Does fluoride exposure affect thyroid function? A systematic review and dose-response meta-analysis.

INTRODUCTION: Fluoride exposure may have various adverse health effects, including affecting thyroid function and disease risk, but the pattern of such relation is still uncertain. METHODS: We systematically searched human studies assessing the relation between fluoride exposure and thyroid function and disease. We compared the highest versus the lowest fluoride category across these studies, and we performed a one-stage dose-response meta-analysis for aggregated data to explore the shape of the association. RESULTS: Most retrieved studies (27 of which with a cross-sectional design) were conducted in Asia and in children, assessing fluoride exposure through its concentrations in drinking water, urine, serum, or dietary intake. Twenty-four studies reported data on thyroid function by measuring thyroid-related hormones in blood (mainly thyroid-stimulating-hormone - TSH), 9 reported data on thyroid disease, and 4 on thyroid volume. By comparing the highest versus the lowest fluoride categories, overall mean TSH difference was 1.05 µIU/mL. Dose-response curve showed no change in TSH concentrations in the lowest water fluoride exposure range, while the hormone levels started to linearly increase around 2.5 mg/L, also dependending on the risk of bias of the included studies. The association between biomarkers of fluoride exposure and TSH was also positive, with little evidence of a threshold. Evidence for an association between fluoride exposure and blood concentrations of thyroid hormones was less evident, though there was an indication of inverse association with triiodothyronine. For thyroid disease, the few available studies suggested a positive association with goiter and with hypothyroidism in both children and adults. CONCLUSIONS: Overall, exposure to high-fluoride drinking water appears to non-linearly affect thyroid function and increase TSH release in children, starting above a threshold of exposure, and to increase the risk of some thyroid diseases.

Fluoride exposure and cognitive neurodevelopment: Systematic review and dose-response meta-analysis.

Many uncertainties still surround the possible harmful effect of fluoride exposure on cognitive neurodevelopment in children. The aim of this systematic review and meta-analysis was to characterize this relation through a dose-response approach, by comparing the intelligence quotient (IQ) scores in the highest versus the lowest fluoride exposure category with a random-effects model, within a one-stage dose-response meta-analysis based on a cubic spline random-effects model. Out of 1996 potentially relevant literature records, 33 studies were eligible for this review, 30 of which were also suitable for meta-analysis. The summary mean difference of IQ score, comparing highest versus lowest fluoride categories and considering all types of exposure, was -4.68 (95% confidence interval-CI -6.45; -2.92), with a value of -5.60 (95% CI -7.76; -3.44) for drinking water fluoride and -3.84 (95% CI -7.93; 0.24) for urinary fluoride. Dose-response analysis showed a substantially linear IQ decrease for increasing water fluoride above 1 mg/L, with -3.05 (95% CI -4.06; -2.04) IQ points per 1 mg/L up to 2 mg/L, becoming steeper above such level. A weaker and substantially linear decrease of -2.15 (95% CI -4.48; 0.18) IQ points with increasing urinary fluoride emerged above 0.28 mg/L (approximately reflecting a water fluoride content of 0.7 mg/L). The inverse association between fluoride exposure and IQ was particularly strong in the studies at high risk of bias, while no adverse effect emerged in the only study judged at low risk of bias. Overall, most studies suggested an adverse effect of fluoride exposure on children's IQ, starting at low levels of exposure. However, a major role of residual confounding could not be ruled out, thus indicating the need of additional prospective studies at low risk of bias to conclusively assess the relation between fluoride exposure and cognitive neurodevelopment.

