Systematic review of epidemiological and toxicological evidence on health effects of fluoride in drinking water.

INTRODUCTION: Fluoride is a naturally occurring substance that is also added to drinking water, dental hygiene products, and food supplements for preventing dental caries. Concerns have been raised about several other potential health risks of fluoride. OBJECTIVE: To conduct a robust synthesis of evidence regarding human health risks due to exposure to fluoride in drinking water, and to develop a point of departure (POD) for setting a health-based value (HBV) for fluoride in drinking water. METHODS: A systematic review of evidence published since recent reviews of human, animal, and in vitro data was carried out. Bradford Hill considerations were used to weigh the evidence for causality. Several key studies were considered for deriving PODs. RESULTS: The current review identified 89 human studies, 199 animal studies, and 10 major in vitro reviews. The weight of evidence on 39 health endpoints was presented. In addition to dental fluorosis, evidence was considered strong for reduction in IQ scores in children, moderate for thyroid dysfunction, weak for kidney dysfunction, and limited for sex hormone disruptions. CONCLUSION: The current review identified moderate dental fluorosis and reduction in IQ scores in children as the most relevant endpoints for establishing an HBV for fluoride in drinking water. PODs were derived for these two endpoints, although there is still some uncertainty in the causal weight of evidence for causality for reducing IQ scores in children and considerable uncertainty in the derivation of its POD. Given our evaluation of the overall weight of evidence, moderate dental fluorosis is suggested as the key endpoint until more evidence is accumulated on possible reduction of IQ scores effects. A POD of 1.56 mg fluoride/L for moderate dental fluorosis may be preferred as a starting point for setting an HBV for fluoride in drinking water to protect against moderate and severe dental fluorosis. Although outside the scope of the current review, precautionary concerns for potential neurodevelopmental cognitive effects may warrant special consideration in the derivation of the HBV for fluoride in drinking water.

Relevance and feasibility of principles for health and environmental risk decision-making.

Globally, national regulatory authorities are both responsible and accountable for health and environmental decisions related to diverse products and risk decision contexts. These authorities provided regulatory oversight and expedited market authorizations of vaccines and other therapeutic products during the COVID-19 pandemic. Regulatory decisions regarding such products and situations depend upon well-established risk assessment and management steps. The underlying processes supporting such decisions were outlined in frameworks describing the complex interactions between factors including risk assessment and management steps as well as principles which help guide risk decision-making. In 2022, experts in risk science proposed a set of 10 guiding principles, further examining the intersection and utility of these principles using 10 diverse risk contexts, and inviting a broader discourse on the application of these principles in risk decision-making. To add to this information, Canadian regulatory practitioners responsible for evaluating health and environmental risks and establishing policies convened at a Health Canada workshop on Principles for Risk Decision-Making. This review reports the results derived from this interactive engagement and provides a first pragmatic analysis of the relevance, importance, and feasibility of such principles for health and environmental risk decision-making within the Canadian regulatory context.

Validation of mobile phone use recall in the multinational MOBI-kids study.

Potential differential and non-differential recall error in mobile phone use (MPU) in the multinational MOBI-Kids case-control study were evaluated. We compared self-reported MPU with network operator billing record data up to 3 months, 1 year, and 2 years before the interview date from 702 subjects aged between 10 and 24 years in eight countries. Spearman rank correlations, Kappa coefficients and geometric mean ratios (GMRs) were used. No material differences in MPU recall estimates between cases and controls were observed. The Spearman rank correlation coefficients between self-reported and recorded MPU in the most recent 3 months were 0.57 and 0.59 for call number and for call duration, respectively. The number of calls was on average underestimated by the participants (GMR = 0.69), while the duration of calls was overestimated (GMR = 1.59). Country, years since start of using a mobile phone, age at time of interview, and sex did not appear to influence recall accuracy for either call number or call duration. A trend in recall error was seen with level of self-reported MPU, with underestimation of use at lower levels and overestimation of use at higher levels for both number and duration of calls. Although both systematic and random errors in self-reported MPU among participants were observed, there was no evidence of differential recall error between cases and controls. Nonetheless, these sources of exposure measurement error warrant consideration in interpretation of the MOBI-Kids case-control study results on the association between children's use of mobile phones and potential brain cancer risk.

