A biokinetic model for manganese

Science of the Total Environment 409 (2011) 4179–4186

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Review

A biokinetic model for manganese R.W. Leggett ⁎ Building 5700, Environmental Sciences Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831, United States

a r t i c l e

i n f o

Article history: Received 4 May 2011 Received in revised form 29 June 2011 Accepted 1 July 2011 Available online 29 July 2011 Keywords: Manganese Biokinetics Model Humans Radionuclides

a b s t r a c t The International Commission on Radiological Protection (ICRP) is updating its biokinetic models used to derive dose coefficients and assess bioassay data for intake of radionuclides. This paper reviews biokinetic data for manganese and proposes a biokinetic model for systemic manganese in adult humans. The proposed model provides a more detailed and physiologically meaningful description of the behavior of absorbed manganese in the body than the current ICRP model. The proposed model and current ICRP model yield broadly similar estimates of dose per unit activity of inhaled or ingested radio-manganese but differ substantially with regard to interpretation of bioassay data. The model is intended primarily for use in radiation protection but can also serve as a baseline model for evaluation of potentially excessive intakes of stable manganese in occupational settings. © 2011 Elsevier B.V. All rights reserved.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Primary information used in model development . . . . . . . . . . . . . . 2.2. Model formulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Overview of manganese biokinetics and balance . . . . . . . . . . . . . . 3.2. Summary of the biokinetic database for human subjects . . . . . . . . . . 3.3. Summary of the biokinetic database for laboratory animals . . . . . . . . . 3.4. Proposed biokinetic model for systemic manganese . . . . . . . . . . . . . 4. Discussion and conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Comparison of model predictions with observations . . . . . . . . . . . . 4.2. Comparison of dose estimates based on the proposed model and current ICRP Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Manganese is an essential trace element required for metabolism of amino acids, proteins, carbohydrates, and lipids in mammals. Manganese deficiency has been associated with abnormal glucose tolerance, impaired growth, skeletal defects, reduced reproductive function, and altered lipid and carbohydrate metabolism in laboratory animals. Manganese deficiency is rarely reported in human popula-

⁎ Tel.: + 1 865 576 2079; fax: + 1 865 574 7569. E-mail address: [email protected]. 0048-9697/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.scitotenv.2011.07.003

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tions because of a generally adequate supply of manganese in human diet. Excessive manganese accumulation can result in adverse health effects including progressive neurodegenerative damage with an associated motor dysfunction syndrome similar to that seen in Parkinson's disease. Most reported cases of manganese intoxication have been linked to chronic occupational exposure to airborne manganese, particularly among manganese miners, welders, smelters, and workers in dry cell battery factories (Andersen et al., 1999; Aschner et al., 2005; Cotzias et al., 1968; Crossgrove and Zheng, 2004; Dorman et al., 2001; WHO, 1999). Manganese is used to increase the strength and durability of steel alloys and is present in relatively high concentrations in structural components of many nuclear reactors. The radionuclides 54Mn

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(radiological half-life, 312 d) and 56Mn (2.6 h) are produced in these reactors by neutron activation of corrosion products that circulate through the systems. Significant occupational intakes of the longerlived 54Mn could occur, for example, during reactor maintenance or decommissioning, or during decontamination or transport of spent fuel casks. Environmental exposures to 54Mn could occur following its release in reactor effluents. Reports of the International Commission on Radiological Protection (ICRP) provide biokinetic models for manganese and dose coefficients (estimates of radiation dose per unit intake) for inhalation or ingestion of 54Mn and other selected radioisotopes of manganese. For example, ICRP Publication 68 (1994a) provides inhalation dose coefficients for relatively soluble or moderately soluble particulate forms of manganese isotopes (i.e., for the ICRP's generic respiratory absorption Types F and M, respectively) and ingestion dose coefficients for these isotopes based on a reference gastrointestinal absorption fraction of 0.1. The ICRP's current systemic biokinetic model for manganese (i.e., model describing the biokinetics of activity after its absorption to blood) is shown in Fig. 1. The model was introduced in ICRP Publication 30 (1979) and modified in ICRP Publication 68 (1994a) to depict explicit excretion pathways, i.e., excretion via the colon and urinary bladder, because doses to these tissues were required for calculation of the effective dose as redefined in ICRP Publication 60 (1991). The model was designed to yield reasonable estimates of committed doses to tissues from intake of manganese isotopes and was not intended to provide a realistic description of the time-dependent behavior of manganese in the body. The ICRP is updating its reports on occupational intakes of radionuclides and subsequently will revisit its models and dose coefficients for members of the public. The updated reports continue a trend toward more physiologically realistic models that can be applied to a variety of problems in radiation protection. In addition to predicting the cumulative activity of radionuclides in major repositories in the body, the models are intended for bioassay interpretation and for later extension and application to special problems such as transfer of radionuclides from the mother to the fetus or nursing infant. The updated model structures generally include one or more compartments representing blood, depict recycling of activity between tissues and blood, and, where feasible, reflect physiological processes that help to determine rates of transfer of internally deposited radionuclides. This paper summarizes the biokinetic database for manganese and proposes a biokinetic model for systemic manganese in adult humans for use in radiation protection. The proposed model provides a more

