Comparative Evaluation of the Cytotoxicity of Glyphosate-Based Herbicides and Glycine in L929 and Caco2 Cells.

Introduction: Glyphosate, an amino acid analog of glycine, is the most widely applied organophosphate pesticide worldwide and it is an active ingredient of all glyphosate-based herbicides (GBHs), including the formulation "Roundup. " While glycine is an essential amino acid generally recognized safe, both epidemiological and toxicological in vivo and in vitro studies available in literature report conflicting findings on the toxicity of GBHs. In our earlier in vivo studies in Sprague-Dawley rats we observed that exposure to GBHs at doses of glyphosate of 1.75 mg/kg bw/day, induced different toxic effects relating to sexual development, endocrine system, and the alteration of the intestinal microbiome. In the present work, we aimed to comparatively test in in vitro models the cytotoxicity of glycine and GBHs. Methods: We tested the cytotoxic effects of glycine, glyphosate, and its formulation Roundup Bioflow at different doses using MTT and Trypan Blue assays in human Caco2 and murine L929 cell lines. Results: Statistically significant dose-related cytotoxic effects were observed in MTT and Trypan Blue assays in murine (L929) and human (Caco2) cells treated with glyphosate or Roundup Bioflow. No cytotoxic effects were observed for glycine. In L929, Roundup Bioflow treatment showed a mean IC50 value that was significantly lower than glyphosate in both MTT and Trypan Blue assays. In Caco2, Roundup Bioflow treatment showed a mean IC50 value that was significantly lower than glyphosate in the MTT assays, while a comparable IC50 was observed for glyphosate and Roundup Bioflow in Trypan Blue assays. IC50 for glycine could not be estimated because of the lack of cytotoxic effects of the substance. Conclusion: Glyphosate and its formulation Roundup Bioflow, but not glycine, caused dose-related cytotoxic effects in in vitro human and murine models (Caco2 and L929). Our results showed that glycine and its analog glyphosate presented different cytotoxicity profiles. Glyphosate and Roundup Bioflow demonstrate cytotoxicity similar to other organophosphate pesticides (malathion, diazinon, and chlorpyriphos).

An updated systematic review on the association between Cd exposure, blood pressure and hypertension.

BACKGROUND: Since the first report by Perry et al. (1955), most studies affirmed the hypertensive effects of cadmium (Cd) in humans. Nonetheless, conclusions between studies remain inconsistent. OBJECTIVE: The aim of this study was to reevaluate the evidence for a potential relationship between Cd exposure and altered blood pressure and/or hypertension, focusing on studies published between January 2010 and March 2020. METHODS: We reviewed all observational studies from database searches (PubMed and SCOPUS) on Cd exposure and blood pressure or hypertension. We extracted information from studies that provided sufficient data on population characteristics, smoking status, exposure, outcomes, and design. RESULTS: Thirty-eight studies met our inclusion criteria; of those, twenty-nine were cross sectional, three case control, five cohort and one interventional study. Blood or urinary Cd levels were the most commonly used biomarkers. CONCLUSIONS: A positive association between blood Cd levels and blood pressure and/or hypertension was identified in numerous studies at different settings. Limited number of representative population-based studies of never-smokers was observed, which may have confounded our conclusions. The association between urinary Cd and blood pressure and/or hypertension remains uncertain due to conflicting results, including inverse relationships with lack of strong mechanistic support. We point to the urgent need for additional longitudinal studies to confirm our findings.

Blood cadmium levels and sources of exposure in an adult urban population in southern Brazil.

