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National Toxicology Program. Report on Carcinogens Monograph on Antimony Trioxide: RoC Monograph 13 [Internet]. Research Triangle Park (NC): National Toxicology Program; 2018 Oct.
Report on Carcinogens Monograph on Antimony Trioxide: RoC Monograph 13 [Internet].
Show detailsDisposition and toxicokinetics refer to how a chemical enters and leaves the body, what happens to it within the body, and the rates of these processes. Disposition includes absorption, distribution, metabolism, and excretion (ADME), all of which can affect a chemical’s toxicity. This monograph focuses on antimony(III) trioxide (Section 3.1); however, exposure also occurs to other forms of antimony (Section 3.2), such as antimony salts or organic molecules used to treat leishmaniasis or schistosomiasis. Separate subsections discuss absorption and distribution (Sections 3.1.1 [trioxide] and 3.2.1 [other forms]) and excretion (Sections 3.1.2 [trioxide] and 3.2.2 [other forms]) of antimony. Similar to metals in general, antimony is metabolized by changing its valence state, which generally varies between +3, i.e., antimony(III) (trivalent), and +5, i.e., antimony(V) (pentavalent), in vivo, and data for these conversions are discussed in Section 3.3. Toxicokinetic studies are discussed in Section 3.4 and an overall synthesis and summary is provided in Section 3.5. The mechanistic implications of these data are discussed in Section 6.
3.1. Antimony(III) Trioxide
Absorption of antimony via the lung or gastrointestinal (GI) tract in humans and experimental animals is indicated through measurement of elemental antimony in blood, urine, or body tissues. Antimony is initially distributed to the blood, where it tends to accumulate mainly in red blood cells. Tissue distribution is generally to spleen, liver, and bone marrow, all of which are rich in reticuloendothelial cells, although the thyroid may also accumulate antimony in some species. Antimony(III) accumulates in tissues with repeated oral administration (Stemmer 1976).
3.1.1. Absorption and Distribution
The main sources for information on absorption and distribution of antimony(III) trioxide are authoritative reports from governmental and international agencies (EU 2008; Mak 2007) and recent reviews summarizing many older publications (Belzile et al. 2011; Tylenda and Fowler 2015). The quality of the data was critically assessed in Belzile et al. and in the EU (2008) risk assessment report for antimony(III) trioxide. Only two recent studies with exposure to antimony(III) trioxide comply with current research standards: TNO Quality of Life (2005), conducted according to OECD Guidelines and Good Laboratory Practice (GLP), and NTP (2017a), conducted according to U.S. Food and Drug Administration GLP.
Human Studies
The bioavailability of antimony is generally low because of its limited water solubility, but absorption does occur from various routes, including inhalation and oral ingestion (Belzile et al. 2011). (See Section 1.1 and Table 1-3 for a discussion of the bioaccessibility of several antimony compounds.)
Inhalation. The highest exposures of people to antimony by inhalation are from occupational exposure. Antimony has been detected in the lungs, blood, and urine of workers who had inhaled antimony identified as antimony(III) trioxide or likely to be antimony(III) trioxide; inhaled antimony compounds are retained long term in the lung (HSDB 2013; NTP 2017a). Elevated urinary excretion of antimony has been reported for workers exposed to antimony(III) trioxide in lead battery production (Kentner et al. 1995) (see Table 2-3) and for port workers in Valparaiso, Chile exposed to elevated air concentrations of antimony from heavy vehicular traffic when antimony sulfide or sulfate in brake pads is oxidized to antimony(III) trioxide at temperatures achieved during braking (see Sections 2.1 and 2.3.2) (Quiroz et al. 2009). Accumulation of antimony in the lung was demonstrated for seven workers accidentally exposed to radioactive antimony (125Sb, described as antimony oxides, but likely including antimony(III) trioxide). Biomonitoring of whole-body radioactivity found the antimony to be almost entirely confined to the lungs (Garg et al. 2003). However, workers occupationally exposed to antimony(III) trioxide had detectable antimony in urine as well as lungs even after their exposure ceased (HSDB 2013).
The EU (2008) risk assessment report used data from humans to predict absorption from inhalation exposure based on the Multiple Path Particle Deposition (MPPD) model prediction using particle size and density from collected antimony(III) trioxide samples and gastrointestinal tract absorption in humans. Absorption was predicted to be 6.82% resulting from deposition in the alveolar region (6.0%) and the upper airways (0.82%, based on transportation via mucociliary transport of 81.6% of the inhaled amount to the gastrointestinal tract, where 1% is assumed to be absorbed).
