Cerium

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The publication is a recent review oficially published by the U.S. Environmental Protection Agency.

Data source

Reference

Reference Type:

review article or handbook

Title:

Toxicological Review of Cerium Oxide and Cerium Compounds

Author:

U.S. Environmental Protection Agency

Year:

2009

Bibliographic source:

EPA/635/R-08/002F

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

Principles of method if other than guideline:

The review summarizes the results from several key publications which describe the effect of cerium-compounds (ion Ce3+) in vivo. For an overview of the methods used see the results section below.

Test material

Test material information

Constituent 1

Reference substance name:

Cerium

EC Number:

231-154-9

EC Name:

Cerium

Cas Number:

7440-45-1

Molecular formula:

Ce

IUPAC Name:

cerium(3+)

Details on test material:

Many of the studies of the toxicokinetics of cerium were conducted using radioactive cerium. Stable and radioactive cerium are expected to behave ini a similar toxicokinetic manner and possess the same chemical properties. The test material used for the studies described in this review were 141Ce-ceric nitrate, 144Ce-ceric nitrate, 141Ce-cerous chloride, 144Ce-cerous chloride, 144Ce-cerous citrate and 144ce-oxide aerosols to study inhalation effects.

Radiolabelling:

yes

Remarks:

141Ce, 144Ce

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

ABSORPTION
1. Oral Exposure
Studies evaluating the absorption of cerium compounds following oral exposure in humans are not available.
In adult animals, cerium compounds are poorly absorbed following oral exposure, while suckling animals exhibit higher absorption and retention of cerium in the gastrointestinal (GI) tissues. Observed absorption of radioactive cerium salts from the GI tract of adult rats ranged from 0.05% to less than 0.1% of the administered dose (Kostial et al., 1989b; Inaba and Lengemann, 1972; Shiraishi and Ichikawa, 1972). Suckling rats, however, absorbed 40–98% of administered dose, with the youngest rats retaining the largest percentage of the dose (Kostial et al., 1989a, b; Inaba and Lengemann, 1972).

Four litters of Sprague-Dawley rats (n = 7–9), age 0, 7, 14, or 26 days, were given a single dose of [141Ce]-ceric nitrate of unreported concentration by intragastric dosing (Inaba and Lengemann, 1972). Subsequent, periodic whole-body radioactivity measurements were taken immediately after dosing and periodically thereafter. In another experiment in this study, two litters of 1-day-old newborn rats were given single doses of [141Ce]-ceric nitrate, and one rat from each litter was sacrificed at 1, 3, 5, 7, and 10 days after dosing, after which radioactivity in the GI tract and whole body was measured and macro-autoradiographs of the GI tract were produced.

It was observed that on or about day 16 of life, rats began consuming a solid, grain-based diet and were completely weaned by day 26 (Inaba and Lengemann, 1972). In weanling rats (rats dosed at 26 days of age), only 0.04% of the administered radioactivity remained in the body by 3 days after dosing. However, radioactivity in newborns diminished more slowly, dropping from 98% of administered dose on day 1 to 29% on day 16. The GI tract accounted for nearly 100% of whole-body retention on day 1 and 93% on day 16. After the onset of weaning in the suckling rats dosed as newborns, whole-body radioactivity fell to 3% of administered dose by day 24, of which only 17% was measured in the GI tract. Autoradiographs of the GI tract from the two litters dosed as 1-day-old newborns suggest rapid transit of radioactivity to the lower small intestine 1 day after exposure. Autoradiography of rats 5 days after dosing (6 days old) suggests that the intestinal radioactivity is restricted to the upper two-thirds of the epithelial villi, which the study authors associated with cerium concentration in the vacuoles.

Kostial et al. (1989b) administered single oral doses of an unreported concentration of [141Ce]-cerous chloride by intragastric dosing to 6-day-old and 6–8-week-old rats (strain unreported) to investigate whether distribution of cerium (and other metals) in the GI tract differed in suckling versus mature rats. Six-day-old rats were measured for whole-body and gut radioactivity 2, 4, 6, and 12 days after dosing, while adult rats were measured 2 days after dosing. Orally administered cerium chloride was more readily retained in the whole body, gut, and carcass of suckling rats than in older rats. The ileum was the main site for cerium chloride accumulation in the suckling rats following oral administration, while the stomach and large intestine were the main sites for cerium chloride accumulation in the 6–8-week-old rats. Whole-body radioactivity 6 days postexposure in 2-week-old suckling rats orally dosed with [141Ce] was 40% of the administered dose, of which 95% was found in the gut. However, whole-body radioactivity 6 days postexposure in adult (6–8-week-old) rats was only 0.05%, of which 66% was found in the gut, mostly in the stomach and cecum.