Fig. 1. The ICRP's current biokinetic model for systemic manganese in workers (ICRP, 1979, 1994a).

detailed picture of the time-dependent distribution and more realistic paths of movement of absorbed manganese in the body than does the current ICRP model. The proposed model and ICRP model yield broadly similar estimates of dose per unit intake of radio-manganese but substantially different estimates of dose based on measurement of radio-manganese in urine. 2. Methods 2.1. Primary information used in model development The proposed biokinetic model is intended to represent the typical behavior of manganese in healthy adult humans as determined from a review of information on the distribution, retention, and excretion of manganese in human subjects and laboratory animals. Data for human subjects used in model development include measurements of stable manganese in diet, blood, and excreta of subjects with no occupational exposure to manganese; stable manganese concentrations in tissues as determined in autopsy studies of subjects with no occupational exposure to manganese; radioactivity in blood, excreta, liver, or total body following acute oral or intravenous administration of radioisotopes of manganese; and gastrointestinal uptake of radioisotopes of manganese. Preference was given to data for healthy subjects, but data for unhealthy subjects were used where information for healthy subjects was lacking. Data from animal studies involving administration of radioactive or stable manganese were used to fill gaps in the database for humans, particularly with regard to the time-dependent distribution of systemic manganese during or after short-term intake. 2.2. Model formulation The structure of the proposed biokinetic model for systemic manganese is shown in Fig. 2. This is a modification of the ICRP's generic model structure for bone-surface-seeking radionuclides. The pancreas and brain were added to the ICRP's generic model structure as separate compartments for manganese based on findings in animal studies that the concentration in the pancreas is elevated at early times after exposure and the retention time in the brain is longer than in other soft tissues. Some compartments and paths of movement in the ICRP's generic model structure were removed because they did not appear to be useful for describing the biokinetics of manganese as currently understood. Transport of manganese between compartments is assumed to follow first-order kinetics. Parameter values are expressed as transfer

Fig. 2. Structure of the proposed biokinetic model for systemic manganese. RBC = red blood cells; SI = small intestine; ST0, ST1, and ST2 represent fast, moderate, and slow return to plasma from soft tissues other than those explicitly identified in the diagram.

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coefficients (d−1), which describe fractional transfer per unit time from one compartment to another. These transfer coefficients were derived from reference deposition fractions and biological half-times, selected for consistency with the typical behavior of systemic manganese in healthy adult humans or in laboratory animals where human data were inadequate. Deposition fractions describe the division of manganese that leaves plasma. For example, a deposition fraction of 0.05, or 5%, for the kidneys means that 5% of outflow of manganese from plasma is assumed to deposit in the kidneys. The biological half-time for a compartment is the half-time that one would observe for stable manganese if outflow from that compartment continued while feeds from all other compartments were stopped. For example, manganese is assumed to leave plasma with a biological half-time of 1 min, although the apparent half-time would be longer than 1 min due to recycling of manganese from tissues to plasma. The transfer coefficient corresponding to a biological half-time of 1 min is 1000 d −1, which is calculated as follows: ln 2/1 min = 0.693/0.000694 d = 1000 d−1 (after rounding), where ln 2 is the natural logarithm of 2. The transfer coefficient from plasma to the kidneys is calculated from the deposition fraction for kidneys and the biological half-time for removal from plasma: 0.05 × 1000 d −1 = 50 d−1. 3. Results 3.1. Overview of manganese biokinetics and balance Dietary intake of manganese typically is about 4 (2.5–6) mg d −1 for adult males and 3 (2–5) mg d −1 for adult females (Anke et al., 1991; Becker and Kumpulainen, 1991; Biego et al., 1998; Bro et al., 1990; Buchet et al., 1983; Hunt and Meacham, 2001; Iyengar et al., 2000; Noel et al., 2003; Pennington et al., 1989; Suzuki et al., 2003; Tsuda et al., 1995). The mass of manganese in the body normally is maintained at a nearly constant level by homeostatic controls involving regulation of gastrointestinal uptake and intestinal secretions. Typically, 1–5% of ingested manganese reaches the systemic circulation (Aschner et al., 2005; Davis et al., 1993; Davidsson et al., 1988, 1989; Finley et al., 1994, 1999; Furchner et al., 1966). As demonstrated in animal studies, high dietary manganese enhances metabolism of manganese in the liver and increases secretion of manganese into the gastrointestinal contents (Andersen et al., 1999; Dorman et al., 2001). Excretion of systemic manganese is predominantly in feces and arises mainly from biliary secretion, although there is also appreciable secretion in pancreatic juices and other intestinal fluids (Dorman et al., 2001; Mahoney and Small, 1968; Maynard and Fink, 1956). Manganese absorbed from the gut via the portal vein is removed by the liver as required to achieve homeostasis. Manganese entering blood by other routes initially bypasses the control processes in the liver and ultimately becomes largely bound to transferrin, which may be transferred to the brain or other tissues by transferrin receptors. Thus, intake of manganese by routes other than ingestion may affect its biokinetics and homeostatic balance and result in elevated accumulation in some organs including the brain. Isotopic studies on laboratory animals show that absorbed or intravenously injected manganese leaves blood rapidly and initially concentrates largely in organs rich in mitochondria, most notably the liver, pancreas, and kidneys (Chauncey et al., 1977; Dastur et al., 1971; Dorman et al., 2006; Kato, 1963). Mitochondria appear to represent the main pool of manganese turnover shortly after injection into mammals (Borg and Cotzias, 1958). With passing time other organs, particularly brain, bone, and muscle, contain increasingly greater portions of the retained activity (Dastur et al., 1969, 1971; Furchner et al., 1966). The adult human body typically contains about 10 mg of manganese. Human and animal studies indicate that the biological half-time of manganese depends on body stores. Reported long-term