Oral exposure. Antimony(III) trioxide is generally considered to be poorly absorbed from the GI tract (Stemmer 1976). No data for oral exposure to antimony(III) trioxide in humans was identified, but absorption is likely low. The EU (2008) calculated a rate of 0.3% for oral absorption from antimony(III) trioxide; however, concerns were expressed because the absorption was based on one study of oral exposure of rats to antimony(III) trioxide, with antimony levels two to three orders of magnitude higher than human exposures and on human studies using protocols that do not meet current standards.
Experimental Animal Studies
Inhalation. Animals exposed to antimony(III) trioxide by inhalation showed increased concentrations of antimony in blood in the studies by Newton et al. (1994) and NTP (2017a). In the Newton et al. (1994) study, antimony (III) trioxide levels were detected at several timepoints in red blood cells, but not plasma, from male and female Fisher 344 rats exposed to antimony trioxide by inhalation (at 0.055, 0.51, or 4.50 mg/m3) for up to 12 months and observed for another 12 months (Table B-1). The antimony levels increased proportionally with exposure level and nearly so with an exposure duration of 12 months compared with 6 months. Lung burdens also increased with exposure concentrations during the 2-year study in male and female Fischer 344 rats (Newton et al. 1994) (see Table 3-1 in Section 3.4, Toxicokinetics).
Table 3-1
Antimony(III) Trioxide Levelsa (μg/g) in Lung Tissue During a One-year Chronic Exposure (Six-month and 12-month Samples) and a One-year Observation Period (Six-month and 12-month Samples) in Fischer 344 Male and Female Rats.
NTP (2017a) exposed rats and mice of both sexes to antimony(III) trioxide by inhalation with either short-term inhalation exposure (2 weeks plus a 4-week recovery period) to 0, 3.75, 7.5, 15, 30, or 60 mg/m3 for 6 hours plus T90 (12 minutes) per day, 5 days per week, or long-term exposure for 2 years at concentrations of 0, 3, 10, or 30 mg/m3 with the same 5 days per week exposure. Blood levels increased with exposure concentration in rats and mice for both the short-term (data not shown) and the long-term exposure periods. Blood levels for the long-term exposure period were measured on days 61, 124, 269, 369, and 551 (see Appendix B, Table B-2 and Figure 3-1). Blood concentrations increased with exposure duration for rats by approximately 4 to 5-fold when concentration at day 551 was compared with that at day 61. Although NTP (2017a) concluded that the increase over time was not as clear for mice in the 2-year study, no statistical comparisons for different time points were reported. Blood concentrations were also normalized by division of the blood levels by the exposure concentration; the normalized blood levels decreased with increasing exposure concentration, particularly at higher concentrations (data not shown).
Figure 3-1
Blood Antimony Levels (μg/L) in Female Mice (Panel A) and Rats (Panel B) Exposed to Antimony(III) Trioxide by Inhalation at 0, 3, 10, or 30 mg/m3 in a Two-year Study
Another difference observed for the short-term exposure was a continued increase in blood antimony concentrations relative to the concentrations in lung. During the 4-week recovery period in rats the percentage in blood relative to lung concentrations increased from 0.8% in both sexes at the end of exposure to 2% in female rats at 4 weeks post exposure [only females were examined post exposure]. In contrast, the blood concentrations in mice were only 0.004% of lung concentrations in the same animals for males and 0.005% for females at both time points. In the 2-year study, blood concentration was 7% of lung concentration in rats, but only 0.002% in mice.
Intratracheal instillation. Leffler et al. (1984) exposed adult male Syrian golden hamsters to 19.5-μm or 7-μm particles of antimony(III) trioxide by intratracheal instillation. In addition to a large percentage in the lung, antimony was detected in the liver (12.6% of 19.5-μm particles and 7.2% of 7-μm particles), with lesser amounts in the kidney, stomach, and trachea (the only other tissues examined). Based on this study, the EU (2008) risk assessment concluded that absorption following intratracheal instillation was >12.6%.
Oral exposure. Absorption from the GI tract is generally slow (Stemmer 1976). In Sprague-Dawley Crl:CD rats exposed orally (by daily gavage) to antimony(III) trioxide, it took 24 hours to reach the maximum concentration (Cmax) in blood for either a 100 mg/kg or a 1,000 mg/kg dose (T. N. O. Quality of Life 2005). However, the Cmax reached after exposure to 1,000 mg/kg for that time period was only about twice that observed at 100 mg/kg. Bioavailability calculated from the area under the curve was 0.3% for the low dose and 0.05% for the high dose.