Shiraishi and Ichikawa (1972) administered single oral doses of an unreported concentration of [144Ce]-cerous chloride by intragastric dosing to 0-, 7-, 14-, and 21-day-old juvenile and 100-day-old adult Wistar rats. Cortisone acetate, which alters the morphology of the absorptive epithelium of the small intestine, was injected to a group of 7-day-old rats 4 days prior to [144Ce]-cerous chloride exposure to observe its effect on whole-body retention. Periodically (up to 70 days after dosing), small groups of rats from all age groups were sacrificed and measured for radioactivity in the whole-body, gut, and various excised tissues. The decrease in retention of whole-body radioactivity among suckling rats dosed at 0, 7, and 14 days after birth was approximately 11, 6.5, and 1.5%, respectively, of the administered dose. Weanling and adult rats exhibited a rapid decrease in whole-body radioactivity through 10 days following dosing. At 2 weeks after dosing, the 21- and 100-day-old adults had whole-body radioactivity of 0.08 and 0.018%, respectively, of the administered dose. The intestinal content accounted for most of the retained radioactivity in neonates until the age of weaning. Cortisone acetate treatment resulted in a more rapid loss of the oral dose from young rats, although whether this is due to lower uptake by intestinal cells or a more rapid release to feces is not presently clear. This investigation demonstrated that the whole-body retention of cerium chloride by suckling rats was greater than the retention by weanling and adult rats, and this increased retention by suckling rats may be due to increased pinocytic activity in the absorptive epithelium of sucklings (Shiraishi and Ichikawa, 1972).

Yorkshire piglets treated with [144Ce]-cerous chloride by gavage on the first or fourth day after birth and sacrificed 4 or 18 or 3 or 21 days, respectively, after dosing absorbed 2.5–8% of the administered dose (Mraz and Eisele, 1977). Absorption was threefold greater in piglets treated at 1 day of age versus those treated at 4 days of age. Body content of cerium chloride did not differ significantly between piglets sacrificed at the earlier dates and those sacrificed later, indicating that absorption was almost complete within 3–4 days.

Eisele et al. (1980) gave single gavage doses of either [144Ce]-cerous chloride or [144Ce]-cerous citrate (concentration unreported) to 0–6- or 6–24-hour-old C3H mice and Sprague-Dawley rats and to 6–24-hour-old Yorkshire piglets. Radioactivity levels were measured in the GI tract and other tissues, including the remaining carcass, at days 1, 5, 7, 9, 12, 15, 17, 19, and 21. In the 0–6-hour-old mice, a high of 31% of the administered dose of cerium chloride was retained in the body 9 days following exposure. At 21 days post administration, the amount of pooled cerium citrate and chloride retained was approximately 25%. The mice dosed 0–6 hours after birth retained more cerium in the GI tract throughout the 21-day observation period than the mice dosed 6–24 hours after birth. The 0–6- and 6–24-hour-old rats exhibited absorption of 9–10% of administered cerium 21 days after exposure. In the Yorkshire piglets, the absorbed dose did not differ significantly over the 21-day observation period.

Two studies in adult rats also reported low absorption of soluble cerium following oral exposures. Durbin et al. (1956) administered single [144Ce]-ceric nitrate (unreported concentrations) intramuscular and intragastric doses to adult female Sprague-Dawley rats. The rats dosed intramuscularly were sacrificed at post-administration days 1, 4, 64, and 256, while the intragastric-dosed rats were sacrificed 4 days after administration. Less than 0.1% of the intragastric-administered dose was absorbed from the GI tract.

Stineman et al. (1978) administered single intragastric [141Ce]-cerous chloride doses of 1000 mg/kg (lethal to 5% of the animals [LD5]) and 1163 (LD25) mg/kg to 6–8-week-old male Swiss ICR mice and sacrificed them at 4 hours or at 1, 3, or 7 days later. No measurements were made of whole-body radioactivity; however, 97–99% of radioactivity in the 12 sampled tissues was found in the gut (stomach + duodenum).