BACKGROUND: Cadmium (Cd) is a toxic metal that is widely present in the environment due to geologic and anthropogenic sources. Exposures to high Cd levels may cause nephrotoxicity, carcinogenicity, pulmonary and cardiovascular disease, among others. The goal of this study was to investigate in an adult urban population whether an association exists between sources and levels of Cd exposure and blood Cd concentrations. METHODS: Using a census-based design, a total of 959 adults, aged 40 years or older, were randomly selected. Information on socio-demographics, dietary, and lifestyle background was obtained by household interviews. Blood Cd levels were measured by inductively coupled-plasma mass spectrometry. Geometric means (GM) (95% CI) and the 50th percentile were determined, stratified by sex, age, race, education, income class, smoking status, consumption of vegetables, red meat and milk, occupation and blood pressure. To assess the association between Cd exposure and the aforementioned variables, we estimated the geometric mean ratio (GMR) (95%CI) of blood Cd concentrations. RESULTS AND CONCLUSION: The geometric mean (95%CI) of blood Cd levels in the total population was 0.25 (0.22, 0.27) ug/dL. In a univariate analysis, significantly higher blood Cd levels were found in men (p < 0.001), current and former smokers (p < 0.001), alcohol drinkers (p < 0.001), those who never or almost never consumed milk (p < 0.001), and in subjects with higher diastolic blood pressure (p = 0.03). Significant correlations were found between the number of cigarettes consumed daily and blood Cd levels. Multivariate analysis confirmed higher blood Cd concentrations were associated with alcohol consumption (GMR 95%CI = 1.28, 1.04-1.59) and in former and current smokers (GMR 95% IC = 1.33, 1.06-1.67 and 4.23, 3.24-5.52, respectively). Our results shed novel information on variables associated with blood Cd levels in an urban Brazilian population, and should encourage additional research to prevent environmental Cd exposure, both in Brazil and globally.

RoB-SPEO: A tool for assessing risk of bias in studies estimating the prevalence of exposure to occupational risk factors from the WHO/ILO Joint Estimates of the Work-related Burden of Disease and Injury.

BACKGROUND: The World Health Organization (WHO) and the International Labour Organization (ILO) are developing joint estimates of the work-related burden of disease and injury (WHO/ILO Joint Estimates). For this, systematic reviews of studies estimating the prevalence of exposure to selected occupational risk factors will be conducted to provide input data for estimations of the number of exposed workers. A critical part of systematic review methods is to assess risk of bias (RoB) of individual studies. In this article, we present and describe the development of such a tool, called the Risk of Bias in Studies estimating Prevalence of Exposure to Occupational risk factors (RoB-SPEO) tool; report results from RoB-SPEO's pilot testing; note RoB-SPEO's limitations; and suggest how the tool might be tested and developed further. METHODS: Selected existing RoB tools used in environmental and occupational health systematic reviews were reviewed and analysed. From existing tools, we identified domains for the new tool and, if necessary, added new domains. For each domain, we then identified and integrated components from the existing tools (i.e. instructions, domains, guiding questions, considerations, ratings and rating criteria), and, if necessary, we developed new components. Finally, we elicited feedback from other systematic review methodologists and exposure scientists and agreed upon RoB-SPEO. Nine experts pilot tested RoB-SPEO, and we calculated a raw measure of inter-rater agreement (Pi) for each of its domain, rating Pi < 0.4 as poor, 0.4 ≤ Pi ≥ 0.8 as substantial and Pi > 0.80 as almost perfect agreement. RESULTS: Our review found no standard tool for assessing RoB in prevalence studies of exposure to occupational risk factors. We identified six existing tools for environmental and occupational health systematic reviews and found that their components for assessing RoB differ considerably. With the new RoB-SPEO tool, assessors judge RoB for each of eight domains: (1) bias in selection of participants into the study; (2) bias due to a lack of blinding of study personnel; (3) bias due to exposure misclassification; (4) bias due to incomplete exposure data; (5) bias due to conflict of interest; (6) bias due to selective reporting of exposures; (7) bias due to difference in numerator and denominator; and (8) other bias. The RoB-SPEO's ratings are low, probably low, probably high, high or no information. Pilot testing of the RoB-SPEO tool found substantial inter-rater agreement for six domains (range of Pi for these domains: 0.51-0.80), but poor agreement for two domains (i.e. Pi of 0.31 and 0.33 for biases due to incomplete exposure data and in selection of participants into the study, respectively). Limitations of RoB-SPEO include that it has not yet been fully performance-tested. CONCLUSIONS: We developed the RoB-SPEO tool for assessing RoB in prevalence studies of exposure to occupational risk factors. The tool will be applied and its performance tested in the ongoing systematic reviews for the WHO/ILO Joint Estimates.