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biological half-times for intravenously injected radio-manganese based on observation periods of a few weeks or months are about 5–6 weeks for human subjects with no occupational exposure to manganese, but the half-time is as much as a factor of three lower in workers with high exposure to airborne manganese (Cotzias et al., 1968; Mahoney and Small, 1968; Mena et al., 1967).

3.2. Summary of the biokinetic database for human subjects The concentration of manganese in whole blood of healthy adult subjects typically is about 9 (8–11) μg/L (Kristiansen et al., 1997; Milne et al., 1990; Pleban and Pearson, 1979). The preponderance of blood manganese is found in red blood cells (Milne et al., 1990). Reported concentrations of manganese in blood plasma are highly variable (Baruthio et al., 1988; Versieck and Cornelis, 1980; Versieck et al., 1988), apparently due to difficulties in obtaining reliable measurements. According to Versieck et al. (1988), results based on measurement techniques that minimize sample contamination indicate that the concentration of manganese in plasma may be homeostatically controlled at about 0.6 μg/L in adult humans. Reported median or mean concentrations of manganese in human tissues collected at autopsy (Benes et al., 2000; Bush et al., 1995; Garcia et al., 2001; Kitamura et al., 1974; Subramanian et al., 1985; Tipton and Cook, 1963; Tipton and Shafer, 1964) are broadly consistent for soft organs but vary from less than 0.05 mg kg −1 to about 2 mg kg −1 for bone. The large variation for bone may result in part from differences in bone sampling sites and measurement techniques and in part from an apparent long-term component of retention in bone that reflects cumulative exposure to manganese and hence variability in exposure in the population. Reference concentrations and total masses of stable manganese in blood and tissues of adult humans are listed in Table 1. The reference concentrations in whole blood and soft tissues are medians of central estimates determined in the studies cited above. The reference concentration in blood plasma is based on data and conclusions of Versieck et al. (1988). The reference concentration in bone was taken as the midpoint of the range 0.06–0.3 mg Mn/kg bone, in which most of the reported bone concentrations fall. The reference total masses of manganese in blood and tissues are based on the reference concentrations together with reference masses of blood and tissues of adult males and females given in ICRP Publication 89 (2002). Table 1 Reference contents of stable manganese in adult humans. Tissue

Whole blood Blood plasma Liver Pancreas Kidney Brain Bone Muscle plus adipose tissue Remainderb Total bodyb

Reference concentrationa (mg/kg)

Reference mass (mg) Male

Female

0.009 0.0006 1.3 1.0 0.9 0.3 0.18 0.07 0.25c –

0.05 0.002 2.3 0.15 0.30 0.45 1.0 3.3 2.5 10

0.04 0.0016 1.8 0.12 0.23 0.40 0.7 2.8 1.9 8

a The reference whole blood concentration is the median of central values reported by Pleban and Pearson, 1979 (mean, n = 60), Milne et al., 1990 (mean, n = 48), and Kristiansen et al., 1997 (median, n = 188). The reference blood plasma concentration is based on the mean value determined by Versieck et al., 1988 (n = 12). Reference concentrations in soft tissues are based on central values reported by Tipton and Cook, 1963 (medians, n ~ 140), Kitamura et al., 1974 (medians, n = 30), Subramanian et al., 1985 (medians, n = 143), Bush et al., 1995 (means, n = 30), Benes et al., 2000 (medians, n = 70), and Garcia et al., 2001 (means, n = 78). b Excludes manganese in the gastrointestinal contents. c Based on heart, lungs, spleen, stomach, intestines, and skin.

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Borg and Cotzias (1958) measured the time-dependent content of intravenously administered 56Mn in blood and liver of 14 medical patients with various illnesses including rheumatoid arthritis, essential hypertension, diabetes, Parkinson's disease, cancer with metastases to liver, and cancer without metastases to liver. The results were interpreted as indicating that 56Mn exchanged with a pool representing virtually all of the systemic manganese within 45– 60 min after injection. The following blood clearance curve was derived as a fit to the collective blood retention data for all 14 subjects: RðtÞ = 0:845expð−0:77 tÞ + 0:141expð−0:26 tÞ + 0:014expð−0:023 tÞ;