In young (suckling) animals, soluble cerium appears to be retained in intestinal cells, particularly in the ileum, possibly resulting in a much greater absorption than in adult animals (Kostial et al., 1989a, b; Inaba and Lengemann, 1972). However, cerium retained in intestinal cells has been demonstrated to be unavailable systemically (Inaba and Lengemann, 1972). The high gut retention of cerium in young animals may be associated with high pinocytotic activity of the newborn intestinal cells (Kostial et al., 1989b). Glucocorticoids, such as methylprednisolone, stimulate production of endogenous corticosteroids, which cause precocious gut closure (decreased pinocytosis) and maturation of the metal absorptive process (Kargacin and Landeka, 1990). Administration of methylprednisolone in conjunction with artificial feeding of [141Ce]-cerous chloride in cows’ milk to 4-day-old suckling rats (strain not reported) resulted in a nearly 40-fold reduction in the amount of cerium chloride detected in gut tissue (Kargacin and Landeka, 1990). This finding suggests that the pinocytotic activity of the intestinal cells contributed to the differences. Similarly, injection with cortisone acetate resulted in a more rapid loss of an oral dose to feces of young rats (Shiraishi and Ichikawa, 1972), although whether this is due to lower uptake by intestinal cells or a more rapid release is not presently clear.

2. Inhalation Exposure
Studies evaluating the deposition or absorption of cerium compounds following inhalation exposure in humans are not available. However, cerium has been detected in the lung tissue and alveolar macrophages of subjects believed to have been exposed to cerium occupationally.

Case reports and a retrospective occupational investigation provide support for the limited absorption of cerium deposited in the lung following inhalation exposure. Transbronchial biopsies in a 60-year-old movie projectionist showed cerium concentrations of 11 μg/g wet weight after 12 years of exposure (Porru et al., 2001). McDonald et al. (1995) demonstrated particulate material (diameter range from <1 μm to 5–10 μm) localized within lung biopsy cells by using a scanning electron microscope. Analysis of bronchioalveolar lavage fluid from a 58-year-old patient exposed to rare earth dusts and asbestos revealed cerium and phosphorus in the alveolar macrophages (Pairon et al., 1995). The cerium particles accounted for 70% of the particles observed in the lung tissue and were also identified in the interstitial macrophages.

Microscopic examination of the tracheobronchial lymph nodes of a movie projectionist of 25 years revealed grey granules in large macrophages, which were characterized as calcium and rare earth elements (cerium, lanthanum, and neodymium) by energy-dispersive analysis of X-rays (Waring and Watling, 1990). Energy-dispersive X-ray also characterized dark particles (diameter of 1 to 6 μm) as cerium, unidentifiable by optical microscopy, in the bronchioalveolar lavage of a 13-year photoengraver.

Lung tissues from a photoengraver exposed to smoke from cored carbon arc lamps for 46 years (Pietra et al., 1985) were found to have cerium concentrations 2,800–207,000 times higher than those of urine, blood, or nails, suggesting that cerium particles in the lung are poorly mobilized. The concentration of cerium in the lung and lymph nodes of a subject exposed to cerium for 46 years as a photoengraver was 167 and 5 μg/g wet tissue weight, respectively, and 2,400- and 53-times higher, respectively, than the concentration in unexposed control subjects (Vocaturo et al., 1983; Sabbioni et al., 1982).

Pairon et al. (1994) performed a retrospective evaluation of retention of cerium-containing particles in the lungs of workers previously exposed to mineral dusts. Bronchioalveolar lavage and lung tissue samples from mineral dust exposed workers and controls were examined for cerium content. In the seven cases that were judged to have high cerium particle retention (as defined by having lavage fluid or tissue cerium concentrations at least 5 times higher than those of controls), time since last exposure ranged from present to 29 years, with one patient’s exposure time not available.

