CIIT Centers for Health Research, 6 Davis Drive, P.O. Box 12137, Research Triangle Park, North Carolina 277092137
Received October 12, 2000; accepted December 20, 2000
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ABSTRACT |
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Key Words: manganese; inhalation dietary interactions; biliary elimination; toxicokinetics; rat..
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INTRODUCTION |
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In contrast to the numerous reports describing manganese toxicity following inhalation exposure in humans, there are relatively few reports of manganism arising from water or dietary sources. In part, this trend is due to the relatively low levels of manganese found in these media. For example, most diets in North America result in manganese intakes below the current reference dose of 10 mg/day (Finley and Davis, 1999). Water concentrations of manganese typically range from 1 to 100 µg/l with most values below 10 µg/l (Keen and Zidenberg-Cherr, 1994
). On rare occasions, manganese toxicity results from ingestion. For example, Kawamura and coworkers (1941) and Kondakis et al. (1989) documented outbreaks of manganism in Japan and Greece due to the consumption of water from wells contaminated with extremely high levels of manganese (1.8 to 14 mg Mn/l).
A number of physiological mechanisms also exist to maintain relatively constant tissue manganese concentrations despite wide fluctuations in oral manganese intake (Schroeder et al., 1966). When dietary manganese levels are high, adaptive changes often include reduced gastrointestinal absorption of manganese, enhanced manganese liver metabolism, and increased biliary and pancreatic excretion of manganese (Britton and Cotzias, 1966
; Davis et al., 1993
; Finley and Davis, 1999
; Mahoney and Small, 1968
; Malecki et al., 1996
; Papavasiliou et al., 1966
). Thus, the fraction of ingested manganese retained by the body is tightly regulated in order to maintain normal tissue manganese concentrations under different dietary conditions. It has not been clearly established whether inhaled manganese is controlled similarly in individuals with different manganese body burdens. Absent such data, concerns exist that individuals with either deficient or excessive manganese tissue burdens may be at increased risk for manganese toxicity following inhalation exposure (Weiss, 1999
).
Manganese deficiency in animals results in skeletal abnormalities and an irreversible congenital ataxia syndrome (Freeland-Graves and Llanes, 1994). This syndrome has not been reported to occur spontaneously in humans. Suboptimal manganese status, however, may occur in patients with epilepsy, osteoporosis, or exocrine pancreatic insufficiency, in individuals undergoing chronic hemodialysis, and in children with Perthes' disease or phenylketonuria (Carl and Gallagher, 1994
; Freeland-Graves and Llanes, 1994
). Relative manganese excess may also occur. People on strict vegetarian diets, individuals consuming manganese-enriched mineral supplements, and patients undergoing total parenteral nutrition often have elevated manganese intake when compared to the general United States population (Finley and Davis, 1999
; Fitzgerald et al., 1999
; Nagatomo et al., 1999
). Manganese concentrations in the nervous system are influenced by hepatic manganese metabolism. For example, Hauser and coworkers (1996) have reported that some individuals with chronic hepatic encephalopathy have elevated blood manganese concentrations and develop brain magnetic resonance imaging changes consistent with elevated basal ganglial manganese levels.
Public attention to manganese neurotoxicity is increasing and has been stimulated in part by the use of the unleaded gasoline additive methylcyclopentadienyl manganese tricarbonyl (MMT). Exposure to the combustion products of MMT is of primary concern since the parent chemical is photosensitive and rapidly degrades in the air. Modern automobiles that are equipped with catalytic converters and use MMT-containing fuel emit manganese primarily in the phosphate and sulfate (MnSO4) forms, although lesser amounts of manganese oxides (e.g., Mn3O4) may also be discharged (Lynam et al., 1999; Ressler et al., 1999
; Zayed et al., 1999a
).
A critical issue in assessing the risks of chronic, low-level manganese exposure arising from MMT use is the ability to develop a predictive pharmacokinetic model for inhaled manganese (Andersen et al., 1999). Such predictive pharmacokinetic models will relate lung, brain, and other tissue manganese concentrations with exposure concentrations of MMT combustion products. Ideally, this model will account for differences in the chemical species of manganese, the route of exposure, and potentially susceptible human subpopulations. Individuals with either relative manganese deficiency or excess could represent susceptible subpopulations at risk for developing elevated tissue manganese concentrations following the inhalation of MnSO4 and other MMT combustion products.