Temporal Variability of Escherichia coli Diversity in the Gastrointestinal Tracts of Tanzanian Children with and without Exposure to Antibiotics.

The stability of the Escherichia coli populations in the human gastrointestinal tract is not fully appreciated, and represents a significant knowledge gap regarding gastrointestinal community structure, as well as resistance to incoming pathogenic bacterial species and antibiotic treatment. The current study examines the genomic content of 240 Escherichia coli isolates from 30 children, aged 2 to 35 months old, in Tanzania. The E. coli strains were isolated from three time points spanning a six-month time period, with and without antibiotic treatment. The resulting isolates were sequenced, and the genomes compared. The findings in this study highlight the transient nature of E. coli strains in the gastrointestinal tract of these children, as during a six-month interval, no one individual contained phylogenomically related isolates at all three time points. While the majority of the isolates at any one time point were phylogenomically similar, most individuals did not contain phylogenomically similar isolates at more than two time points. Examination of global genome content, canonical E. coli virulence factors, multilocus sequence type, serotype, and antimicrobial resistance genes identified diversity even among phylogenomically similar strains. There was no apparent increase in the antimicrobial resistance gene content after antibiotic treatment. The examination of the E. coli from longitudinal samples from multiple children in Tanzania provides insight into the genomic diversity and population variability of resident E. coli within the rapidly changing environment of the gastrointestinal tract of these children.IMPORTANCE This study increases the number of resident Escherichia coli genome sequences, and explores E. coli diversity through longitudinal sampling. We investigate the genomes of E. coli isolated from human gastrointestinal tracts as part of an antibiotic treatment program among rural Tanzanian children. Phylogenomics demonstrates that resident E. coli are diverse, even within a single host. Though the E. coli isolates of the gastrointestinal community tend to be phylogenomically similar at a given time, they differed across the interrogated time points, demonstrating the variability of the members of the E. coli community in these subjects. Exposure to antibiotic treatment did not have an apparent impact on the E. coli community or the presence of resistance and virulence genes within E. coli genomes. The findings of this study highlight the variable nature of specific bacterial members of the human gastrointestinal tract.

Genomic differences between nasal Staphylococcus aureus from hog slaughterhouse workers and their communities.

New human pathogens can emerge from the livestock-human interface and spread into human populations through many pathways including livestock products. Occupational contact with livestock is a risk factor for exposure to those pathogens and may cause further spreading of those pathogens in the community. The current study used whole genome sequencing to explore nasal Staphylococcus aureus obtained from hog slaughterhouse workers and their community members, all of whom resided in a livestock-dense region in rural North Carolina. Sequence data were analyzed for lineage distribution, pathogenicity-related genomic features, and mobile genetic elements. We observed evidence of nasal S. aureus differences between hog workers and non-workers. Nasal S. aureus from hog workers showed a greater lineage diversity than nasal S. aureus from community residents. Hog worker isolates were less likely to carry the φSa3 prophage and human-specific immune evasion cluster genes than community resident isolates (φSa3 prophage: 54.5% vs. 91.7%, Benjamini-Hochberg (BH) corrected p = 0.035; immune evasion cluster genes: 66.7% vs. 100%, BH p = 0.021). Hog worker isolates had a lower prevalence and diversity of enterotoxins than community resident isolates, particularly lacking the enterotoxin gene cluster (39.4% vs. 70.8%, BH p = 0.125). Moreover, hog worker isolates harbored more diverse antibiotic resistance genes, with a higher prevalence of carriage of multiple resistance genes, than community resident isolates (75.8% vs. 29.2%, BH p = 0.021). Phylogenetic analysis of all ST5 isolates, the most abundant lineage in the collection, further supported separation of isolates from hog workers and non-workers. Together, our observations suggest impact of occupational contact with livestock on nasal S. aureus colonization and highlight the need for further research on the complex epidemiology of S. aureus at the livestock-human interface.

Modulators of mercury risk to wildlife and humans in the context of rapid global change.

