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.

Should we screen aging physicians for cognitive decline?

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

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.

The application of PBPK models in estimating human brain tissue manganese concentrations.

Mn is an essential element that causes neurotoxicity in humans when inhaled at high concentrations. This metal has well-recognized route-dependent differences in absorption, with greater proportionate uptake for inhalation versus dietary exposure. Physiologically-based pharmacokinetic (PBPK) models for Mn have included these route specific differences in uptake and their effect on delivery of Mn to target tissues via systemic circulation. These PBPK models include components describing ingestion and inhalation, homeostatic control (concentration dependent biliary elimination and gastrointestinal absorption), and delivery to target sites within the brain. The objective of this study was to combine PBPK modeling of target tissue Mn concentration and categorical regression analysis to identify Mn intake levels (both by food and air) that are expected to cause minimal toxicity. We first used the human PBPK model to describe blood Mn data from three occupational exposure studies, demonstrating consistency between model predictions and measured data. The PBPK model was then used to predict concentrations of Mn in the globus pallidus (the presumed target tissue for motor function disruption in humans) for various epidemiological studies. With the predicted globus pallidus concentration of Mn, we conducted categorical regression modeling between globus pallidus Mn and severity-scored neurological outcome data from the human cohorts. This structured tissue dose - response analysis led to an estimated 10% extra risk concentration (ERC10) of 0.55µg/g Mn in the globus pallidus, which is comparable to similar values estimated by the Agency of Toxic Substances and Disease Registry and Health Canada (after translation from external exposure to tissue dose). The steep dose-response curve below this ERC10 value may be used to inform the choice of adjustment factor to translate the ERC10 as a point of departure to a reference concentration for occupational or environmental exposure to Mn. Because these results are based on human epidemiological data and a human PBPK model, adjustment or translation of results from animals to humans is not required.

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.

Database of radiogenic cancer in experimental animals exposed to low doses of ionizing radiation.

For decades, there have been debates regarding the nature of the relationship between exposure to low doses of ionizing radiation and cancer risk. Under the linear no-threshold hypothesis, which serves as a theoretical basis for current radiation protection standards, the risk of cancer at low levels of exposure is presumed to be directly proportional to dose. Opponents of this hypothesis claim that there are threshold doses for radiation carcinogenesis, or even a reduction in cancer risk at low doses (a phenomenon referred to as "radiation hormesis"). Epidemiological, animal, molecular, and cellular studies were conducted to resolve this controversy, although each of these study types has its strengths and limitations. Although the results of animal experiments are not directly applicable to humans, data can substantially add to our knowledge on the form of relationship between radiation dose and cancer risk in a wide range of doses. Laboratory animals are a homogeneous population with little biological variability; animal experiments are conducted under controlled conditions with good estimates of radiation doses. In order to address the question of whether or not the dose-response curve for radiation carcinogens is linear at low doses, a comprehensive database of animal carcinogenesis experiments was assembled involving exposure to different types of ionizing gradation. The database includes virtually all publicly accessible data on the induction of radiogenic cancer in laboratory mammals. This review provides a descriptive overview of the experiments included in the database, along with a qualitative assessment of the shape of the dose-response relationship for radiation carcinogenesis at low doses in experimental animals.

A meta-analysis of evidence for hormesis in animal radiation carcinogenesis, including a discussion of potential pitfalls in statistical analyses to detect hormesis.

