Publications by authors named "Daniele Mandrioli"

38 Publications

A Protocol for the Use of Case Reports/Studies and Case Series in Systematic Reviews for Clinical Toxicology.

Front Med (Lausanne) 2021 6;8:708380. Epub 2021 Sep 6.

Univ Angers, CHU Angers, Univ Rennes, INSERM, EHESP, Institut de Recherche en Santé, Environnement et Travail-UMR_S 1085, Angers, France.

Systematic reviews are routinely used to synthesize current science and evaluate the evidential strength and quality of resulting recommendations. For specific events, such as rare acute poisonings or preliminary reports of new drugs, we posit that case reports/studies and case series (human subjects research with no control group) may provide important evidence for systematic reviews. Our aim, therefore, is to present a protocol that uses rigorous selection criteria, to distinguish high quality case reports/studies and case series for inclusion in systematic reviews. This protocol will adapt the existing Navigation Guide methodology for specific inclusion of case studies. The usual procedure for systematic reviews will be followed. Case reports/studies and case series will be specified in the search strategy and included in separate sections. Data from these sources will be extracted and where possible, quantitatively synthesized. Criteria for integrating cases reports/studies and case series into the overall body of evidence are that these studies will need to be well-documented, scientifically rigorous, and follow ethical practices. The instructions and standards for evaluating risk of bias will be based on the Navigation Guide. The risk of bias, quality of evidence and the strength of recommendations will be assessed by two independent review teams that are blinded to each other. This is a protocol specified for systematic reviews that use case reports/studies and case series to evaluate the quality of evidence and strength of recommendations in disciplines like clinical toxicology, where case reports/studies are the norm.
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http://dx.doi.org/10.3389/fmed.2021.708380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450367PMC
September 2021

Toolkit for detecting misused epidemiological methods.

Environ Health 2021 08 19;20(1):90. Epub 2021 Aug 19.

Center for Bioethics and Humanities, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Background: Critical knowledge of what we know about health and disease, risk factors, causation, prevention, and treatment, derives from epidemiology. Unfortunately, its methods and language can be misused and improperly applied. A repertoire of methods, techniques, arguments, and tactics are used by some people to manipulate science, usually in the service of powerful interests, and particularly those with a financial stake related to toxic agents. Such interests work to foment uncertainty, cast doubt, and mislead decision makers by seeding confusion about cause-and-effect relating to population health. We have compiled a toolkit of the methods used by those whose interests are not aligned with the public health sciences. Professional epidemiologists, as well as those who rely on their work, will thereby be more readily equipped to detect bias and flaws resulting from financial conflict-of-interest, improper study design, data collection, analysis, or interpretation, bringing greater clarity-not only to the advancement of knowledge, but, more immediately, to policy debates.

Methods: The summary of techniques used to manipulate epidemiological findings, compiled as part of the 2020 Position Statement of the International Network for Epidemiology in Policy (INEP) entitled Conflict-of-Interest and Disclosure in Epidemiology, has been expanded and further elucidated in this commentary.

Results: Some level of uncertainty is inherent in science. However, corrupted and incomplete literature contributes to confuse, foment further uncertainty, and cast doubt about the evidence under consideration. Confusion delays scientific advancement and leads to the inability of policymakers to make changes that, if enacted, would-supported by the body of valid evidence-protect, maintain, and improve public health. An accessible toolkit is provided that brings attention to the misuse of the methods of epidemiology. Its usefulness is as a compendium of what those trained in epidemiology, as well as those reviewing epidemiological studies, should identify methodologically when assessing the transparency and validity of any epidemiological inquiry, evaluation, or argument. The problems resulting from financial conflicting interests and the misuse of scientific methods, in conjunction with the strategies that can be used to safeguard public health against them, apply not only to epidemiologists, but also to other public health professionals.

Conclusions: This novel toolkit is for use in protecting the public. It is provided to assist public health professionals as gatekeepers of their respective specialty and subspecialty disciplines whose mission includes protecting, maintaining, and improving the public's health. It is intended to serve our roles as educators, reviewers, and researchers.
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http://dx.doi.org/10.1186/s12940-021-00771-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375462PMC
August 2021

Commentary: Novel strategies and new tools to curtail the health effects of pesticides.

Environ Health 2021 08 3;20(1):87. Epub 2021 Aug 3.

Gene Expression and Therapy Group, Department of Medical and Molecular Genetics, King's College London, Faculty of Life Sciences and Medicine, Guy's Hospital, London, UK.

Background: Flaws in the science supporting pesticide risk assessment and regulation stand in the way of progress in mitigating the human health impacts of pesticides. Critical problems include the scope of regulatory testing protocols, the near-total focus on pure active ingredients rather than formulated products, lack of publicly accessible information on co-formulants, excessive reliance on industry-supported studies coupled with reticence to incorporate published results in the risk assessment process, and failure to take advantage of new scientific opportunities and advances, e.g. biomonitoring and "omics" technologies.

Recommended Actions: Problems in pesticide risk assessment are identified and linked to study design, data, and methodological shortcomings. Steps and strategies are presented that have potential to deepen scientific knowledge of pesticide toxicity, exposures, and risks. We propose four solutions: (1) End near-sole reliance in regulatory decision-making on industry-supported studies by supporting and relying more heavily on independent science, especially for core toxicology studies. The cost of conducting core toxicology studies at labs not affiliated with or funded directly by pesticide registrants should be covered via fees paid by manufacturers to public agencies. (2) Regulators should place more weight on mechanistic data and low-dose studies within the range of contemporary exposures. (3) Regulators, public health agencies, and funders should increase the share of exposure-assessment resources that produce direct measures of concentrations in bodily fluids and tissues. Human biomonitoring is vital in order to quickly identify rising exposures among vulnerable populations including applicators, pregnant women, and children. (4) Scientific tools across disciplines can accelerate progress in risk assessments if integrated more effectively. New genetic and metabolomic markers of adverse health impacts and heritable epigenetic impacts are emerging and should be included more routinely in risk assessment to effectively prevent disease.