Environmental mercury (Hg) contamination is an urgent global health threat. The complexity of Hg in the environment can hinder accurate determination of ecological and human health risks, particularly within the context of the rapid global changes that are altering many ecological processes, socioeconomic patterns, and other factors like infectious disease incidence, which can affect Hg exposures and health outcomes. However, the success of global Hg-reduction efforts depends on accurate assessments of their effectiveness in reducing health risks. In this paper, we examine the role that key extrinsic and intrinsic drivers play on several aspects of Hg risk to humans and organisms in the environment. We do so within three key domains of ecological and human health risk. First, we examine how extrinsic global change drivers influence pathways of Hg bioaccumulation and biomagnification through food webs. Next, we describe how extrinsic socioeconomic drivers at a global scale, and intrinsic individual-level drivers, influence human Hg exposure. Finally, we address how the adverse health effects of Hg in humans and wildlife are modulated by a range of extrinsic and intrinsic drivers within the context of rapid global change. Incorporating components of these three domains into research and monitoring will facilitate a more holistic understanding of how ecological and societal drivers interact to influence Hg health risks.

World Health Organization (WHO) guidelines on use of medically important antimicrobials in food-producing animals.

Background: Antimicrobial use in food-producing animals selects for antimicrobial resistance that can be transmitted to humans via food or other transmission routes. The World Health Organization (WHO) in 2005 ranked the medical importance of antimicrobials used in humans. In late 2017, to preserve the effectiveness of medically important antimicrobials for humans, WHO released guidelines on use of antimicrobials in food-producing animals that incorporated the latest WHO rankings. Methods: WHO commissioned systematic reviews and literature reviews, and convened a Guideline Development Group (GDG) of external experts free of unacceptable conflicts-of-interest. The GDG assessed the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, and formulated recommendations using a structured evidence-to-decision approach that considered the balance of benefits and harms, feasibility, resource implications, and impact on equity. The resulting guidelines were peer-reviewed by an independent External Review Group and approved by the WHO Guidelines Review Committee. Results: These guidelines recommend reductions in the overall use of medically important antimicrobials in food-producing animals, including complete restriction of use of antimicrobials for growth promotion and for disease prevention (i.e., in healthy animals considered at risk of infection). These guidelines also recommend that antimicrobials identified as critically important for humans not be used in food-producing animals for treatment or disease control unless susceptibility testing demonstrates the drug to be the only treatment option. Conclusions: To preserve the effectiveness of medically important antimicrobials, veterinarians, farmers, regulatory agencies, and all other stakeholders are urged to adopt these recommendations and work towards implementation of these guidelines.

State of the Science in Dried Blood Spots.

BACKGROUND: Advancements in the quality and availability of highly sensitive analytical instrumentation and methodologies have led to increased interest in the use of microsamples. Among microsamples, dried blood spots (DBS) are the most well-known. Although there have been a variety of review papers published on DBS, there has been no attempt at describing the full range of analytes measurable in DBS, or any systematic approach published for characterizing the strengths and weaknesses associated with adoption of DBS analyses. CONTENT: A scoping review of reviews methodology was used for characterizing the state of the science in DBS. We identified 2018 analytes measured in DBS and found every common analytic method applied to traditional liquid samples had been applied to DBS samples. Analytes covered a broad range of biomarkers that included genes, transcripts, proteins, and metabolites. Strengths of DBS enable its application in most clinical and laboratory settings, and the removal of phlebotomy and the need for refrigeration have expanded biosampling to hard-to-reach and vulnerable populations. Weaknesses may limit adoption in the near term because DBS is a nontraditional sample often requiring conversion of measurements to plasma or serum values. Opportunities presented by novel methodologies may obviate many of the current limitations, but threats around the ethical use of residual samples must be considered by potential adopters. SUMMARY: DBS provide a wide range of potential applications that extend beyond the reach of traditional samples. Current limitations are serious but not intractable. Technological advancements will likely continue to minimize constraints around DBS adoption.

Erratum: "An Integrated Experimental Design for the Assessment of Multiple Toxicological End Points in Rat Bioassays".