Effective communications strategies to increase the impact of environmental health research.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are the subject of a growing body of research with the potential to positively impact public and ecological health. However, to effect positive change, findings must be communicated beyond the scientific community. OBJECTIVE: We sought to (a) evaluate the relationships between communications strategy, media attention, and scholarly citations of PFAS research and (b) offer guidance for researchers and communications professionals who would like to publicize future work and increase its impact. METHODS: We analyzed 273 peer-reviewed epidemiological studies on PFAS human health impacts with publication years 2018-2020, as collected by a pre-existing database. We investigated whether a press release was issued, open-access status, abstract and press release readability, timing of publication and press release distribution, journal impact factor, study type and sample size, statistical significance of finding(s), number of scholarly citations, and the Altmetric Attention Score (a measure of media attention). DISCUSSION: Of papers reporting a statistically significant association with health harm, those with a press release received 20 times more media attention (as assessed by Altmetric scores) than those that did not. However, only 6.2% of all papers and 7.8% of significant papers issued one. Among papers with a press release, media attention was positively correlated with better abstract and press release readability and speed in issuing the press release. Scholarly citations were positively correlated with media attention, presence of a press release, and open-access status. CONCLUSION: Most papers with significant findings on PFAS are published without a press release and receive little or no media attention. This reduces the likelihood that important research is reaching the public and decisionmakers who can translate science into action. Issuing a press release and receiving media attention also appear to increase scholarly citations. We provide recommendations for authors to increase the reach and impact of future papers.

Advancing the science on chemical classes.

BACKGROUND: Hazard identification, risk assessment, regulatory, and policy activity are usually conducted on a chemical-by-chemical basis. Grouping chemicals into categories or classes is an underutilized approach that could make risk assessment and management of chemicals more efficient for regulators. OBJECTIVE AND METHODS: While there are some available methods and regulatory frameworks that include the grouping of chemicals (e.g.,same molecular mechanism or similar chemical structure) there has not been a comprehensive evaluation of these different approaches nor a recommended course of action to better consider chemical classes in decision-making. This manuscript: 1) reviews current national and international approaches to grouping; 2) describes how groups could be defined based on the decision context (e.g., hazard/risk assessment, restrictions, prioritization, product development) and scientific considerations (e.g., intrinsic physical-chemical properties); 3) discusses advantages of developing a decision tree approach for grouping; 4) uses ortho-phthalates as a case study to identify and organize frameworks that could be used across agencies; and 5) discusses opportunities to advance the class concept within various regulatory decision-making scenarios. RESULTS: Structural similarity was the most common grouping approach for risk assessment among regulatory agencies (national and state level) and non-regulatory organizations, albeit with some variations in its definition. Toxicity to the same target organ or to the same biological function was also used in a few cases. The phthalates case study showed that a decision tree approach for grouping should include questions about uses regulated by other agencies to encourage more efficient, coherent, and protective chemical risk management. DISCUSSION AND CONCLUSION: Our evaluation of how classes of chemicals are defined and used identified commonalities and differences based on regulatory frameworks, risk assessments, and business strategies. We also identified that using a class-based approach could result in a more efficient process to reduce exposures to multiple hazardous chemicals and, ultimately, reduce health risks. We concluded that, in the absence of a prescribed method, a decision tree approach could facilitate the selection of chemicals belonging to a pre-defined class (e.g., chemicals with endocrine-disrupting activity; organohalogen flame retardants [OFR]) based on the decision-making context (e.g., regulatory risk management).

A science-based agenda for health-protective chemical assessments and decisions: overview and consensus statement.

The manufacture and production of industrial chemicals continues to increase, with hundreds of thousands of chemicals and chemical mixtures used worldwide, leading to widespread population exposures and resultant health impacts. Low-wealth communities and communities of color often bear disproportionate burdens of exposure and impact; all compounded by regulatory delays to the detriment of public health. Multiple authoritative bodies and scientific consensus groups have called for actions to prevent harmful exposures via improved policy approaches. We worked across multiple disciplines to develop consensus recommendations for health-protective, scientific approaches to reduce harmful chemical exposures, which can be applied to current US policies governing industrial chemicals and environmental pollutants. This consensus identifies five principles and scientific recommendations for improving how agencies like the US Environmental Protection Agency (EPA) approach and conduct hazard and risk assessment and risk management analyses: (1) the financial burden of data generation for any given chemical on (or to be introduced to) the market should be on the chemical producers that benefit from their production and use; (2) lack of data does not equate to lack of hazard, exposure, or risk; (3) populations at greater risk, including those that are more susceptible or more highly exposed, must be better identified and protected to account for their real-world risks; (4) hazard and risk assessments should not assume existence of a "safe" or "no-risk" level of chemical exposure in the diverse general population; and (5) hazard and risk assessments must evaluate and account for financial conflicts of interest in the body of evidence. While many of these recommendations focus specifically on the EPA, they are general principles for environmental health that could be adopted by any agency or entity engaged in exposure, hazard, and risk assessment. We also detail recommendations for four priority areas in companion papers (exposure assessment methods, human variability assessment, methods for quantifying non-cancer health outcomes, and a framework for defining chemical classes). These recommendations constitute key steps for improved evidence-based environmental health decision-making and public health protection.