Conclusions: Preventing adverse public health outcomes triggered or made worse by exposure to pesticides will require changes in policy and risk assessment procedures, more science free of industry influence, and innovative strategies that blend traditional methods with new tools and mechanistic insights.
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http://dx.doi.org/10.1186/s12940-021-00773-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8330079PMC
August 2021

Urinary glyphosate concentration in pregnant women in relation to length of gestation.

Environ Res 2021 Jul 30;203:111811. Epub 2021 Jul 30.

Department of Environmental Medicine and Public Heath, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address:

Human exposure to glyphosate-based herbicides (GBH) is increasing rapidly worldwide. Most existing studies on health effects of glyphosate have focused on occupational settings and cancer outcomes and few have examined this common exposure in relation to the health of pregnant women and newborns in the general population. We investigated associations between prenatal glyphosate exposure and length of gestation in The Infant Development and the Environment Study (TIDES), a multi-center US pregnancy cohort. Glyphosate and its primary degradation product [aminomethylphosphonic acid (AMPA)] were measured in urine samples collected during the second trimester from 163 pregnant women: 69 preterm births (<37 weeks) and 94 term births, the latter randomly selected as a subset of TIDES term births. We examined the relationship between exposure and length of gestation using multivariable logistic regression models (dichotomous outcome; term versus preterm) and with weighted time-to-event Cox proportional hazards models (gestational age in days). We conducted these analyses in the overall sample and secondarily, restricted to women with spontaneous deliveries (n = 90). Glyphosate and AMPA were detected in most urine samples (>94 %). A shortened gestational length was associated with maternal glyphosate (hazard ratio (HR): 1.31, 95 % confidence interval (CI) 1.00-1.71) and AMPA (HR: 1.32, 95%CI: 1.00-1.73) only among spontaneous deliveries using adjusted Cox proportional hazards models. In binary analysis, glyphosate and AMPA were not associated with preterm birth risk (<37 weeks). Our results indicate widespread exposure to glyphosate in the general population which may impact reproductive health by shortening length of gestation. Given the increasing exposure to GBHs and the public health burden of preterm delivery, larger confirmatory studies are needed, especially in vulnerable populations such as pregnant women and newborns.
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http://dx.doi.org/10.1016/j.envres.2021.111811DOI Listing
July 2021

A health-based recommended occupational exposure limit for nitrous oxide using experimental animal data based on a systematic review and dose-response analysis.

Environ Res 2021 Jun 23;201:111575. Epub 2021 Jun 23.

Department for Health Evidence, Radboud Institute for Health Sciences, Radboudumc, Nijmegen, the Netherlands. Electronic address:

Background: Nitrous oxide (NO) is a common inhalation anaesthetic used in medical, paramedical, and veterinary practice. Since the mid 1950's, concerns have been raised regarding occupational exposure to NO, leading to many epidemiological and experimental animal studies. Previous evaluations resulted in the classification of NO as a possible risk factor for adverse reproductive health outcomes based on animal data. Human data were deemed inadequate primarily because of simultaneous co-exposures to other risk factors for adverse reproductive and developmental outcomes, including other anaesthetic gases. Since previous evaluations, controversies regarding NO use remained and new approaches for dose response modelling have been adopted, calling for an update and re-evaluation of the body of evidence. This review aims to assess available animal evidence on NO reproductive and developmental outcomes to inform a health-based recommended occupational exposure limit (OEL) for NO with a benchmark dose-response modelling (BMD) approach.

Methods: Comprehensive searches in PubMed, EMBASE, and Web of Science were performed to retrieve all relevant studies addressing reproductive and developmental outcomes related to inhalation of NO in animals. The articles retrieved were screened based on title-abstract and full text by two independent reviewers. After data extraction, an overview of all studies was created for the different endpoints, namely foetal outcomes (e.g., resorption), female outcomes (e.g. implantations), and male outcomes (e.g. sperm count). A subset of studies reporting on exposure relevant to workplace settings and with a sufficient number of tested doses were included in dose-response modelling using the BMD approach.

Results: In total, 15.816 articles were retrieved, of which 47 articles were finally included while 4 of those were used for the quantitative data synthesis. The overall risk of bias was judged to be probably high (using OHAT risk of bias tool) and unclear (using SYRCLE's risk of bias tool). From eligible rat studies, three studies provided an acceptable result by fitting a Hill model to the dose-response data. The resulting benchmark dose lower bounds (BMDLs) from three studies converged to an average (±sd) exposure level of 925 ± 2 mg/m at an additional risk of one standard deviation of implantation losses above those observed in the control group (i.e. reduced number of live foetuses/mother). For extrapolation from rats to humans, an uncertainty factor of 10 was used and an additional factor of 5 was applied to account for interindividual variability within the population of workers.

Conclusion: With this systematic review, all available evidence for reproductive toxicity and adverse developmental outcomes in animals resulting from inhalation exposure to NO was used to derive a health-based OEL recommendation of 20 mg/m as 8-h time-weighted average.
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http://dx.doi.org/10.1016/j.envres.2021.111575DOI Listing
June 2021

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

Front Public Health 2021 7;9:643898. Epub 2021 May 7.

Department of Agricultural Sciences, University of Bologna, Bologna, Italy.

