Whole-Body Lifetime Occupational Lead Exposure and Risk of Parkinson's
Whole-Body Lifetime Occupational Lead Exposure and Risk of Parkinson's
Background: Several epidemiologic studies have suggested an association between Parkinson's disease (PD) and exposure to heavy metals using subjective exposure measurements.
Objectives: We investigated the association between objective chronic occupational lead exposure and the risk of PD.
Methods: We enrolled 121 PD patients and 414 age-, sex-, and race-, frequency-matched controls in a case-control study. As an indicator of chronic Pb exposure, we measured concentrations of tibial and calcaneal bone Pb stores using Cadmium excited K-series X-ray fluorescence. As an indicator of recent exposure, we measured blood Pb concentration. We collected occupational data on participants from 18 years of age until the age at enrollment, and an industrial hygienist determined the duration and intensity of environmental Pb exposure. We employed physiologically based pharmacokinetic modeling to combine these data, and we estimated whole-body lifetime Pb exposures for each individual. Logistic regression analysis produced estimates of PD risk by quartile of lifetime Pb exposure.
Results: Risk of PD was elevated by > 2-fold [odds ratio = 2.27 (95% confidence interval, 1.13-4.55) ; p= 0.021] for individuals in the highest quartile for lifetime lead exposure relative to the lowest quartile, adjusting for age, sex, race, smoking history, and coffee and alcohol consumption. The associated risk of PD for the second and third quartiles were elevated but not statistically significant at the α= 0.05 level.
Conclusions: These results provide an objective measure of chronic Pb exposure and confirm our earlier findings that occupational exposure to Pb is a risk factor for PD.
Parkinson's disease (PD) is a neurologic movement disorder in which neurons of the substantia nigra, which are responsible for dopamine production, attenuate in number or become functionally impaired. Resultant symptoms include resting tremor in the extremities and head, limb and/or trunk rigidity, bradykinesia, and postural instability. Although the primary cause of the destruction or failure of substantia nigra cells is unknown, mounting evidence exists for both environmental and genetic determinants. A growing body of evidence suggests that heavy metal cations stimulate free radical formation in the brain and can lead to neurodegeneration via peroxidative damage to the cell membrane (Sandhir et al. 1994). Increasing levels of heavy metal cations stimulate the conformational changes that can lead to fibrillation of recombinant α-synuclein. The aggregation and fillibration of α-synuclein provoked by the presence of heavy metal cations could directly cause the intracellular protein inclusions that are observed in the substantia nigra of PD patients (Uversky et al. 2001). Results from several epidemiologic studies further support an association between PD and exposure to heavy metals (Aquilonius and Hartvig 1986; Rybicki et al. 1993; Tanner et al. 1989). Our previous results demonstrated a 2-fold increase in the risk of PD among workers with > 20 years of occupational exposure to Pb. Associations of such chronic occupational exposure to combinations of Pb-iron and Pb-copper were even more robust (Gorell et al. 1997).
Although several studies have examined the relationship between blood Pb levels and environmental Pb exposure, results from blood Pb analysis are not noteworthy. Research into long-term or distant past Pb exposures is confounded by the body's ability to purge metals quickly from the blood stream. Because the half-life of Pb in blood is approximately 1 month, blood Pb levels only reveal if the individual has experienced a relatively current exposure to environmental Pb. Thus, blood Pb levels indicate only acute and recent exposures to Pb rather than representing a chronic and/or extended exposure history. Rather than within circulating blood, the main repository for chronic Pb stores in the body is within bone (Hu et al. 1998). Pb is stored in the bone by replacing calcium of the hydroxy-apatite crystals of the bone mineral. Through a continual process of bone remodeling, synthesis, and reabsorption, Pb is released into the blood stream and circulates throughout the body. In the brain, Pb diffuses easily across the blood brain barrier and binds to sulphydryl groups, resulting in Pb neurotoxicity that leads the neurodegeneration via intracellular oxidative damage (Bradbury and Deane 1993; Popenoe and Schmaeler 1979; Quinlan et al. 1988; Rossman 2006; Sandhir et al. 1994).