Development and application of a systematic and quantitative weighting framework to evaluate the quality and relevance of relative potency estimates for dioxin-like compounds (DLCs) for human health risk assessment.

The toxic equivalency factors (TEFs) approach for dioxin-like chemicals (DLCs) is currently based on a qualitative assessment of a heterogeneous data set of relative estimates of potency (REPs) spanning several orders of magnitude with highly variable study quality and relevance. An effort was undertaken to develop a weighting framework to systematically evaluate and quantitatively integrate the quality and relevance for development of more robust TEFs. Six main-study characteristics were identified as most important in characterizing the quality and relevance of an individual REP for human health risk assessment: study type, study model, pharmacokinetics, REP derivation method, REP derivation quality, and endpoint. Subsequently, a computational approach for quantitatively integrating the weighting framework parameters was developed and applied to the REP2004 database. This was accomplished using a machine learning approach which infers a weighted TEF distribution for each congener. The resulting database, weighted for quality and relevance, provides REP distributions from >600 data sets (including in vivo and in vitro studies, a range of endpoints, etc.). This weighted database provides a flexible platform for systematically and objectively characterizing TEFs for use in risk assessment, as well as providing information to characterize uncertainty and variability. Collectively, this information provides risk managers with information for decision making.

Problems in evaluating the health impacts of radio frequency radiation.

In an effort to clarify the nature of causal evidence regarding the potential impacts of RFR on biological systems, this paper relies on a well-established framework for considering causation expanded from that of Bradford Hill, that combines experimental and epidemiological evidence on carcinogenesis of RFR. The Precautionary Principle, while not perfect, has been the effective lodestone for establishing public policy to guard the safety of the general public from potentially harmful materials, practices or technologies. Yet, when considering the exposure of the public to anthropogenic electromagnetic fields, especially those arising from mobile communications and their infrastructure, it seems to be ignored. The current exposure standards recommended by the Federal Communications Commission (FCC) and International Commission on Non-Ionizing Radiation Protection (ICNIRP) consider only thermal effects (tissue heating) as potentially harmful. However, there is mounting evidence of non-thermal effects of exposure to electromagnetic radiation in biological systems and human populations. We review the latest literature on in vitro and in vivo studies, on clinical studies on electromagnetic hypersensitivity, as well as the epidemiological evidence for cancer due to the action of mobile based radiation exposure. We question whether the current regulatory atmosphere truly serves the public good when considered in terms of the Precautionary Principle and the principles for deducing causation established by Bradford Hill. We conclude that there is substantial scientific evidence that RFR causes cancer, endocrinological, neurological and other adverse health effects. In light of this evidence the primary mission of public bodies, such as the FCC to protect public health has not been fulfilled. Rather, we find that industry convenience is being prioritized and thereby subjecting the public to avoidable risks.

Conducting evaluations of evidence that are transparent, timely and can lead to health-protective actions.

BACKGROUND: In February 2021, over one hundred scientists and policy experts participated in a web-based Workshop to discuss the ways that divergent evaluations of evidence and scientific uncertainties are used to delay timely protection of human health and the environment from exposures to hazardous agents. The Workshop arose from a previous workshop organized by the European Environment Agency (EEA) in 2008 and which also drew on case studies from the EEA reports on 'Late Lessons from Early Warnings' (2001, 2013). These reports documented dozens of hazardous agents including many chemicals, for which risk reduction measures were delayed for decades after scientists and others had issued early and later warnings about the harm likely to be caused by those agents. RESULTS: Workshop participants used recent case studies including Perfluorooctanoic acid (PFOA), Extremely Low Frequency - Electrical Magnetic Fields (ELF-EMF fields), glyphosate, and Bisphenol A (BPA) to explore myriad reasons for divergent outcomes of evaluations, which has led to delayed and inadequate protection of the public's health. Strategies to overcome these barriers must, therefore, at a minimum include approaches that 1) Make better use of existing data and information, 2) Ensure timeliness, 3) Increase transparency, consistency and minimize bias in evidence evaluations, and 4) Minimize the influence of financial conflicts of interest. CONCLUSION: The recommendations should enhance the production of "actionable evidence," that is, reliable evaluations of the scientific evidence to support timely actions to protect health and environments from exposures to hazardous agents. The recommendations are applicable to policy and regulatory settings at the local, state, federal and international levels.

