Human Health Risk Assessment for Inhaled Manganese - Results of Public Consultation: Major Comments and Responses

This content was archived on June 24, 2013.

Manganese is an essential nutrient, but at sufficiently high levels of exposure it can affect human health, including the functioning of the central nervous system. Health Canada published a draft science assessment document entitled Human Health Risk Assessment for Inhaled Manganese on April 19^th, 2008 for public comment. In response to the public consultation on the draft manganese risk assessment document, Health Canada received comments from interested parties.

Major comments and responses to them are summarized in the document below. In addition, the final science assessment document for inhaled manganese addresses the submitted comments as appropriate. The final version of Human Health Risk Assessment for Inhaled Manganese is now available upon request from the following website: healthcanada.gc.ca/air. This document provides a detailed technical review of the science of the health effects of manganese, and includes a new health-based reference concentration for manganese in air.

Major Comments and Responses

Response:

Health Canada is unable to disclose the dataset of Dr. Lucchini and colleagues as this was provided on condition that we treat it as confidential. However, the risk assessment document includes a section (Appendix A: Summary Data from Lucchini et al.[1999]) that provides a data summary of the variables from the Lucchini et al. study. This is consistent with publishing practices relating to scientific documents. In addition, the risk assessment document includes a section (7.4 An alternative analysis of the Lucchini et al. (1999) dataset) which presents an analysis of only the information presented in the published paper (Lucchini et al., 1999). The results of this analysis support the more detailed analysis presented in the risk assessment document that makes use of the original dataset.

Response:

While recognizing that the recent developments in PBPK modeling of manganese are important and informative, the science is not appropriate at this point in time for establishing a health-based reference concentration for inhaled manganese. A validated, peer-reviewed human inhalation PBPK model for manganese parameterized for the various subgroups of concern is not available at this time.

Response:

The Health Canada risk assessment document is based on a review of approximately 400 scientific articles. This material was thoroughly reviewed and employed in a weight-of-evidence approach to provide substantial support for the manganese risk derivation from toxicokinetics research, animal toxicology and human studies, as described in the risk assessment document.

The Lucchini et al. (1999) study was selected for a variety of factors: it considered an extensive battery of relevant neurofunctional outcomes; it included data on a large number of potential confounders; exposure was well characterized and included historical monitoring data; and respirable manganese was assessed. The published study provided evidence of subtle changes in motor function, memory, cognitive function and tremor at concentrations lower than those affecting outcomes in Roels et al. (1992). In addition, the workers had been exposed for longer and were older than in the Roels et al. (1992) study, both relevant considerations in examining the neurotoxicity of manganese. The primary disadvantage of the Lucchini et al. (1999) study was the relatively small sample size, which can limit the ability to detect significant differences due to reduced statistical power. That a large number of significant, biologically plausible models were identified in the Health Canada risk assessment, in spite of the small sample size, further supports the quality of this dataset.

The dataset from the Roels et al. (1992) study has been used by international regulatory agencies in the derivation of a health-based reference concentration for inhaled manganese, including the WHO (2000), the US EPA (1993, 1994), ATSDR (2000, 2008), the California EPA (2008) and Health Canada (1994). The Roels et al. (1992) study is a very well done study, consisting of 92 workers from a dry alkaline battery plant and 101 controls. However, the Roels et al. (1992) dataset has certain limitations. Although personal monitoring data were available for each worker, these were collected only at the time of testing, and no historical monitoring data were available. There were no substantial changes to the plant in the previous 15 years and therefore manganese levels were assumed to have remained constant in individual job categories. In addition, the average duration of exposure was relatively short (5.3±3.5 years) and resulted in the use of an uncertainty factor to account for sub-chronic exposure in both the US EPA (1993, 1994) and Health Canada (1994) risk analyses. The average age of the workers was quite young (31.3±7.4 years) compared to the Lucchini et al. workers (42.1±8.3 years), and there is substantial evidence that older individuals are more susceptible to the neurofunctional deficits elicited by manganese exposure. Regarding confounders, the dataset provided by Roels et al. contains individual data for age but not for other potential confounders. In addition, the Roels et al. dataset was provided as the presence or absence of abnormal scores on neurofunctional tests. This discretization of scores and subsequent use of these data in benchmark concentration analysis results in some loss of information regarding the dose-response relationship.