Limited animal data are available regarding total deposition of cerium aerosols within the respiratory tract. Thomas et al. (1972) exposed 4-month-old, mixed sex Holtzman rats to two concentrations (unreported) of aerosolized 1.4 μm median aerodynamic diameter (GSD of 2.0) [144Ce]-ceric hydroxide for 10 minutes. Whole-body radioactivity measurements were used to identify a 28% deposition rate of inhaled cerium aerosol. Boecker and Cuddihy (1974) reported an average deposition of 71% in beagles exposed to [144Ce]-cerous chloride for 4–10 minutes. In both studies, cerium was deposited in the lungs with evidence of absorption from the lung provided by the subsequent detection of cerium in the skeleton, liver, and kidneys.


LITERATURE:

Boecker, BB; Cuddihy, RG. (1974) Toxicity of 144Ce Inhaled as 144CeCl3 by the beagle: metabolism and dosimetry. Radiat Res 60(1):133–154.

Durbin, PW; Williams, MH; Gee, M; et al. (1956) Metabolism of the lanthanons in the rat. Proc Soc Exper Biol Med 91:78–85.

Eisele, GR; Mraz, FR; Woody, MC. (1980) Gastrointestinal uptake of 144Ce in the neonatal mouse, rat and pig. Health Phys 39:185–192.

Inaba, J; Lengemann, FW. (1972) Intestinal uptake and whole-body retention of 141Ce by suckling rats. Health Phys 22:169–175.

Kargacin, B; Landeka, M. (1990) Effect of glucocorticoids on metal retention in rats. Bull Environ Contam Toxicol 45(5):655–661.

Kostial, K; Kargacin, B; Landeka, M. (1989a) Gut retention of metals in rats. Biol Trace Elem Res 21:213–218.

Kostial, K; Kargacin, B; Blanusa, M; et al. (1989b) Location of mercury, cerium, and cadmium in the gut of suckling and weaned rats. Period Biol 91(3):321–326.

McDonald, JW; Ghio, AJ; Sheehan, CE; et al. (1995) Rare earth (cerium oxide) pneumoconiosis―analytical scanning electron microscopy and literature review. Mod Pathol 8(8):859–865.

Mraz, FR; Eisele, GR. (1977) Gastrointestinal absorption and distribution of 144Ce in the suckling pig. Health Phys 33:494–495.

Pairon, JC; Roos, F; Iwatsubo, Y; et al. (1994) Lung retention of cerium in humans. Occup Environ Med 51(3):195–199.

Pairon, JC; Roos, F; Sebastien, P; et al. (1995) Biopersistence of cerium in the human respiratory tract and ultrastructural findings. Am J Indus Med 27(3):349–358.

Pietra, R; Sabbioni, E; Ubertalli, L; et al. (1985) Trace elements in tissues of a worker affected by rare-earth pneumoconiosis. A study carried out by neutron activation analysis. J Radioanal Nucl Chem 92(2):247–269.

Porru, S; Placidi, D; Quarta, C; et al. (2001) The potential role of rare earths in the pathogenesis of interstitial lung disease: a case report of movie projectionist as investigated by neutron activation analysis. J Trace Elem Med Biol 14(4):232–236.

Sabbioni, E; Pietra, R; Gaglione, P; et al. (1982) Long-term occupational risk of rare-earth pneumoconiosis: a case report as investigated by neutron activation analysis. Sci Total Environ 26:19–32.

Shiraishi, Y; Ichikawa, R. (1972) Absorption and retention of 144Ce and 95Zr-95Nb in newborn, juvenile and adult rats. Health Phys 22:373–378.

Stineman, CH; Massaro, EJ; Lown, BA; et al. (1978) Cerium tissue/organ distribution and alterations in open field and exploratory behavior following acute exposure of the mouse to cerium (citrate). J Environ Pathol Toxicol 2(2):553–570.

Thomas, RL; Scott, JK; Chiffelle, TL. (1972) Metabolism and toxicity of inhaled 144Ce in rats. Radiat Res 49:589–610.

Vocaturo, G; Colombo, F; Zanoni, M; et al. (1983) Human exposure to heavy metals: rare earth pneumoconiosis in occupational workers. Chest 83(5):780–783.

Waring, PM; Watling, RJ. (1990) Rare earth deposits in a deceased movie projectionist: a new case of rare earth pneumoconiosis? Med J Aust 153(11/12):726–730.