A PBPK model describing the pharmacokinetics of γ-HBCD exposure in mice.

The brominated flame retardant, hexabromocyclododecane (HBCD), is added-but not bound-to consumer products and is eventually found in the environment and human tissues. Commercial-grade HBCD mixtures contain three major stereoisomers, alpha (α), beta (ß), and gamma (γ), that are typically at a ratio of 12%:6%:82%, respectively. Although HBCD is widely used, the toxicological effects from its exposure in humans are not clearly understood. Using a physiologically based pharmacokinetic (PBPK) model could help improve our understanding of the toxicity of HBCD. The aim of this work was to develop a PBPK model, consisting of five permeability limited compartments (i.e., brain, liver, adipose tissue, blood, and rest of the body), to evaluate the pharmacokinetics of γ-HBCD in C57BL/6 mice. Physiological parameters related to body size, organ weights, and blood flow were taken from the literature. All partition coefficients were calculated based on the log Kow. The elimination in urine and feces was optimized to reflect the percent dose eliminated, as published in the literature. Compared with data from the literature for brain, liver, blood, and adipose tissue, the model simulations accurately described the mouse data set within 1.5-fold of the data points. Also, two examples showing the utility of the PBPK model supplement the information regarding the internal dose that caused the health effects observed during these studies. Although this version of the PBPK model expressly describes γ-HBCD, more efforts are needed to clarify and improve the model to discriminate between the α, ß, and γ stereoisomers.

Telomeres as targets for the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and polychlorinated biphenyls (PCBs) in rats.

Telomere length (TL) can be affected by various factors, including age and oxidative stress. Changes in TL have been associated with chronic disease, including a higher risk for several types of cancer. Environmental exposure of humans to PCBs and dioxins has been associated with longer or shorter leukocyte TL. Relative telomere length (RTL) may serve as a biomarker associated with neoplastic and/or non-neoplastic responses observed with chronic exposures to TCDD and PCBs. RTL was measured in DNA isolated from archived frozen liver and lung tissues from the National Toxicology Program (NTP) studies conducted in female Harlan Sprague Dawley rats exposed for 13, 30, and 52 weeks to TCDD, dioxin-like (DL) PCB 126, non-DL PCB 153, and a mixture of PCB 126 and PCB 153. RTL was assessed by quantitative polymerase chain reaction (qPCR). Consistent with literature, decreased liver and lung RTL was seen with aging. Relative to time-matched vehicle controls, RTL was increased in both the liver and lung tissues of rats exposed to TCDD, PCB 126, PCB 153, and the mixture of PCB 126 and PCB 153, which is consistent with most epidemiological studies that found PCB exposures were associated with increased leukocyte RTL. Increased RTL was observed at doses and/or time points where little to no pathology was observed. In addition to serving as a biomarker of exposure to these compounds in rats and humans, increases in RTL may be an early indicator of neoplastic and non-neoplastic responses that occur following chronic exposure to TCDD and PCBs.

Relationship between serum trimethylamine N-oxide and exposure to dioxin-like pollutants.