Additionally, while the half-life of Pb in blood is very short, the half-life of Pb in bone is measured in years and decades, depending on the type of bone [the hard bone of the tibia (half-life of approximately 20 years) releases Pb more slowly over time than the soft, spongy bone of the calcaneus (half-life of ≤ 10 years)] and the individual's metabolic rate of leaching and clearance (Patterson 1980). Measuring Pb concentration in bone using K-shell X-ray fluorescence (K-XRF) provides a proxy for current whole-body Pb content, independent of whether the exposure is current (Hu et al. 1991; Todd and Chettle 1994). Because K-XRF measurements estimate the current level of blood stores in the body, they can be used to construct an indirect assessment of an individual's past exposures to Pb. If the exposure to Pb was experienced at some time in the past, the individual's body will have cleared some amount of Pb between the last period of exposure and the time of the K-XRF measurement. This clearance rate of Pb from bone is predictable and can be used in a physiologically based pharmacokinetic (PBPK) model to estimate the level of Pb in the body at the actual time of the exposure. Kinetic modeling allows for a more complete picture of the individual's lifetime occupational Pb exposure by combining current body stores, as detected by bone Pb levels; current exposures, as indicated by blood Pb levels; and both current and past environmental exposures, as reported by the individual and qualified by industrial hygienist assessment to assess the timing and intensity of the exposure (Leggett 1993).
In this study, we further evaluated the risk of PD in response to the total body Pb burden. To accomplish this, we conducted a case-control study with the following objectives: a) to integrate historical exposure information with current measurements of cortical and trabecular bone Pb obtained by current K-XRF and blood Pb; b) to reconstruct the Pb exposure history using PBPK models; and c) to use the resultant estimate of the net body Pb burden over time (dose) to calculate a quantitative relationship between the lifetime exposure and the risk of PD.
Abstract and Introduction
Abstract
Background: Several epidemiologic studies have suggested an association between Parkinson's disease (PD) and exposure to heavy metals using subjective exposure measurements.
Objectives: We investigated the association between objective chronic occupational lead exposure and the risk of PD.
Methods: We enrolled 121 PD patients and 414 age-, sex-, and race-, frequency-matched controls in a case-control study. As an indicator of chronic Pb exposure, we measured concentrations of tibial and calcaneal bone Pb stores using Cadmium excited K-series X-ray fluorescence. As an indicator of recent exposure, we measured blood Pb concentration. We collected occupational data on participants from 18 years of age until the age at enrollment, and an industrial hygienist determined the duration and intensity of environmental Pb exposure. We employed physiologically based pharmacokinetic modeling to combine these data, and we estimated whole-body lifetime Pb exposures for each individual. Logistic regression analysis produced estimates of PD risk by quartile of lifetime Pb exposure.
Results: Risk of PD was elevated by > 2-fold [odds ratio = 2.27 (95% confidence interval, 1.13-4.55) ; p= 0.021] for individuals in the highest quartile for lifetime lead exposure relative to the lowest quartile, adjusting for age, sex, race, smoking history, and coffee and alcohol consumption. The associated risk of PD for the second and third quartiles were elevated but not statistically significant at the α= 0.05 level.
Conclusions: These results provide an objective measure of chronic Pb exposure and confirm our earlier findings that occupational exposure to Pb is a risk factor for PD.
