Manganese Neurotoxicity: Applying Epidemiological Results to the General Population.

Expert Meeting, Dec. 5 and 6, 2002
Report Summary¹

Table of Contents

• Background
• Health Canada staff in attendance
• Discussions - Part 1 - (Questions 1 and 2)
• Discussions - Part 2 - (Questions 3,4,5,6 and 7)

Background

Due to the substantial body of new information on manganese that had become available since its 1994 risk assessment², Health Canada began preparations in 2002 to revisit the risk assessment, beginning with preparation of a review of all recent epidemiological literature. Health Canada then hosted a meeting of experts in manganese neurotoxicity in order to determine the state of scientific knowledge on several issues directly relevant to risk assessment, and to seek guidance on how to interpret the primarily occupational results (mostly from young healthy adult males) in terms of the implications for the general population (which includes the very young, the elderly and other subpopulations of varying degrees of sensitivity).

A reference concentration for airborne manganese of 0.11 mg/m³ was established by Health Canada in 1994, and current risk assessment activities will result in confirming that guideline or developing a new one. Panel members were asked for their input on the significance of the health endpoints, and on additional qualitative evidence available to support any quantitative risk assessment. They were also asked to consider other points, including the enhanced sensitivity of various subpopulations, and what exposure metric(s) and time frame would provide optimum protection from the health effects of manganese.

Expert panel members were selected to provide a broad range of expertise, including neurology, medical epidemiology, occupational hygiene, research toxicology, and risk assessment. The expert panel consisted of:

Harry Roels, Université catholique de Louvain, Belgium. Occupational hygienist and epidemiological researcher, working for many years assessing workers exposed to manganese and other industrial chemicals. His neurological testing work on Belgian battery plant workers was used for risk assessment purposes by four agencies, including Health Canada, the United States Environmental Protection Agency (US EPA), and the World Health Organization (WHO), as well as two private U.S. companies.

Donna Mergler, Université de Québec à Montréal. Primary interest in neurotoxicity related to environmental pollutants, and principal investigator of both an occupational and a general population study of manganese neurotoxicity in/near an industrial plant near Montreal. Her experience with the effects of manganese in the general population was of particular interest to the discussions.

Roberto Lucchini, University of Brescia, Italy. Medical epidemiologist; principal investigator in several recent epidemiological investigations of workers in a ferromanganese alloy plant in northern Italy, as well as current involvement in a study of inhabitants of a valley with high industrial emissions of manganese, with respect to the prevalence of parkinsonism.

Oksana Suchowersky, University of Calgary. Clinical neurologist, with expertise in movement disorders. She does both clinical and research work on Parkinson's Disease and other related disorders. Her perspective on the gradient from severe parkinsonian symptoms to the subclinical effects of manganese was sought by other meeting participants.

David Bellinger, Children's Hospital, Boston. Neurologist and epidemiologist; principal investigator in a key longitudinal study on the effects of prenatal lead exposure on subsequent mental development in children. He has also written about the interpretation of small health deficits at the individual level, their implications for the population as a whole, and their integration into risk assessment.

Mike Davis, US EPA, Office of Research and Development. Risk assessor, lead author for the U.S. EPA 1994 health risk assessment of inhaled manganese, and prepared the background document for the WHO European air quality guideline for manganese.

Grace Wood, retired, formerly Health Canada, Environmental Health Directorate. Co-author of the 1994 risk assessment and author of the newer epidemiological review sent to meeting participants. Responsible for fuel issues at Health Canada, including both lead and manganese, from 1985 to 1998.

Health Canada staff in attendance were:

Barry Jessiman, meeting Chairman. Health Canada, Head, Air and Fuel Risk Assessment Section, with overall responsibility for development of risk assessments for various air pollutants.

Marika Egyed, Health Canada, Air and Fuel Risk Assessment Section, working on fuel issues, co-author of the 1994 manganese health risk assessment, currently working on manganese.

