Diagnosis of manganism and manganese neurotoxicity: A workshop report.

With declining exposures to manganese (Mn) in occupational settings, there is a need for more sensitive exposure assessments and clinical diagnostic criteria for manganism and Mn neurotoxicity. To address this issue, a workshop was held on November 12-13, 2020, with international experts on Mn toxicity. The workshop discussions focused on the history of the diagnostic criteria for manganism, including those developed by the Institut de Recherche Robert-Sauvé en Santé et en Sécurité du Travail (IRSST) in Quebec in 2005 and criteria developed by the Chinese government in 2002 and updated in 2006; the utility of biomarkers of exposure; recent developments in magnetic resonance imaging (MRI) for assessing Mn accumulation in the brain and diagnosing manganism; and potential future applications of metabolomics. The suggestions of the participants for updating manganism diagnostic criteria included the consideration of: i) A history of previous occupational and environmental exposure to Mn; ii) relevant clinical symptoms such as dystonia; iii) MRI imaging to document Mn accumulation in the neural tissues, including the basal ganglia; and iv) criteria for the differential diagnosis of manganism and other neurological conditions. Important research gaps include the characterization of Mn exposure and other co-exposures, exploration of the roles of different brain regions with MRI, understanding the complexity of metal ion transporters involved in Mn homeostasis, and a need for information on other neurotransmitter systems and brain regions underlying the pathophysiology of manganism.

Biomarkers of environmental manganese exposure.

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

Biomarkers for occupational manganese exposure.

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

The REACH registration process: A case study of metallic aluminium, aluminium oxide and aluminium hydroxide.

The European Union's REACH Regulation requires determination of potential health and environmental effects of chemicals in commerce. The present case study examines the application of REACH guidance for health hazard assessments of three high production volume (HPV) aluminium (Al) substances: metallic aluminium, aluminium oxide, and aluminium hydroxide. Among the potential adverse health consequences of aluminium exposure, neurotoxicity is one of the most sensitive targets of Al toxicity and the most critical endpoint. This case study illustrates integration of data from multiple lines of evidence into REACH weight of evidence evaluations. This case study then explains how those results support regulatory decisions on classification and labelling. Challenges in the REACH appraisal of Al compounds include speciation, solubility and bioavailability, application of assessment factors, read-across rationale and differences with existing regulatory standards. Lessons learned from the present case study relate to identification and evaluation of toxicologic and epidemiologic data; assessing data relevance and reliability; development of derived no-effect levels (DNELs); addressing data gaps and preparation of chemical safety reports.

Overview of REACH: Issues Involved in the Registration of Metals.

New European legislation known as REACH (Registration, Evaluation, Authorization and Restriction of Chemicals) was introduced in 2007 to increase the speed at which the health and/or environmental risks of industrial chemicals were being assessed and managed (REACH (EC) No 1907/2006). REACH consolidated earlier chemicals-control statutes and placed the burden of assessing, and identifying the means to manage risks on industry. This paper details the REACH process for controlling and managing hazardous chemicals and challenges encountered in applying the provisions of REACH and the guidance documents available from European Chemical Agency. Special attention is paid to challenges in evaluating potential health risks of metals such as aluminum and aluminum compounds. Lessons learned from over a decade of experience with REACH legislation are also noted.

Data on systematic review and meta-analysis of epidemiologic evidence on the association between perineal use of talc powder and risk of ovarian cancer.

This paper describes data from a systematic review and meta-analysis [1] conducted to identify and evaluate published peer reviewed evidence on the association between perineal use of talc powder and risk of ovarian cancer. These data were collected from multiple electronic bibliographic databases, as well as from grey literature sources, without applying time, language or other filters. A meta-analysis was conducted to quantitatively assess the ovarian cancer risk in relation to talc use and other potential risk factors.

Critical review of the association between perineal use of talc powder and risk of ovarian cancer.

Over the past four decades, there has been increasing concern that perineal use of talc powder, a commonly used personal care product, might be associated with an increased risk of ovarian cancer. OBJECTIVES: To critically review all available human epidemiological data on the relationship between perineal use of talc powder and ovarian cancer, with consideration of other relevant experimental evidence. METHODOLOGY: We identified 30 human studies for qualitative assessment of evidence, including 27 that were retained for further quantitative analysis. RESULTS: A positive association between perineal use of talc powder and ovarian cancer was found [OR: 1.28 (95% CI: 1.20-1.37)]. A significant risk was noted in Hispanics and Whites, in women applying talc to underwear, in pre-menopausal women and in post-menopausal women receiving hormonal therapy. A negative association was noted with tubal ligation. CONCLUSION: Perineal use of talc powder is a possible cause of human ovarian cancer.

Severity scoring of manganese health effects for categorical regression.

