Grantee Research Project Results
Final Report: Aluminum Toxicokinetics Oral Absorption from Drinking Water and Brain Retention
EPA Grant Number: R825357Title: Aluminum Toxicokinetics Oral Absorption from Drinking Water and Brain Retention
Investigators: Yokel, Robert A. , McNamara, Patrick J. , Elmore, David
Institution: University of Kentucky , Purdue University
EPA Project Officer: Aja, Hayley
Project Period: November 25, 1996 through November 24, 1999
Project Amount: $346,543
RFA: Exploratory Research - Human Health (1996) RFA Text | Recipients Lists
Research Category: Human Health
Objective:
The objectives of this research project were to: (1) determine the bioavailability of aluminum (Al) from drinking water; (2) assess the influence of water hardness of on oral Al bioavailability; (3) assess the influence of food in the stomach on oral Al bioavailability; (4) determine the fraction of circulating Al that enters the brain; and (5) determine if the brain is a "one-way sink" for Al, and if not, the rate of brain Al elimination.The first three objectives were addressed in a study conducted in rats. Oral Al was delivered into the rats' stomachs. Concurrent 27Al was given by intravenous infusion. Oral Al bioavailability was determined from the concentrations of 26Al and 27Al in serum determined repeatedly up to 120 hours after 26Al administration. Oral Al bioavailability was calculated from the relationship: AUCpo/AUCiv ' doseiv/dosepo, where Cls was calculated to replace the equivalent term doseiv/AUCiv. Cls was replaced by serum Aliv/infusion rateiv.
The influence of water hardness was assessed by determining the bioavailability of Al delivered in "hard water" containing the equivalent of 300 mg/l CaCO3 equivalent compared to "soft water" containing <10 mg/l CaCO3 equivalent.
The influence of food in the stomach was assessed in rats that had stomach
contents compared to those that did not. The presence of food in the stomach was
produced by permitting rats to eat 1 gram lab chow within the two hours
preceding intragastric administration of the 26Al. All rats had access to 2 ml drinking water 2
hours prior to 26Al administration. A
preliminary study demonstrated that consumption of water alone resulted in no
significant stomach contents whereas consumption of 1 gram food and 2 ml water
resulted in an average of 1.7 gram stomach contents.
Objective 4 was
addressed by administration of 26Al, as Al
transferrin, the major chemical species of Al in blood plasma, and collection of
blood and brain from rats 0.17, 1, 4, and 16 days later.
Objective 5 was addressed by an extension of the study addressing objective 4 by obtaining brain 32, 64, 128 and 256 days after 26Al transferrin dosing. Additionally, some rats received injections three times weekly of the Al chelator desferrioxamine whereas other rats received saline injections.
Blood samples from the studies addressing objectives 1-3 were analyzed to determine their total Al concentration, which was interpreted as 27Al because the contribution of 26Al was insignificant. Blood samples from studies addressing objectives 1-4 also were analyzed to determine their 26Al concentration by accelerator mass spectrometry (AMS). Brain samples from the studies addressing objectives 4 and 5 were analyzed by AMS. We developed a method to separate the Al from phosphate to improve sample preparation for AMS analysis.
Summary/Accomplishments (Outputs/Outcomes):
The oral bioavailability of Al was not significantly influenced by its delivery in "hard" versus "soft" water or in the presence versus absence of food in the stomach. Overall, oral Al bioavailability from water averaged 0.28 percent. This is consistent with two human studies that utilized 26Al to determine oral Al bioavailabilty in two humans in each study and one study that utilized 27Al to determine oral Al bioavailabilty in 21 humans.After its intravenous injection as 26Al transferrin, serum 26Al declined ~ 40-fold over 16 days whereas brain 26Al increased to a maximum 4 days after its injection. The maximum was ~ 0.005 percent of the 26Al dose/gram brain. This estimate of the fraction of Al that reaches the brain from blood is similar to several previous studies. Most of these previous studies were conducted at one time point and some had as few as one subject or one subject/time. Over the 256 days after its intravenous injection, 26Al decreased in the brain to ~ 30 percent of its peak brain concentration. The estimated half-life of the brain Al appeared to be >100 days. In the presence of repeated desferrioxamine injections, brain Al 256 days after its injection was ~ 10 percent of its peak concentration. The brain Al half-life in the desferrioxamine-treated rats was ~ 55 days. This result substantiated the observation that brain Al can be mobilized, as shown in the saline-treated rats. It also demonstrated the ability of repeated chelation therapy to enhance the reduction of brain Al, in the absence of repeated Al treatments.