Should we screen aging physicians for cognitive decline?

OBJECTIVES: To synthesize evidence relevant for informed decisions concerning cognitive testing of older physicians. METHODS: Relevant literature was systematically searched in Medline, EMBASE, PsycInfo, and ERIC, with key findings abstracted and synthesized. RESULTS: Cognitive abilities of physicians may decline in an age range where they are still practicing. Physician competence and clinical performance may also decline with age. Cognitive scores are lower in physicians referred for assessment because of competency or performance concerns. Many physicians do not accurately self-assess and continue to practice despite declining quality of care; however, perceived cognitive decline, although not an accurate indicator of ability, may accelerate physicians' decision to retire. Physicians are reluctant to report colleagues' cognitive problems. Several issues should be considered in implementing cognitive screening. Most cognitive assessment tools lack normative data for physicians. Scientific evidence linking cognitive test results with physician performance is limited. There is no known level of cognitive decline at which a doctor is no longer fit to practice. Finally, relevant domains of cognitive ability vary across medical specialties. CONCLUSION: Physician cognitive decline may impact clinical performance. If cognitive assessment of older physicians is to be implemented, it should consider challenges of cognitive test result interpretation.

Concomitant use of statins and sodium-glucose co-transporter 2 inhibitors and the risk of myotoxicity reporting: A disproportionality analysis.

AIMS: Recent case reports have suggested that sodium-glucose co-transporter 2 (SGLT2) inhibitors may interact with statins to increase their risk of myotoxicity. We assessed the risk of myotoxicity reporting associated with concomitant use of SGLT2 inhibitors and statins. METHODS: We queried the US Food and Drug Administration Adverse Event Reporting System (FAERS) from 2013 to 2021 for reports including SGLT2 inhibitors, statins or both. We estimated several measures of disproportionate reporting of myopathy and rhabdomyolysis associated with concomitant use of SGLT2 inhibitors and statins: reporting odds ratio (ROR) with 95% confidence interval (CI), Ω shrinkage measure (safety signal if >0) and an extension of the proportional reporting ratio (PRR) (two-criteria set, safety signal if both criteria are met), using the full FAERS dataset as the reference set. In sensitivity analyses, we focussed on specific SGLT2 inhibitor-statin pairs with higher interaction potential (canagliflozin-rosuvastatin, empagliflozin-rosuvastatin) and accounted for stimulated reporting. RESULTS: There were 456 myopathy and 77 rhabdomyolysis reports involving both an SGLT2 inhibitor and a statin. Concomitant use of SGLT2 inhibitors and statins was not associated with an increased risk of myopathy (ROR 0.79, 95% CI 0.70 to 0.89) or rhabdomyolysis (ROR 0.58, 95% CI 0.41 to 0.83) reporting. For both outcomes, the Ω shrinkage measure was negative and only one criterion of the PRR extension was met. SGLT2 inhibitor-statin pairs with higher interaction potential yielded potential signals for rhabdomyolysis; these signals disappeared after accounting for stimulated reporting. CONCLUSION: There was no increased risk of myotoxicity reporting associated with concomitant use of SGLT2 inhibitors and statins or for specific drug pairs.

Adjusting for Berkson error in exposure in ordinary and conditional logistic regression and in Poisson regression.

BACKGROUND: INTEROCC is a seven-country cohort study of occupational exposures and brain cancer risk, including occupational exposure to electromagnetic fields (EMF). In the absence of data on individual exposures, a Job Exposure Matrix (JEM) may be used to construct likely exposure scenarios in occupational settings. This tool was constructed using statistical summaries of exposure to EMF for various occupational categories for a comparable group of workers. METHODS: In this study, we use the Canadian data from INTEROCC to determine the best EMF exposure surrogate/estimate from three appropriately chosen surrogates from the JEM, along with a fourth surrogate based on Berkson error adjustments obtained via numerical approximation of the likelihood function. In this article, we examine the case in which exposures are gamma-distributed for each occupation in the JEM, as an alternative to the log-normal exposure distribution considered in a previous study conducted by our research team. We also study using those surrogates and the Berkson error adjustment in Poisson regression and conditional logistic regression. RESULTS: Simulations show that the introduced methods of Berkson error adjustment for non-stratified analyses provide accurate estimates of the risk of developing tumors in case of gamma exposure model. Alternatively, and under some technical assumptions, the arithmetic mean is the best surrogate when a gamma-distribution is used as an exposure model. Simulations also show that none of the present methods could provide an accurate estimate of the risk in case of stratified analyses. CONCLUSION: While our previous study found the geometric mean to be the best exposure surrogate, the present study suggests that the best surrogate is dependent on the exposure model; the arithmetic means in case of gamma-exposure model and the geometric means in case of log-normal exposure model. However, we could present a better method of Berkson error adjustment for each of the two exposure models. Our results provide useful guidance on the application of JEMs for occupational exposure assessments, with adjustment for Berkson error.