In a study of oral exposure to antimony(III) trioxide (T. N. O. Quality of Life 2005), rats exposed to a single dose of 100 mg/kg showed little increase in tissue concentrations above control levels (data not shown), but at a dose of 1,000 mg/kg for 14 days, tissue levels increased at least 10 fold, and sometimes >100-fold in thyroid, lung, spleen, heart, kidney, liver, bone marrow, bone or femur, muscle and whole blood levels in males and females (see Appendix B, Table B-3). Two additional studies, Westrick (1953), which exposed male Sprague-Dawley rats to 2% antimony(III) trioxide in the diet for 49 days, and Gross et al. (1955), which also exposed rats (sex and strain not specified) to 2% antimony(III) trioxide in the diet but for a total period of 8 months, reported tissue levels of antimony. If food consumption by the rats is assumed to be 5 g per day per 100 g body weight (Johns Hopkins University 2017) then the exposures by either gavage or dietary consumption would be approximately 0.1 g per 100 g body weight and the tissue levels can be compared across the different studies (see Appendix B, Table B-3). The oral exposure of rats to antimony(III) trioxide in the diet for 49 days (Westrick 1953) resulted in a general increase in tissue antimony levels compared with rats exposed by repeated gavage for 14 days (T. N. O. Quality of Life 2005), but the differences between tissue levels at 49 days and 8 months (Gross et al. 1955) were relatively small and levels were lower after 8 months of exposure in some tissues. Different experimental conditions likely contributed to differences across these studies, but the general pattern of increasing tissue levels with increasing duration of oral exposure is likely meaningful.
3.1.2. Excretion
Antimony is eliminated mainly in the urine, regardless of the exposure route, but it can also appear in the feces when some ingested antimony passes through the GI tract without being absorbed or is absorbed and then excreted in the bile where it fails to form a complex with glutathione (GSH) and is not reabsorbed via enterohepatic circulation (EU 2008). Clearance of antimony from the lung follows a biphasic pattern in both humans and experimental animals, with a rapid early phase likely mediated by mucociliary transport and a slower second phase due to dissolution and absorption. Antimony cleared from the lung by mucociliary action can be swallowed and excreted in the feces. In general, antimony(III) has a greater affinity for red blood cells than antimony(V) and antimony(III) is preferentially excreted in the feces compared with antimony(V), which is more likely to be excreted in the urine (Tylenda and Fowler 2015).
Human Studies (Occupational Exposures)
Urinary levels of antimony resulting from exposure to antimony(III) trioxide by inhalation have been reported for a few occupational uses of antimony(III) trioxide. Urinary excretion of antimony by exposed workers generally increases with the exposure level. Three studies were identified that reported both exposure to antimony(III) trioxide in air and urinary excretion for the same workers (see Section 2.2 and Table 2-4). The geometric mean or median air levels reported in these studies were mostly below the current threshold limit value for antimony and antimony compounds in air of 500 μg/m3 (ACGIH 2017), but one study (Kim et al. 1999) reported a geometric mean air level of 766 μg/m3, which was associated with a urinary excretion level of approximately 420 μg/L. This level was much higher than the 15.2 μg/g creatine excretion reported by Kentner et al. (1995) for a mean air level of 12.4 μg/m3 in a starter battery factory using antimony(III) trioxide. The half-life for elimination of antimony in the urine following inhalation of antimony(III) trioxide was estimated as 95.1 hours for these 14 employees (Kentner et al. 1995).
Experimental Animal Studies
Inhalation and intratracheal instillation. In experimental animals, elimination of inhaled antimony(III) trioxide is generally slow. As in humans, animals eliminate antimony in a relatively rapid phase, likely mediated by mucociliary transport, followed by a slower phase. In hamsters exposed to antimony(III) trioxide by intratracheal instillation, biological half-lives were 40 hours for the rapid phase and 20 to 40 days for the slower phase of clearance from the lung (EU 2008).
3.2. Other Antimony Compounds
The absorption, distribution, and excretion of other antimony compounds are discussed here because they may provide useful information for discussion of potential mechanisms in Section 6.