Few investigators have examined whether dietary manganese levels can influence the pharmacokinetics of inhaled manganese. Moore and coworkers (1975) evaluated tissue manganese concentrations in rats fed either a 5- or 42.2-ppm manganese diet and exposed subchronically (8 h/day for 56 consecutive days) to irradiated exhaust from an automobile engine using gasoline containing MMT. These authors reported that brain, kidney, and liver manganese concentrations were lower in air-exposed control animals fed a 5-ppm manganese diet compared to animals fed the 42.2-ppm manganese diet. When compared with air-exposed controls, animals fed either the 5- or 42.2-ppm manganese diet and exposed to irradiated exhaust (containing approximately 117 µg Mn/m3) developed a 45 or 84% increase in total brain manganese concentrations, respectively. However, the results of this study were not analyzed in such a manner as to determine whether diet and inhalation interactive effects occurred. Although not determined directly during this study, the most likely form of manganese in the engine exhaust was the tetroxide, Mn3O4 (Ter Haar et al., 1975).
Our laboratory has recently characterized the pharmacokinetics of manganese phosphate, manganese sulfate, and manganese tetroxide in rats following 14 consecutive days of inhalation exposure (Dorman et al., 2001; Vitarella et al., 2000
). These studies showed that inhalation exposure to more soluble forms of manganese (e.g., MnSO4) results in higher brain and liver manganese concentrations than those achieved following exposure to a more insoluble form of manganese (e.g., Mn3O4). Each of these studies used a standard rodent diet (NIH-07) containing approximately 100 ppm manganese. Thus these studies did not address the fundamental question of whether different dietary manganese levels can influence the pharmacokinetics of inhaled MMT combustion products. The present study was therefore undertaken to address this research need. Our hypothesis was that brain and other target tissue manganese concentrations resulting from inhalation exposure would be influenced by dietary manganese concentrations. However, our data do not support this hypothesis.
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MATERIALS AND METHODS |
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Animals.
The study was conducted under federal guidelines for the care and use of laboratory animals (National Research Council, 1996) and was approved by the Institutional Animal Care and Use Committee of the Chemical Industry Institute of Toxicology. Fifty primiparous pregnant (sperm-plug-positive = gestation day [GD] 0) Crl:CD®(SD)BR rats were purchased on GD 14 from Charles River Laboratories, Inc. (Raleigh, NC) for this experiment. All presumed pregnant rats were initially fed a pelleted, semipurified AIN-93G certified diet from Bio-Serv (Frenchtown, NJ) that nominally contained 10 ppm manganese and 50 ppm iron. Pregnant rats and lactating dams with their pups were individually housed in polycarbonate cages with stainless steel lids (Laboratory Products, Inc., Rochelle Park, NJ) with Alpha-DriTM cellulose fiber chip bedding (Shepherd Specialty Papers, Kalamazoo, MI). Following parturition, 24 litters with at least 6 male and 4 female F1 rats per litter were assigned, on PND 10, to one of 3 AIN-93G certified diets (Bio-Serv, Frenchtown, NJ) containing 2, 10, or 100 ppm manganese and 50 ppm iron. All diets were fed ad libitum except during inhalation exposures. Reverse osmosis purified water containing < 0.002 µg Mn/ml was also available ad libitum. On PND 21, each litter was weaned, and rat pups were individually identified with an eartag, and maintained on their respective diets throughout the duration of the study. All parental (F0) female rats were euthanized after weaning on PND 23 ± 2. Weaned F1 animals were individually housed in suspended stainless steel cages. The animal rooms and exposure chambers were maintained at 22 ± 2°C, relative humidity of 3070%, and an air flow rate sufficient to provide 1015 air changes per h. Fluorescent lighting was controlled by automatic controls (lights on 06001800 h). The general condition of all animals was checked daily. Clinical examinations and body weights were recorded at least once weekly.
Manganese exposures.