A database containing 800 datasets on the incidence of specific tumor types from 262 radiation carcinogenicity experiments identified in a comprehensive literature search through September 2000 was analyzed for evidence of hormesis. This database includes lifetime studies of tumorigenic responses in mice, rats, and dogs to exposures to alpha, beta, gamma, neutron, or x-ray radiation. A J-shaped dose response, in the form of a significant decreased response at some low dose followed by a significant increased response at a higher dose, was found in only four datasets from three experiments. Three of these datasets involved the same control animals and two also shared dosed animals; the J shape in the fourth dataset appeared to be the result of an outlier within an otherwise monotonic dose response. A meta-analysis was conducted to determine whether there was an excess of dose groups with decreases in tumor response below that in controls at doses below no-observed-effect levels (NOELs) in individual datasets. Because the probability of a decreased response is generally not equal to the probability of an increased response even in the null case, the meta-analysis focused on comparing the number of statistically significant diminished responses to the number expected, assuming no dose effect below the NOEL. Only 54 dose groups out of the total of 2579 in the database had doses below the dataset-specific NOEL and that satisfied an a priori criterion for sufficient power to detect a reduced response. Among these 54, a liberal criterion for defining a significant decreases identified 15 such decreases, versus 54 × 0.2 = 10.8 expected. The excess in significant reductions was accounted for almost entirely by the excess from neutron experiments (10 observed, 6.2 expected). Nine of these 10 dose groups involved only 2 distinct control groups, and 2 pairs from the 10 even shared dosed animals. Given this high degree of overlap, this small excess did not appear remarkable, although the overlap prevented a formal statistical analysis. A comprehensive post hoc evaluation using a range of NOEL definitions and alternative ways of restricting the data entering the analysis did not produce materially different results. A second meta-analysis found that, in every possible low dose range ([0, d] for every dose, d) of each of the radiation types, the number of dose groups with significantly increased tumorigenic responses was either close to or exceeded the number showing significantly reduced responses. This meta-analysis was considered to be the more definitive one. Not only did it take dose into account by looking for consistent evidence of hormesis throughout defined low-dose ranges, it was also potentially less susceptible to limitations in experimental protocols that would cause individual animals to respond in a non-independent fashion. Overall, this study found little evidence in a comprehensive animal radiation database to support the hormesis hypothesis. However, the ability of the database to detect a hormetic effect was limited both by the small number of dose groups with doses below the range where positive effects have been found in epidemiological studies (≤ 0.1 Gy) and by the limited power of many of these dose groups for detecting a decrease in response.

Health outcomes of low-dose ionizing radiation exposure among medical workers: a cohort study of the Canadian national dose registry of radiation workers.

BACKGROUND: Medical workers can be exposed to low-dose ionizing radiation from various sources. The potential cancer risks associated with ionizing radiation exposure have been derived from cohort studies of Japanese atomic bomb survivors who had experienced acute, high-level exposure. Since such extrapolations are subject to uncertainty, direct information is needed on the risk associated with chronic low-dose occupational exposure to ionizing radiation. OBJECTIVES: To determine the occupational doses of ionizing radiation and examine possible associations with mortality rates and cancer incidence in a cohort of medical workers deriving from the National Dose Registry of Canada (NDR) over the period of 1951-1987. METHODS: Standardized mortality and incidence ratios (SMR and SIR, respectively) were ascertained by linking NDR data for a cohort of 67 562 medical workers (23 580 males and 43 982 females) with the data maintained by the Canadian Mortality, and Cancer Incidence databases. Dosimetry information was obtained from the National Dosimetry Services. RESULTS: During the follow-up period, 1309 incident cases of cancer (509 in males, 800 in females) and 1325 deaths (823 in males, 502 in females) were observed. Mortality from cancer and non-cancer causes was generally below expected as compared to the general Canadian population. Thyroid cancer incidence was significantly elevated both among males and females, with a combined SIR of 1.74 and 90% CI: 1.40-2.10. CONCLUSIONS: The findings confirm previous reports on an increased risk of the thyroid cancer among medical workers occupationally exposed to ionizing radiation. Over the last 50 years, radiation protection measures have been effective in reducing radiation exposures of medical workers to the current very low levels.

Low dose ionizing radiation exposure and cardiovascular disease mortality: cohort study based on Canadian national dose registry of radiation workers.

