Marissa G. Baker

Blood Manganese as an Exposure Biomarker: State of the Evidence

Despite evidence of adverse health effects resulting from exposure to manganese (Mn), biomarkers of exposure are poorly understood. To enhance understanding, mean blood Mn (MnB) and mean air Mn (MnA) were extracted from 63 exposure groups in 24 published papers, and the relationship was modeled using segmented regression. On a log/log scale, a positive association between MnA and MnB was observed among studies reporting MnA concentrations above about 10 μg/m3, although interpretation is limited by largely cross-sectional data, study design variability, and differences in exposure monitoring methods. Based on the results of the segmented regression, we hypothesize that below the concentration of about 10 μg/m3, Mn in the body is dominated by dietary Mn, and additional inhaled Mn only causes negligible changes in Mn levels unless the inhaled amount is substantial. However, stronger study designs are required to account for temporal characteristics of the MnA to MnB relationships that reflect the underlying physiology and toxicokinetics of Mn uptake and distribution. Thus, we present an inception cohort study design we have conducted among apprentice welders, and the analytical strengths this study design offers. To determine if blood could be a useful biomarker for Mn to be utilized by industrial hygienists in general industry requires additional time-specific analyses, which our inception cohort study design will allow.

Neurological outcomes associated with low-level manganese exposure in an inception cohort of asymptomatic welding trainees

OBJECTIVE Long-term, high-level exposure to manganese (Mn) is associated with impaired central nervous system (CNS) function. We quantitatively explored relations between low-level Mn exposure and selected neurological outcomes in a longitudinal inception cohort of asymptomatic welder trainees. METHODS Welders with no previous occupational Mn exposure were observed approximately every three months over the course of the five-quarter traineeship. Fifty-six welders were assessed for motor function using the Unified Parkinson Disease Rating Scale motor subsection part 3 (UPDRS3) and Grooved Pegboard tests. A subset of 17 also had MRI scans to assess T1-weighted indices. Personal exposure to Mn in welding fume was quantitatively assessed during the study period using a mixed model to obtain estimates of subject-specific exposure level by welding type. These estimates were summed to estimate cumulative exposure at the time of each neurological outcome test. RESULTS When adjusting for possible learning effects, there were no associations between cumulative exposure and UPDRS3 score or Grooved Pegboard time. T1-weighted indices of the basal ganglia (caudate, anterior putamen, posterior putamen, and combined basal ganglia, but not the pallidal index) exhibited statistically significant increases in signal intensity in relation to increased cumulative Mn exposure. CONCLUSIONS This study demonstrates that T1-weighted changes can be detected in the brain even at very low levels of exposure among humans before any clinically evident deficits. This suggests that with continued follow-up we could identify a T1 threshold of toxicity at which clinical symptoms begin to manifest.

Variance components of short-term biomarkers of manganese exposure in an inception cohort of welding trainees

Various biomarkers of exposure have been explored as a way to quantitatively estimate an internal dose of manganese (Mn) exposure, but given the tight regulation of Mn in the body, inter-individual variability in baseline Mn levels, and variability in timing between exposure and uptake into various biological tissues, identification of a valuable and useful biomarker for Mn exposure has been elusive. Thus, a mixed model estimating variance components using restricted maximum likelihood was used to assess the within- and between-subject variance components in whole blood, plasma, and urine (MnB, MnP, and MnU, respectively) in a group of nine newly-exposed apprentice welders, on whom baseline and subsequent longitudinal samples were taken over a three month period. In MnB, the majority of variance was found to be between subjects (94%), while in MnP and MnU the majority of variance was found to be within subjects (79% and 99%, respectively), even when controlling for timing of sample. While blood seemed to exhibit a homeostatic control of Mn, plasma and urine, with the majority of the variance within subjects, did not. Results presented here demonstrate the importance of repeat measure or longitudinal study designs when assessing biomarkers of Mn, and the spurious associations that could result from cross-sectional analyses.

