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Essentiality, Toxicity and Uncertainty in the Risk Assessment of Manganese
Citation:
BOYES, W. K. Essentiality, Toxicity and Uncertainty in the Risk Assessment of Manganese . JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. Taylor & Francis, Inc., Philadelphia, PA, 73(2):159-165, (2010).
Impact/Purpose:
The contents of this document summarize remarks to a workshop on Health Risk Assessment of Essential Metals held May 6-7, 2008 at the University of Ottawa. The overall objective of the workshop was to discuss issues regarding the risk assessment of three elements that are essential nutrients at low doses, but become toxic at high doses, namely cooper, zinc and manganese. The comments in this document refer only to data on manganese collected in response to a test rule under Clean Air Act section 211(b) dealing with combustion of fuels with a manganese-containing fuel additive. The essence of the document is that the test rule data will enable physiologically based pharmacokinetic models of manganese to be developed for use in future risk assessments of manganese, and thereby account for manganese mass balance and target tissue contributions across oral and inhalation routes of exposure. In addition, a proposal from Dr. Mel Anderson (Hamner Institute) is described briefly in which he suggests control of manganese exposures so that brain manganese concentration would not be exceeded beyond some normal range of variation. This would reflect a novel approach to manganese risk assessment.
Description:
Risk assessments of manganese by inhalation or oral routes of exposure typically acknowledge the duality of manganese as an essential element at low doses and a toxic metal at high doses. Previously, however, risk assessors were unable to describe manganese pharmacokinetics quantitatively across dose levels and routes of exposure, to account for mass balance, and to incorporate this information into a quantitative risk assessment. In addition, the prior risk assessment of inhaled manganese conducted by the U.S. Environmental Protection Agency (EPA) identified a number of specific factors that contributed to uncertainty in the risk assessment. In response to a petition regarding the use of a fuel additive containing manganese, methylcyclopentadienyl manganese tricarbonyl (MMT), the U.S. EPA developed a test rule under the U.S. Clean Air Act that required, among other things, the generation of pharmacokinetic information. This information was intended not only to aid in the design of health outcome studies, but also to help address uncertainties in the risk assessment of manganese. To date, the work conducted in response to the test rule has yielded substantial pharmacokinetic data. This information will enable the generation of physiologically based pharmacokinetic (PBPK) models capable of making quantitative predictions of tissue manganese concentrations following inhalation and oral exposure, across dose levels, and accounting for factors such as duration of exposure, different species of manganese, and changes of age, gender, and reproductive status. The work accomplished in response to the test rule, in combination with other scientific evidence, will enable future manganese risk assessments to consider tissue dosimetry more comprehensively than was previously possible.