Trimethylamine N-oxide (TMAO) is a diet and gut microbiota-derived metabolite that has been linked to cardiovascular disease risk in human studies and animal models. TMAO levels show wide inter and intra individual variability in humans that can likely be accounted for by multiple factors including diet, the gut microbiota, levels of the TMAO generating liver enzyme Flavin-containing monooxygenase 3 (FMO3) and kidney function. We recently found that dioxin-like (DL) environmental pollutants increased FMO3 expression to elevate circulating diet-derived TMAO in mice, suggesting that exposure to this class of pollutants might also contribute to inter-individual variability in circulating TMAO levels in humans. To begin to explore this possibility we examined the relationship between body burden of DL pollutants (reported by serum lipid concentrations) and serum TMAO levels (n = 340) in the Anniston, AL cohort, which was highly exposed to polychlorinated biphenyls (PCBs). TMAO concentrations in archived serum samples from the Anniston Community Health Survey (ACHS-II) were measured, and associations of TMAO with 28 indices of pollutant body burden, including total dioxins toxic equivalent (TEQ), were quantified. Twenty-three (22 after adjustment for multiple comparisons) of the 28 indices were significantly positively associated with TMAO. Although the design of ACHS-II does not enable quantitative assessment of the contributions of previously known determinants of TMAO variability to this relationship, limited multivariate modeling revealed that total dioxins TEQ was significantly associated with TMAO among females (except at high BMIs) but not among males. Our results from this cross-sectional study indicate that exposure to DL pollutants may contribute to elevated serum TMAO levels. Prospective longitudinal studies will be required to assess the joint relationship between DL pollutant exposures, other determinants of TMAO, and health outcomes.

Disposition of the emerging brominated flame retardant, bis(2-ethylhexyl) tetrabromophthalate, in female Sprague Dawley rats: effects of dose, route and repeated administration.

1. Bis(2-ethylhexyl)-tetrabromophthalate (BEH-TEBP; CAS No. 26040-51-7; PubChem CID: 117291; MW 706.15 g/mol, elsewhere: TeBrDEPH, TBPH, or BEHTBP) is used as an additive brominated flame retardant in consumer products. 2. Female Sprague Dawley rats eliminated 92-98% of [14C]-BEH-TEBP unchanged in feces after oral administration (0.1 or 10 µmol/kg). A minor amount of each dose (0.8-1%) was found in urine after 72 h. Disposition of orally administered BEH-TEBP in male B6C3F1/Tac mice was similar to female rats. 3. Bioaccumulation of [14C]-radioactivity was observed in liver and adrenals following 10 daily oral administrations (0.1 µmol/kg/day). These tissues contained 5- and 10-fold higher concentrations of [14C]-radioactivity, respectively, versus a single dose. 4. IV-administered [14C]-BEH-TEBP (0.1 µmol/kg) was slowly eliminated in feces, with >15% retained in tissues after 72 h. Bile and fecal extracts from these rats contained the metabolite mono-ethylhexyl tetrabromophthalate (TBMEHP). 5. BEH-TEBP was poorly absorbed, minimally metabolized and eliminated mostly by the fecal route after oral administration. Repeated exposure to BEH-TEBP led to accumulation in some tissues. The toxicological significance of this effect remains to be determined. This work was supported by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health (Project ZIA BC 011476).

The biological fate of decabromodiphenyl ethane following oral, dermal or intravenous administration.

1. It was important to investigate the disposition of decabromodiphenyl ethane (DBDPE) based on concerns over its structural similarities to decabromodiphenyl ether (decaBDE), high potential for environmental persistence and bioaccumulation, and high production volume. 2. In the present study, female Sprague Dawley rats were administered a single dose of [14C]-DBDPE by oral, topical or IV routes. Another set of rats were administered 10 daily oral doses of [14C]-DBDPE. Male B6C3F1/Tac mice were administered a single oral dose. 3. DBDPE was poorly absorbed following oral dosing, with 95% of administered [14C]-radioactivity recovered in the feces unchanged, 1% recovered in the urine and less than 3% in the tissues at 72 h. DBDPE excretion was similar in male mice and female rats. Accumulation of [14C]-DBDPE was observed in liver and the adrenal gland after 10 daily oral doses to rats. 4. Rat and human skin were used to assess potential dermal uptake of DBDPE. The dermis was a depot for dermally applied DBDPE; conservative estimates predict ∼14 ± 8% of DBDPE may be absorbed into human skin in vivo; ∼7 ± 4% of the parent chemical is expected to reach systemic circulation following continuous exposure (24 h). 5. Following intravenous administration, ∼70% of the dose remained in tissues after 72 h, with the highest concentrations found in lung (1223 ± 723 pmol-eq/g), spleen (1096 ± 369 pmol-eq/g) and liver (366 ± 98 pmol-eq/g); 5 ± 1% of the dose was recovered in urine and 26 ± 4% in the feces.

Disruption of estrogen homeostasis as a mechanism for uterine toxicity in Wistar Han rats treated with tetrabromobisphenol A.