Details on distribution in tissues:

DISTRIBUTION
1. Oral Exposure
Although cerium appears to be poorly absorbed from the GI tract, the bone and liver were the organs with the highest cerium levels in rats following oral gavage of cerium chloride (Shiraishi and Ichikawa, 1972). The concentration of cerium in the kidney, liver, lung, and spleen of male ICR mice was significantly elevated relative to controls following 6 and 12 weeks of oral exposure to 20 or 200 ppm cerium chloride (Kawagoe et al., 2005). The lung and spleen contained the highest cerium concentrations in male ICR mice.

Manoubi et al. (1998) gave a single intragastric dose of stable cerium nitrate (20 mg/mL) to Wistar rats. Three hours after dosing, cerium was found in the lysosomes of the duodenal villosity but not in the liver or spleen. In 1-day-old Sprague-Dawley rats given a single intragastric dose of [141Ce]-ceric nitrate of unreported concentration, Inaba and Lengermann (1972) found cerium to be localized centrally, likely in the vacuoles, within epithelial cells of the small intestine.

Cerium is capable of crossing the placenta and entering the fetal circulation in mice, but the amounts found in the uterus and placenta were generally less than 5% of the maternal body burden and decreased rapidly with increased time after exposure (Naharin et al., 1969). Fetal body burdens in rodents were generally less than 1% of the initial maternal body burden after either injected or oral administration (Levack et al., 2002; Inaba et al., 1992; Naharin et al., 1969). Small amounts of injected cerium were also found in the maternal milk of mice (Naharin et al., 1974), although at a small proportion (<0.01%) of the maternal body burden.

2. Inhalation Exposure
As poorly soluble particles, cerium oxide particles behave like other airborne particles, depositing within the respiratory tract based on aerodynamic character (Schulz et al., 2000). Hamsters inhaling [144Ce]-cerium oxide aerosols with particle activity median diameters of 0.11 and 0.06 μm exhibited lung burdens of 3.6% at 5 hours and 50% at 3 hours after exposure, respectively, of initial body burden (Kanapilly and Luna, 1975).

Once deposited in the lung, insoluble cerium compounds may dissolve slowly, as evidenced by the low percentage of cerium found in other tissues. In an investigation of the toxicity of insoluble cerium, Hahn et al. (2001) exposed beagles to aerosolized [144Ce]-fused aluminosilicate particles for 2–48 minutes and collected a variety of tissues (tissues studied not reported) at death (up to 6,205 days following exposure). Cerium was dissolved from the lung into the systemic circulation and observed in the liver, skeleton, and tracheobronchial lymph nodes. Hahn et al. (2001) found between 1.0 and 10% of the initial lung burden of [144Ce]-fused aluminosilicate particle aerosol in the liver and skeleton of beagles observed for 800 days following 2–48-minute inhalation exposures. Hahn et al. (1999) also observed [144Ce]-fused aluminosilicate particle translocation to the tracheobronchial lymph nodes following acute inhalation of the particles. Lundgren et al. (1992) exposed adult F344/Crl rats to [144Ce]-cerium oxide for 5–50 minutes or to bimonthly exposures of 25 minutes for 1 year; rats were sacrificed at 1 hour and 3, 7, 14, 28, 56, 112, 224, 448, 560, and 672 days after exposure. The lungs, heart, liver, spleen, kidney, and skeleton (remaining carcass) were measured for cerium. Cerium was detected in the liver and skeleton in increasing percentages of body burden with respect to time, while cerium was not detected in the spleen and kidneys.

More soluble forms of cerium (e.g., cerium citrate) may be systemically absorbed more easily from the lung due to the increased solubility of the compound. Morgan et al. (1970) exposed Swiss mice to aerosols of [144Ce] in the form of chloride, citrate, or fused clay, with activity median diameters from 1.3 to 2.75 μm, in unreported concentrations or durations. While the initial body burden of all forms decreased rapidly during the first 2 weeks, likely due to mucociliary elimination to the GI tract, the remaining lung burden for the relatively insoluble fused clay remained higher than the chloride or citrate for the duration of the study (130 days). Conversely, the liver burdens of the citrate and chloride forms remained higher than the fused clay by about an order of magnitude. Further, as lung burdens of the chloride and citrate forms decreased, the bone burdens of these forms increased. The bone burden for the fused clay form, like the liver, was about an order of magnitude lower than the citrate or chloride forms.
Sturbaum et al. (1970) exposed 40 Chinese hamsters via the nose to [144Ce]-cerous chloride aerosol, activity median diameter of 0.83 μm and a GSD of 1.7, for 20 minutes and sacrificed small groups (n = 4) at 2, 8, 16, 28, 64, 128, and 256 days after exposure. Whole-body and tissue (types unreported) measurements of cerium radioactivity were made. The liver and skeleton exhibited between 1 and 10% of the initial body burden throughout the post-administration measurements, while the lung portion of the initial body burden diminished from approximately 20 at two hours to <1% by study’s end.