A value of information framework for assessing the trade-offs associated with uncertainty, duration, and cost of chemical toxicity testing.

A number of investigators have explored the use of value of information (VOI) analysis to evaluate alternative information collection procedures in diverse decision-making contexts. This paper presents an analytic framework for determining the value of toxicity information used in risk-based decision making. The framework is specifically designed to explore the trade-offs between cost, timeliness, and uncertainty reduction associated with different toxicity-testing methodologies. The use of the proposed framework is demonstrated by two illustrative applications which, although based on simplified assumptions, show the insights that can be obtained through the use of VOI analysis. Specifically, these results suggest that timeliness of information collection has a significant impact on estimates of the VOI of chemical toxicity tests, even in the presence of smaller reductions in uncertainty. The framework introduces the concept of the expected value of delayed sample information, as an extension to the usual expected value of sample information, to accommodate the reductions in value resulting from delayed decision making. Our analysis also suggests that lower cost and higher throughput testing also may be beneficial in terms of public health benefits by increasing the number of substances that can be evaluated within a given budget. When the relative value is expressed in terms of return-on-investment per testing strategy, the differences can be substantial.

Biomarkers of environmental manganese exposure.

We conducted a critical review on biomarkers of environmental manganese (Mn) exposure to answer the following questions: 1) are there reliable biomarkers of internal Mn exposure (Mn in biological matrices) associated with external metrics of Mn exposure (Mn in environmental media)? and 2) are there accurate reference values (RVs) for Mn in biological matrices? Three bibliographic databases were searched for relevant references and identified references were screened by two independent reviewers. Of the 6342 unique references identified, 86 articles were retained for data abstraction. Our analysis of currently available evidence suggests that Mn levels in blood and urine are not useful biomarkers of Mn exposure in non-occupational settings. The strength of the association between Mn in environmental media and saliva was variable. Findings regarding the utility of hair Mn as a biomarker of environmental Mn exposure are inconsistent. Measurements of Mn in teeth are technically challenging and findings on Mn in tooth components are scarce. In non-occupationally exposed individuals, bone Mn measurements using in vivo neutron activation analysis (IVNAA) are associated with large uncertainties. Findings suggest that Mn in nails may reflect Mn in environmental media and discriminate between groups of individuals exposed to different environmental Mn levels, although more research is needed. Currently, there is no strong evidence for any biological matrix as a valid biomarker of Mn exposure in non-occupational settings. Because of methodological limitations in studies aimed at derivation of RVs for Mn in biological materials, accurate RVs are scarce.

Biomarkers for occupational manganese exposure.

Long-term inhalation exposure to manganese (Mn) metal or its inorganic compounds can result in manganism or subclinical neurofunctional deficits. Studies have described affected workers in Mn dioxide mining, Mn-containing ore crushing and milling facilities, manufacturing of dry-cell batteries, Mn steel and alloy production plants, and in welders. The objective of this study was to critically review existing evidence on the reliability of potential biomarkers of Mn exposure, specifically the relationship between inhalation exposure to Mn particulates in different occupational settings and Mn concentrations in blood and other biological fluids and tissues, with a particular focus on whole blood as a potentially useful medium for measuring internal tissue dose. We also examined available evidence on the relationship between Mn levels in blood and adverse clinical and subclinical neurotoxic outcomes. Three bibliographic databases were searched for relevant studies and identified references were screened by two independent reviewers. Of the 6338 unique references identified, 76 articles were retained for data abstraction. Findings indicate that the relationships between Mn in blood and both external Mn exposure indices and neurofunctional impairments are limited and inconsistent. Different sources of exposure to Mn compounds, heterogeneity in the methodological approaches, and inadequate reporting of essential information limited direct comparison of the reported findings. Among the Mn-exposure biomarkers considered in this review - including biomarkers in blood, plasma, serum, erythrocytes, urine, bone, toenails, fingernails, hair, saliva - biomarkers in whole blood may provide to be most useful in Mn biomonitoring and risk assessment.