Mike Inskip, Health Canada, Environment and Occupational Toxicology Division. Experimental toxicologist; has worked extensively in research on other neurotoxicants, specifically lead and methyl mercury in primates.

Jill Kearney, Health Canada, Air Health Effects Division. Involved in exposure assessment science, in both risk assessment and research projects. She is conducting research on characterizing particulate matter (PM) in a city with large industrial sources of manganese and in another large urban centre.

Wayne Bowers, Health Canada, Environment and Occupational Toxicology Division. Experimental toxicologist, involved with neurological research dealing with pesticides, PCBs and mercury.

Mike Walker, Health Canada, Biostatistics Division. Involved in many quantitative risk assessments done within the Environmental Contaminants Bureau of Health Canada.

Expert Meeting, Dec. 5 and 6, 2002
Report Summary¹

Discussions - Part 1 - (Questions 1 and 2)

Participants were provided with a recent review of the epidemiological literature and with a series of questions for their consideration before the meeting. The questions acted as a framework for discussion at the meeting, and are reproduced at the beginning of the summary of each discussion. There was broad general consensus on all major and some minor questions and a summary of the discussion of the questions is reported below.

Question 1a:

Manganese inhalation exposure in occupational settings has been associated with reduced performance on standardized neurofunctional tests. These performance reductions represent the most sensitive health endpoints, with regard to manganese toxicity, that have been quantitatively assessed by scientific study.

• What is the significance of these subclinical changes in terms of general population health?
• Should these outcomes be considered adverse?
• What percentile of control populations exhibit "abnormal" scores for these subclinical outcomes?
• Can these subclinical effects be considered predictive of clinical outcomes?

It was noted that the subtle neurofunctional changes observed in worker cohorts are biomarkers of effect. The degree of adversity of the subtle subclinical neurofunctional changes observed in workers exposed to manganese was discussed with respect to whether these subclinical outcomes need to be predictive of future clinical outcomes (eg. parkinsonism) in order to be considered adverse.

It was agreed that it is not possible to predict a progression from subclinical to clinical effects for any one individual, since the predominant factors in response are individual sensitivity and variability. More long-term longitudinal and follow-up studies are required in order to better assess the link between subclinical and clinical effects at the individual level.

The best working hypothesis regarding the significance of these effects with regard to degree of adversity was considered to be that of a "continuum of effects". High manganese exposure (eg. miners, foundry workers) can lead to clinical symptoms of manganism in individuals, irreversible and often progressive after removal from exposure. Moderate exposure (occupational, ferromanganese plants, etc) is associated with subclinical signs such as reduced ability in tests of fine motor skills, usually visible only in the group as a whole and not in the individual. These occupational outcomes have been well documented. It is hypothesized that low level environmental exposures are associated with subtle changes in motor and cognitive function of the same type as seen in the occupational studies, visible at the group level only. There are preliminary indications in the literature to support this.

The key to the significance of this continuum of effects from clinical parkinsonism down to subtle signs of dysfunction is the coherence of the results in the scientific literature and the consistency of the effects profile for inhaled manganese within and across the different studies, despite the lack of evidence for a direct link at the individual level between subclinical and clinical effects.

For the purposes of risk assessment, participants were in agreement that the subclinical effects of manganese should be considered as adverse outcomes at the community or population level. The key factor is not whether these subclinical signs are directly predictive of clinical outcomes, but rather the implications for a diminished well-being of the population as a whole. In risk assessment, which is aimed at the entire population, scores are generally considered adverse or abnormal if they are within the worst 5% of scores in a control population. For an exposed population, the distribution of scores may shift downwards, resulting in more than 5% of scores being "adverse". Outcomes which can result in a significant impact on the population as a whole should be viewed in the same way as the small changes in children's I.Q. due to lead exposure, which are not noticeable at the level of the individual child, but which would have a profound societal effect by shifting the bell curve of IQ scores downward in the whole population. It is possible that exposure to airborne manganese could result in a downward shift in the general population distribution of fine motor skills and possibly cognitive function. These effects could therefore be associated with a loss of well-being in a substantial portion of the population.