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 and studies available in literature report conflicting findings on the toxicity of GBHs. In our earlier 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 models the cytotoxicity of glycine and GBHs. 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. 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. Glyphosate and its formulation Roundup Bioflow, but not glycine, caused dose-related cytotoxic effects in 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).
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http://dx.doi.org/10.3389/fpubh.2021.643898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138571PMC
May 2021

Multi-omics phenotyping of the gut-liver axis reveals metabolic perturbations from a low-dose pesticide mixture in rats.

Commun Biol 2021 04 14;4(1):471. Epub 2021 Apr 14.

Gene Expression and Therapy Group, King's College London, Faculty of Life Sciences & Medicine, Department of Medical and Molecular Genetics, Guy's Hospital, London, UK.

Health effects of pesticides are not always accurately detected using the current battery of regulatory toxicity tests. We compared standard histopathology and serum biochemistry measures and multi-omics analyses in a subchronic toxicity test of a mixture of six pesticides frequently detected in foodstuffs (azoxystrobin, boscalid, chlorpyrifos, glyphosate, imidacloprid and thiabendazole) in Sprague-Dawley rats. Analysis of water and feed consumption, body weight, histopathology and serum biochemistry showed little effect. Contrastingly, serum and caecum metabolomics revealed that nicotinamide and tryptophan metabolism were affected, which suggested activation of an oxidative stress response. This was not reflected by gut microbial community composition changes evaluated by shotgun metagenomics. Transcriptomics of the liver showed that 257 genes had their expression changed. Gene functions affected included the regulation of response to steroid hormones and the activation of stress response pathways. Genome-wide DNA methylation analysis of the same liver samples showed that 4,255 CpG sites were differentially methylated. Overall, we demonstrated that in-depth molecular profiling in laboratory animals exposed to low concentrations of pesticides allows the detection of metabolic perturbations that would remain undetected by standard regulatory biochemical measures and which could thus improve the predictability of health risks from exposure to chemical pollutants.
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http://dx.doi.org/10.1038/s42003-021-01990-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046807PMC
April 2021

Maternal urinary levels of glyphosate during pregnancy and anogenital distance in newborns in a US multicenter pregnancy cohort.

Environ Pollut 2021 Jul 22;280:117002. Epub 2021 Mar 22.

Department of Environmental Medicine and Public Heath, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address:

Human exposure to glyphosate has become ubiquitous because of its increasing agricultural use. Recent studies suggest endocrine disrupting effects of glyphosate. Specifically, in our work in rodents, low-dose early-life exposure to Roundup® (glyphosate-based herbicide) lengthened anogenital distance (AGD) in male and female offspring. AGD is a marker of the prenatal hormone milieu in rodents and humans. The relationship between glyphosate exposure and AGD has not been studied in humans. We conducted a pilot study in 94 mother-infant pairs (45 female and 49 male) from The Infant Development and the Environment Study (TIDES). For each infant, two AGD measurements were collected after birth; the anopenile (AGD-AP) and anoscrotal (AGD-AS) distances for males, and anoclitoral (AGD-AC) and anofourchette distances (AGD-AF) for females. We measured levels of glyphosate and its degradation product aminomethylphosphonic acid (AMPA) in 2nd trimester maternal urine samples using ultra-high-performance liquid chromatography-tandem mass spectrometry. We assessed the relationship between exposure and AGD using sex-stratified multivariable linear regression models. Glyphosate and AMPA were detected in 95% and 93% of the samples (median 0.22 ng/mL and 0.14 ng/mL, respectively). Their concentrations were moderately correlated (r = 0.55, p = 5.7 × 10). In female infants, high maternal urinary glyphosate (above the median) was associated with longer AGD-AC (β = 1.48, 95%CI (-0.01, 3.0), p = 0.05), but this was not significant after covariate adjustment. Increased AMPA was associated with longer AGD-AF (β = 1.96, 95%CI (0.44, 3.5), p = 0.01) after adjusting for infant size and age at AGD exam. No associations were detected in male offspring. These preliminary findings partially reproduce our previous results in rodents and suggest that glyphosate is a sex-specific endocrine disruptor with androgenic effects in humans. Given the increasing glyphosate exposures in the US population, larger studies should evaluate potential developmental effects on endocrine and reproductive systems.
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http://dx.doi.org/10.1016/j.envpol.2021.117002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165010PMC
July 2021

Response to "Cancerogenic effects of radiofrequency radiation: A statistical reappraisal".

Environ Res 2021 06 26;197:111067. Epub 2021 Mar 26.

Ramazzini Institute, Bologna, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.envres.2021.111067DOI Listing
June 2021

Low-dose exposure of glyphosate-based herbicides disrupt the urine metabolome and its interaction with gut microbiota.

Sci Rep 2021 Feb 5;11(1):3265. Epub 2021 Feb 5.

Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY, USA.

Glyphosate-based herbicides (GBHs) can disrupt the host microbiota and influence human health. In this study, we explored the potential effects of GBHs on urinary metabolites and their interactions with gut microbiome using a rodent model. Glyphosate and Roundup (equal molar for glyphosate) were administered at the USA glyphosate ADI guideline (1.75 mg/kg bw/day) to the dams and their pups. The urine metabolites were profiled using non-targeted liquid chromatography-high resolution mass spectrometry (LC-HRMS). Our results found that overall urine metabolite profiles significantly differed between dams and pups and between female and male pups. Specifically, we identified a significant increase of homocysteine, a known risk factor of cardiovascular disease in both Roundup and glyphosate exposed pups, but in males only. Correlation network analysis between gut microbiome and urine metabolome pointed to Prevotella to be negatively correlated with the level of homocysteine. Our study provides initial evidence that exposures to commonly used GBH, at a currently acceptable human exposure dose, is capable of modifying urine metabolites in both rat adults and pups. The link between Prevotella-homocysteine suggests the potential role of GBHs in modifying the susceptibility of homocysteine, which is a metabolite that has been dysregulated in related diseases like cardiovascular disease or inflammation, through commensal microbiome.
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http://dx.doi.org/10.1038/s41598-021-82552-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864973PMC
February 2021

Use of Shotgun Metagenomics and Metabolomics to Evaluate the Impact of Glyphosate or Roundup MON 52276 on the Gut Microbiota and Serum Metabolome of Sprague-Dawley Rats.