Principles of risk decision-making.

Risk management decisions in public health require consideration of a number of complex, often conflicting factors. The aim of this review was to propose a set of 10 fundamental principles to guide risk decision-making. Although each of these principles is sound in its own right, the guidance provided by different principles might lead the decision-maker in different directions. For example, where the precautionary principle advocates for preemptive risk management action under situations of scientific uncertainty and potentially catastrophic consequences, the principle of risk-based decision-making encourages decision-makers to focus on established and modifiable risks, where a return on the investment in risk management is all but guaranteed in the near term. To evaluate the applicability of the 10 principles in practice, one needs to consider 10 diverse risk issues of broad concern and explore which of these principles are most appropriate in different contexts. The 10 principles presented here afford substantive insight into the process of risk management decision-making, although decision-makers will ultimately need to exercise judgment in reaching appropriate risk decisions, accounting for all of the scientific and extra-scientific factors relevant to the risk decision at hand.

Association of allergic diseases and epilepsy with risk of glioma, meningioma and acoustic neuroma: results from the INTERPHONE international case-control study.

We investigated the association of allergic diseases and epilepsy with risk of brain tumours, in Interphone, a 13-country case-control study. Data were obtained from 2693 glioma cases, 2396 meningioma cases, and 1102 acoustic neuroma cases and their 6321 controls. Conditional logistic regression models were used to estimate pooled odds ratios (ORs) and their respective 95% confidence intervals (CIs), adjusted for education and time at interview. Reduced ORs were observed for glioma in relation to physician-diagnosed asthma (OR = 0.73; CI 0.58-0.92), hay fever (OR 0.72; CI 0.61-0.86), and eczema (OR 0.78, CI 0.64-0.94), but not for meningioma or acoustic neuroma. Previous diagnosis of epilepsy was associated with an increased OR for glioma (2.94; CI 1.87-4.63) and for meningioma (2.12; CI 1.27-3.56), but not for acoustic neuroma. This large-scale case-control study adds to the growing evidence that people with allergies have a lower risk of developing glioma, but not meningioma or acoustic neuroma. It also supports clinical observations of epilepsy prior to the diagnosis of glioma and meningioma.

Systemic quinolones and risk of retinal detachment III: a nested case-control study using a US electronic health records database.

BACKGROUND: Quinolones are popular antibiotics that are known for their potency, broad coverage, and reasonable safety. Concerns have been raised about a possible association between quinolones and retinal detachment (RD). METHODS: We conducted a nested case-control study using electronic health records (EHR) from the Health Facts® Database. The initial cohort included all patients who were admitted between 2000 and 2016, with no history of eye disease, and had a minimum medical history of one year. Eligible cases comprised inpatients who were first admitted with a primary diagnosis of RD between 2010 and 2015. Each eligible case was matched without replacement to five unique controls by sex, race, age, and period-at-risk. We used conditional logistic regression to calculate RD risk, adjusting for exposure to other medications, and major risk factors. RESULTS: We identified 772 cases and 3860 controls. Whereas our primary analysis of all subjects revealed no quinolone-associated RD risk, elevated but non-significant risks were noted in African Americans (ciprofloxacin and levofloxacin), those aged 56-70 years old (moxifloxacin), and women (ciprofloxacin). CONCLUSION: Our study did not identify an elevated RD risk within 30 days following systemic administration of quinolone antibiotics. Suggestions of increased risk observed in some population subgroups warrant further investigation.

Prevalence of eczema between cesarean-born and vaginal-born infants within 1 year of age: a systematic review and meta-analysis.