where t is in minutes. The three components of the clearance curve correspond to removal half-times of roughly 0.9 min, 2.7 min, and 30 min, respectively. The first component was interpreted by the investigators as representing transcapillary exchange. The second and third components were interpreted as representing accumulation of manganese in mitochondria and exchange with manganese pools other than the mitochondrial portion, respectively. External measurements showed that much of the activity leaving blood accumulated in the liver. The liver content increased rapidly over the first 4– 5 min after injection but only slightly thereafter. Mena et al. (1967) measured total-body retention of intravenously injected carrier-free 54Mn in eight healthy control subjects (four males and four females in the age range of 20–30 y), 14 current manganese miners in good health (age range 23–60 y), and 10 former manganese miners with chronic manganese poisoning (age range 18– 56 y). Nine of the subjects with manganese poisoning were studied 2– 25 y after termination of exposure and the tenth was studied immediately after termination of work in the mines. Total-body removal half-times were 35.5 +/− 8.4 d (mean +/− standard deviation) in the control group, 12.5 +/− 2.3 d in the healthy miners, and 26.5 +/− 4.8 d in the subjects with manganese poisoning. The rate of loss of 54Mn from the subject with manganese poisoning who had just stopped working in the mines was much greater than that of the other subjects with manganese poisoning. Mahoney and Small (1968) measured the retention of intravenously injected 54Mn in six volunteer subjects (ages 25–45 y) including both sexes and studied factors affecting the rate of biological removal of the tracer from the body. Average retention could be described as a sum of two exponential terms. About 30% was removed with a half-time of 4 d and 70% with a half-time of 39 d. Low manganese intake increased the size of the slow component to 84% and the retention half-time to 90 d but did not change the half-time of the fast component. Administration of a large mass of stable manganese 2 months after the start of the study markedly increased the elimination rate. A mildly iron-deficient subject showed a marked decrease in the size of the slow component and some decrease in the associated half-time compared with other subjects. Oral iron therapy corrected the mild anemia and caused a decrease in the elimination rate. Preloading two subjects with manganese resulted in a large decrease in the slow fraction but had less effect on the slow half-time. The subject with the largest preloading dose showed no slow component. In a normal subject, an estimated 0.14% of injected 54 MnC12 appeared in the red blood cells 17 d after injection. Manganese deprivation, manganese loading, or low iron stores reduced the fraction in red blood cells by about a factor of two. Davidsson et al. (1989) measured gastrointestinal uptake, retention, and excretion of 54Mn in 14 healthy adults after its ingestion in infant formula. Inter-individual variation of manganese absorption and retention was high. Gastrointestinal uptake was estimated as 5.9 +/− 4.8% (mean +/− standard deviation) and varied from 0.8 to 16% in 26 studies on these subjects (one study on each of eight subjects and three studies on each of the other six subjects). Retention at day 10 was estimated as 2.9 +/− 1.8% and varied from

0.6 to 9.2%. The rate of excretion from days 10–30 corresponded to a mean biological half-life of 16.4 d with a range of 6–32 d. Following intravenous administration of 54Mn to two of the 14 subjects, the turnover rate during days 10–30 corresponded to biological halftimes of 74 and 24 d, compared with 27 and 8 d, respectively, in the same subjects following oral administration. Finley et al. (1994, 1999) studied the effects of gender, dietary levels of manganese, and serum ferritin status on absorption and retention of manganese in healthy adult human subjects. In one study, absorption and retention of acutely ingested 54Mn were measured over 70 d in 20 males and 20 females (ages 18–40 y) with diets adequate in manganese (Finley et al., 1994). Males absorbed significantly less 54Mn than the females but had a longer retention time in the body. Retention data for days 10–20 indicated mean whole-body biological half-times of about 15 d for men and 12 d for women. Data for days 19 to 70 indicated mean half-times of about 48 d for men and 34 d for women. Significant associations were found between manganese absorption and plasma ferritin concentrations and between manganese absorption and biological half-life. The investigators concluded that men and women differ in manganese metabolism and that such differences may be related to iron status. In a later study involving 26 healthy women (ages 20–45 y), the interaction of serum ferritin status and dietary manganese was found to affect both gastrointestinal absorption of 54Mn and the biological half-life of absorbed 54Mn (Finley, 1999). In subjects with low ferritin concentrations, mean absorption was ~ 4.9% when consuming a low manganese diet and ~2.3% when consuming a high manganese diet. In subjects with high ferritin concentrations, mean absorption was ~ 1% when consuming either a low manganese diet or a high manganese diet. The biological half-life was longest when subjects with high ferritin concentrations consumed a low manganese diet and shortest in subjects consuming a high manganese diet. Manganese balance was affected by the level of manganese in the diet. In each of two ambulatory hospital patients with no evidence of renal or gastrointestinal dysfunction, fecal excretion of activity was about 40 times greater than urinary excretion over the first 6 d following intravenous injection of 52Mn in water (Maynard and Fink, 1956). Mahoney and Small (1968) found virtually no 54Mn in urine following its intravenous injection as chloride into three healthy subjects. Davidsson et al. (1989) found that fecal excretion accounted for virtually all of the biological removal of absorbed activity following ingestion of 54Mn by two healthy subjects. In seven subjects with occupational exposures to manganese for 8–26 y, the concentration of manganese in urine was on average about 64% (range, 30–100%) of that in blood (Crossgrove and Zheng, 2004). Assuming that a similar relation between blood and urine concentrations holds for non-occupationally exposed subjects, the reference blood concentration of 9 μg/kg given in Table 1 would correspond to daily urinary excretion of about 9 and 7 μg of manganese in a reference adult male and female, respectively. 3.3. Summary of the biokinetic database for laboratory animals Dastur et al. (1971) studied the biokinetics of 54Mn over 278 d following intraperitoneal injection of maleate 54Mn into 12 rhesus monkeys. The highest initial concentration was observed in the liver, followed by the kidneys and pancreas. By the end of the 278-d study the concentrations in these three organs decreased in the order pancreas N kidneys N liver, and several other organs including the adrenals and thyroid gland had higher concentrations of 54Mn than the pancreas, kidneys, and liver. With passing time the carcass (mainly bone, muscle, and skin with hair) contained increasingly greater portions of total-body activity. The carcass contained 17–53% of the retained activity over the first 70 d and 75% or more after 100 d. The content of 54Mn in the tissues of the central nervous system