Environ Health Perspect 2021 01 27;129(1):17005. Epub 2021 Jan 27.

Gene Expression and Therapy Group, Department of Medical and Molecular Genetics, King's College London, Faculty of Life Sciences & Medicine, Guy's Hospital, London, UK.

Background: There is intense debate on whether glyphosate can inhibit the shikimate pathway of gastrointestinal microorganisms, with potential health implications.

Objectives: We tested whether glyphosate or its representative EU herbicide formulation Roundup MON 52276 affects the rat gut microbiome.

Methods: We combined cecal microbiome shotgun metagenomics with serum and cecum metabolomics to assess the effects of glyphosate [0.5, 50, ] or MON 52276 at the same glyphosate-equivalent doses, in a 90-d toxicity test in rats.

Results: Glyphosate and MON 52276 treatment resulted in ceca accumulation of shikimic acid and 3-dehydroshikimic acid, suggesting inhibition of 5-enolpyruvylshikimate-3-phosphate synthase of the shikimate pathway in the gut microbiome. Cysteinylglycine, , and valylglycine levels were elevated in the cecal microbiome following glyphosate and MON 52276 treatments. Altered cecum metabolites were not differentially expressed in serum, suggesting that the glyphosate and MON 52276 impact on gut microbial metabolism had limited consequences on physiological biochemistry. Serum metabolites differentially expressed with glyphosate treatment were associated with nicotinamide, branched-chain amino acid, methionine, cysteine, and taurine metabolism, indicative of a response to oxidative stress. MON 52276 had similar, but more pronounced, effects than glyphosate on the serum metabolome. Shotgun metagenomics of the cecum showed that treatment with glyphosate and MON 52276 resulted in higher levels of spp., , , and . was higher only with MON 52276 exposure. culture assays with strains showed that Roundup GT plus inhibited growth at concentrations at which MON 52276 and glyphosate had no effect.

Discussion: Our study highlights the power of multi-omics approaches to investigate the toxic effects of pesticides. Multi-omics revealed that glyphosate and MON 52276 inhibited the shikimate pathway in the rat gut microbiome. Our findings could be used to develop biomarkers for epidemiological studies aimed at evaluating the effects of glyphosate herbicides on humans. https://doi.org/10.1289/EHP6990.
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http://dx.doi.org/10.1289/EHP6990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839352PMC
January 2021

Identification of aspartame-induced haematopoietic and lymphoid tumours in rats after lifetime treatment.

Acta Histochem 2020 Jul 20;122(5):151548. Epub 2020 May 20.

Cesare Maltoni Cancer Research Center, Ramazzini Institute, via Saliceto 3, 40010 Bentivoglio, Bologna, Italy. Electronic address:

Lymphomas and leukaemias involving the lung have in some cases been hard to distinguish from respiratory tract infection in Sprague-Dawley (SD) rats from long-term bioassays. In order to differentiate between tumours and immune cell infiltrates, updated pathological criteria and nomenclature were used and immunohistochemistry (IHC) was applied to haematopoietic and lymphoid tissue tumours (HLTs) in the original prenatal long-term Aspartame (APM) study performed by the Ramazzini Institute (RI). All 78 cases of HLTs from treated and control groups were re-examined based on light microscopic morphological characteristics and subjected to a panel of IHC markers including Ki67, CD3, PAX5, CD20, CD68, TdT, CD45, CD14 and CD33. The analysis confirmed the diagnoses of HLTs in 72 cases, identified 3 cases of preneoplastic lesions (lymphoid hyperplasia), and categorized 3 cases as inflammatory lesions. A statistically significant increase in total HLTs (p = 0.006), total lymphomas (p = 0.032) and total leukaemias (p = 0.031) in treated female rats was confirmed (high dose vs control), and a statistically significant linear trend for each HLT type was also observed. After the HLT cases re-evaluation, the results obtained are consistent with those reported in the previous RI publication and reinforce the hypothesis that APM has a leukaemogenic and lymphomatogenic effect.
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http://dx.doi.org/10.1016/j.acthis.2020.151548DOI Listing
July 2020

Protocol for a systematic review and meta-analysis of human exposure to pesticide residues in honey and other bees' products.

Environ Res 2020 07 3;186:109470. Epub 2020 Apr 3.

Cesare Maltoni Cancer Research Center, Ramazzini Institute, Bologna, Italy.

Background: The presence of pesticides in honey and related products is an increasing concern for consumers and producers, although there is lack of data on the current burden of exposure of the general human population through these products. We present a protocol for a systematic review and meta-analysis of contamination to insecticides, herbicides and fungicides of products from honeybees, and an estimation of how much the consumption of these products contributes to the ADI (Acceptable Daily Intake) of selected substances.

Objectives: We aim to systematically review and meta-analyse studies on the contamination to plant protection products in honey, royal jelly, beeswax and propolis, applying the Navigation Guide and WHO-ILO systematic review methodology as an organizing framework.

