Exploring biomarkers of manganese exposure in humans and animals: The manganese-iron ratio as a potential tool for identification of early -onset manganism

Dallas M Cowan, Purdue University

Abstract

Reliable biomarkers for manganese (Mn) exposure and/or effect are not available at present. Without such a tool, it is not possible to identify or prevent workers with potential for developing manganism. In the absence of fully characterized exposure assessment it is not possible to establish a guideline for public policy to protect the general population from environmental Mn Exposure. The purpose of this cross-sectional study was (i) to establish a distinct biomarker that is capable of distinguishing Mn-exposed subjects from the general, Mn-unexposed healthy population, (ii) to use a neurobehavioral test battery to identify subtle changes in Mn-induced motor and memory dysfunction, (iii) to relate the quantified neurological dysfunction to an established biomarker of Mn exposure. Mn-exposed ferroalloy smelters (n=95), power distributing and office workers (122), and unexposed control subjects (106) were recruited to the high, low and control groups, respectively. Airborne Mn levels were 0.003 mg/m3, 0.03 mg/m3 and 0.18 mg/m 3 for control, low and high exposure groups, respectively. Mn concentrations in saliva, plasma, erythrocytes, urine and hair were significantly higher in both exposure groups than those in controls. The Fe concentration in plasma and erythrocytes, however, was significantly lower in Mn-exposed workers than in controls. A concept of the Mn/Fe ratio (MIR) was developed with the numerator (Mn) reflecting Mn exposure and the denominator (Fe) indicating a biological alteration. The MIRs for erythrocytes (eMIR) and plasma (pMIR) exhibited significant exposure-group related increases. Linear regression analysis revealed that the airborne Mn level was significantly associated with the eMIR (r=0.77, p<0.01) and pMIR (r=0.70, p<0.01). The cut-off value (COV), above which workers were considered to be Mn-exposed was established using the receiver-operator characteristic analysis. At the eMIR COV of 8.8, about 88% of the high exposure smelters had an eMIR above the COV, while 87% of controls had an eMIR below the COV. Taken together, this exposure assessment study suggests that chronic occupational exposure to Mn in smelters increases Mn and decreases Fe concentrations in erythrocytes and in plasma. The eMIR exhibits an excellent correlation between airborne Mn levels. Using a cut-off eMIR value of 8.8, we are accurately able to distinguish Mn-exposed workers from the unexposed, control population. To define the early onset of Mn neurotoxicity, a neurobehavioral test battery was used, which includes the nine-hole and groove-type steadiness tester, Benton visual retention test, and Purdue pegboard coordination test. No significant health problems or clinically identifiable neurological dysfunction were observed except for the increased blood pressure in Mn-exposed smelters. Benton test did not reveal any abnormal memory deficits among Mn-exposed smelters, nor did the groove and nine-hole tests detect any abnormality in dynamic and static steadiness in tested subjects. The Purdue pegboard test showed a remarkable age-related decline in fine movement coordination among all study participants regardless the Mn exposure condition. Mn exposure significantly exacerbated this age-related deterioration. Statistical modeling revealed that the plasma and erythrocyte MIR were associated with Purdue pegboard scores. Among all subjects whose MIR were above the COV, pMIR was significantly correlated with pegboard scores (r= -0.261, p=0.002), whereas for those whose age were above 40 years old, the eMIR, but not pMIR, was associated with the declined pegboard performance (r=-0.219, p=0.069). When both factors were taken into account (i.e., age >40 and MIR > the COV), only pMIR was inversely associated with pegboard scores. Considering their utility in the aforementioned Mn exposure assessment, the current data suggest that the blood Mn-Fe ratio may serve as a reasonable biomarker not only for judgment of Mn exposure but also for health risk assessment.

Degree

Ph.D.

Advisors

Zheng, Purdue University.

Subject Area

Toxicology

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