3.2.1. Absorption and Distribution
As for antimony(III) trioxide, absorption of other or unspecified forms of antimony via the lung or gastrointestinal (GI) tract in humans and experimental animals is indicated through measurement of antimony in body tissues or urine.
Human Studies
When humans are exposed to antimony, usually by occupational exposure, the initial retention of antimony(V) in blood is primarily in the plasma rather than in red blood cells in contrast with antimony(III), but equilibration of antimony between plasma and cells occurs over a period of hours, and intracellular antimony concentrations increase (see Section 3.3). Repeated administration results in both higher plasma levels and increased urinary excretion. Antimony(III) concentration is generally highest in liver, while antimony(V) concentration is higher than that of antimony(III) in the spleen. A high concentration in spleen is considered a necessary condition for cure of leishmaniasis and thus may be related to therapeutic effects of antimony.
For people without known exposure to antimony, potential reference ranges for blood or serum levels of total antimony and either whole-body burden or levels in individual organs include a mean body burden of 0.7 mg, with the highest levels in skin and hair for a Japanese autopsy study (Sumino et al. 1975), the presence of 28% of the body’s antimony content in the skeleton in Chinese men (Zhu et al. 2010), and serum antimony levels of 0.09 to 0.25 μg/L in Irish infants less than a year old (Cullen et al. 1998).
Inhalation. Occupational and environmental exposure to antimony is mainly via inhalation. Elevated urinary excretion of antimony was reported in workers exposed to antimony trisulfide in the production of resinoid grinding wheels (Brieger et al. 1954) or to stibine (SbH3) in lead battery production (Kentner et al. 1995). (Exposure to antimony(III) trioxide in this facility was discussed in Section 3.1.2.) Pregnant or lactating women in an antimony plant were exposed occupationally to unspecified amounts of antimony(III) trioxide, metallic antimony, or antimony(V) pentasulfide as aerosols, and antimony was detected in breast milk (3.3 ± 2.2 mg/L), placenta (3.2 to 12.6 mg% [units as reported in EU (2008) and HSDB (2013)]), amniotic fluid (0.62 ± 0.28 mg/L), and umbilical cord blood, indicating absorption and potential exposure to fetuses and breast-fed infants (Belyaeva 1967). Mean levels in blood and urine were generally higher for workers in areas with high dust levels.
Evidence also indicates that long-term retention of inhaled antimony compounds occurred in seven workers accidentally exposed to radioactive antimony (125Sb); biomonitoring of whole-body radioactivity found the antimony to be almost entirely confined to the lungs (Garg et al. 2003). In addition, concentrations of antimony in lung tissue were 12 times as high in 40 retired and deceased smelter plant workers (315 μg/kg) as in 11 controls (26 μg/kg) (Gerhardsson et al. 1982).
Accumulation of antimony in lung tissue correlated with age for deceased individuals in Belgium (Vanoeteren et al. 1986a; Vanoeteren et al. 1986b; Vanoeteren et al. 1986c), and lung tissue from 15 deceased individuals in Scotland (Molokhia and Smith 1967) had concentrations in the apex of the lung (0.084 ppm wet weight) that were more than twice as high as those at the base (0.033 ppm wet weight). The work and living environment, and smoking habits of individuals were investigated by Vanoeteren and co-workers, but no information was reported by Molokhia and Smith. In both studies, the authors concluded that the source of the accumulated antimony was from inhalation of atmospheric contaminants, likely airborne dust.
Oral exposure. Belzile et al. (2011) reported poisoning from either accidental or intentional consumption of antimony compounds, indicating absorption sufficient to cause toxicity (Bailly et al. (1991); Dunn (1928); Lauwers et al. (1990) as cited by Belzile et al. (2011)). One of four exposed adults died after consuming a cake made with 6 g of tartar emetic (antimony potassium tartrate, APT) instead of cream of tartar and was found to have 15 to 20 mg (approximately 5% of the amount ingested) as a total body pool of antimony, compared with an estimated body burden of 7.9 mg in antimony-exposed workers (ATSDR 1992). In a woman who attempted suicide by ingesting an unknown amount of antimony trisulfide, blood and urine levels of antimony remained elevated a week after ingestion (Bailly et al. 1991).
ICRP (2012) recommended a single fractional absorption value of 0.05 for situations where no specific information is available. ICRP’s conclusions were based on studies reporting fractional absorption rates ranging from >0.01 to approximately 0.2. Human GI absorption of antimony compounds in general has been estimated in older literature as 5% to 15%; however, neither Belzile et al. (2011) nor NTP could identify any quantitative data to support this estimate.