Based on an extensive review of the literature, Health Canada has selected the Lucchini et al. study for the basis of quantitative risk assessment. Further details have been incorporated into the final risk assessment document Section 6.1 (Choice of a Critical Study) highlighting the evidence for selection as the critical study. A section (6.9. Supporting Studies) has also been included which documents evidence from other studies regarding the health endpoints considered in the risk assessment and the results of benchmark concentration analyses of the Roels et al. (1992) dataset by other jurisdictions.

Response:

As discussed in the risk assessment (Section 7.3 Derivation of a reference concentration for inhaled manganese in Canada) there is evidence for both the accumulation of manganese in the brain under conditions of chronic exposure, and for the fact that manganese is cleared from the brain over a time frame of months to years. The Health Canada analysis found that ARE5 is a more sensitive indicator of the critical manganese exposure as 10 health endpoints were significantly associated with exposure measured as ARE5, whereas only three endpoints were associated with exposure measured as ARE. There remains the possibility that this may be due to less accurate historical monitoring data, but this cannot be ascertained at this time, and text stating this has been added to Section 7.3. It should be noted that although other manganese risk assessments have considered work history average exposure to manganese, these were based on the Roels et al. (1992) dataset in which the arithmetic mean duration of exposure was only 5.3 years, i.e. not dissimilar to ARE5 used in the Health Canada analysis. In addition, the WHO (2000) derived an air quality guideline for manganese based on current exposure using the Roels et al. (1992) dataset, which produced similar results to those using the work history average.

Response:

The size fraction of particulate matter refers to the mass median aerodynamic diameter of the particles in the sample, and is determined by the sampling equipment used.

The size fraction collected for the respirable samples in the Lucchini et al. (1999) study were PM_3.5. This is consistent with the definition of respirable aerosols employed by occupational hygienists. There is no information as to how this size fraction relates to PM_2.5 or PM₁₀ for aerosols or manganese in the occupational setting in question.

Stationary environmental monitoring of particulate matter in Canada (and elsewhere) is conducted for the PM_2.5 and PM₁₀ size fractions. Similarly, population exposure studies such as those reported in the risk assessment document generally assess exposures in the PM_2.5 or PM₁₀ size fractions. There is little information relating these size fractions with the PM_3.5 size fraction in ambient Canadian data or in exposure studies, and it is reasonable to believe that any relationship (PM_3.5:PM_2.5 or PM_3.5:PM₁₀) would vary both spatially and temporally depending on source influences and other factors.

The reference concentration presented in the final risk assessment document refers to manganese in the PM_3.5 size fraction.

References

• ATSDR (Agency for Toxic Substances and Disease Registry). 2000. "Toxicological Profile for Manganese (Update)."
• ATSDR (Agency for Toxic Substances and Disease Registry). 2008. "Draft Toxicological Profile for Manganese. " http://www.atsdr.cdc.gov/toxprofiles/tp151.html
• California EPA (Environmental Protection Agency). 2008 Manganese and Compounds Reference Exposure Levels. http://www.oehha.ca.gov/air/hot_spots/2008/AppendixD1_final.pdf#page=170
• Health Canada. 1994. "Risk Assessment for the Combustion Products of Methylcyclopentadienyl Manganese Tricarbonyl (MMT) in Gasoline."
• Lucchini, R., P. Apostoli, C. Perrone, D. Placidi, E. Albini, P. Migliorati, D. Mergler, M. P. Sassine, S. Palmi, and L. Alessio. 1999. Long-term exposure to "low levels" of manganese oxides and neurofunctional changes in ferroalloy workers. Neurotoxicology 20, no. 2-3: 287-97.
• Roels, H. A., P. Ghyselen, J. P. Buchet, E. Ceulemans, and R. R. Lauwerys. 1992. Assessment of the permissible exposure level to manganese in workers exposed to manganese dioxide dust. Br J Ind Med 49, no. 1: 25-34.
• U.S. EPA (United States Environmental Protection Agency) . 1993. "Reference Concentration for Chronic Inhalation Exposure: Manganese. IRIS Database." http://www.epa.gov/iris/subst/0373.htm#refinhal
• U.S. EPA (United States Environmental Protection Agency). 1994. "Reevaluation of Inhalation Health Risks Associated with Methylcyclopentadienyl Manganese Tricarbonyl (MMT) in Gasoline. EPA 600/R-94/062."
• WHO (World Health Organization). 2001. Manganese. Air Quality Guidelines. 2^nd Ed. WHO Regional Office for Europe.