The 1-m3 stainless steel and glass inhalation exposure chambers (Lab Products, Seaford, DE), airflows, chamber temperature and humidity monitoring procedures, animal rotation schedule, and methods used to check for uniformity of distribution of the aerosol have been previously described (Vitarella et al., 2000). The MnSO4 atmospheres were generated using a commercially available dry powder (Aldrich Chemical Co., Milwaukee, WI). A Wright Dust Feeder packed to 2000 psi, with a 20-psi air delivery pressure, and a Trost Airjet Mill (Garlock Corp., Newton, PA) were used to generate the initial aerosol. The MnSO4 aerosol was delivered into an approximately 38-l stainless steel prechamber (fitted with a 85Kr discharging unit) that allowed settling of larger (>10 µm) particles. The aerosol then went through a polyvinyl chloride distribution line tuned to allow equal residence time of particles in the pathway to each 1-m3 exposure chamber. The aerosol was diluted to the appropriate concentrations in the inlet air stream to each 1-m3 inhalation chamber. The aerosol in the prechamber and in each 1-m3 inhalation chamber was monitored continuously using an optical particle sensor (Realtime Aerosol Monitor, Model RAM-S, MIE Inc., Bedford, MA) precalibrated for a standard dust (Arizona road dust). The particle size distribution was measured with an aerosol particle spectrometer (APS) (Aerodynamic Particle Sizer, TSI, Inc., Minneapolis, MN), and, whenever possible, a microorifice uniform deposit cascade impactor (MOUDI, MSP Corp., Minneapolis, MN) was used to confirm the APS results. The APS uses a time-of-flight method to determine aerodynamic diameter of individual particles and is capable of sampling the low concentration aerosols used in this study. The APS reports the count median aerodynamic diameter (CMAD) and geometric standard deviation (
g). The traditionally reported mass median aerodynamic diameter (MMAD) was calculated from the CMAD and
g using the standard Hatch-Choate equations (Hinds, 1982
). Nominal MnSO4 exposure concentrations were 0, 0.092, and 0.92 mg MnSO4/m3, corresponding to 0, 0.03, and 0.3 mg Mn/m3. The target particle size distribution was 1.52 µm MMAD with a
g < 2. Control groups were exposed to HEPA-filtered air only. The mean daily inhalation chamber temperature was maintained between 21.7 and 23.8°C, and relative humidity was maintained at 48 to 54%.
Tissue collection and manganese analysis.
Whenever possible, striatal and liver manganese concentrations were determined in CO2-euthanized F1 female rats on PND 21, 49 ± 1, 63 ± 2, and 77 ± 2 (n = 1 rat/litter/time point). Litters without at least 5 live F1 female rats per litter were sampled in a manner to maintain an adequate sample size at the latest sampling time points. On PND 91 ± 2, the remaining F1 female rats (n = 1 rat/litter) were fasted overnight and anesthetized with pentobarbital (50 mg/kg, ip). The common bile duct was then cannulated using polyethylene (PE-10) tubing (Intramedic, Sparks, MD). Bile (0.51 ml) was collected from individual animals for approximately 1 h. A 3- to 5-ml sample of blood was collected by cardiac puncture immediately following the collection of bile. Serum was then obtained by centrifugation of clotted blood at room temperature for 20 min at 3000 g. The F1 female rats were then euthanized by exsanguination, and the striatum, olfactory bulb, cerebellum, lung, liver, proximal portion of the left femur, and ovary samples were collected for tissue manganese determination.
Tissue manganese concentrations were also determined in MnSO4-exposed F1 male rats. The PND 91 F1 male rats (n = 1 rat/litter/MnSO4 exposure group) were fasted overnight prior to their last inhalation exposure. Immediately after their last (i.e., 14th) inhalation exposure, the F1 male rats (n = 1 rat/litter/MnSO4 exposure group) were anesthetized with pentobarbital (50 mg/kg, ip), and a sample (1-ml) of bile and serum was collected using previously described methods. The F1 male rats were then euthanized by exsanguination, and striatum, olfactory bulb, cerebellum, lung, liver, proximal portion of the left femur, and testes samples were collected for tissue manganese determination.
All tissue, serum, and bile samples had their weight or volume measured and were placed in high purity linear polyethylene vials, frozen in liquid nitrogen, and stored at approximately 70°C until analysis. Total tissue manganese concentrations were determined by neutron activation analysis at the Nuclear Energy Services, North Carolina State University. Samples were irradiated individually for 20 to 60 s at a flux of 1.5 x 1013 n/cm2-s. After a monitored decay, each sample vial was counted for 200 s on Ortec 38% and 42% GeLi detectors coupled to Ortec Omnigam-N computerized gamma detection systems. Method blanks and reference liver samples obtained from the National Institute of Standards and Technology (Gaithersburg, MD) were also irradiated and analyzed with the samples.
54Mn tracer studies.
Immediately after the last MnSO4 inhalation exposure, the remaining F1 male rats from each exposure group (n = 1 rat/litter/MnSO4 exposure group) were given 0.5 µCi of 54MnCl2 (in sterile saline) by tail vein injection (0.4 ml injection volume). Whole-body gamma spectrometry was performed immediately after injection and at 1, 2, 4, 6, 9, and 12 weeks after 54Mn tracer administration. An integrated spectrometry system, consisting of a multichannel analyzer with 2 perpendicular 10.2-cm diameter sodium iodide scintillation detectors, preamplifier, amplifier, and high voltage power supply (Nuclear Data, Inc., Schaumburg, IL), was used to determine total radioactivity of 54Mn in the animal's body. Animals were placed in plastic restraint tubes during whole-body gamma spectrometry (live time < 2 min).