[This corrects the article DOI: 10.1289/EHP419.].

Managing hazards in place: The risks of residual risks.

Managing hazards in place (MHP) is a policy instrument in environmental health that allows less than complete removal, abatement, or remediation of environmental hazards. The practice of minimizing exposure to hazards rather than removing them is widely recognized as part of the toolbox of environmental protection for human and ecosystem health. The concept of managing hazards in place is embedded in several environmental statutes and regulations in the US notably the waste management regulations, as well as in the Safe Drinking Water Act and the Clean Water Act. While this commentary focuses largely on applications of MHP in the US, this policy is also utilized by agencies in many other countries for managing hazardous waste sites, lead in housing and drinking water systems, and environmental contamination of rivers and estuaries. The rationale for this concept is not difficult to understand: MHP policies can reduce the costs of meeting environmental goals; it can provide opportunities for access to resources that have been contaminated by past actions such as waste disposal, and it can enhance land and property values as well as tax revenues all of which are important to home owners and communities. The concerns related to this concept are also not difficult to understand: an incompletely abated or contained hazard may present future exposure risks to humans and environmental biota. Further, the compromise implicit in MHP is the assurance of indefinite oversight and monitoring to detect any releases. To that extent, MHP involves both sociology as well as toxicology and the exposure sciences. Because of the prevalence of managing hazards in place, this commentary suggests that evaluation of its performance is needed.

An Integrated Experimental Design for the Assessment of Multiple Toxicological End Points in Rat Bioassays.

BACKGROUND: For nearly five decades long-term studies in rodents have been the accepted benchmark for assessing chronic long-term toxic effects, particularly carcinogenicity, of chemicals. The European Food Safety Authority (EFSA) and the World Health Organization (WHO) have pointed out that the current set of internationally utilized test methods capture only some of the potential adverse effects associated with exposures to these agents over the lifetime. OBJECTIVES: In this paper, we propose the adaption of the carcinogenicity bioassay to integrate additional protocols for comprehensive long-term toxicity assessment that includes developmental exposures and long-term outcomes, capable of generating information on a broad spectrum of different end points. DISCUSSION: An integrated study design based on a stepwise process is described that includes the priority end points of the Economic Co-operation and Development and the National Toxicology Program guidelines on carcinogenicity and chronic toxicity and developmental and reproductive toxicity. Integrating a comprehensive set of relevant toxicological end points in a single protocol represents an opportunity to optimize animal use in accordance with the 3Rs (replacement, reduction and refinement). This strategy has the potential to provide sufficient data on multiple windows of susceptibility of specific interest for risk assessments and public health decision-making by including prenatal, lactational, neonatal exposures and evaluating outcomes over the lifespan. CONCLUSION: This integrated study design is efficient in that the same generational cohort of rats used for evaluating long-term outcomes can be monitored in satellite parallel experiments to measure biomarkers and other parameters related to system-specific responses including metabolic alterations and endocrine disturbances. Citation: Manservisi F, Babot Marquillas C, Buscaroli A, Huff J, Lauriola M, Mandrioli D, Manservigi M, Panzacchi S, Silbergeld EK, Belpoggi F. 2017. An integrated experimental design for the assessment of multiple toxicological end points in rat bioassays. Environ Health Perspect 125:289-295; http://dx.doi.org/10.1289/EHP419.

The Microbiome.

The microbiome is increasingly recognized as a critical component in human development, health, and disease. Its relevance to toxicology and pharmacology involves challenges to current concepts related to absorption, metabolism, gene:environment, and pathways of response. Framing testable hypotheses for experimental and epidemiological studies will require attention to study designs, biosampling, data analysis, and attention to confounders.

Association of Low-Moderate Arsenic Exposure and Arsenic Metabolism with Incident Diabetes and Insulin Resistance in the Strong Heart Family Study.