Characterizing the U-shaped exposure response relationship for manganese (Mn) is necessary for estimating the risk of adverse health from Mn toxicity due to excess or deficiency. Categorical regression has emerged as a powerful tool for exposure-response analysis because of its ability to synthesize relevant information across multiple studies and species into a single integrated analysis of all relevant data. This paper documents the development of a database on Mn toxicity designed to support the application of categorical regression techniques. Specifically, we describe (i) the conduct of a systematic search of the literature on Mn toxicity to gather data appropriate for dose-response assessment; (ii) the establishment of inclusion/exclusion criteria for data to be included in the categorical regression modeling database; (iii) the development of a categorical severity scoring matrix for Mn health effects to permit the inclusion of diverse health outcomes in a single categorical regression analysis using the severity score as the outcome variable; and (iv) the convening of an international expert panel to both review the severity scoring matrix and assign severity scores to health outcomes observed in studies (including case reports, epidemiological investigations, and in vivo experimental studies) selected for inclusion in the categorical regression database. Exposure information including route, concentration, duration, health endpoint(s), and characteristics of the exposed population was abstracted from included studies and stored in a computerized manganese database (MnDB), providing a comprehensive repository of exposure-response information with the ability to support categorical regression modeling of oral exposure data.

Modeling U-shaped dose-response curves for manganese using categorical regression.

INTRODUCTION: Manganese is an essential nutrient which can cause adverse effects if ingested to excess or in insufficient amounts, leading to a U-shaped exposure-response relationship. Methods have recently been developed to describe such relationships by simultaneously modeling the exposure-response curves for excess and deficiency. These methods incorporate information from studies with diverse adverse health outcomes within the same analysis by assigning severity scores to achieve a common response metric for exposure-response modeling. OBJECTIVE: We aimed to provide an estimate of the optimal dietary intake of manganese to balance adverse effects from deficient or excess intake. METHODS: We undertook a systematic review of the literature from 1930 to 2013 and extracted information on adverse effects from manganese deficiency and excess to create a database on manganese toxicity following oral exposure. Although data were available for seven different species, only the data from rats was sufficiently comprehensive to support analytical modelling. The toxicological outcomes were standardized on an 18-point severity scale, allowing for a common analysis of all available toxicological data. Logistic regression modelling was used to simultaneously estimate the exposure-response profile for dietary deficiency and excess for manganese and generate a U-shaped exposure-response curve for all outcomes. RESULTS: Data were available on the adverse effects of 6113 rats. The nadir of the U-shaped joint response curve occurred at a manganese intake of 2.70mg/kgbw/day with a 95% confidence interval of 2.51-3.02. The extremes of both deficient and excess intake were associated with a 90% probability of some measurable adverse event. CONCLUSION: The manganese database supports estimation of optimal intake based on combining information on adverse effects from systematic review of published experiments. There is a need for more studies on humans. Translation of our results from rats to humans will require adjustment for interspecies differences in sensitivity to manganese.

Systematic review of potential health risks posed by pharmaceutical, occupational and consumer exposures to metallic and nanoscale aluminum, aluminum oxides, aluminum hydroxide and its soluble salts.

Abstract Aluminum (Al) is a ubiquitous substance encountered both naturally (as the third most abundant element) and intentionally (used in water, foods, pharmaceuticals, and vaccines); it is also present in ambient and occupational airborne particulates. Existing data underscore the importance of Al physical and chemical forms in relation to its uptake, accumulation, and systemic bioavailability. The present review represents a systematic examination of the peer-reviewed literature on the adverse health effects of Al materials published since a previous critical evaluation compiled by Krewski et al. (2007) . Challenges encountered in carrying out the present review reflected the experimental use of different physical and chemical Al forms, different routes of administration, and different target organs in relation to the magnitude, frequency, and duration of exposure. Wide variations in diet can result in Al intakes that are often higher than the World Health Organization provisional tolerable weekly intake (PTWI), which is based on studies with Al citrate. Comparing daily dietary Al exposures on the basis of "total Al"assumes that gastrointestinal bioavailability for all dietary Al forms is equivalent to that for Al citrate, an approach that requires validation. Current occupational exposure limits (OELs) for identical Al substances vary as much as 15-fold. The toxicity of different Al forms depends in large measure on their physical behavior and relative solubility in water. The toxicity of soluble Al forms depends upon the delivered dose of Al(+3) to target tissues. Trivalent Al reacts with water to produce bidentate superoxide coordination spheres [Al(O2)(H2O4)(+2) and Al(H2O)6 (+3)] that after complexation with O2(•-), generate Al superoxides [Al(O2(•))](H2O5)](+2). Semireduced AlO2(•) radicals deplete mitochondrial Fe and promote generation of H2O2, O2 (•-) and OH(•). Thus, it is the Al(+3)-induced formation of oxygen radicals that accounts for the oxidative damage that leads to intrinsic apoptosis. In contrast, the toxicity of the insoluble Al oxides depends primarily on their behavior as particulates. Aluminum has been held responsible for human morbidity and mortality, but there is no consistent and convincing evidence to associate the Al found in food and drinking water at the doses and chemical forms presently consumed by people living in North America and Western Europe with increased risk for Alzheimer's disease (AD). Neither is there clear evidence to show use of Al-containing underarm antiperspirants or cosmetics increases the risk of AD or breast cancer. Metallic Al, its oxides, and common Al salts have not been shown to be either genotoxic or carcinogenic. Aluminum exposures during neonatal and pediatric parenteral nutrition (PN) can impair bone mineralization and delay neurological development. Adverse effects to vaccines with Al adjuvants have occurred; however, recent controlled trials found that the immunologic response to certain vaccines with Al adjuvants was no greater, and in some cases less than, that after identical vaccination without Al adjuvants. The scientific literature on the adverse health effects of Al is extensive. Health risk assessments for Al must take into account individual co-factors (e.g., age, renal function, diet, gastric pH). Conclusions from the current review point to the need for refinement of the PTWI, reduction of Al contamination in PN solutions, justification for routine addition of Al to vaccines, and harmonization of OELs for Al substances.