Creating a Future for Occupational Health

Objectives: Economic, social, technical, and political drivers are fundamentally changing the nature of work and work environments, with profound implications for the field of occupational health. Nevertheless, researchers and practitioners entering the field are largely being trained to assess and control exposures using approaches developed under old models of work and risks. Methods: A speaker series and symposium were organized to broadly explore current challenges and future directions for the occupational health field. Broad themes identified throughout these discussions are characterized and discussed to highlight important future directions of occupational health. Findings: Despite the relatively diverse group of presenters and topics addressed, some important cross‐cutting themes emerged. Changes in work organization and the resulting insecurity and precarious employment arrangements change the nature of risk to a large fraction of the workforce. Workforce demographics are changing, and economic disparities among working groups are growing. Globalization exacerbates the ‘race to the bottom’ for cheap labor, poor regulatory oversight, and limited labor rights. Largely, as a result of these phenomena, the historical distinction between work and non‐work exposures has become largely artificial and less useful in understanding risks and developing effective public health intervention models. Additional changes related to climate change, governmental and regulatory limitations, and inadequate surveillance systems challenge and frustrate occupational health progress, while new biomedical and information technologies expand the opportunities for understanding and intervening to improve worker health. Conclusion: The ideas and evidences discussed during this project suggest that occupational health training, professional practice, and research evolve towards a more holistic, public health‐oriented model of worker health. This will require engagement with a wide network of stakeholders. Research and training portfolios need to be broadened to better align with the current realities of work and health and to prepare practitioners for the changing array of occupational health challenges.

Hair Manganese as an Exposure Biomarker among Welders

Quantifying exposure and dose to manganese (Mn) containing airborne particles in welding fume presents many challenges. Common biological markers such as Mn in blood or Mn in urine have not proven to be practical biomarkers even in studies where positive associations were observed. However, hair Mn (MnH) as a biomarker has the advantage over blood and urine that it is less influenced by short-term variability of Mn exposure levels because of its slow growth rate. The objective of this study was to determine whether hair can be used as a biomarker for welders exposed to manganese. Hair samples (1cm) were collected from 47 welding school students and individual air Mn (MnA) exposures were measured for each subject. MnA levels for all days were estimated with a linear mixed model using welding type as a predictor. A 30-day time-weighted average MnA (MnA30d) exposure level was calculated for each hair sample. The association between MnH and MnA30d levels was then assessed. A linear relationship was observed between log-transformed MnA30d and log-transformed MnH. Doubling MnA30d exposure levels yields a 20% (95% confidence interval: 11-29%) increase in MnH. The association was similar for hair washed following two different wash procedures designed to remove external contamination. Hair shows promise as a biomarker for inhaled Mn exposure given the presence of a significant linear association between MnH and MnA30d levels.

0290 Investigating the reproducibility of metabolomics profiles of washington state metal workers

Manganese (Mn) is a known neurotoxicant, and given its health effects and ubiquitous nature in metal-working settings, identification of a valid and reproducible biomarker of exposure is of interest. Global metabolomics were previously utilised to determine metabolites that differ between occupational groups defined by Mn exposure status, in hopes of informing a biomarker of exposure. Nine metabolites were found to differ between exposure groups in urine samples collected October 2014. To test the reproducibility of these metabolites, these nine metabolites were investigated in a second set of urine samples collected January 2015 from the same workers. Levels of the nine metabolites found in October 2014 were compared to the January 2015 data using principal components analysis and descriptive measures. Also, an elastic net regression was fit using the nine metabolites from the October 2014 data; this model was tested in the January 2015 data. Four of the nine ions remained significantly different between exposed and unexposed workers in the January data, though levels of most ions also exhibited regression to the mean. The elastic net model was able to correctly classify exposure status in 66% of the January samples; slightly better than classification by chance alone. Metabolomics is a novel technique for exposure assessment, but few studies have looked at the reproducibility of metabolomics data by collecting repeat samples from the same workers. This analysis found several ions that do seem to remain stable over time, and identification of these ions should be pursued as potential biomarkers of Mn exposure.