OBJECTIVES: The purpose of our study was to assess the risk of cardiovascular disease (CVD) mortality in a Canadian cohort of 337 397 individuals (169 256 men and 168 141 women) occupationally exposed to ionizing radiation and included in the National Dose Registry (NDR) of Canada. MATERIAL AND METHODS: Exposure to high doses of ionizing radiation, such as those received during radiotherapy, leads to increased risk of cardiovascular diseases. The emerging evidence of excess risk of CVDs after exposure to doses well below those previously considered as safe warrants epidemiological studies of populations exposed to low levels of ionizing radiation. In the present study, the cohort consisted of employees at nuclear power stations (nuclear workers) as well as medical, dental and industrial workers. The mean whole body radiation dose was 8.6 mSv for men and 1.2 mSv for women. RESULTS: During the study period (1951-1995), as many as 3 533 deaths from cardiovascular diseases have been identified (3 018 among men and 515 among women). In the cohort, CVD mortality was significantly lower than in the general population of Canada. The cohort showed a significant dose response both among men and women. Risk estimates of CVD mortality in the NDR cohort, when expressed as excess relative risk per unit dose, were higher than those in most other occupational cohorts and higher than in the studies of Japanese atomic bomb survivors. CONCLUSIONS: The study has demonstrated a strong positive association between radiation dose and the risk of CVD mortality. Caution needs to be exercised when interpreting these results, due to the potential bias introduced by dosimetry uncertainties, the possible record linkage errors, and especially by the lack of adjustment for non-radiation risk factors.

Lung, liver and bone cancer mortality in Mayak workers.

Workers at the Mayak nuclear facility in the Russian Federation offer the only adequate human data for evaluating cancer risks from exposure to plutonium. Risks of mortality from cancers of the lung, liver and bone, the organs receiving the largest doses from plutonium, were evaluated in a cohort of 17,740 workers initially hired 1948-1972 using, for the first time, recently improved individual organ dose estimates. Excess relative risk (ERR) models were used to evaluate risks as functions of internal (plutonium) dose, external (primarily gamma) dose, gender, attained age and smoking. By December 31, 2003, 681 lung cancer deaths, 75 liver cancer deaths and 30 bone cancer deaths had occurred. Of these 786 deaths, 239 (30%) were attributed to plutonium exposure. Significant plutonium dose-response relationships (p < 0.001) were observed for all 3 endpoints, with lung and liver cancer risks reasonably described by linear functions. At attained age 60, the ERRs per Gy for lung cancer were 7.1 for males and 15 for females; the averaged-attained age ERRs for liver cancer were 2.6 and 29 for males and females, respectively; those for bone cancer were 0.76 and 3.4. This study is the first to present and compare dose-response analyses for cancers of all 3 organs. The unique Mayak cohort with its high exposures and well characterized doses has allowed quantification of the plutonium dose-response for lung, liver and bone cancer risks based on direct human data. These results will play an important role in plutonium risk assessment.

Canadian National Dose Registry of radiation workers: overview of research from 1951 through 2007.

The National Dose Registry (NDR) of Canada is a unique resource for a direct estimation of the potential health risks associated with low doses of ionizing radiation. This is the largest national occupational radiation exposure database, comprising records for about 600,000 nuclear, industrial, medical and dental workers. An analysis of the NDR data based on a cohort of about 200,000 workers first exposed before 1984 and followed through 1987 and 1988 for mortality and cancer incidence, respectively, revealed that the mortality from most causes of death considered was lower than that in the general population, which is typical of occupational cohorts. Although the same was also observed for cancer incidence, there was a significant increase in the incidence of thyroid cancer and melanoma which, however, was not clearly related to radiation exposure. A significant dose-response was found for mortality from all causes, all cancers, lung cancer, cardiovascular diseases, accidents, for incidence of all cancers, cancers of the rectum and lung, leukaemia, all cancers except lung, and all cancers except leukaemia. In addition, in male workers, a significant dose-response was found for the incidence of colon, pancreatic, and testicular cancers. The estimates of cancer risks (mortality and incidence) were higher than those in most other occupational cohorts and in the studies on atomic bomb survivors. The biologically based dose-response models used to describe lung cancer incidence in the NDR showed that for a protracted exposure to low radiation doses there was a significant radiation effect on the promotion and malignant conversion, but not on the initiation stage of carcinogenesis. This stands in contrast to the findings for high-dose acute exposures in A-bomb survivors, where the initiation and possibly promotion were found to be affected by radiation exposure. Evidence of an inverse dose-rate effect (i.e. an increase in the risk with a protraction of a given cumulative dose) was found in the NDR cohort.