There is only limited evidence to date suggesting a link between manganese inhalation exposure and neurofunctional deficits at the level of exposure experienced by the general population. Validation and characterization of this dose-response in the general population is a critical area for future manganese research. It was noted that the subclinical effects of manganese have been considered adverse by several different regulatory agencies in the past, including Health Canada (1994 risk assessment), the US EPA, and the World Health Organization (Air Quality Guidelines for Europe).

Questions 1b and 2:

If these subclinical effects can be considered predictive of clinical outcomes, would the early neurotoxic insult exacerbate the normal neuro-aging later in life? What are the potential impacts of manganese neurotoxicity on the neurofunctional capacity of an aging population?

Excess blood manganese concentrations had a disproportionately stronger effect on motor function and cognition in middle-aged and older adults than on younger people in the general population study. Meeting participants were unanimous in their concern over a potential shift in the population distribution of abilities such that a greatly increased number of older people in the population as a whole would function less well than they would have done in the absence of manganese exposure, and some might become unable to carry out their daily routines and/or require increased medications. The resultant changes in quality of life should not be underestimated. These early effects should also be viewed as flags pointing to a potential for adverse effects in the future, particularly for fine motor skills.

While everyone is subject to some age-related loss of neurons in the brain, the consistency of effects observed in the epidemiological studies provides an indication that excess inhaled manganese is an agent responsible for additional loss of dopaminergic neurons, thus accelerating the decline. The effect of this increased rate of loss, particularly in older individuals and those with a genetic predisposition to parkinsonism may be to reach a minimum functional neuronal capacity earlier in life. The cost implications to society of an acceleration of just 1/10 of 1% in the loss of dopaminergic neurons have recently been calculated to be high (B. Weiss, for U.S. EPA), based on the substantial lowering of the age at which a threshold for clinical effects might be seen, and the greatly increased number of people who would be affected.

Expert Meeting, Dec. 5 and 6, 2002
Report Summary¹

Discussions Part 2 - (Questions 3,4,5,6 and 7)

Question 3a:

Specific subpopulations have been identified as being especially sensitive to the neurotoxic effects of manganese, due to their biology. These include: 1) older individuals; 2) the very young; 3) individuals predisposed to Parkinson's Disease; 4) individuals with anemia; 5) individuals with liver disease; 6) gender-based differences in sensitivity; and 7) other sensitive subpopulations. How sensitive are these subpopulations relative to the general population?

1) Middle-aged and older individuals have been shown to be a high-risk group, as discussed under questions 1b and 2 above.

2) Infants and children: Several participants, including the clinical neurologist, pointed out the extremely important fact that the neurobehavioral responses of children to manganese are largely unquantified; moreover, childrens' responses may be qualitatively different from those of adults. In utero and neonatal exposure are of particular concern due to the complete lack in these age groups of homeostatic mechanisms for the clearance of manganese from the body. The effect of manganese on developing brain cells is unknown. Studies on the impacts of lead in infants and young children should be used as a first step to direct research on the neurological effects of manganese on this group, in which brain development is still occurring. Participants agreed that studies on effects of airborne manganese on brain development and cognition in children are badly needed to fill this information gap. Although technically difficult and expensive to run, they are a viable possibility and can be done well if sufficient resources are made available. Some preliminary work has been done on uptake of inhaled manganese in prenatal and neonatal exposure. In view of these unknowns, a conservative approach to uncertainty factors was recommended for infants and children.

3) Parkinson's Disease (PD): Manganism is a parkinsonian disorder clinically distinguishable from PD. Both genetic and environmental factors are operative in PD, and most probably also in manganism. The current hypothesis is that manganese inhalation exposure may affect people with some genetic/physiological predisposition to parkinsonian disturbances, who are at risk of developing symptoms. There is limited evidence that the onset of parkinsonism is hastened by a number of years in this predisposed group by exposure to inhaled manganese. This observation is in concordance with the hypothesis that manganese exposure can increase the rate of neuron destruction in the brains of older persons. Attention should also be paid to other neurodegenerative diseases, such as Multi-System Atrophy and Progressive Supranuclear Palsy which are clinically more similar to manganism than PD is.