Data Sources: We will search electronic academic databases for potentially relevant records from PubMed, TOXNET and EMBASE. We will include quantitative studies analysing the contamination from insecticides, herbicides and fungicides in honey, propolis, royal jelly and beeswax. In particular, we will evaluate the presence of the following substances and classes of pesticides: Glyphosate, Chlorpyrifos, pyrethroid and neonicotinoid pesticides, fungicides and acaricides.

Study Appraisal And Synthesis Methods: At least two authors will independently screen titles and abstracts at a first stage of review, and full texts at a second stage, of potentially eligible records against the eligibility criteria; data extraction of included studies will then be performed by at least two authors, in blind. At least two authors will assess risk of bias and the quality of evidence, using the most suited tools currently available. The data on prevalence of contaminated samples and concentration of pesticides in the products will be combined using meta-analysis: when more than three studies reporting the necessary measures to fit the models are available, meta-analysis will be performed separately by product and by exposure; otherwise, weighted descriptive analysis will be performed. We will report the results using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA).
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http://dx.doi.org/10.1016/j.envres.2020.109470DOI Listing
July 2020

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.

Environ Int 2020 02 18;135:105039. Epub 2019 Dec 18.

Cesare Maltoni Cancer Research Center, Ramazzini Institute, Bologna, Italy.

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 (P) for each of its domain, rating P < 0.4 as poor, 0.4 ≤ P ≥ 0.8 as substantial and P > 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 P for these domains: 0.51-0.80), but poor agreement for two domains (i.e. P 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.
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http://dx.doi.org/10.1016/j.envint.2019.105039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479507PMC
February 2020

The Contribution of In Vivo Mammalian Studies to the Knowledge of Adverse Effects of Radiofrequency Radiation on Human Health.

Int J Environ Res Public Health 2019 09 12;16(18). Epub 2019 Sep 12.

Cesare Maltoni Cancer Research Center, Ramazzini Institute, Castello di Bentivoglio, via Saliceto 3, Bentivoglio, 40010 Bologna, Italy.

The proliferation of cellular antennas and other radiofrequency radiation (RFR) generating devices of the last decades has led to more and more concerns about the potential health effects from RFR exposure. Since the 2011 classification as a possible carcinogen by the International Agency for Research on Cancer (IARC), more experimental studies have been published that support a causal association between RFR exposure and health hazards. As regard cancer risk, two long-term experimental studies have been recently published by the US National Toxicology Program (NTP) and the Italian Ramazzini Institute (RI). Despite important experimental differences, both studies found statistically significant increases in the development of the same type of very rare glial malignant tumors. In addition to carcinogenicity, reproductive organs might be particularly exposed, as well as sensitive to RFR. In this work, we reviewed the currently available evidence from in vivo studies on carcinogenicity and reproductive toxicity studies in order to summarize the contribution of experimental research to the prevention of the adverse effects of RFR on human health.
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http://dx.doi.org/10.3390/ijerph16183379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6765993PMC
September 2019

Establishing a health-based recommended occupational exposure limit for nitrous oxide using experimental animal data - A systematic review protocol.

Environ Res 2019 11 7;178:108711. Epub 2019 Sep 7.

Department for Health Evidence, Radboud Institute for Health Sciences, Radboudumc, Nijmegen, the Netherlands. Electronic address:

Nitrous oxide (NO) is widely used as inhalation analgesic and anaesthetic in medical, paramedical, and veterinary practice. Previous evaluations resulted in classification of NO as a possible risk factor for adverse reproductive health outcomes based on evidence from animal data. Available human data were considered inadequate, partly due to the possibility that other risk factors, such as co-exposures to other inhalation anaesthetics may have contributed to the adverse outcomes. As no substantial new human evidence has emerged since previous evaluations, this protocol describes a planned systematic review of the evidence obtained from animal studies. The aim is to assess the available evidence on the effects of NO on reproductive and developmental outcomes in animals to inform a health-based recommended occupational exposure limit (OEL) for NO. Comprehensive search strategies were designed to retrieve animal studies addressing NO exposure from PubMed, EMBASE, and Web of Science. Screening of the studies retrieved will be performed by at least two independent reviewers, while discrepancies will be resolved by reaching consensus through repeated review and discussions. Articles will be included according to criteria specified in this protocol. Outcome data relevant for reproduction and development will be extracted and risk of bias will be assessed by two independent reviewers using the SYRCLE's risk of bias tool. Primary reproductive and developmental outcomes of interest will be the number of resorptions, malformations, and birth weight. We will focus on dose-response studies that allow to derive an OEL with the benchmark dose (BMD) approach. Adverse outcomes occurring at doses that are equivalent to the exposures occurring in human occupational settings will be particularly relevant for dose-response modelling. The proposed review has not been performed before. We will follow the procedures specified in this protocol. We will adhere to guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), adapted for animal studies. Ethical approval will not be required, as the review will use existing data available in the public domain.
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http://dx.doi.org/10.1016/j.envres.2019.108711DOI Listing
November 2019

Effects of short and long-term alcohol-based fixation on Sprague-Dawley rat tissue morphology, protein and nucleic acid preservation.

Acta Histochem 2019 Aug 3;121(6):750-760. Epub 2019 Jul 3.