Cerium has been observed to be localized in the cell, particularly in the lysosomes, where it is concentrated and precipitated in an insoluble form in association with phosphorus. Wistar rats were exposed to stable cerium chloride aerosol, mean diameter of 0.1 μm, 5 hours/day for either 5 days or 4 days/week for 4 weeks (Galle et al., 1992; Berry et al., 1989, 1988). Several hours after exposure, cerium was deposited in the lysosomes of alveolar macrophages. The cerium deposits appeared to be in the form of aggregates of fine granules or fine needles that varied in length from 30 to 60 nm, with the longer needles resulting from the 4-week exposure. Cerium was found in the lysosomal fraction of liver centrifugate collected from rats (strain unreported) given an intravenous (i.v.) injection of 1.3 mg/kg [141Ce]-cerous chloride (Wiener-Schmuck et al., 1990). Cerium was also found in the lysosomes of the duodenal villosity, but not in the liver or spleen of Wistar rats following intragastric dosing. Cerium was also localized centrally, likely in the vacuoles, within epithelial cells of the small intestine of Sprague-Dawley rats.

LITERATURE:
Berry, JP; Meignan, M; Escaig, F; et al. (1988) Inhaled soluble aerosols insolubilised by lysosomes of alveolar cells. Application to some toxic compounds; electron microprobe and ion microprobe studies. Toxicology 52(1–2):127–139.

Berry, JP; Masse, R; Escaig, F; et al. (1989) Intracellular localization of cerium. A microanalytical study using an electron microprobe and ionic microanalysis. Hum Toxicol 8(6):511–520.

Galle, P; Berry, JP; Galle, C. (1992) Role of alveolar macrophages in precipitation of mineral elements inhaled as soluble aerosols. Environ Health Perspect 97:145–147.

Hahn, FF; Muggenberg, BA; Guilmette, RA; et al. (1999) Comparative stochastic effects of inhaled alpha- and beta-particle-emitting radionuclides in beagle dogs. Radiat Res 152:S19-S22

Hahn, FF; Muggenburg, BA; Snipes, MB; et al. (2001) The toxicity of insoluble cerium-144 inhaled by beagle dogs: non-neoplastic effects. Radiat Res 155(1):95–112.

Inaba, J; Nishimura, Y; Takeda, H; et al. (1992) Placental transfer of cerium in the rat with special reference to route of administration. Radiat Prot Dosimet 41(2/4):119–122.

Kanapilly, GM; Luna, RJ. (1975) Deposition and retention of inhaled condensation aerosols of 144CeO2 in Syrian hamsters. In: Boecker, BB; Rupprecht, FC; eds. Annual report of the Inhalation Toxicology Research Institute. Lovelace Foundation for Medical Education and Research, Albuqueque, NM; Report No. LF-52; pp. 79–83.

Kawagoe, M; Hirasawa, F; Wang, SC; et al. (2005) Orally administered rare earth element cerium induces metallothionein synthesis and increases glutathione in the mouse liver. Life Sci 77:922–937.

Levack, VM; Hone, PA; Phipps, AW; et al. (2002) The placental transfer of cerium: experimental studies and estimates of doses to the human fetus from 141Ce and 144Ce. Int J Radiat Biol 78:227–235.

Lundgren, DL; Hahn, FF; Diel, JH; et al. (1992) Repeated inhalation exposure of rats to aerosols of 144CeO2. I. Lung, liver, and skeletal dosimetry. Radiat Res 132(3):312–24.