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generally increased over the first 2 months and then showed a slow decline. A gradual increase in activity in the central nervous system was also seen in an earlier 34-day study by Dastur et al. (1969) involving intraperitoneal injection of maleate 54Mn into rats. Dorman et al. (2006) measured tissue manganese concentrations in 36 male rhesus monkeys following subchronic (6 h/d, 5 d/week) manganese sulfate (MnSO4) inhalation at different exposure levels for 65 exposure days. Tissue manganese concentrations increased to levels that depended on the tissue and the aerosol concentration. Tissue manganese concentrations returned to control levels by 90 d after the end of exposure. Results were consistent with occupational studies suggesting only a weak association between the concentrations of manganese in urine and inhaled air (Lucchini et al., 1995; Mergler et al., 1994). Monkeys exposed to MnSO4 at the highest exposure concentration (1.5 mg Mn/m 3) for 90 d showed an increased manganese concentration in bone. Roels et al. (1997) studied the absorption and distribution of manganese administered as MnCl2 or MnO2 once a week for 4 weeks to rats by oral gavage, intraperitoneal (i.p.) injection, or intratracheal (i.t.) instillation. Each study of a given compound and exposure mode involved six treated rats and six control rats. The concentration of manganese was measured in blood, liver, and cerebral tissues (cortex, cerebellum, and striatum) at 4 d after the last administration. Compared with controls, the liver concentration was not affected by the treatments regardless of the chemical form or route of administration. Administration of MnCl2 by any route and MnO2 by i.p. injection or i.t. instillation produced substantially higher concentrations in the blood and brain cortex than in controls. Uptake of manganese into the striatum was consistently higher when delivered to the lung than when ingested by the oral route, regardless of the administered form. MnO2 given orally did not significantly increase blood and cerebral tissue manganese concentrations, presumably due to low absorption from the intestines. The results of the study indicate that homeostatic mechanisms are able to prevent substantial increases of manganese in the brain when the manganese compounds are administered orally but not when administered by the other two routes. Chauncey et al. (1977) studied the uptake of intravenously administered 54Mn by selected tissues of 25 rats and six dogs. On average the liver, kidneys, heart, and lungs of dogs contained 41.4%, 8.5%, 2.1%, and 2.1%, respectively, of the injected activity after 4 h. At this time the concentration of 54Mn in liver was about 320 times that in blood. In rats, the concentration ratio liver:blood was about 87 at 30 min, 150 at 1 h, 290 at 2 h, and N500 at 4–6 h. The ratio kidney: blood was about 98 at 30 min, 220 at 1 h, 290 at 2 h, and N500 at 4– 6 h. Furchner et al. (1966) administered 54Mn as chloride to mice and rats by the oral, intravenous, and intraperitoneal routes and to dogs and monkeys by the oral and intravenous routes. Following intravenous administration, mice (n = 12) showed four components of retention with mean biological half-times 0.46 d (16.2%), 4.9 d (39.1%), 26 d (38.4%), and 192 d (6.4%); rats (n = 6) showed four components with mean half-times 0.67 d (12.9%), 5.6 d (46.4%), 24 d (36.1%), and 274 d (4.6%); monkeys (n = 3) showed three components with mean half-times 2.3 d (13.2%), 19 d (39.8%), and 145 d (47.0%); and dogs (n = 4) showed three components with mean halftimes 3.1 d (14.8%), 19 d (52.5%), and 87 d (32.7%); detailed studies on 44 rats indicated that for most tissues the concentration as a function of time roughly paralleled whole-body retention, but bone and brain had slower loss than other tissues. Clearance of 54Mn from blood and its secretion in bile were measured over the first 2 h after intravenous administration to rats (Klaassen, 1974). The investigator interpreted the results as indicating that manganese is secreted in bile against a concentration gradient. Comparison with earlier studies on rabbits and dogs indicated that the rate of biliary secretion varied with species.