This study aims to quantify the difference in prevalence of eczema between cesarean-born and vaginal-born infants within 1 year of age through a systematic review and meta-analysis. Six electronic databases were searched from inception to August 31, 2021. Studies were included if they reported the prevalence of eczema in infants within 1 year of age with specified mode of delivery. The quality of included studies was assessed using the Joanna Briggs Instrument Critical Appraisal Checklist. Pooled prevalence and odds ratio (OR) were estimated by meta-analyses of included studies. Meta-regression was conducted to explore factors affecting heterogeneity of the prevalence of eczema. Nine studies were included with 3,758 cesarean-born infants and 9,631 vaginal-born infants. The prevalence of eczema in cesarean-born infants [27.8%; 95% confidence interval (CI): 17.7-39.2] was higher than in vaginal-born infants (20.1%; 95% CI: 13.9-28.1), with a pooled OR of 1.31 (95% CI: 1.04-1.65). Subgroup analyses showed that the prevalence of eczema in cesarean-born infants varied according to country, study design, and method of ascertainment. Additionally, the pooled prevalence of eczema in vaginal-born infants differed by age at which eczema was identified. Meta-regression analysis showed that study design and eczema ascertainment method were significant sources of heterogeneity. CONCLUSION: About 28% of cesarean-born infants within 1 year of age developed eczema, significantly higher than the 20% rate or occurrence seen in vaginal-born infants. PROTOCOL REGISTRATION: CRD 42,020,152,437. WHAT IS KNOWN: • Eczema, a complex inflammatory cutaneous disorder characterized by immune mediated inflammation and epidermal barrier dysfunction, is one of the most common allergic disorders in infants. • Eczema may increase the risk of immune-mediated inflammatory disease such as food allergy, asthma, and allergic rhinitis, leading to psychological and social burdens on affected individuals and their families. • Mode of delivery may be associated with the risk of developing eczema, although further studies are needed to clarify such differences. WHAT IS NEW: • This is the first systematic review designed to estimate the prevalence of eczema in cesarean- and vaginal-born infants within 1 year of age. • Cesarean delivery may increase the risk of developing eczema in infants within the first year of life.

A Framework that Considers the Impacts of Time, Cost, and Uncertainty in the Determination of the Cost Effectiveness of Toxicity-Testing Methodologies.

Regulatory agencies are required to evaluate the impacts of thousands of chemicals. Toxicological tests currently used in such evaluations are time-consuming and resource intensive; however, advances in toxicology and related fields are providing new testing methodologies that reduce the cost and time required for testing. The selection of a preferred methodology is challenging because the new methodologies vary in duration and cost, and the data they generate vary in the level of uncertainty. This article presents a framework for performing cost-effectiveness analyses (CEAs) of toxicity tests that account for cost, duration, and uncertainty. This is achieved by using an output metric-the cost per correct regulatory decision-that reflects the three elements. The framework is demonstrated in two example CEAs, one for a simple decision of risk acceptability and a second, more complex decision, involving the selection of regulatory actions. Each example CEA evaluates five hypothetical toxicity-testing methodologies which differ with respect to cost, time, and uncertainty. The results of the examples indicate that either a fivefold reduction in cost or duration can be a larger driver of the selection of an optimal toxicity-testing methodology than a fivefold reduction in uncertainty. Uncertainty becomes of similar importance to cost and duration when decisionmakers are required to make more complex decisions that require the determination of small differences in risk predictions. The framework presented in this article may provide a useful basis for the identification of cost-effective methods for toxicity testing of large numbers of chemicals.

Treatment for grade 4 peripheral intravenous infiltration with type 3 skin tears: A case report and literature review.