Chronic oral treatment of tetrabromobisphenol A (TBBPA) to female Wistar Han rats resulted in increased incidence of cell proliferation at 250mg/kg and tumor formation in the uterus at higher doses. The present study was designed to test the hypothesis that disruption of estrogen homeostasis was a major mode-of-action for the observed effects. Biological changes were assessed in serum, liver, and the proximal (nearest the cervix) and distal (nearest the ovaries) sections of the uterine horn of Wistar Han rats 24h following administration of the last of five daily oral doses of 250mg/kg. Expression of genes associated with receptors, biosynthesis, and metabolism of estrogen was altered in the liver and uterus. TBBPA treatment also resulted in changes in expression of genes associated with cell division and growth. Changes were also observed in the concentration of thyroxine in serum and in expression of genes in the liver and uterus associated with thyroid hormone receptors. Differential expression of some genes was tissue-dependent or specific to tissue location in the uterus. The biological responses observed in the present study support the hypothesis that perturbation of estrogen homeostasis is a major mode-of-action for TBBPA-mediated cell proliferation and tumorigenesis previously observed in the uterus of TBBPA-treated Wistar Han rats.

Estimation of human percutaneous bioavailability for two novel brominated flame retardants, 2-ethylhexyl 2,3,4,5-tetrabromobenzoate (EH-TBB) and bis(2-ethylhexyl) tetrabromophthalate (BEH-TEBP).

2-Ethylhexyl-2,3,4,5-tetrabromobenzoate (EH-TBB) and bis(2-ethylhexyl)tetrabromophthalate (BEH-TEBP) are novel brominated flame retardants used in consumer products. A parallelogram approach was used to predict human dermal absorption and flux for EH-TBB and BEH-TEBP. [14C]-EH-TBB or [14C]-BEH-TEBP was applied to human or rat skin at 100nmol/cm2 using a flow-through system. Intact rats received analogous dermal doses. Treated skin was washed and tape-stripped to remove "unabsorbed" [14C]-radioactivity after continuous exposure (24h). "Absorbed" was quantified using dermally retained [14C]-radioactivity; "penetrated" was calculated based on [14C]-radioactivity in media (in vitro) or excreta+tissues (in vivo). Human skin absorbed EH-TBB (24±1%) while 0.2±0.1% penetrated skin. Rat skin absorbed more (51±10%) and was more permeable (2±0.5%) to EH-TBB in vitro; maximal EH-TBB flux was 11±7 and 102±24pmol-eq/cm2/h for human and rat skin, respectively. In vivo, 27±5% was absorbed and 13% reached systemic circulation after 24h (maximum flux was 464±65pmol-eq/cm2/h). BEH-TEBP in vitro penetrance was minimal (<0.01%) for rat or human skin. BEH-TEBP absorption was 12±11% for human skin and 41±3% for rat skin. In vivo, total absorption was 27±9%; 1.2% reached systemic circulation. In vitro maximal BEH-TEBP flux was 0.3±0.2 and 1±0.3pmol-eq/cm2/h for human and rat skin; in vivo maximum flux for rat skin was 16±7pmol-eq/cm2/h. EH-TBB was metabolized in rat and human skin to tetrabromobenzoic acid. BEH-TEBP-derived [14C]-radioactivity in the perfusion media could not be characterized. <1% of the dose of EH-TBB and BEH-TEHP is estimated to reach the systemic circulation following human dermal exposure under the conditions tested. CHEMICAL COMPOUNDS STUDIED IN THIS ARTICLE: 2-Ethylhexyl 2,3,4,5-tetrabromobenzoate (PubChem CID: 71316600; CAS No. 183658-27-7 FW: 549.92g/mol logPest: 7.73-8.75 (12)) Abdallah et al., 2015a. Other published abbreviations for 2-ethylhexyl-2,3,4,5-tetrabromobenzoate are TBB EHTeBB or EHTBB Abdallah and Harrad, 2011. bis(2-ethylhexyl) tetrabromophthalate (PubChem CID: 117291; CAS No. 26040-51-7 FW: 706.14g/mol logPest: 9.48-11.95 (12)). Other published abbreviations for bis(2-ethylhexyl)tetrabromophthalate are TeBrDEPH TBPH or BEHTBP.