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Koshida et al. (1963) examined the early distribution of 52Mn in adult (n = 5) and embryo (n = 8) mice using autoradiography. In the kidney 52Mn accumulated more in the cortex than the medulla and concentrated mainly in the epithelial cells of renal tubules. In the intestinal villi 52Mn concentrated in the epithelium and in the mucus covering its free surface. Activity was seen in the exocrine portion of the pancreas but not in the islets of Langerhorns. Activity concentrations in bone decreased in the order epiphysis N outer diaphysis N inner diaphysis and bone marrow. Male rats (n = 6) received daily intraperitoneal injections of 3 mg Mn/g for 30 d (Scheuhammer and Cherian, 1983). Timedependent manganese concentrations during exposure were compared with values in control animals (n = 6) for liver, kidney, pancreas, duodenum, spleen, testes, lungs, brain, skeletal muscle, bone, and blood. The concentration increased in all tissues except liver. Largest increases were seen for pancreas and bone, for which the concentration increased to about 6 and 90, respectively, times that in controls. For other solid tissues the concentration increased to 3–4 times that in control animals. The concentration in blood increased by a factor of 4 or more times the concentration in controls, with the increase almost totally accounted for by an increase in red blood cells. 3.4. Proposed biokinetic model for systemic manganese The structure of the biokinetic model for systemic manganese is shown in Fig. 2. Transfer coefficients are listed in Table 2. These transfer coefficients were derived from reference deposition fractions and biological half-times selected for reasonable agreement with reported biokinetic data for manganese, as illustrated in the following section. The selected reference deposition fractions and half-times are summarized below. Manganese initially entering the systemic circulation, e.g., by absorption from the GI (gastrointestinal) or respiratory tract, is assigned to Plasma. Manganese is assumed to leave Plasma with a half-time of 1 min, corresponding to a rounded outflow rate of 1000 d −1. Outflow from Plasma is divided as follows: 30% to Liver, 5% to Kidneys, 5% to Pancreas, 1% to Colon contents, 0.2% to Urinary Table 2 Transfer coefficients for systemic manganese. From

To

Transfer coefficient (d−1)

Plasma Plasma Plasma Plasma Plasma Plasma Plasma Plasma Plasma Plasma Plasma Plasma Liver 1 Liver 1 Liver 2 Kidneys Pancreas Pancreas ST0 ST1 ST2 Cortical bone surface Cortical bone surface Trabecular bone surface Trabecular bone surface Cortical bone volume Trabecular bone volume Brain RBC

Liver 1 Kidneys Pancreas Urinary bladder contents Right colon contents ST0 ST1 ST2 Cortical bone surface Trabecular bone surface Brain RBC Small intestine contents Liver 2 Plasma Plasma Plasma Small intestine contents Plasma Plasma Plasma Plasma Cortical bone volume Plasma Trabecular bone volume Plasma Plasma Plasma Plasma

300 50 50 2 10 391.8 150 40 2.5 2.5 1.0 0.2 0.139 0.555 0.347 0.347 0.347 0.347 33.3 0.347 0.0173 0.01716 0.0001733 0.01716 0.0001733 0.0000821 0.000493 0.00462 0.00833

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bladder contents, 0.5% to the bone surface compartments, 0.02% to RBC (red blood cells), 0.1% to Brain, and the remaining 58.18% to Other soft tissues. Liver is divided into two compartments called Liver 1 and Liver 2. Manganese moves from Plasma to Liver 1 and leaves Liver 1 with a half-time of 1 d, with 20% of outflow going to SI (small intestine) contents via biliary secretion and 80% entering Liver 2. Activity transfers from Liver 2 to Plasma with a half-time of 2 d. Activity entering Pancreas is removed with a half-time of 1 d, with outflow divided equally between Plasma and SI contents. The transfer from Pancreas to SI contents represents secretion in pancreatic juice. The transfer coefficients describing reabsorption of secreted manganese from the SI contents to plasma and transfer through the colon to feces are intended to be user-supplied values and hence are not specified in Table 2. That is, the systemic model may be used in conjunction with any user-supplied absorption fraction from the SI contents to plasma and user-supplied transit rates through the gastrointestinal contents. Activity transfers from Kidneys to Plasma with a half-time of 2 d. Activity transfers from Brain to Plasma with a half-time of 150 d. The transfer coefficient from RBC to Plasma (0.00833 d −1) is derived from the assumption that the residence time of manganese in red blood cells equals the mean lifetime of red blood cells, estimated as 120 d (ICRP, 1995). Activity depositing on bone surfaces is divided equally between Cortical bone surface and Trabecular bone surface. Activity leaves Cortical bone surface or Trabecular bone surface with a half-time of 40 d, with 99% returning to Plasma and 1% entering the corresponding bone volume compartment. Activity is removed from Cortical bone volume or Trabecular bone volume to Plasma at the reference turnover rate for the specific bone type in adults as given in ICRP Publication 89 (2002). “Other soft tissues” is divided into compartments ST0, ST1, and ST2 representing fast, intermediate, and slow turnover of manganese. ST1 receives 15% of activity leaving plasma, ST2 receives 4%, and ST0 receives 39.18% (the amount remaining after all other deposition fractions in the model were assigned). Activity is returned from ST0, ST1, and ST2 to plasma with half-times of 30 min, 2 d, and 40 d, respectively.

4. Discussion and conclusions 4.1. Comparison of model predictions with observations The deposition fractions and removal half-times indicated in the preceding section were designed to reproduce the biokinetic database summarized earlier with reasonable accuracy. This is illustrated below for some datasets that figured prominently in the construction of the model.

Fig. 3. Clearance of intravenously injected manganese from blood as predicted by the present model and observed in human subjects.

