altered at the cerebral and peripheral levels. The cholinergic system exhibits a reduction in signalling and an increase in cortisol levels. Our results clarified the mechanisms involved in the toxicity elicited by the abusive use of MPH. Overall, our results demonstrated that chronic administration of an abusive dose of MPH in individuals without a diagnosis of attention deficit hyperactivity disorder (ADHD) can cause important damage.
Improving and Expanding Estimates of the Global Burden of Disease Due to Environmental Health Risk Factors
Abstract Background: The Global Burden of Disease (GBD) study, coordinated by the Institute for Health Metrics and Evaluation (IHME), produces influential, data-driven estimates of the burden of disease and premature death due to major risk factors. Expanded quantification of disease due to environmental health (EH) risk factors, including climate change, will enhance accuracy of GBD estimates, which will contribute to developing cost-effective policies that promote prevention and achieving Sustainable Development Goals. Objectives: We review key aspects of the GBD for the EH community and introduce the Global Burden of Disease–Pollution and Health Initiative (GBD-PHI), which aims to work with IHME and the GBD study to improve estimates of disease burden attributable to EH risk factors and to develop an innovative approach to estimating climate-related disease burden—both current and projected. Methods: We discuss strategies for improving GBD quantification of specific EH risk factors, including air pollution, lead, and climate change. We highlight key methodological challenges, including new EH risk factors, notably evidence rating and global exposure assessment. Discussion: A number of issues present challenges to the scope and accuracy of current GBD estimates for EH risk factors. For air pollution, minimal data exist on the exposure–risk relationships associated with high levels of pollution; epidemiological studies in high pollution regions should be a research priority. For lead, the GBD’s current methods do not fully account for lead’s impact on neurodevelopment; innovative methods to account for subclinical effects are needed. Decisions on inclusion of additional EH risk–outcome pairs need to be guided by findings of systematic reviews, the size of exposed populations, feasibility of global exposure estimates, and predicted trends in exposures and diseases. Neurotoxicants, endocrine-disrupting chemicals, and climate-related factors should be high priorities for incorporation into upcoming iterations of the GBD study. Enhancing the scope and methods will improve the GBD’s estimates and better guide prevention policy. https://doi.org/10.1289/EHP5496
Can profiles of poly- and Perfluoroalkyl substances (PFASs) in human serum provide information on major exposure sources?
Humans are exposed to poly- and perfluoroalkyl substances (PFASs) from diverse sources and this has been associated with negative health impacts. Advances in analytical methods have enabled routine detection of more than 15 PFASs in human sera, allowing better profiling of PFAS exposures. The composition of PFASs in human sera reflects the complexity of exposure sources but source identification can be confounded by differences in toxicokinetics affecting uptake, distribution, and elimination. Common PFASs, such as perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS) and their precursors are ubiquitous in multiple exposure sources. However, their composition varies among sources, which may impact associated adverse health effects.
Bone mass density following developmental exposures to perfluoroalkyl substances (PFAS): a longitudinal cohort study
Environmental exposures to industrial chemicals, including perfluoroalkyl substances (PFAS), may play a role in bone development and future risk of osteoporosis. However, as prospective evidence is limited, the role of developmental PFAS exposures in bone density changes in childhood is unclear. The objective of this study was to estimate associations between serum-PFAS concentrations measured in infancy and early childhood and areal bone mineral density (aBMD) measured at age 9 years in a birth cohort of children from the Faroe Islands.
Methylphenidate Treatment and Risk of Psychotic Disorder
This cohort study of a Finnish national multiyear birth cohort uses instrumental variable analysis to investigate whether methylphenidate alters the long-term risk of psychotic disorder in children with attention-deficit/hyperactivity disorder.