Pharmacokinetic estimates were made after fitting a nonlinear regression curve to the individual whole-body 54Mn concentration-time profiles data by model-dependent methods (WinNonlin, Pharsight Corp., Cary, NC). The use of a two-compartment model provided the best-fit curve to the data (Vitarella et al., 2000). Pharmacokinetic parameters were calculated from standard kinetic formulas (Shargel and Yu, 1985
) and included estimates of total body clearance (Clb), initial and terminal phase elimination half-lives (t1/2
and t1/2ß), and the area under the curve (AUC0
).
Statistics.
Following an assessment for homogeneity of variance (Levene's test), the data for quantitative, continuous variables (e.g., body weights, tissue manganese concentrations) collected from all female rats and male rats prior to their assignment to the inhalation phase of the study were intercompared for the 3 diet groups by analysis of variance (ANOVA). A Tukey's honestly significant difference test was used to perform pairwise multiple comparisons. All experimental data obtained from MnSO4-exposed F1 male rats (e.g., tissue manganese concentrations, pharmacokinetic parameters) were analyzed by an analysis of variance appropriate for a split-plot experimental design to test for the main effects of diet and exposure and also their interactions. If the diet`s main effect was significant, a Tukey's honestly significant difference test was used to determine which diet levels were different. If the exposure`s main effect was significant, a Dunnett's test was used to compare the two MnSO4 exposure levels to the air-exposed controls. Statistical analyses were performed using SAS Statistical Software (JMP, SAS Institute, Inc., Cary, NC). Unless otherwise noted, data presented are for the mean values ± standard error of the mean (SEM). A probability value of 0.01 was used for Levene's test, while p < 0.05 was used as the critical level of significance for all other statistical tests.
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RESULTS |
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Body Weight Gain, Clinical Signs, and Necropsy Findings
At 8 weeks after the start of the diet, male rats given the 2-ppm diet from PND 10 to 77 ± 2 had significantly lower PND 77 body weights than those observed in rats given the 100-ppm manganese diet (Fig. 2). Short-term (14-day) inhalation exposure to MnSO4 did not affect F1 male rat body weight (data not shown). Adverse treatment-related clinical effects were not observed in any animals.
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DISCUSSION |
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Frank manganese deficiency has been rarely reported in humans, therefore, the lowest level of dietary manganese used in this study (2 ppm) was intended to provide a marginally deficient level of manganese as may occur in humans with suboptimal manganese status. The 10-ppm manganese diet used meets current rodent dietary guidelines (NRC, 1995). The high-normal diet contains supplemental manganese at a level (100 ppm) similar to that found in the NIH-07 rodent diet used in previous manganese inhalation studies conducted by our laboratory (Dorman et al., 2001
; Vitarella et al., 2000
).
As expected, the feeding of the 2-ppm manganese diet was associated with a number of effects, including reduced body weight gain, decreased liver manganese concentrations, and reduced whole-body manganese clearance rates. Male rats given either the marginally deficient diet or the diet containing the current NRC-recommended level (10 ppm) of manganese had equivalent growth rates resulting in similar terminal body weights. However, male rats given the 2-ppm diet had pre-MnSO4 exposure (PND 77) body weights that were significantly approximately 5% lower than those observed in rats given the 100-ppm manganese diet. This observation likely reflects both growth-retarding and growth-promoting effects associated with diets that are either low or high in manganese (Keen et al., 1999).
Despite developing modest decreases in pup growth, manganese concentrations in most tissues remained unaffected by our dietary manipulations. This finding most likely reflects the use of a low manganese diet (2 ppm) rather than a more severely depleted diet containing < 1 ppm manganese. For example, Malecki and coworkers (1994) reported a 40 to 50% decrease in tissue manganese concentrations in rats fed a 1-ppm manganese diet for 2 months. It is also likely that a more profound alteration in tissue manganese concentration would have occurred if a longer period of dietary restriction were used in our study. Animals will develop frank manganese deficiency under these more extreme dietary conditions. However, as stated earlier, clinical manganese deficiency is rarely reported in humans. Thus, our results are most relevant for people with suboptimal levels of manganese in their diets.