Model predictions of blood clearance of intravenously injected manganese are compared in Fig. 3 with a curve fit to collective blood clearance data for 14 subjects with a variety of illnesses (listed earlier). It is not known whether any of the illnesses affected blood clearance of manganese, but the collective data did not show particularly large scatter. An estimated 0.14% of administered 54Mn was contained in RBC of a normal subject 17 d after intravenous administration of 54MnC12 (Mahoney and Small, 1968) The model predicts an RBC content of 0.10% at this time. Model predictions of the rate of biological removal of manganese from the body are compared in Fig. 4 with data for healthy human subjects injected intravenously with 54Mn (Mahoney and Small, 1968; Mena et al., 1967). The retention curves in Fig. 4 appear reasonably consistent with plotted retention data of Davidsson et al. (1989) for two healthy subjects receiving 54Mn by intravenous injection. Davidsson et al. (1989) found shorter removal half-times for 54Mn absorbed to blood following ingestion than for intravenously injected 54Mn. The model predicts a fecal to urinary excretion ratio of about 45 for intravenously injected manganese. Maynard and Fink (1956) determined a ratio of about 40 over the first 6 d following intravenous injection of 52Mn as chloride into hospital patients. Mahoney and Small (1968) found virtually no 54Mn in urine following its intravenous injection as chloride into healthy subjects. Davidsson et al. (1989) found that fecal excretion accounted for virtually all of the biological removal of absorbed activity following ingestion of 54Mn by healthy subjects. Model predictions are consistent with the following findings for laboratory animals. Soon after acute or subchronic exposure, highest concentrations of manganese are found in the liver, kidneys, and pancreas (Chauncey et al., 1977; Dastur et al., 1971; Dorman et al., 2006; Kato, 1963). Over a period of weeks or months the concentrations in these three organs fall below the concentrations in some tissues with slower accumulation of manganese (Dastur et al., 1971). In the early period after intravenous injection the liver accumulates up to half of the injected amount, and the kidneys accumulate 8% or more (Chauncey et al., 1977). The brain shows substantially longer retention of manganese than other soft tissues (Furchner et al., 1966; Dastur et al., 1971). There is a gradual increase in the activity in the brain over a period of months following acute input of manganese into blood (Dastur et al., 1969, 1971). There is a component of long-term retention of manganese in bone (Dorman et al., 2006; Furchner et al., 1966; Scheuhammer and Cherian, 1983). The model parameter values were selected in part to approximate the reference tissue and total-body contents of manganese in adult

Fig. 4. Total-body retention of intravenously injected manganese as predicted by the present model and observed in healthy adult human subjects. Dashed curves are fits to retention data for three individual subjects of Mahoney and Small (1968). Solid curve through circles represents median total-body retention in eight subjects of Mena et al. (1967).

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males and females listed in Table 1, based on typical dietary intake of manganese (taken as 4 mg d −1 for males and 3 mg d −1 for females) and a reference gastrointestinal absorption fraction of 0.05. Model predictions for males are compared in Table 3 with the reference tissue and total-body contents of manganese given in Table 1. A similar level of agreement between model projections and reference values is obtained for females. For compartments other than brain and bone the predictions closely approximate reference tissue contents of manganese by 1 y after the start of intake. The model predicts that the brain content of manganese reaches a steady state by a few years after the start of a constant intake rate but the bone content continues to rise slowly over a period of decades. Sensitivity analyses indicate that the model predictions in Table 3 depend strongly on the assumed mass of manganese transferred daily from diet to blood (i.e., 0.05 ×4 mg d −1 or 0.2 mg d−1) but are relatively insensitive to the particular dietary intake and gastrointestinal uptake values that yield this mass, within realistic bounds on daily intake of manganese and fractional uptake to blood. For example, nearly the same time-dependent tissue contents as those shown in Table 3 are predicted if dietary intake is changed to 2.5 mg d −1 and gastrointestinal uptake to 0.08 (because 0.08× 2.5 mg d−1 =0.2 mg d−1), or if intake is changed to 5 mg d −1 and uptake to 0.04. This result seems consistent with experimental data, which indicate that the mass of manganese reaching systemic tissues via the gut is homeostatically controlled. 4.2. Comparison of dose estimates based on the proposed model and current ICRP model The proposed biokinetic model (defined in Fig. 2 and Table 2) and current ICRP biokinetic model for systemic manganese (Fig. 1) yield broadly similar estimates of dose per unit intake of radio-manganese but generally much different estimates of dose based on measurement of radio-manganese in urine. This is illustrated in Table 4, which compares 50-y committed equivalent dose estimates based on the two models for the case of acute inhalation of a moderately soluble form of 54Mn (Type M as defined in ICRP Publication 66, 1994b). The comparisons of dose estimates are expressed as ratios A:B, where A is the estimated dose per unit intake (Sv Bq −1) for a given tissue based on the proposed systemic model and B is the corresponding value based on the current ICRP model. The only difference in the calculations of A and B is the systemic model applied. The respiratory model, gastrointestinal transit model, gastrointestinal absorption fraction, and dosimetric models and assumptions (i.e., the models and assumptions used to convert nuclear transformations in source regions to equivalent doses to target regions) used in both sets of