Cesare Maltoni Cancer Research Center (CMCRC), Ramazzini Institute (RI), Bentivoglio, Bologna, Italy. Electronic address:

Safety concerns on the toxic and carcinogenic effects of formalin exposure have drawn increasing attention to the search for alternative low risk fixatives for processing tissue specimens in laboratories worldwide. Alcohol-based fixatives are considered some of the most promising alternatives. We evaluated the performance of alcohol-fixed paraffin-embedded (AFPE) samples from Sprague-Dawley (SD) rats analyzing tissue morphology, protein and nucleic acid preservation after short and extremely long fixation times (up to 7 years), using formalin-fixed paraffin-embedded (FFPE) samples as a comparator fixative. Following short and long-term alcohol fixation, tissue morphology and cellular details in tissues, evaluated by scoring stained sections (Hematoxylin-Eosin and Mallory's trichrome), were optimally preserved if compared to formalin fixation. Immunoreactivity of proteins (Ki67, CD3, PAX5, CD68), evaluated by immunohistochemistry, showed satisfactory results when the fixation period did not exceed 1 year. Finally, we confirm the superiority of alcohol fixation compared to formalin, in terms of quantity of nucleic acid extracted from paraffin blocks, even after an extremely long time of alcohol fixation. Our results confirm that alcohol fixation is a suitable and safe alternative to formalin for pathological evaluations. There is a need for standardization of formalin-free methods and harmonization of diagnosis in pathology department worldwide.
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http://dx.doi.org/10.1016/j.acthis.2019.05.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939362PMC
August 2019

Historical evidence of glyphosate exposure from a US agricultural cohort.

Environ Health 2019 05 7;18(1):42. Epub 2019 May 7.

Department of Environmental and Occupational Health, Milken Institute School of Public Health, The George Washington University, 950 New Hampshire Ave, Washington, DC, 20052, USA.

In response to the recent review by Gillezeau et al., The evidence of human exposure to glyphosate: A review, Environmental Health 1/19/19, here we report additional glyphosate biomonitoring data from a repository of urine samples collected from United States farmers in 1997-98. To determine if glyphosate exposure could be identified historically, we examined urine samples from a biorepository of specimens collected from US dairy farmers between 1997 and 98. We compared samples from farmers who self-reported glyphosate application in the 8 h prior to sample collection to samples from farm applicators who did not report using glyphosate. Of 18 applicator samples tested, 39% showed detectable levels of glyphosate (mean concentration 4.04 μg/kg; range:1.3-12) compared to 0% detections among 17 non glyphosate applicator samples (p-value < 0.01). One of the applicator samples that tested positive for glyphosate also tested positive for AMPA. Concentrations of glyphosate were consistent with levels reported in the prior occupational biomonitoring studies reviewed by Gillezeau et al.Accurately detecting both glyphosate and AMPA in this small sample of Wisconsin farmers demonstrates a) glyphosate exposures among farmers were occurring 20 years ago, which was prior to the widespread planting of genetically engineered glyphosate tolerant crops first approved in 1996; and b) liquid chromatography tandem mass spectrometry (LC-MS/MS) can be used for sensitive characterization in cryopreserved urine samples. These data offer an important historical benchmark to which urinary levels from current and future biomonitoring studies can be compared.
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http://dx.doi.org/10.1186/s12940-019-0474-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503538PMC
May 2019

The Ramazzini Institute 13-week pilot study glyphosate-based herbicides administered at human-equivalent dose to Sprague Dawley rats: effects on development and endocrine system.

Environ Health 2019 03 12;18(1):15. Epub 2019 Mar 12.

Cesare Maltoni Cancer Research Center (CMCRC), Ramazzini Institute (RI), Via Saliceto, 3, 40010, Bentivoglio, Bologna, Italy.

Background: Glyphosate-based herbicides (GBHs) are broad-spectrum herbicides that act on the shikimate pathway in bacteria, fungi, and plants. The possible effects of GBHs on human health are the subject of an intense public debate for both its potential carcinogenic and non-carcinogenic effects, including potential effects on the endocrine system The present pilot study examine whether exposure to GBHs at the dose of glyphosate considered to be "safe" (the US Acceptable Daily Intake - ADI - of 1.75 mg/kg bw/day), starting from in utero life, affect the development and endocrine system across different life stages in Sprague Dawley (SD) rats.

Methods: Glyphosate alone and Roundup Bioflow, a commercial brand of GBHs, were administered in drinking water at 1.75 mg/kg bw/day to F0 dams starting from the gestational day (GD) 6 (in utero) up to postnatal day (PND) 120. After weaning, offspring were randomly distributed in two cohorts: 8 M + 8F/group animals belonging to the 6-week cohort were sacrificed after puberty at PND 73 ± 2; 10 M + 10F/group animals belonging to the 13-week cohort were sacrificed at adulthood at PND 125 ± 2. Effects of glyphosate or Roundup exposure were assessed on developmental landmarks and sexual characteristics of pups.

Results: In pups, anogenital distance (AGD) at PND 4 was statistically significantly increased both in Roundup-treated males and females and in glyphosate-treated males. Age at first estrous (FE) was significantly delayed in the Roundup-exposed group and serum testosterone concentration significantly increased in Roundup-treated female offspring from the 13-week cohort compared to control animals. A statistically significant increase in plasma TSH concentration was observed in glyphosate-treated males compared with control animals as well as a statistically significant decrease in DHT and increase in BDNF in Roundup-treated males. Hormonal status imbalances were more pronounced in Roundup-treated rats after prolonged exposure.

Conclusions: The present pilot study demonstrate that GBHs exposure, from prenatal period to adulthood, induced endocrine effects and altered reproductive developmental parameters in male and female SD rats. In particular, it was associated with androgen-like effects, including a statistically significant increase of AGDs in both males and females, delay of FE and increased testosterone in female.
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http://dx.doi.org/10.1186/s12940-019-0453-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413565PMC
March 2019

WHO/ILO work-related burden of disease and injury: Protocol for systematic reviews of occupational exposure to dusts and/or fibres and of the effect of occupational exposure to dusts and/or fibres on pneumoconiosis.