Injection. After intravenous (i.v.) injections of radiolabeled sodium antimony dimercaptosuccinate to male volunteers, body scans found the highest levels in liver, thyroid, and heart (ICRP 1981; ICRP 2012).
Experimental Animal Studies
A few publications have reported levels of antimony in blood and tissues of control animals that had not been experimentally exposed to antimony. In male and female Sprague-Dawley rats, the levels in thyroid, bone marrow, liver, spleen, and whole blood ranged from 0.028 (2.8 ng Sb/g in whole blood) to 0.195 μg/g (195 ng Sb/g in thyroid) (T. N. O. Quality of Life 2005) (see Table B-3, column for controls [M/F]). Higher levels in liver were reported for 50 dogs (26 females, 23 males, and one of unknown sex) (12.2 μg/kg [ng/g] in males and 135 μg/kg [ng/g] in females) (Paßlack et al. 2015) and for 47 cats (22 males and 25 females) (132 μg/kg [ng/g] for males and females combined) (Paßlack et al. 2014). However, the tissue samples were collected from dogs and cats euthanized for medical reasons and no information on the animals was reported by the authors except for the age range of 3 days to 15 years for the dogs and 2 months to 18 years for the cats. The diet consumed by the dogs and cats could have been an important factor in the difference in antimony levels compared with rats, but the dietary composition was not specified.
Numerous studies have reported that antimony binds to red blood cells and that tissue concentrations are generally highest in spleen, liver, bone marrow, and thyroid; however, the order varies among studies, which used various species, routes of exposure, and forms of antimony. For example, in mice exposed to antimony via either inhalation (as antimony tartrate), i.p. injection (tartar emetic [antimony(III) potassium tartrate] or Astiban [sodium antimony(III) 2,3-mesodimercaptosuccinate]), or oral administration (tartar emetic), up to half of antimony that entered the systemic circulation was deposited in the liver, but the fraction was smaller in rats, hamsters, and dogs (ICRP 1981). In dogs, inhaled antimony also accumulated in the thyroid.
Inhalation and intratracheal instillation. In general, aerosols of antimony oxides with small particle sizes and low water solubility (Newton et al. 1994) were retained in the lungs longer than larger particles with high water solubility (antimony tartrates) (Felicetti et al. 1974b). Large differences in blood levels of antimony following intratracheal instillation have been reported for different species. For example, following exposure to antimony(III) trichloride, blood levels in rabbits and dogs were <1% of those in rats (Tylenda and Fowler 2015).
Oral exposure or injection. Tylenda and Fowler (2015) reported that at least 15% of a single oral dose of labeled antimony(III) as the soluble compound antimony potassium tartrate was absorbed (i.e., recovered in urine and tissues) compared with the estimated oral absorption of 1% for antimony(III) trioxide. Antimony(V) administered orally as meglumine antimoniate(V) or complexed with N-alkyl-N-methylglucamide surfactant was rapidly absorbed by mice and accumulated in liver (Fernandes et al. 2013). Pregnant rats exposed to antimony(V) (meglumine antimoniate(V)) by subcutaneous (s.c.) injections transferred antimony to fetuses via the placenta (Coelho et al. 2014; Miranda et al. 2006), and exposure during lactation resulted in transfer of antimony(V) in milk to suckling pups (Coelho et al. 2014).
Blood levels of antimony in rats exposed to antimony(III) potassium tartrate by oral exposure (in drinking water) or by intraperitoneal (i.p.) injection were compared in the NTP (1992) study. Blood levels following administration in drinking water (14 days) were only about twice those observed after repeated daily i.p. injections (12 injections over 16 days) even though the oral exposure was 10 times higher, suggesting limits on absorption from the GI tract (NTP 1992). No blood levels were detected in mice exposed via drinking water or i.p. injection following the same protocol as for rats, but antimony was detected in liver (24 μg/g with 273 mg/kg antimony(III) potassium tartrate in drinking water or with 50 mg/kg by i.p. injection) and spleen (5 μg/g with 50 mg/kg by i.p. injection).