4 and 5) Individuals with anemia and those with liver disease are considered to have predisposing factors for increased risk due to increased uptake of manganese in anemia, and decreased ability of the liver to get rid of excess manganese in those with liver disease.

6) Gender-based differences in sensitivity to manganese have always been a concern because most studies have focused on relatively young adult males. The issue is complicated by the fact that women's reactions to manganese intake differ with age, with pregnant women and women in general between ages 20 and 35 having higher levels of blood manganese than men in the same community and age group. However despite this, (non-pregnant) women in the general population study appeared to be less sensitive than men to the disruptive effects of manganese on neurobehavioral function.

7) Genetic differences with respect to the alpha-synuclein protein or enzymes that act on this protein were suggested as a possibly fruitful area for further research. Alpha-synuclein forms tangles called Lewy bodies in PD patients and those with related neurodegenerative diseases, but it is unknown if this protein is implicated in the subclinical effects of manganese or manganism. Research has suggested that alpha-synuclein-induced pathology could be caused by environmental agents such as mercury and certain pesticides, but no investigations have been undertaken with manganese.

Question 3b:

Recent scientific research has identified several potential activity-related factors that may interact with manganese exposure to affect performance on neurofunctional tests. These include 1): smoking, and 2): alcohol consumption. How strong is the evidence? Are there any other such factors?

1) Evidence is weak for a combined effect of smoking and manganese exposure. Results have been equivocal with both increased effects and protective effects reported in different, apparently equally valid studies.

2) In most studies, alcohol effects have been treated as confounders and factored out. In the Montreal population study and in a new analysis of the occupationally exposed workers in the same region, manganese was reported to accentuate adverse mental health effects (mood) associated with a tendency toward alcoholism as well as with excessive alcohol use.

3) It was suggested that people who have undergone coronary artery bypass grafting should be examined for increased susceptibility to the effects of manganese. This operation is known to result in some cases in damage to the basal ganglia, especially the globus pallidus, which is also the target organ for manganese toxicity. To date, this has not been investigated

Question 4:

There is some evidence that certain negative health outcomes associated with manganese exposure may be reversible once the exposure is terminated. What is the weight of evidence for or against this reversibility? Is there evidence that certain categories of neurofunctional health outcomes are reversible while other are not? What is the role of exposure in the reversibility of effects?

The panel agreed that there was sufficient evidence from the literature that no reversibility (improvement in symptoms) occurrs if the original exposures have been high enough to elicit frank manganism, and in people who had suffered very high exposures, symptoms continued to worsen for years after removal from exposure. However there appears to be an earlier subclinical stage during which, if manganese exposure ceases or is removed from the body by chelation, reversibility of some symptoms may be possible. In the newer occupational studies under consideration here, only subclinical effects were noted and exposures were much lower than those in which clinical manganism resulted. Up to 8 years of follow-up is now available for some of these studies, during which time airborne manganese decreased for some groups, or stayed the same for other groups. While there was no progression of adverse effects, scores for most tests remained the same, and partial or complete recovery occurred for only one (motor control) of three test endpoints in one cohort of workers. Workers who had been least exposed recovered completely in terms of subclinical deficits, while medium and highly exposed subjects showed some improvement. Thus reversibility might be considered a function of both the endpoint and the exposure. However, until these results are confirmed by other studies, the weight of evidence for reversibility remains limited.

Questions 5 and 6:

What parameters could be monitored in the general population to reflect manganese exposure or adverse health effects?
In terms of the health outcomes, what is the relative importance of the various manganese inhalation exposure measures, including, but not limited to: short-term vs. chronic exposures, cumulative vs. recent exposures, and past vs. recent exposures?
Based on what we know regarding manganese toxicity, what manganese exposure metric is the most appropriate?
How could exposure peaks be taken into consideration?
Should chemical characterization of manganese be included in exposure measurements?