Integration of the above results shows that Al is poorly absorbed after its oral administration. Whether drinking water would be expected to significantly contribute to the brain Al burden cannot be directly determined due to the lack of similar information on the oral bioavailability of Al from food, which contributes ~ 95 percent of oral Al exposure, whereas drinking water usually contributes only 1-2 percent of daily Al intake. However, if the bioavailability of Al from food is only 10 percent of that from water (e.g., if it is ~ 0.03 percent, changes in water Al concentration could measurably impact on the contribution of water to systemic Al, and therefore the Al available to enter the brain). Although only a very small fraction of Al in blood enters the brain, brain Al persists for quite a long time. There are not sufficient guidelines to extrapolate the persistence of Al in the rat brain, determined in the present work, to the human. It is likely that the duration of residence of Al in the human brain is longer than in the rat. Interspecies scaling from the rat to the human, based on the maximum life span of these species, suggests this. The few reports of organ Al half-life suggest an increase from rat to rabbit to the human. Limited studies in the human suggest a whole-body Al half-life of ~ 5 -10 years. This may reflect the slow release of Al from bone that would produce a parallel slow release from brain. Assuming a human brain Al half-life of years and considerably lower oral Al bioavailability of Al from food than water, significant differences in drinking water Al concentration would be predicted to have an effect on brain Al concentration in the adult human.
Journal Articles on this Report : 5 Displayed | Download in RIS Format
Other project views: | All 9 publications | 5 publications in selected types | All 5 journal articles |
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Brauer RD, Robertson JD, Sharma P, Yokel RA. Aluminum and phosphorus separation: application to preparation of target from brain tissue for 26Al determination by accelerator mass spectrometry. Nuclear Instruments and Methods In Physics Research, Section B--Beam Interactions with Materials and Atoms 1999;152(1):129-134. |
R825357 (1998) R825357 (Final) |
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Yokel RA, Allen DD, Ackley DC. The distribution of aluminum into and out of the brain. Journal of Inorganic Biochemistry ,1999;76(2):127-132. |
R825357 (Final) |
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Yokel RA, Rhineheimer SS, Brauer RD, Sharma P, Elmore D, McNamara PJ. Aluminum bioavailability from drinking water is very low and is not appreciably influenced by stomach contents or water hardness. Toxicology 2001;161(1-2):93-101. |
R825357 (Final) |
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Yokel RA, Rhineheimer SS, Sharma P, Elmore D, McNamara PJ. Entry, half-life, and desferrioxamine-accelerated clearance of brain aluminum after a single (26)Al exposure. Toxicological Sciences 2001;64(1):77-82. |
R825357 (Final) |
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Yokel RA. Brain uptake, retention, and efflux of aluminum and manganese Environmental Health Perspectives 2002;110(S5):699-704. |
R825357 (Final) |
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Supplemental Keywords:
drinking water, absorption, animal, mammalian, metals, analytical, measurement methods., RFA, Health, Scientific Discipline, Water, Toxicology, Environmental Chemistry, Health Risk Assessment, Risk Assessments, Biochemistry, Drinking Water, ecological risk assessment, neurotoxic, public water systems, brain retention, other - exposure, contaminant transport, biomarkers, human health effects, exposure and effects, animal model, exposure, kinetics, community water system, human exposure, dietary exposure, biokentics, dietary ingestion exposures, drinking water contaminants, bioaccumulation, biomarker, drinking water system, toxicokineticsProgress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.