In vivo measurement of bone manganese and association with manual dexterity: A pilot study.

We used neutron activation analysis (NAA) to measure hand bone manganese (BnMn) in 19 adult males. Median BnMn was 0.89µg/g dry bone (interquartile range = 1.07). After adjustment for age and occupation, higher ln(BnMn) was significantly associated with lower manual dexterity based on the Purdue Pegboard assembly task: ß = -1.77, standard error = 0.79, p = 0.04. Due to the small sample size, these results should be interpreted cautiously. BnMn appears to be a promising biomarker, and should be further studied.

The association of bone and blood manganese with motor function in Chinese workers.

Manganese (Mn) is an essential element. However, Mn overexposure is associated with motor dysfunction. This cross-sectional study assessed the association between bone Mn (BnMn) and whole blood Mn (BMn) with motor function in 59 Chinese workers. BnMn and BMn were measured using a transportable in vivo neutron activation analysis system and inductively coupled plasma mass spectrometry, respectively. Motor function (manual coordination, postural sway, postural hand tremor, and fine motor function) was assessed using the Coordination Ability Test System (CATSYS) and the Purdue Pegboard. Relationships between Mn biomarkers and motor test scores were analyzed with linear regression models adjusted for age, education, current employment, and current alcohol consumption. BMn was significantly inversely associated with hand tremor intensity (dominant hand (ß=-0.04, 95 % confidence interval (CI):-0.07, -0.01; non-dominant hand ß=-0.05, 95 % CI:-0.08, -0.01) hand tremor center frequency (non-dominant hand ß=-1.61, 95 % CI:-3.03, -0.19) and positively associated with the Purdue Pegboard Assembly Score (ß = 4.58, 95 % CI:1.08, 8.07). BnMn was significantly inversely associated with finger-tapping performance (non-dominant hand ß=-0.02, 95 % CI:-0.04,-0.004), mean sway (eyes closed and foam ß=-0.68, 95 % CI:-1.31,-0.04), and positively associated with hand tremor center frequency (dominant hand, ß = 0.40, 95 % CI:0.002, 0.80). These results suggest BMn is related to better postural hand tremor and fine motor control and BnMn is related to worse motor coordination and postural hand tremor but better (i.e., less) postural sway. The unexpected positive results might be explained by choice of biomarker or confounding by work-related motor activities. Larger, longitudinal studies in this area are recommended.

Endpoint in ovarian cancer xenograft model predicted by nighttime motion metrics.

Despite several therapeutics showing promise in nonclinical studies, survival from ovarian cancer remains poor. New technologies are urgently needed to optimize the translation of nonclinical studies into clinical successes. While most nonclinical settings utilize subjective measures of physiological parameters, which can hamper the accuracy of the results, this study assessed the physical activity of mice in real time using an objective, non-invasive, cloud-based, digital vivarium monitoring platform. An initial range-finding study in which varying numbers of ovarian cancer cells were inoculated in mice was conducted to characterize disease progression using digital metrics such as motion and breathing rate. Data from the range-finding study were used to establish a motion threshold (MT) that might predict terminal endpoint. Using the MT, the efficacies of cisplatin and OS2966, an anti-CD29 antibody, were assessed. Results showed that MT predicted terminal endpoint significantly earlier than traditional parameters and correlated with therapeutic efficacy. Thus, continuous motion monitoring sensitively predicts terminal endpoint in nonclinical ovarian cancer models and could be applicable for drug efficacy testing.

Characterization of bone aluminum, a potential biomarker of cumulative exposure, within an occupational population from Zunyi, China.

OBJECTIVES: Aluminum (Al) is a neurotoxicant; however, efforts to understand Al toxicity are limited by the lack of a quantitative biomarker of cumulative exposure. Bone Al measurements may address this need. Here, we describe and compare non-invasive bone Al measurements with fingernail Al and Al cumulative exposure indices (CEIs). METHODS: We completed a cross-sectional study of 43 factory workers in Zunyi, China. Bone Al measurements were taken with a compact in-vivo neutron activation analysis system (IVNAA). Fingernail samples were analyzed using inductively coupled plasma mass spectrometry. CEIs, based on self-reported work history and prior literature, were calculated for the prior 5, 10, 15, 20 years and lifetime work history. Linear regressions adjusted for age and education compared fingernail Al and Al CEIs with bone Al. RESULTS: Median (interquartile range (IQR)) Al measurements were: 15 µg/g dry bone (IQR = 28) for bone Al; 34.9 µg/g (43.3) for fingernail; and 24 (20) for lifetime CEI. In adjusted regression models, an increase in 15-year CEI was significantly associated with increased bone Al (ß = 0.91, 95% confidence interval (CI): 0.16, 1.66). Associations of bone Al with 10- and 20-year CEI were approaching statistical significance (ß = 0.98, 95% CI: -0.14, 2.1; ß = 0.59, 95% CI: -0.01, 1.18, respectively). Other models were not statistically significant. CONCLUSIONS: Bone Al was significantly associated with 15-year Al CEI, but not other Al CEIs or fingernail Al. Bone Al may be a useful measure of cumulative, rather than short-term, Al exposure. Additional refinement of this method is ongoing.