Pharmaco- and toxicokinetics of selected exogenous and endogenous estrogens: a review of the data and identification of knowledge gaps.

Chemicals with estrogenic activity are derived from many different natural and synthetic processes and products, including endogenous production (e.g., estradiol, conjugated estrogens), drugs (e.g., ethinyl estradiol, conjugated estrogens), plants used as foods (phytoestrogens such as genistein, daidzein, S-equol), and man-made chemicals (xenoestrogens such as bisphenol A). Human exposure to low doses of endogenous estrogens, estrogenic drugs, phytoestrogens, and xenoestrogens has the potential to improve health or disrupt normal endocrine activity, as well as impact the diverse systems with which estrogens interact, including the cardiovascular system, and lipid and carbohydrate metabolism. Mechanisms of action and diversity of adverse and non-adverse effects following human exposure to low doses of estrogen active chemicals (EACs, defined as chemicals which interact with an estrogen receptor [ER]) are poorly understood. This review summarizes our current understanding of the pharmacological action with a focus on pharmacokinetics (PK) and toxicokinetics (TK) of several representative EACs in both physiological and pathological processes. The goal of this review is to assess the current state-of-the-science on: (i) the potential for EACs to interfere with endocrine activity, (ii) factors which contribute to endocrine-related clinical outcomes, and (iii) existing knowledge gaps. While classical PK approaches (compartmental or non-compartmental) can be used to characterize absorption, distribution, metabolism, and elimination of EACs, many of the detailed pharmacological characteristics necessary to understand benefit-risk balance have not yet been clarified. Pharmacological complexities mirror the complexity of determining whether and under what conditions exposure to estrogens in drugs, foods or to xenoestrogenic chemicals are beneficial or harmful to human health.

Assessing and managing risks arising from exposure to endocrine-active chemicals.

Managing risks to human health and the environment produced by endocrine-active chemicals (EAC) is dependent on sound principles of risk assessment and risk management, which need to be adapted to address the uncertainties in the state of the science of EAC. Quantifying EAC hazard identification, mechanisms of action, and dose-response curves is complicated by a range of chemical structure/toxicology classes, receptors and receptor subtypes, and nonlinear dose-response curves with low-dose effects. Advances in risk science including toxicogenomics and quantitative structure-activity relationships (QSAR) along with a return to the biological process of hormesis are proposed to complement existing risk assessment strategies, including that of the Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC 1998). EAC represents a policy issue that has captured the public's fears and concerns about environmental health. This overview describes the process of EAC risk assessment and risk management in the context of traditional risk management frameworks, with emphasis on the National Research Council Framework (1983), taking into consideration the strategies for EAC management in Canada, the United States, and the European Union.

A psychosocial risk assessment and management framework to enhance response to CBRN terrorism threats and attacks.

Evidence in the disaster mental health literature indicates that psychosocial consequences of terrorism are a critical component of chemical, biological, radiological, and nuclear (CBRN) events, both at the clinical level and the normal behavioral and emotional levels. Planning for such psychosocial aspects should be an integral part of emergency preparedness. As Canada and other countries build the capacity to prevent, mitigate, and manage CBRN threats and events, it is important to recognize the range of social, psychological, emotional, spiritual, behavioral, and cognitive factors that may affect victims and their families, communities, children, the elderly, responders, decision makers, and others at all phases of terrorism, from threat to post-impact recovery. A structured process to assist CBRN emergency planners, decision makers, and responders in identifying psychosocial risks, vulnerable populations, resources, and interventions at various phases of a CBRN event to limit negative psychosocial impacts and promote resilience and adaptive responses is the essence of our psychosocial risk assessment and management (P-RAM) framework. This article presents the evidence base and conceptual underpinnings of the framework, the principles underlying its design, its key elements, and its use in the development of decision tools for responders, planners, decision makers, and the general public to better assess and manage psychosocial aspects of CBRN threats or attacks.