Although manganese concentrations in many tissues were unaffected, our dietary manipulations did induce altered hepatic metabolism of manganese. Liver manganese concentrations observed in the F1 female littermates maintained on the 100-ppm manganese diet were highest at weaning and stabilized at a lower concentration by PND 49. This decline in liver manganese level was probably associated with the maturation of biliary manganese excretion mechanisms that emerge in rats near weaning (Keen et al., 1981; Miller et al., 1975
; Rehnberg et al., 1982
). Despite this decline, liver manganese concentrations in PND 6391 female F1 rats given manganese-sufficient diets (10 or 100 ppm) remained 33 to 40% higher than those observed in female rats given the 2-ppm manganese diet. Our results also show that biliary excretion of manganese was influenced by oral manganese intake. When compared to animals maintained on manganese-sufficient diets, female rats kept on the marginally manganese-deficient diet had reduced bile manganese concentrations. Similarly, male rats kept on the marginally manganese-deficient diet had decreased biliary manganese excretion as evidenced by their reduced whole-body elimination of a 54Mn tracer when compared with rats given manganese-sufficient diets.
The highest MnSO4 exposure level used in the present study (0.92 mg MnSO4/m3) is several orders of magnitude higher than those found in the ambient air or in metropolitan areas where the gasoline additive MMT has been widely used for the past 10 years (Clayton et al., 1999; Loranger and Zayed, 1997
; Pellizzari et al., 1999
; Zayed et al., 1999b
). Short-term exposure of rats to 0.92 mg MnSO4/m3 is associated with elevated olfactory bulb, lung, and testis manganese concentrations in male rats maintained on an open diet containing approximately 100 ppm manganese (Dorman et al., 2001
). The manganese exposure concentrations used in our study are orders of magnitude higher than those found in the ambient air or in metropolitan areas where the gasoline additive MMT has been widely used for the past 10 years (Clayton et al., 1999
; Loranger and Zayed, 1997
; Pellizzari et al., 1999
; Zayed et al., 1999b
). Our previous results suggested that the lowest exposure level (0.092 mg MnSO4/m3) would not alter manganese concentrations in any of the tissues examined in our present study. The results of our current study are qualitatively similar to this previous experiment. In our previous experiment, for example, rats exposed to 0.92 mg MnSO4/m3 had striatal manganese concentrations that were approximately 26% higher than their respective air-exposed controls, although this increase was not found to be statistically significant. In our present experiment, we observed a similar 33% increase in striatal manganese concentrations that was statistically significant. Similar trends were observed with other tissues. Although tissues identified as having increased manganese concentrations differ between these two experiments, these differences likely reflect the small sample sizes used in these experiments rather than a biologically significant difference in manganese metabolism or distribution.
Manganese concentrations in the brain and other target tissues may be influenced by biliary excretion of manganese. For example, liver pathology or surgical or pharmacological manipulations that result in biliary stasis can result in increased brain manganese concentrations (Davis et al., 1998, Hauser et al., 1996
). The use of a 2-ppm manganese diet was intended to induce a state of relative manganese deficiency resulting in reduced biliary excretion of manganese. Our observation of decreased whole-body 54Mn clearance rates and reduced biliary manganese concentrations in rats given the marginally deficient manganese diet indicate that this objective was indeed achieved. Therefore we were surprised that we did not find an interaction between dietary manganese level and inhalation exposure to manganese. Our inability to detect an interaction is most likely the result of an animal's ability to adjust its manganese clearance rates in response to the MnSO4 inhalation exposure. For example, despite being in a relatively manganese-deficient state, rats given the 2-ppm manganese diet and exposed to 0.92 mg MnSO4/m3 increased their rate of manganese excretion by approximately 45% when compared to their respective air-exposed control group. This observation suggests that, at least initially, animals will not retain inhaled manganese to compensate for relative nutritional deficiencies in this essential metal. Likewise, rats given either the 10- or 100-ppm manganese diet and exposed to 0.92 mg MnSO4/m3 also increased their manganese clearance rates when compared to their respective air-exposed control groups. Collectively, these data provide strong evidence that dose-dependent biliary excretion of manganese will serve to regulate the percentage of inhaled manganese retained by manganese-deficient animals, thereby limiting available manganese that could result in increased systemic tissue manganese concentrations. Additional studies evaluating route-to-route differences between the metabolism of inhaled and ingested manganese should be able to determine exposure conditions under which these homeostatic mechanisms begin to fail, resulting in elevated brain manganese concentrations. Our results suggest that even moderately manganese-deficient individuals are not likely to develop elevated brain manganese concentrations following short-term inhalation exposure to moderately high levels of manganese.
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ACKNOWLEDGMENTS |
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NOTES |
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