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.

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.

Evaluation of particulate matter emissions from manganese alloy production using life-cycle assessment.

Life-cycle assessments (LCAs) provide a wealth of industry data to assist in evaluating the environmental impacts of industrial processes and product supply chains. In this investigation, data from a recent LCA covering global manganese alloy production was used to evaluate sources of particulate matter (PM) emissions associated with the manganese alloy supply chain. The analysis is aimed at providing an empirical, industry-averaged breakdown of the contribution that processes and emissions controls have on total emissions, manganese releases and occupational exposure. The assessment shows that 66% of PM emissions associated with manganese production occur beyond manganese facilities. Direct or on-site emissions represent 34% of total PM and occur predominantly as disperse sources during mineral extraction and hauling, and as primary furnace emissions. The largest contribution of manganese-bearing PM at ground-level is associated with fugitive emissions from metal and slag tapping, casting, crushing and screening. The evaluation provides a high-level ranking of emissions by process area, to assist in identifying priority areas for industry-wide initiatives to reduce emissions and occupational exposure of manganese. The range of PM emission levels in industry indicate that further enhancements in PM emissions can be achieved by sharing of best practices in emissions controls, limiting furnace conditions which lead to by-passing of emissions controls and application of secondary emission controls to capture fugitive emissions during tapping and casting. The LCA approach to evaluating PM emissions underscores the important role that process optimization and resource efficiency have on reducing PM emissions throughout the manganese supply chain.

Setting evidence-based occupational exposure limits for manganese.

In 2004, a review by the Institute of Environment and Health (IEH) made recommendations on occupational exposure limits (OELs) for manganese and its inorganic compounds for inhalable and respirable fractions respectively. These OELs were based on a detailed comprehensive evaluation of all the scientific data available at that time. Since then, more published studies have become available and a number of occupational standard-setting committees (EU SCOEL, US ACGIH-TLV, and German MAK) have proposed OEL's for manganese and its inorganic compounds that are somewhat lower that those proposed in the 2004 review. Based on current understanding, the key toxicological and human health issues that are likely to influence a health-based recommendation relate to: neurotoxicology; reproductive and developmental toxicology; and mutagenicity/carcinogenicity. Of these, it is generally considered that neurotoxicity presents the most sensitive endpoint. As such, many of the studies that have been reported since the IEH review have sought to use those neurofunctional tests that appear to be particularly sensitive at identifying the subtle neurological changes thought to associate with manganese toxicity. These recent studies have, however, continued to be limited to a significant extent by reliance on cross-sectional designs and also by use of unreliable exposure estimation methods. Consequently the strength of the potential association between manganese exposure and these subtle subclinical cognitive or neuromotor changes is still poorly characterised and the relevance of these minor differences in terms of either their clinical or quality of life consequences remains unknown. Based upon the overall evidence, it is concluded that the 8-h time weighted averages (TWA) for respirable (0.05mg/m3 as Mn) and inhalable (0.2mg/m3 as Mn) fractions as recommended by the SCOEL in 2011 are the most methodologically-sound, as they are based on the best available studies, most suited to the development of health-based OELs for both respirable and inhalable fractions. The dose-response characterisation informed by the examined studies used can be considered to establish a true human NOAEL for all the neurofunctional endpoints examined within the selected studies.

Aquatic environmental risk assessment of manganese processing industries.

An environmental risk assessment (ERA) has been conducted for sites producing and processing manganese and its inorganic compounds, focussing on potential risks to freshwater. A site specific questionnaire was used to collect information. Sites fall into three broad categories: mining sites, refining sites, and sites producing chemicals and pigments. Waste disposal is principally carried out by the treatment of liquid wastes to separate solids for disposal off-site with a consented wastewater discharge, or disposal on-site using evaporation or settlement ponds in order to maintain the waste materials in a suitable manner following site closure. The main source of emissions from refining and alloying sites is from the treatment of emissions to air using wet scrubber air filters. There is also the potential for fugitive environmental emissions of manganese from stockpiles of raw material held on-site. Data provided from the questionnaires were both site-specific and also commercially sensitive. Therefore, this paper has undertaken the manganese exposure assessment, using a probabilistic approach to reflect the distribution of emissions of manganese and also to maintain the confidentiality of site specific data. An inverse correlation was observed between the total annual tonnage of manganese processed at the site and the emission factor, such that sites processing larger quantities resulted in lower emissions of manganese per tonne processed. The hazard assessment determined a Predicted No Effect Concentration (PNEC) for freshwater using a species sensitivity distribution approach, resulting in a freshwater PNEC of 0.075mgL-1 for soluble manganese. Based on the exposure data and the freshwater PNEC derived for this study, the distributions of risk characterisation ratios using the probabilistic approach indicates that two thirds of manganese processing sites would not be expected to pose a potential risk to the local aquatic environment due to wastewater emissions, although local risks are possible at some sites.

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.

A two-generation inhalation reproductive toxicity study upon the exposure to manganese chloride.

A number of published studies have suggested that high levels of exposure to manganese, especially those found in occupational settings, can adversely affect the reproductive system. The objective of this study was therefore to investigate if these findings can be replicated using the Sprague Dawley rat and, if so, to identify those parts of the reproductive system are more susceptible. Male and female rats were exposed to manganese dichloride (MnCl2) via inhalation at concentrations of 0 (air-control); 5, 10 and 20µg/L air over 10 weeks (F0) and over 11 weeks (F1) prior to mating, and then throughout mating, gestation and lactation until termination after the F1 and F2 generation had reached Day 21 of lactation respectively. Animals were monitored for clinical signs of toxicity and for effects on body weight, food consumption, effects on the entire reproductive system including maternal care. The offspring were monitored for survival and growth up to weaning. Blood samples were taken from all adult animals for bioanalytical of manganese analysis prior to dosing, prior to mating and prior to weaning/necropsy. There were no deaths related to treatment, though respiratory tract effects were observed in F0 animals in the mid and high dose animals. Body weight and food consumption were affected at high dose in both generation. There were no treatment-related effects on the oestrous cycles, mating performance, sexual maturity, fertility or duration of gestation or litter size, the sperm motility, count of morphology (sperm) or the ovary follicle scoring in either generation. The No Observed Effect Level (NOEL) for reproductive performance was considered to be the target dose level of 20µg/L. Based on these findings, manganese chloride could not be considered a reprotoxicant under these conditions of exposure. Therefore, soluble and insoluble forms of inorganic manganese compounds by extrapolation cannot be considered as reprotoxicants.