Manoubi, L; Hocine, N; Jaafoura, H; et al. (1998) Subcellular localization of cerium in intestinal mucose, liver, kidney, suprarenal and testicle glands, after cerium administration in the rat. J Trace Microprobe Techniques 16(2):209–219.

Morgan, BN; Thomas, RG; McClellan, RO. (1970) Influence of chemical state of cerium-144 on its metabolism following inhalation by mice. Am Ind Hyg Assoc J 31(4):479–484.

Naharin, A; Lubin, E; Feige, Y. (1969) Transfer of 144Ce to mouse embryos and offspring via placenta and lactation. Health Phys 17:717–722.

Schulz, H; Brand, P; Heyder, J. (2000) Particle deposition in the respiratory tract. In: Gehr, P; Heyder, J; eds. Particle-lung interactions. New York, NY: Marcel Dekker; pp. 229–290.

Shiraishi, Y; Ichikawa, R. (1972) Absorption and retention of 144Ce and 95Zr-95Nb in newborn, juvenile and adult rats. Health Phys 22:373–378.

Wiener-Schmuck, M; Lind, I; Polzer, G; et al. (1990) In vivo and in vitro effects of rare earth compounds. J Aerosol Sci 21(1):S505–S508.

Details on excretion:

ELIMINATION
Following inhalation exposure, the initial rapid elimination of insoluble cerium from the body is due primarily to transport up the respiratory tract by the mucociliary escalator and eventual swallowing of the material, as with other poorly soluble particles (Boecker and Cuddihy, 1974). Initial short-term clearance rates range from 35 to 95% of initial cerium body burden, depending on the species tested and length of clearance time investigated. Lundgren et al. (1992) exposed adult F344/Crl rats to [144Ce]-cerium oxide aerosol for 5–50 minutes, with clearance of approximately 90% of the initial body burden by 7 days. Kanapilly and Luna (1975) exposed hamsters to [144Ce]-cerium oxide aerosols with particle activity median aerodynamic diameters of 0.11 and 0.06 μm and observed decreases in initial body burden of 95 and 60%, respectively, 4 days after exposure. Differences in clearance rates may have been dependent on particle size differences, with the smaller particles taking more time for elimination; however, the authors also stated that the difference may have resulted from a leak in the inhalation chamber used for the first dose group. Boecker and Cuddihy (1974) observed an early clearance of initial body burden from 35–80% for individual dogs 4 days after exposure. Thomas et al. (1972) exposed Holtzman rats to two concentrations (unreported) of aerosolized [144Ce]-ceric hydroxide for 10 minutes and observed approximately 75–95% clearance of initial body burden within 2 weeks of exposure (Thomas et al, 1972). Sturbaum et al. (1970) reported clearance of 80% of initial cerium body burden by 7 days in Chinese hamsters exposed to [144Ce]-cerous chloride aerosol for 20 minutes. After the initial clearance of cerium particles from the upper respiratory tract, pulmonary clearance is slower, with reported slow-phase clearance half-times ranging from 100 to 190 days in rodents (Lundgren et al., 1974; Thomas et al., 1972; Morgan et al., 1970; Sturbaum et al., 1970). The slow-phase clearance was slightly faster in beagles, with an estimated half-time of 63 days (Boecker and Cuddihy, 1974). Slow-phase clearance from the lung is a combination of cerium dissolution and absorption (Morgan et al., 1970) and mechanical clearance from the respiratory tract (Sturbaum et al., 1970).

Elimination of orally administered soluble cerium has been shown to be age dependent in animals, with suckling animals absorbing cerium into the GI tissues (Inaba and Lengemann, 1972). This cerium may remain in the intestinal cells, may not be available systemically, and may eventually be eliminated in the feces.

Although quantitative estimates of cerium elimination are rare, it appears that the primary route of elimination for cerium, whether inhaled, ingested, or injected, is through the feces, with small (generally <10%) amounts eliminated in the urine (Lustgarten et al., 1976; Durbin et al., 1956). It has been suggested that the fecal excretion of systemically absorbed cerium is due to elimination in the bile (Lustgarten et al., 1976), since hepatic clearance was due primarily to biliary function.

Literature:
Boecker, BB; Cuddihy, RG. (1974) Toxicity of 144Ce Inhaled as 144CeCl3 by the beagle: metabolism and dosimetry. Radiat Res 60(1):133–154.