Grade 4 peripheral intravenous infiltration with skin tears has seldom been reported. On 4 August 2020, a 35-year-old female patient was admitted to the emergency department of our hospital because of postprandial abdominal pain for 2 hours. She was diagnosed with a severe acute pancreatitis with type II diabetes mellitus. On 7 August, a vein detained needle was inserted into the dorsal vein of her right foot to infuse drugs. On 9 August, a grade 4 infiltration, discoloured and bruised skin with a swollen area of 11 cm × 9 cm around the infusion part of her right foot, was discovered. The infusion was stopped immediately and the residual drug was aspirated at the infusion site. When removing the vein detained needle, the skin surrounding the infusion site on the right foot was torn by the adhesive dressing. The size of the skin tears was 6 cm × 3 cm (type 3). The patient was provided with appropriate dressing, manual lymphatic drainage, and surgical intervention. Two months later, she was fully recovered with no functional impairment of the affected foot. Timely local wound interventions could lead to a satisfactory outcome for severe peripheral intravenous infiltration with skin tears.

Systemic quinolones and risk of acute liver failure III: A nested case-control study using a US electronic health records database.

BACKGROUND AND AIM: Quinolones are globally popular antibiotics with proven potency, broad coverage, and reasonable safety. However, some concerns were raised as to their possible association with acute liver failure (ALF). The aim of this study is to assess ALF risk within 30 days of receiving a systemically administered quinolone antibiotic, in individuals with no history of liver/diseases. METHODS: We conducted a nested case-control study using electronic health records from the Cerner Health Facts. The initial cohort (n = 35 349 943) included all patients who were admitted between 2000 and 2016, with no history of liver diseases, and had a minimum medical history of one year. Eligible cases were inpatients who were first diagnosed with ALF between 2010 and 2015. Using incidence density sampling, each case was matched with up to five unique controls by sex, race, age at index encounter, and period-at-risk. We used conditional logistic regression to calculate the odds ratio and 95% confidence interval for ALF risk, upon adjusting for exposure to other medications, and major confounders (diabetes mellitus and alcohol abuse). We used the STROBE Statement for reporting on our study. RESULTS: We identified 3151 cases and 15 657 controls. Our primary analysis did not reveal an association between quinolones and ALF risk. However, some risk was identified among those with no or few comorbidities, those ≤ 60 years of age, women, men, African Americans, and Caucasians. CONCLUSION: Although our study does not suggest an overall association between quinolones and ALF, elevated risks seen in some subgroups warrant further investigation.

Cell phone use and the risk of glioma: are case-control study findings consistent with Canadian time trends in cancer incidence?

BACKGROUND: There remains controversy as to whether cell phones cause cancer. We evaluated whether temporal changes in cell phone use and the incidence of glioma in Canada were consistent with the hypothesis of an increased risk. DESIGN: We used data from the Canadian Cancer Registry to calculate annual incidence rates for glioma between 1992 and 2015. The annual number of new cell phone subscribers was determined using national industry statistics. The number of newly diagnosed gliomas was compared to the predicted number by applying risks from epidemiological studies to age-specific population estimates. Specifically, we calculated the "predicted" number of incident gliomas by determining the annual prevalence of cell phone users and years of use. These estimates were multiplied by the corresponding risk estimates to determine the predicted number of gliomas. RESULTS: The number of cellular subscriptions in Canada increased from nil in the early-1980s to approximately 29.5 million in 2015. In contrast, age-standardized glioma incidence rates remained stable between 1992 and 2015. When applying risk estimates from i) a recent pooled analysis of Swedish case-control studies, ii) the 13 country INTERPHONE study, and iii) more recent results from data collected from the Canadian component of the INTERPHONE these risks overestimated the observed number of glioma cases diagnosed in Canada in 2015 by 50%, 86%, and 63%, respectively. INTERPRETATION: Predictions of glioma incidence counts using estimates of the relative risk of glioma due to cell phone use from case-control studies over-estimated the incidence rates of glioma in Canada. The absence of an elevation in incidence rates of glioma in conjunction with marked increases in cell phone use suggests that there may not be a causal link between cellphones and glioma.

Exposure to drinking water trihalomethanes and nitrate and the risk of brain tumours in young people.

