Characterization of bone aluminum, a potential biomarker of cumulative exposure, and the association between olfactory and cognitive function tests with aluminum biomarkers in an occupationally exposed population

Aluminum (Al) is the third most abundant metal on the earth’s surface. An association of Al with Alzheimer’s disease has been suggested, but, given limited human evidence, is controversial. It is possible that exploration of long-term, or cumulative, exposure to Al will help clarify this debate. Therefore, our study hypothesis was that occupational exposure to Al, particularly long-term exposure, is associated with adverse cognitive and olfactory outcomes.

Biomarkers are important tools in epidemiologic research; however, the reliability and quality of various biomarkers may vary. Therefore, in Chapter 2, we reviewed current evidence on Al biomarkers with the goal to synthesize current understanding regarding their utility for use in research. Our review evaluated 78 papers which discussed various biomarkers of Al exposure. Limited evidence is currently available for Al in nails, hair, breastmilk, saliva and semen. Although they have more daily variation than other biomarkers, blood Al concentrations may differentiate between exposed and non-exposed groups. Unlike blood Al, Al concentrations in both urine and bone are not subject to daily fluctuations. Bone Al appears able to quantify long term Al exposure. Therefore, the use of in vivoneutron activation analysis (IVNAA), a novel bone biomarker, can potentially represent cumulative Al exposure.

In Chapter 3, we evaluated the hypothesis that the correlation between bone and CEI measurements will be higher than the correlation between bone with fingernail. A cross-sectional cohort of 61 ferroalloy and manufacturing factory workers from Zunyi, China were used in this secondary analysis. Correlations of bone Al with other Al measures (fingernail and cumulative exposure index (CEI)) were assessed for 43 of the factory workers who had bone Al samples. Fingernail samples were analyzed using inductively coupled plasma mass spectrometry. Bone measurements were taken with a compact IVNAA developed by our research team. CEI was calculated as CEI_i=, where C_iis estimated Al exposure based on job title (low/medium/high) and Y_iis the years employed. The CEI was calculated for the prior 5, 10, 15, 20 years and lifetime work history. Median Al values were: 34.4 mg/g (IQR=46) fingernail; 15 mg/g (IQR=28) bone; and 26 (IQR=21) total CEI. Adjusting for age and education, the linear regression model suggests that bone Al is reflective of 15 years of exposure based off the significant association between bone Al and 15-year CEI (b=0.91, p<0.02). Other models with CEI were not statistically significant.

In Chapter 4, we evaluated the association between bone, CEI and fingernail Al measurements with olfactory and cognitive function. The relationship between cognitive and olfactory function was compared with bone Al (N=43), fingernail Al (FnAl) (N=56), 5 year Al CEI and lifetime Al CEI (N=61) measurements. Olfactory function was assessed with the University of Pennsylvania Smell Identification Test and cognitive function was assessed with the WHO/UCLA Auditory Verbal Learning Test (AVLT). Verbal fluency was assessed using Fruit Naming and Animal Naming. Additional variables were assessed via questionnaire. Linear regression models, adjusted for age, education, current alcohol consumption and current smoking status, showed a significant association between higher BnAl and higher recall on the AVLT interference list (b=0.04, 95% Confidence interval (CI)=0.01, 0.08) and higher 5-year CEI with higher recall on the fifth AVLT trial (b=-0.23, 95% CI=-0.45, -0.01). No significant association between FnAl and lifetime CEI with olfactory and cognitive function was observed.

In Chapter 5, we explored the potential for interactions of Al with another metal to impact the potential association of Al with cognitive and olfactory function. Interaction models used the natural log of fingernail Al with each of copper (Cu), manganese (Mn), lead (Pb) and zinc (Zn) for the 56 male workers. The linear regression models controlled for age, education current alcohol consumption, current smoking status, and all five fingernail metals. Higher ln(FnMn) was associated with lower recall for several AVLT trials. The interaction term for ln(FnAl) and ln(FnZn) was significantly associated with AVLT Trial 1 (β= 1.99, 95% CI=0.07, 3.93), AVLT Trial 5 (β= 2.71, 95% CI= 0.02, 5.41) and AVLT average (β=2.11, 95% CI=0.01, 4.21).

Overall, this research presents valuable information regarding noninvasive, in vivoassessment of BnAl and its relationship with other Al biomarkers and measures of cognitive function. To the best of our knowledge, this is the largest study to use INVAA BnAl measurements to quantify long-term aluminum exposures within an occupational population, the first to compare BnAl with an estimate of cumulative Al exposure. Additionally, we are not aware of prior studies which have examined the interaction of fingernail metals, including Al, with olfactory and cognitive tests. Our results suggest BnAl is significantly associated with the prior 15-years of Al exposure and that IVNAA to assess BnAl can be used in field epidemiology studies. For our study, there was limited evidence of an association of BnAl and 5-year CEI with cognitive function. Most comparisons did not show any evidence of an association of Al with cognitive or olfactory function, but a statistically significant interaction between Al and Zn with some measures of cognitive function was observed. It is recommended that our findings be confirmed with larger studies.