BACKGROUND: High arsenic exposure has been related to diabetes, but at low-moderate levels the evidence is mixed. Arsenic metabolism, which is partly genetically controlled and may rely on certain B vitamins, plays a role in arsenic toxicity. OBJECTIVE: We evaluated the prospective association of arsenic exposure and metabolism with type 2 diabetes and insulin resistance. METHODS: We included 1,838 American Indian men and women free of diabetes (median age, 36 y). Arsenic exposure was assessed as the sum of inorganic arsenic (iAs), monomethylarsonate (MMA), and dimethylarsinate (DMA) urine concentrations (ΣAs). Arsenic metabolism was evaluated by the proportions of iAs, MMA, and DMA over their sum (iAs%, MMA%, and DMA%). Homeostasis model assessment for insulin resistance (HOMA2-IR) was measured at baseline and follow-up visits. Incident diabetes was evaluated at follow-up. RESULTS: Median ΣAs, iAs%, MMA%, and DMA% was 4.4 µg/g creatinine, 9.5%, 14.4%, and 75.6%, respectively. Over 10,327 person-years of follow-up, 252 participants developed diabetes. Median HOMA2-IR at baseline was 1.5. The fully adjusted hazard ratio [95% confidence interval (CI)] for incident diabetes per an interquartile range increase in ΣAs was 1.57 (95% CI: 1.18, 2.08) in participants without prediabetes at baseline. Arsenic metabolism was not associated with incident diabetes. ΣAs was positively associated with HOMA2-IR at baseline but negatively with HOMA2-IR at follow-up. Increased MMA% was associated with lower HOMA2-IR when either iAs% or DMA% decreased. The association of arsenic metabolism with HOMA2-IR differed by B-vitamin intake and AS3MT genetics variants. CONCLUSIONS: Among participants without baseline prediabetes, arsenic exposure was associated with incident diabetes. Low MMA% was cross-sectional and prospectively associated with higher HOMA2-IR. Research is needed to confirm possible interactions of arsenic metabolism with B vitamins and AS3MT variants on diabetes risk. https://doi.org/10.1289/EHP2566.

Aneuploidy: a common and early evidence-based biomarker for carcinogens and reproductive toxicants.

Aneuploidy, defined as structural and numerical aberrations of chromosomes, continues to draw attention as an informative effect biomarker for carcinogens and male reproductive toxicants. It has been well documented that aneuploidy is a hallmark of cancer. Aneuploidies in oocytes and spermatozoa contribute to infertility, pregnancy loss and a number of congenital abnormalities, and sperm aneuploidy is associated with testicular cancer. It is striking that several carcinogens induce aneuploidy in somatic cells, and also adversely affect the chromosome compliment of germ cells. In this paper we review 1) the contributions of aneuploidy to cancer, infertility, and developmental abnormalities; 2) techniques for assessing aneuploidy in precancerous and malignant lesions and in sperm; and 3) the utility of aneuploidy as a biomarker for integrated chemical assessments of carcinogenicity, and reproductive and developmental toxicity.

Longitudinal Comparison of Antibiotic Resistance in Diarrheagenic and Non-pathogenic Escherichia coli from Young Tanzanian Children.

Enteroaggregative, enteropathogenic, and enterotoxigenic Escherichia coli contribute significantly to the burden of diarrheal infections particularly in developing countries. Antibiotic resistance is increasingly common among bacterial pathogens including pathogenic E. coli. We assessed the relationship between pathogenic E. coli carriage and resistance to six antibiotics in E. coli isolated from young children in rural Tanzania. We surveyed temporal stability in antibiotic resistance in 2492 E. coli isolated from fecal samples obtained from young children in rural Tanzania collected over a 6 months period. Approximately half of the 377 children sampled were exposed to an azithromycin mass treatment program for trachoma control and half resided in control villages. Children were sampled at baseline, 1-, 3-, and 6 months following azithromycin treatment. We compared resistance to six antibiotics in pathogenic and non-pathogenic strains at the population level, within fecal specimens, and within individuals over time using chi-square tests, paired odds ratios, and logistic regression, respectively. Resistance to ampicillin and trimethoprim/sulfamethoxazole was highly prevalent (>65%). Resistance to 5 of 6 antibiotics tested and multi-drug resistance occurred more frequently in pathogenic isolates (p ≤ 0.001) within fecal specimens and overall. Azithromycin mass treatment exposure was significantly associated with increased odds of carriage of isolates resistant to erythromycin (OR 3.64, p < 0.001) and trimethoprim/sulfamethoxazole (OR 1.60, p < 0.05). Pathogenic isolates were approximately twice as likely to be resistant to erythromycin, ampicillin, or trimethoprim/sulfamethoxazole compared to non-pathogenic isolates from the same fecal specimen. The potential linkage between resistance and virulence in E. coli suggests hygiene and sanitation interventions aimed at reducing disease burden could play a role in controlling transmission of antibiotic resistance.