Introduction
Parkinson's disease (PD) is a neurologic movement disorder in which neurons of the substantia nigra, which are responsible for dopamine production, attenuate in number or become functionally impaired. Resultant symptoms include resting tremor in the extremities and head, limb and/or trunk rigidity, bradykinesia, and postural instability. Although the primary cause of the destruction or failure of substantia nigra cells is unknown, mounting evidence exists for both environmental and genetic determinants. A growing body of evidence suggests that heavy metal cations stimulate free radical formation in the brain and can lead to neurodegeneration via peroxidative damage to the cell membrane (Sandhir et al. 1994). Increasing levels of heavy metal cations stimulate the conformational changes that can lead to fibrillation of recombinant α-synuclein. The aggregation and fillibration of α-synuclein provoked by the presence of heavy metal cations could directly cause the intracellular protein inclusions that are observed in the substantia nigra of PD patients (Uversky et al. 2001). Results from several epidemiologic studies further support an association between PD and exposure to heavy metals (Aquilonius and Hartvig 1986; Rybicki et al. 1993; Tanner et al. 1989). Our previous results demonstrated a 2-fold increase in the risk of PD among workers with > 20 years of occupational exposure to Pb. Associations of such chronic occupational exposure to combinations of Pb-iron and Pb-copper were even more robust (Gorell et al. 1997).
Although several studies have examined the relationship between blood Pb levels and environmental Pb exposure, results from blood Pb analysis are not noteworthy. Research into long-term or distant past Pb exposures is confounded by the body's ability to purge metals quickly from the blood stream. Because the half-life of Pb in blood is approximately 1 month, blood Pb levels only reveal if the individual has experienced a relatively current exposure to environmental Pb. Thus, blood Pb levels indicate only acute and recent exposures to Pb rather than representing a chronic and/or extended exposure history. Rather than within circulating blood, the main repository for chronic Pb stores in the body is within bone (Hu et al. 1998). Pb is stored in the bone by replacing calcium of the hydroxy-apatite crystals of the bone mineral. Through a continual process of bone remodeling, synthesis, and reabsorption, Pb is released into the blood stream and circulates throughout the body. In the brain, Pb diffuses easily across the blood brain barrier and binds to sulphydryl groups, resulting in Pb neurotoxicity that leads the neurodegeneration via intracellular oxidative damage (Bradbury and Deane 1993; Popenoe and Schmaeler 1979; Quinlan et al. 1988; Rossman 2006; Sandhir et al. 1994).
Additionally, while the half-life of Pb in blood is very short, the half-life of Pb in bone is measured in years and decades, depending on the type of bone [the hard bone of the tibia (half-life of approximately 20 years) releases Pb more slowly over time than the soft, spongy bone of the calcaneus (half-life of ≤ 10 years)] and the individual's metabolic rate of leaching and clearance (Patterson 1980). Measuring Pb concentration in bone using K-shell X-ray fluorescence (K-XRF) provides a proxy for current whole-body Pb content, independent of whether the exposure is current (Hu et al. 1991; Todd and Chettle 1994). Because K-XRF measurements estimate the current level of blood stores in the body, they can be used to construct an indirect assessment of an individual's past exposures to Pb. If the exposure to Pb was experienced at some time in the past, the individual's body will have cleared some amount of Pb between the last period of exposure and the time of the K-XRF measurement. This clearance rate of Pb from bone is predictable and can be used in a physiologically based pharmacokinetic (PBPK) model to estimate the level of Pb in the body at the actual time of the exposure. Kinetic modeling allows for a more complete picture of the individual's lifetime occupational Pb exposure by combining current body stores, as detected by bone Pb levels; current exposures, as indicated by blood Pb levels; and both current and past environmental exposures, as reported by the individual and qualified by industrial hygienist assessment to assess the timing and intensity of the exposure (Leggett 1993).
In this study, we further evaluated the risk of PD in response to the total body Pb burden. To accomplish this, we conducted a case-control study with the following objectives: a) to integrate historical exposure information with current measurements of cortical and trabecular bone Pb obtained by current K-XRF and blood Pb; b) to reconstruct the Pb exposure history using PBPK models; and c) to use the resultant estimate of the net body Pb burden over time (dose) to calculate a quantitative relationship between the lifetime exposure and the risk of PD.
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