Environ Int 2018 10 27;119:174-185. Epub 2018 Jun 27.

Radboud Institute for Health Sciences, Radboudumc, Nijmegen, the Netherlands. Electronic address:

Background: The World Health Organization (WHO) and the International Labour Organization (ILO) are developing a joint methodology for estimating the national and global work-related burden of disease and injury (WHO/ILO joint methodology), with contributions from a large network of experts. In this paper, we present the protocol for two systematic reviews of parameters for estimating the number of deaths and disability-adjusted life years attributable to pneumoconiosis from occupational exposure to dusts and/or fibres, to inform the development of the WHO/ILO joint methodology.

Objectives: We aim to systematically review studies on occupational exposure to dusts and/or fibres (Systematic Review 1) and systematically review and meta-analyse estimates of the effect of occupational exposure to dusts and/or fibres on pneumoconiosis (Systematic Review 2), applying the Navigation Guide systematic review methodology as an organizing framework.

Data Sources: Separately for Systematic Reviews 1 and 2, we will search electronic academic databases for potentially relevant records from published and unpublished studies, including Medline, EMBASE, Web of Science and CISDOC. We will also search electronic grey literature databases, Internet search engines and organizational websites; hand-search reference list of previous systematic reviews and included study records; and consult additional experts.

Study Eligibility And Criteria: We will include working-age (≥15 years) study participants in the formal and informal economy in any WHO and/or ILO Member State but exclude children (<15 years) and unpaid domestic workers. Eligible risk factors will be dusts and/or fibres from: (i) asbestos; (ii) silica; and/or (iii) coal (defined as pure coal dust and/or dust from coal mining). Included outcomes will be (i) asbestosis; (ii) silicosis; (iii) coal worker pneumoconiosis; and (iv) unspecified pneumoconiosis. For Systematic Review 1, we will include quantitative prevalence studies of occupational exposure to dusts and/or fibres (i.e. no versus any exposure) stratified by country, sex, age and industrial sector or occupation. For Systematic Review 2, we will include randomized controlled trials, cohort studies, case-control studies and other non-randomized intervention studies with an estimate of any occupational exposure to dusts and/or fibres on the prevalence of, incidence of or mortality due to pneumoconiosis, compared with the theoretical minimum risk exposure level of no exposure.

Study Appraisal And Synthesis Methods: At least two review authors will independently screen titles and abstracts against the eligibility criteria at a first stage and full texts of potentially eligible records at a second stage, followed by extraction of data from qualifying studies. At least two review authors will assess risk of bias and the quality of evidence, using the most suited tools currently available. For Systematic Review 2, if feasible, we will combine relative risks using meta-analysis. We will report results using the guidelines for accurate and transparent health estimates reporting (GATHER) for Systematic Review 1 and the preferred reporting items for systematic reviews and meta-analyses guidelines (PRISMA) for Systematic Review 2.

Prospero Registration Number: CRD42018084131.
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http://dx.doi.org/10.1016/j.envint.2018.06.005DOI Listing
October 2018

The Ramazzini Institute 13-week pilot study on glyphosate and Roundup administered at human-equivalent dose to Sprague Dawley rats: effects on the microbiome.

Environ Health 2018 05 29;17(1):50. Epub 2018 May 29.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1428 Madison, New York, NY, 10029, USA.

Background: Glyphosate-based herbicides (GBHs) are broad-spectrum herbicides that act on the shikimate pathway in bacteria, fungi, and plants. The possible effects of GBHs on human health are the subject of an intense public debate for both its potential carcinogenic and non-carcinogenic effects, including its effects on microbiome. The present pilot study examines whether exposure to GBHs at doses of glyphosate considered to be "safe" (the US Acceptable Daily Intake - ADI - of 1.75 mg/kg bw/day), starting from in utero, may modify the composition of gut microbiome in Sprague Dawley (SD) rats.

Methods: Glyphosate alone and Roundup, a commercial brand of GBHs, were administered in drinking water at doses comparable to the US glyphosate ADI (1.75 mg/kg bw/day) to F0 dams starting from the gestational day (GD) 6 up to postnatal day (PND) 125. Animal feces were collected at multiple time points from both F0 dams and F1 pups. The gut microbiota of 433 fecal samples were profiled at V3-V4 region of 16S ribosomal RNA gene and further taxonomically assigned and assessed for diversity analysis. We tested the effect of exposure on overall microbiome diversity using PERMANOVA and on individual taxa by LEfSe analysis.

Results: Microbiome profiling revealed that low-dose exposure to Roundup and glyphosate resulted in significant and distinctive changes in overall bacterial composition in F1 pups only. Specifically, at PND31, corresponding to pre-pubertal age in humans, relative abundance for Bacteriodetes (Prevotella) was increased while the Firmicutes (Lactobacillus) was reduced in both Roundup and glyphosate exposed F1 pups compared to controls.

Conclusions: This study provides initial evidence that exposures to commonly used GBHs, at doses considered safe, are capable of modifying the gut microbiota in early development, particularly before the onset of puberty. These findings warrant future studies on potential health effects of GBHs in early development such as childhood.
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http://dx.doi.org/10.1186/s12940-018-0394-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5972442PMC
May 2018

The Ramazzini Institute 13-week study on glyphosate-based herbicides at human-equivalent dose in Sprague Dawley rats: study design and first in-life endpoints evaluation.

Environ Health 2018 05 29;17(1):52. Epub 2018 May 29.