Durbin, PW; Williams, MH; Gee, M; et al. (1956) Metabolism of the lanthanons in the rat. Proc Soc Exper Biol Med 91:78–85.

Inaba, J; Lengemann, FW. (1972) Intestinal uptake and whole-body retention of 141Ce by suckling rats. Health Phys 22:169–175.

Kanapilly, GM; Luna, RJ. (1975) Deposition and retention of inhaled condensation aerosols of 144CeO2 in Syrian hamsters. In: Boecker, BB; Rupprecht, FC; eds. Annual report of the Inhalation Toxicology Research Institute. Lovelace Foundation for Medical Education and Research, Albuqueque, NM; Report No. LF-52; pp. 79–83.

Lundgren, DL; McClellan, RO; Thomas, RL; et al. (1974) Toxicity of inhaled 144CeO2 in mice. Radiat Res 58:448–461.

Lundgren, DL; Hahn, FF; Diel, JH; et al. (1992) Repeated inhalation exposure of rats to aerosols of 144CeO2. I. Lung, liver, and skeletal dosimetry. Radiat Res 132(3):312–24.

Lustgarten, CS; Boecker, BB; Cuddihy, RG; et al. (1976) Biliary excretion of 144Ce after inhalation of 144Ce citrate in rats and Syrian hamsters. III. Annual report of the Inhalation Toxicology Research Institute. Lovelace Foundation for Medical Education and Research, Albuqueque, NM; pp. 84–87.
Morgan, BN; Thomas, RG; McClellan, RO. (1970) Influence of chemical state of cerium-144 on its metabolism following inhalation by mice. Am Ind Hyg Assoc J 31(4):479–484.

Sturbaum, B; Brooks, AL; McClellan, RO. (1970) Tissue distribution and dosimetry of 144Ce in Chinese hamsters. Radiat Res 44:359–367.

Thomas, RL; Scott, JK; Chiffelle, TL. (1972) Metabolism and toxicity of inhaled 144Ce in rats. Radiat Res 49:589–610.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): low bioaccumulation potential based on study results

Executive summary:

METABOLISM

As an element, cerium is neither created nor destroyed within the body. The particular cerium compound (e.g., cerium chloride, cerium oxide) may be altered as a result of various chemical reactions within the body, particularly dissolution, but data have not demonstrated a change in the oxidation state of the cerium cation. Exposure to cerium has been shown to change hepatic levels of some cytochrome (CYP) P450 isozymes in a species- and strain-sensitive manner for mice. Salonpää et al. (1992) gave i.v. cerous chloride injections of 2 mg/kg to adult DBA/2 and C57BL/6 mice and observed increases in expression of CYP2A4 and CYP2A5 in the livers (2 and 3 days after dosing) and in the kidneys (6 hours and 1 day after dosing) of D2 mice but not in B6 mice. Arvela et al. (1991) gave i.v. cerous chloride injections of 0.5, 1, and 2 mg/kg to adult male DBA/2 and C57BL/6 mice and found a greater sensitivity to increased CYP450 expression (isoform not reported) in DBA/2 and C57BL/6 mice 24 hours and 3 days after exposure, respectively. Conversely, Arvela and Karki (1971) observed a 50% reduction, compared to controls, in CYP450 activity in adult Sprague-Dawley rats 3 days after a single i.v. injection of 2 mg/kg cerous chloride. The effect of changes in CYP450 levels on the toxicokinetics or toxicity of cerium, if any, is not known. In addition, the relatively high intravenous bolus doses used in the available studies may not be relevant to oral or inhaled exposure to cerium oxide.

Literature:

Arvela, P; Karki, NT. (1971) Effect of cerium on drug metabolism activity in rat liver. Experientia 27(10):1189–1190.

Arvela, P; Kraul, H; Stenback, F; et al. (1991) The cerium-induced liver injury and oxidative drug metabolism in Dba/2 and C57bl/6 mice (Finland). Toxicology 69(1):1–9.

Salonpää, P; Iscan, M; Pasanen, M; et al. (1992) Cerium-induced strain-dependent increase in Cyp2a-4/5 (cytochrome P4502a-4/5) expression in the liver and kidneys of inbred mice. Biochem Pharmacol 44(7):1269–1274.