GRADE: Assessing the quality of evidence in environmental and occupational health.

There is high demand in environmental health for adoption of a structured process that evaluates and integrates evidence while making decisions and recommendations transparent. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework holds promise to address this demand. For over a decade, GRADE has been applied successfully to areas of clinical medicine, public health, and health policy, but experience with GRADE in environmental and occupational health is just beginning. Environmental and occupational health questions focus on understanding whether an exposure is a potential health hazard or risk, assessing the exposure to understand the extent and magnitude of risk, and exploring interventions to mitigate exposure or risk. Although GRADE offers many advantages, including its flexibility and methodological rigor, there are features of the different sources of evidence used in environmental and occupational health that will require further consideration to assess the need for method refinement. An issue that requires particular attention is the evaluation and integration of evidence from human, animal, in vitro, and in silico (computer modeling) studies when determining whether an environmental factor represents a potential health hazard or risk. Assessment of the hazard of exposures can produce analyses for use in the GRADE evidence-to-decision (EtD) framework to inform risk-management decisions about removing harmful exposures or mitigating risks. The EtD framework allows for grading the strength of the recommendations based on judgments of the certainty in the evidence (also known as quality of the evidence), as well as other factors that inform recommendations such as social values and preferences, resource implications, and benefits. GRADE represents an untapped opportunity for environmental and occupational health to make evidence-based recommendations in a systematic and transparent manner. The objectives of this article are to provide an overview of GRADE, discuss GRADE's applicability to environmental health, and identify priority areas for method assessment and development.

Drinking Water and the Developing Brain.

While the problem of unsafe tap water in Flint, Michigan fueled outrage and better awareness in regard to the hazards of lead in tap water, the problem has existed in city after city for years in the US and in other countries. Our author, a winner of the MacArthur Foundation "genius" grant for her work in identifying preventable causes of human disease related to environmental exposures, points out that problems extend well beyond lead. Many potentially harmful contaminants have yet to be evaluated, much less regulated. Her article examines a number of neurotoxins and related issues as they pertain to brain development.

Challenges for environmental epidemiology research: are biomarker concentrations altered by kidney function or urine concentration adjustment?

Biomonitoring has become a standard approach for exposure assessment in occupational and environmental epidemiology. The use of biological effect markers to identify early adverse changes in target organs has also become widely adopted. However, the potential for kidney function to affect biomarker levels in the body and the optimal approach to adjustment of biomarker concentrations in spot urine samples for hydration status are two important but underappreciated challenges associated with biomarker use. Several unexpected findings, such as positive associations between urine nephrotoxicant levels and estimated glomerular filtration rate (eGFR), have been reported recently in research using biomarkers. These and other findings, discussed herein, suggest an impact of kidney glomerular filtration or tubule processing on biomarker levels. This is more commonly raised in the context of decreased kidney filtration, traditionally referred to as reverse causality; however, recent data suggest that populations with normal kidney filtration may be affected as well. Misclassification bias would result if biomarkers reflect kidney function as well as either exposures or early biological effect outcomes. Furthermore, urine biomarker associations with eGFR that differ markedly by approach used to adjust for urine concentration have been reported. Associations between urine measures commonly used for this adjustment, such as urine creatinine, and specific research outcomes could alter observed biomarker associations with outcomes. Research recommendations to address the potential impact of kidney function and hydration status adjustment on biomarkers are provided, including a range of approaches to study design, exposure and outcome assessment, and adjustment for urine concentration.