While blood manganese has been successfully used as the marker of exposure for examining health effects of manganese in the only relevant population study to date, it has not been found to correlate well with manganese in air, even in most of the occupational studies, in which air manganese levels were several orders of magnitude greater than ambient levels. It is therefore unsuitable for deriving air quality guidelines and deciding on risk management options. Blood manganese is under tight homeostatic control, and reflects exposure from all sources including diet. It is considered more a measure of body burden.

Until recently, lifetime accumulation was thought to be the best overall metric for manganese, but it has become clear from recent work (including a lack of correlation between cumulative exposures and scores on neurobehavioural tests, and return of some scores to normal after current exposure was reduced, although cumulative exposure continued to rise) that a shorter time frame may be more appropriate. Meeting participants were in agreement that manganese, unlike lead, cadmium or mercury, is an essential element and does not bioaccumulate throughout life. Clearance takes place over several months to several years, rather than decades, supporting an intermediate term for exposure. Although current exposure has provided robust correlation coefficients with health outcomes in some studies, most participants agreed that a somewhat longer time frame would be more conservative and appropriate. The best approach would be to develop a range of reference concentrations based on a series of variables.

Particle size is of critical importance with regard to the uptake and toxicity of airborne manganese. Most of the European studies have been conducted using a particulate matter sampler giving 5 microns mass median diameter (PM₅) with an absolute cutoff of 7 microns. Total particulate manganese (including particles much larger than 10 microns) was also measured, since occupational standards are expressed in this metric. Since larger particles do not reach the lung, they are not toxicologically relevant in a non-occupational general population setting. The Canadian ambient monitoring network measures PM_2.5 and PM₁₀. Although based on a study with PM₅ as its exposure metric, the 1994 guideline was expressed in terms of PM₁₀, as being more conservative and more protective of general population health. The consensus was that this approach should be continued. In addition, this would give an allowance for an as yet unquantified risk from direct olfactory uptake of manganese.

Although participants agreed that the solubility of manganese compounds influences the rapidity with which the manganese is delivered to the target organ, the manganese particulate that the general population is exposed to has not been characterized. The epidemiological studies have mostly dealt with insoluble oxides while tailpipe emissions and soil-derived particles are a mixture of oxides and more soluble salts. While the oxides are taken up and cleared from the body more slowly than the more soluble salts, both can reach the target organ and both will eventually be cleared, given enough time. Although the oxides are believed to be slightly more toxic, most participants felt that the toxicity of these different species was not sufficiently different to be of concern, especially under chronic or longer-term conditions. A clearer understanding was called for, particularly of the species emitted from the tailpipe and of their eventual depositional form.

Exposure conditions where peaks might occur, such as for parking garages, subway stops, rush-hour traffic, and mechanics working in closed garages, were discussed but no conclusions were reached as to how to deal with them. Very little is available in the epidemiological or toxicological literature to give guidance. In industrial settings, an upper value based on a 15 minute exposure is used.

Question 7:

Although neurofunctional endpoints appear to be the most sensitive thus far based on the literature, what directions should be pursued with regard to other health effects, specifically reproductive and respiratory outcomes?

In the occupational setting the two target organs are the brain and the lung. It was suggested that more extensive tests might reveal more data about low-level pulmonary effects. Information is lacking about reproductive effects in women; effects of manganese exposure on prolactin levels were suggested as a starting point. Cardiovascular effects, specifically ECG effects, bradycardia, tachycardia, arrhythmia, and blood pressure effects, were suggested for investigation, and abstracts of two Chinese papers made available. It was pointed out that it would be very difficult to separate out the effects of manganese from those of particulate matter, which is known to have a wide range of cardiovascular and cardiopulmonary effects. Olfactory uptake studies on primates are also required for more understanding of the role that this route plays in delivery of manganese to the critical part of the brain involved in manganese toxicity.