The association of bone, fingernail and blood manganese with cognitive and olfactory function in Chinese workers.

Occupational manganese (Mn) exposure has been associated with cognitive and olfactory dysfunction; however, few studies have incorporated cumulative biomarkers of Mn exposure such as bone Mn (BnMn). Our goal was to assess the cross-sectional association between BnMn, blood Mn (BMn), and fingernail Mn (FMn) with cognitive and olfactory function among Mn-exposed workers. A transportable in vivo neutron activation analysis (IVNAA) system was designed and utilized to assess BnMn among 60 Chinese workers. BMn and FMn were measured using inductively coupled plasma mass spectrometry. Cognitive and olfactory function was assessed using Animal and Fruit Naming tests, World Health Organization/University of California-Los Angeles Auditory Verbal Learning Test (AVLT) and the University of Pennsylvania Smell Identification Test (UPSIT). Additional data were obtained via questionnaire. Regression models adjusted for age, education, factory of employment, and smoking status (UPSIT only), were used to assess the relationship between Mn biomarkers and test scores. In adjusted models, increasing BnMn was significantly associated with decreased performance on average AVLT scores [ß (95% confidence interval (CI)) = -0.65 (-1.21, -0.09)] and Animal Naming scores [ß (95% CI) = -1.54 (-3.00, -0.07)]. Increasing FMn was significantly associated with reduced performance measured by the average AVLT [ß (95% CI) = -0.35 (-0.70, -0.006)] and the difference in AVLT scores [ß (95% CI) = -0.40 (-0.77, -0.03)]. BMn was not significantly associated with any test scores; no significant associations were observed with Fruit Naming or UPSIT tests. BnMn and FMn, but not BMn, are associated with cognitive function in Mn-exposed workers. None of the biomarkers were significantly associated with olfactory function.

In vivo neutron activation analysis of bone manganese in workers.

OBJECTIVE: Manganese (Mn) is a neurotoxin. However, the impact of elevated, chronic Mn exposure is not well understood, partially due to the lack of a cumulative exposure biomarker. To address this gap, our group developed a compact in vivo neutron activation analysis (IVNAA) system to quantify Mn concentration in bone (MnBn). APPROACH: In this study, we used this system and determined MnBn among male Chinese workers and compared results to their blood Mn (MnB), a measure of recent exposure, and the years of employment, a measure of cumulative exposure. A cross-sectional study was conducted with 30 ferroalloy smelters (exposed) and 30 general manufacturing workers (controls). MnBn was assessed using IVNAA, MnB was measured with inductively coupled plasma mass spectrometry, and occupational history and demographics were obtained via questionnaire. Mn-doped phantoms were used to generate a calibration curve; spectra from these phantoms were consistent with in vivo spectra. MAIN RESULTS: The median (interquartile range (IQR)) values for Mn biomarkers were 2.7 µg g-1 (7.2) for MnBn and 14.1 µg l-1 (4.0) for MnB. In regression models adjusted for age and education, the natural log transformed MnBn (ln(MnBn)) was significantly associated with the exposed/control status (ß = 0.44, p = 0.047) and years of employment (ß = 0.05, p = 0.002), but not with natural log transformed MnB (ln(MnB)) (ß = 0.54, p = 0.188). SIGNIFICANCE: Our results support the use of IVNAA to quantify MnBn and the use of MnBn as a biomarker of cumulative Mn exposure.

Development of a Cumulative Exposure Index (CEI) for Manganese and Comparison with Bone Manganese and Other Biomarkers of Manganese Exposure.

Manganese (Mn) exposure can result in parkinsonism. However, understanding of manganese neurotoxicity has been limited by the lack of a cumulative Mn biomarker. Therefore, the current goal was to develop Mn cumulative exposure indices (MnCEI), an established method to estimate cumulative exposure, and determine associations of MnCEI with blood Mn (BMn), fingernail Mn (FMn), and bone Mn (BnMn). We completed a cross-sectional study of 60 male Chinese workers. Self-reported occupational history was used to create two MnCEIs reflecting the previous 16 years (MnCEI16) and total work history (MnCEITOT). An in vivo neutron activation analysis system was used to quantify BnMn. BMn and FMn were measured using ICP-MS. Mean (standard deviation) MnCEITOT and MnCEI16 were 37.5 (22.0) and 25.0 (11.3), respectively. Median (interquartile range) BMn, FMn, and BnMn were 14.1 (4.0) μg/L, 13.5 (58.5) μg/g, and 2.6 (7.2) μg/g dry bone, respectively. MnCEI16 was significantly correlated with FMn (Spearman’s ρ = 0.44; p = 0.02), BnMn (ρ = 0.44; p < 0.01), and MnCEITOT (ρ = 0.44; p < 0.01). In adjusted regression models, MnCEI16 was significantly associated with BnMn (β = 0.03; 95% confidence interval = 0.001, 0.05); no other biomarkers were associated with MnCEI. This suggests BnMn may be a useful biomarker of the previous 16 years of Mn exposure, but larger studies are recommended.