Table 3 Comparison of model predictions of manganese content in an adult malea with reference values (Table 1). Tissue

Reference content (mg)

Total blood Blood plasma Liver Pancreas Kidney Brain Bone Otherc Total bodyc

0.05 0.002 2.3 0.15 0.30 0.45 1.0 5.8 10

Model predicted content after indicated period of intakeb 1y

10 y

25 y

50 y

0.05 0.002 2.4 0.15 0.31 0.35 0.63 5.8 9.7

0.05 0.002 2.4 0.16 0.31 0.47 0.88 5.9 10.2

0.05 0.002 2.4 0.16 0.31 0.47 1.1 5.9 10.4

0.05 0.002 2.4 0.16 0.31 0.47 1.2 5.9 10.6

a Adult male assumed to have dietary intake of 4 mg/d and gastrointestinal absorption of 5%. Reference manganese contents in an adult female (Table 1) are fit reasonably well by changing dietary intake to 3 mg/d. b Tabulated values based on an initial value of zero for all compartments. c Excluding gastrointestinal contents.

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Table 4 Comparison of equivalent dose estimates for inhalation of a moderately soluble form (Type M) of 54Mn by a male worker, based on the model proposed in this report (A) and the current ICRP model for manganese in workers (B). Tissue

Bone surfaces Brain Kidneys Liver Pancreas Red marrow Effective dose Other tissues

Ratio of dose estimates A:B Based on intake of 1 Bq

Based on 24-h urinary 54Mn on day 1

Based on 24-h urinary 54Mn on day 10

0.64 1.4 1.8 1.3 1.7 0.80 1.1 1.0–1.4

2.5 5.7 7.1 5.0 6.9 3.2 4.2 4.2–5.5

15 35 43 30 42 19 25 24–34

calculations are those applied in ICRP Publication 68 (1994b). The assumed aerosol size is 5 μm AMAD (Aerodynamic Median Activity Diameter), the default value applied in ICRP Publication 68. The tissue weighting factors used in the derivation of the effective dose are from ICRP Publication 60 (1991). Calculations were made using Oak Ridge National Laboratory's DCAL software (Eckerman et al., 2006). The ratios A:B of dose estimates are in the relatively narrow range of 0.64–1.8 for dose estimates based on a unit intake of 54Mn but differ substantially when intake of 54Mn and the resulting tissue doses are estimated on the basis of 24-h urinary excretion of 54Mn, particularly after the first 24 h post intake. These large differences in model predictions arise mainly because the ICRP model assigns half of total excretion of manganese to urine, while the present model assigns only ~2% to urine. Acknowledgments The work described in this manuscript was sponsored by the Office of Radiation and Indoor Air, U. S. Environmental Protection Agency (EPA), under Interagency Agreement DOE no. 1824-S581-A1, under contract no. DE-AC05-00OR22725 with UT-Battelle. The submitted manuscript has been authored by a contractor of the U.S. Government under contract DE-AC05-00OR22725. Accordingly, the U.S. Government retains a nonexclusive, royalty-free license to publish or reproduce the published form of this contribution, or allow others to do so, for U.S. Government purposes. References Andersen ME, Gearhart JM, Clewell HJ. Pharmacokinetic data needs to support risk assessment for inhaled and ingested manganese. Neurotoxicology 1999;20: 161–72. Anke M, Groppel B, Krause U, Arnhold W, Langer M. Trace element intake (zinc, manganese, copper, molybdenum, iodine and nickel) of humans in Thuringia and Brandenburg of the Federal Republic of Germany. J Trace Elem Electrolytes Health Dis 1991;5:69–74. Aschner M, Erikson KM, Dorman DC. Manganese dosimetry: species differences and implications for neurotoxicity. Crit Rev Toxicol 2005;35:1–32. Baruthio F, Guillard O, Arnaud J, Pierre F, Zawislak R. Determination of manganese in biological materials by electrothermal atomic absorption spectrometry: a review. Clin Chem 1988;34:227–34. Becker W, Kumpulainen J. Contents of essential and toxic mineral elements in Swedish market-basket diets in 1987. Br J Nutr 1991;66:151–60. Benes B, Jakubec K, Smid J, Spevackova V. Determination of thirty-two elements in human autopsy tissue. Biol Trace Elem Res 2000;75:195–203. Biego GH, Joyeux M, Hartemann P, Debry G. Daily intake of essential minerals and metallic micropollutants from foods in France. Sci Total Environ 1998;217:27–36. Borg DC, Cotzias GC. Manganese metabolism in man: rapid exchange of 56Mn with tissues as demonstrated by blood clearance and liver uptake. J Clin Invest 1958;37: 1269–78. Bro S, Sandstrom B, Heydorn K. Intake of essential and toxic trace elements in a random sample of Danish men as determined by the duplicate portion sampling technique. J Trace Elem Electrolytes Health Dis 1990;4:147–55. Buchet JP, Lauwerys R, Vandevoorde A, Pycke JM. Oral daily intake of cadmium, lead, manganese, copper, chromium, mercury, calcium, zinc and arsenic in Belgium: a duplicate meal study. Food Chem Toxicol 1983;21:19–24.

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