Brain tumours (BTs) are one of the most frequent tumour types in young people. We explored the association between tap water, exposure to trihalomethanes (THM) and nitrate and neuroepithelial BT risk in young people. Analysis of tap water consumption were based on 321 cases and 919 appendicitis controls (10-24 years old) from 6 of the 14 participating countries in the international MOBI-Kids case-control study (2010-2016). Available historical residential tap water concentrations of THMs and nitrate, available from 3 countries for 86 cases and 352 controls and 85 cases and 343 for nitrate, respectively, were modelled and combined with the study subjects' personal consumption patterns to estimate ingestion and residential exposure levels in the study population (both pre- and postnatal). The mean age of participants was 16.6 years old and 56% were male. The highest levels and widest ranges for THMs were found in Spain (residential and ingested) and Italy and in Korea for nitrate. There was no association between BT and the amount of tap water consumed and the showering/bathing frequency. Odds Ratios (ORs) for BT in relation to both pre- and postnatal residential and ingestion levels of THMs were systematically below 1 (OR = 0.37 (0.08-1.73)) for postnatal average residential THMs higher than 66 µg/L. For nitrate, all ORs were above 1 (OR = 1.80 (0.91-3.55)) for postnatal average residential nitrate levels higher than 8.5 mg/L, with a suggestion of a trend of increased risk of neuroepithelial BTs with increasing residential nitrate levels in tap water, which appeared stronger in early in life. This, to our knowledge, is the first study on this topic in young people. Further research is required to clarify the observed associations.

Global estimates of mortality associated with long-term exposure to outdoor fine particulate matter.

Exposure to ambient fine particulate matter (PM2.5) is a major global health concern. Quantitative estimates of attributable mortality are based on disease-specific hazard ratio models that incorporate risk information from multiple PM2.5 sources (outdoor and indoor air pollution from use of solid fuels and secondhand and active smoking), requiring assumptions about equivalent exposure and toxicity. We relax these contentious assumptions by constructing a PM2.5-mortality hazard ratio function based only on cohort studies of outdoor air pollution that covers the global exposure range. We modeled the shape of the association between PM2.5 and nonaccidental mortality using data from 41 cohorts from 16 countries-the Global Exposure Mortality Model (GEMM). We then constructed GEMMs for five specific causes of death examined by the global burden of disease (GBD). The GEMM predicts 8.9 million [95% confidence interval (CI): 7.5-10.3] deaths in 2015, a figure 30% larger than that predicted by the sum of deaths among the five specific causes (6.9; 95% CI: 4.9-8.5) and 120% larger than the risk function used in the GBD (4.0; 95% CI: 3.3-4.8). Differences between the GEMM and GBD risk functions are larger for a 20% reduction in concentrations, with the GEMM predicting 220% higher excess deaths. These results suggest that PM2.5 exposure may be related to additional causes of death than the five considered by the GBD and that incorporation of risk information from other, nonoutdoor, particle sources leads to underestimation of disease burden, especially at higher concentrations.

Exposure to Medical Radiation during Fetal Life, Childhood and Adolescence and Risk of Brain Tumor in Young Age: Results from The MOBI-Kids Case-Control Study.

BACKGROUND: We explored the association between ionizing radiation (IR) from pre-natal and post-natal radio-diagnostic procedures and brain cancer risk within the MOBI-kids study. METHODS: MOBI-kids is an international (Australia, Austria, Canada, France, Germany, Greece, India, Israel, Italy, Japan, Korea, New Zealand, Spain, The Netherlands) case-control study including 899 brain tumor (645 neuroepithelial) cases aged 10-24 years and 1,910 sex-, age-, country-matched controls. Medical radiological history was collected through personal interview. We estimated brain IR dose for each procedure, building a look-up table by age and time period. Lifetime cumulative doses were calculated using 2 and 5 years lags from the diagnostic date. Risk was estimated using conditional logistic regression. Neurological, psychological and genetic conditions were evaluated as potential confounders. The main analyses focused on neuroepithelial tumors. RESULTS: Overall, doses were very low, with a skewed distribution (median 0.02 mGy, maximum 217 mGy). ORs for post-natal exposure were generally below 1. ORs were increased in the highest dose categories both for post and pre-natal exposures: 1.63 (95% CI 0.44-6.00) and 1.55 (0.57-4.23), respectively, based on very small numbers of cases. The change in risk estimates after adjustment for medical conditions was modest. CONCLUSIONS: There was little evidence for an association between IR from radio-diagnostic procedures and brain tumor risk in children and adolescents. Though doses were very low, our results suggest a higher risk for pre-natal and early life exposure, in line with current evidence.