Cesare Maltoni Cancer Research Center (CMCRC), Ramazzini Institute (RI), Via Saliceto, 3, 40010 Bentivoglio, Bologna, Italy.

Background: Glyphosate-based herbicides (GBHs) are the most widely used pesticides worldwide, and glyphosate is the active ingredient of such herbicides, including the formulation known as Roundup. The massive and increasing use of GBHs results in not only the global burden of occupational exposures, but also increased exposure to the general population. The current pilot study represents the first phase of a long-term investigation of GBHs that we are conducting over the next 5 years. In this paper, we present the study design, the first evaluation of in vivo parameters and the determination of glyphosate and its major metabolite aminomethylphosphonic acid (AMPA) in urine.

Methods: We exposed Sprague-Dawley (SD) rats orally via drinking water to a dose of glyphosate equivalent to the United States Acceptable Daily Intake (US ADI) of 1.75 mg/kg bw/day, defined as the chronic Reference Dose (cRfD) determined by the US EPA, starting from prenatal life, i.e. gestational day (GD) 6 of their mothers. One cohort was continuously dosed until sexual maturity (6-week cohort) and another cohort was continuously dosed until adulthood (13-week cohort). Here we present data on general toxicity and urinary concentrations of glyphosate and its major metabolite AMPA.

Results: Survival, body weight, food and water consumption of the animals were not affected by the treatment with either glyphosate or Roundup. The concentration of both glyphosate and AMPA detected in the urine of SD rats treated with glyphosate were comparable to that observed in animals treated with Roundup, with an increase in relation to the duration of treatment. The majority of glyphosate was excreted unchanged. Urinary levels of the parent compound, glyphosate, were around 100-fold higher than the level of its metabolite, AMPA.

Conclusions: Glyphosate concentrations in urine showed that most part of the administered dose was excreted as unchanged parent compound upon glyphosate and Roundup exposure, with an increasing pattern of glyphosate excreted in urine in relation to the duration of treatment. The adjuvants and the other substances present in Roundup did not seem to exert a major effect on the absorption and excretion of glyphosate. Our results demonstrate that urinary glyphosate is a more relevant marker of exposure than AMPA in the rodent model.
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http://dx.doi.org/10.1186/s12940-018-0393-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5972408PMC
May 2018

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

Environ Health 2016 10 12;15(1):97. Epub 2016 Oct 12.

Department of Environmental and Occupational Health, Milken Institute School of Public Health, The George Washington University, 950 New Hampshire Ave. NW, 4th Floor, Washington, DC, 20052, USA.

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.
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http://dx.doi.org/10.1186/s12940-016-0180-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5059969PMC
October 2016

Relationship between Research Outcomes and Risk of Bias, Study Sponsorship, and Author Financial Conflicts of Interest in Reviews of the Effects of Artificially Sweetened Beverages on Weight Outcomes: A Systematic Review of Reviews.

PLoS One 2016 8;11(9):e0162198. Epub 2016 Sep 8.

Charles Perkins Centre and Faculty of Pharmacy, University of Sydney, Sydney, New South Wales, Australia.

Background: Artificially sweetened beverage consumption has steadily increased in the last 40 years. Several reviews examining the effects of artificially sweetened beverages on weight outcomes have discrepancies in their results and conclusions.

Objectives: To determine whether risk of bias, results, and conclusions of reviews of effects of artificially sweetened beverage consumption on weight outcomes differ depending on review sponsorship and authors' financial conflicts of interest.

Methods: We performed a systematic review of reviews of the effects of artificially sweetened beverages on weight. Two assessors independently screened articles for inclusion, extracted data, and assessed risks of bias. We compared risk of bias, results and conclusions of reviews by different industry sponsors, authors' financial conflict of interest and journal sponsor. We also report the concordance between review results and conclusions.

Results: Artificial sweetener industry sponsored reviews were more likely to have favorable results (3/4) than non-industry sponsored reviews (1/23), RR: 17.25 (95% CI: 2.34 to 127.29), as well as favorable conclusions (4/4 vs. 15/23), RR: 1.52 (95% CI: 1.14 to 2.06). All reviews funded by competitor industries reported unfavorable conclusions (4/4). In 42% of the reviews (13/31), authors' financial conflicts of interest were not disclosed. Reviews performed by authors that had a financial conflict of interest with the food industry (disclosed in the article or not) were more likely to have favorable conclusions (18/22) than reviews performed by authors without conflicts of interest (4/9), RR: 7.36 (95% CI: 1.15 to 47.22). Risk of bias was similar and high in most of the reviews.

Conclusions: Review sponsorship and authors' financial conflicts of interest introduced bias affecting the outcomes of reviews of artificially sweetened beverage effects on weight that could not be explained by other sources of bias.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0162198PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5015869PMC
August 2017

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

Environ Health Perspect 2017 03 22;125(3):289-295. Epub 2016 Jul 22.

Cesare Maltoni Cancer Research Center, Ramazzini Institute, Bentivoglio, Bologna, Italy.

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.
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http://dx.doi.org/10.1289/EHP419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5332192PMC
March 2017

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

Environ Int 2016 Jul-Aug;92-93:611-6. Epub 2016 Jan 27.

Department of Clinical Epidemiology & Biostatistics, McMaster University, Health Sciences Centre, Room 2C14, 1280 Main Street West, Hamilton, ON L8S 4K1, Canada; Department of Medicine, McMaster University, Health Sciences Centre, Room 2C14, 1280 Main Street West, Hamilton, ON L8S 4K1, Canada. Electronic address:

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.
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http://dx.doi.org/10.1016/j.envint.2016.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4902742PMC
January 2018
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