3.2.2. Excretion
Human Studies
Excretion of inhaled antimony via urine and feces and in breast milk in humans (HSDB 2013) has been reported. The background level of urinary antimony excretion in the general population without occupational exposure has been estimated by (Filella et al. 2013a) as ≤0.1 μg/L, based on their compilation and critical review of recent studies using sensitive detection methods and large numbers of individuals. Filella et al. considered that many older publications likely overestimated urinary antimony levels because of higher detection limits if values below the limit of detection were excluded from their calculations (see Section 2). Urinary levels of antimony have most commonly come from studies of occupational exposure or therapeutic use of antimony-containing drugs for leishmaniasis or schistosomiasis.
Occupational exposure. The highest levels of urinary excretion identified for occupational exposure to antimony was for workers in a resinoid grinding wheel manufacturing plant using antimony(III) trisulfide (Brieger et al. 1954). Urine levels of 800 to 9,600 μg/L were associated with air levels that the authors reported as mostly exceeding 3,000 μg/m3, far above the current threshold limit value for antimony and antimony compounds in air of 500 μg/m3 (ACGIH 2017).
In seven workers exposed to radioactive antimony (reported as 124Sb antimony oxides, but specific form not identified) (Garg et al. 2003; HSDB 2013), biphasic clearance from the lung was reported, with a rapid initial phase of 7 days and a slower second phase (individual half-lives of 600 to 1,100 days calculated for non-smokers and 1,700 to 3,700 days for smokers), which would be consistent with long-term retention of antimony in lung tissue.
Antimony-containing drugs. Excretion of injected antimony, usually therapeutic anti-leishmanial drugs, is primarily via urine and feces, but the predominant route depends largely on the valence state of the antimony injected (CDC 1978; Tylenda and Fowler 2015).
Experimental Animal Studies
Both urinary and fecal elimination have been reported for experimental animals exposed to antimony with variations for different routes of exposure.
Inhalation and intratracheal instillation. Following exposure by inhalation or intratracheal instillation, larger and more soluble particles were generally cleared most quickly from the lungs (EU 2008). A study in 20 hamsters compared two soluble radioactive (124Sb) antimony aerosols, one Sb(III) and one Sb(V), each with median aerodynamic diameters of 1.6 μm (CDC 1978). Whole-body clearance of both aerosols was biphasic with a rapid phase during the first 24 hours and a slower clearance with a half-life of 16 days; excretion of the two forms did not differ significantly. Two hours after exposure, <1% of body burden remained in the lungs, but a high antimony content was reported in the GI tract shortly after the first exposure. By day 7, 90% of the body burden on day 1 had been cleared.
Other routes. Oral ingestion of radiolabeled antimony(III) potassium tartrate by rats resulted in slow excretion, primarily in the feces but also in the urine (NTP 1992). In rats, i.v. injection of antimony(III) trichloride (SbCl3) resulted in excretion of 30% of total antimony in feces and 12% in urine during the first 24 hours, indicating that biliary excretion exceeded urinary excretion (T. N. O. Quality of Life 2005). Enterohepatic cycling occurs due to binding of antimony(III) to GSH; in adult rats, depletion of GSH decreased fecal excretion and increased urinary excretion after i.v. or i.p. injection of antimony(III) trichloride (Bailly et al. 1991).
3.3. Metabolism and Valence States
Mammalian metabolism of antimony consists primarily of interconversion of the valence state between +3 and +5. Evidence for methylation of antimony in vivo is limited to one study of two workers occupationally exposed to antimony during lead battery production (Krachler and Emons 2001). However, other studies in humans (Miekeley et al. 2002; Quiroz et al. 2011) and animals (Bailly et al. 1991) were negative for formation of methylated antimony.
Major forms of antimony under physiological conditions are an uncharged form of antimony(III) as Sb(OH)3 and an electrically charged form of antimony(V) as Sb(OH)6− (Mak 2007) (see Section 1). The uncharged antimony(III) form should pass more easily through cell membranes than the charged form of antimony(V), which would remain in the plasma and be subject to excretion, consistent with the shorter half-life of antimony(V) in vivo.
The relative distribution of antimony between red blood cells and plasma differed with valence state. Quiroz and coworkers (Barrera et al. 2016; Quiroz et al. 2013) separated antimony(III) and antimony(V) chromatographically and demonstrated that antimony(V) can enter human erythrocytes in vitro via protein channels through the membrane, where antimony(V) is reduced intracellularly, at least in part, to antimony(III) through interaction with glutathione (GSH) via its redox couple with glutathione disulfide (GSSG). This could explain the equilibration over time of the distribution of antimony(V) between red blood cells and plasma. In rats administered antimony(III) and antimony(V) by i.p. injection, uptake by red blood cells was more rapid for antimony(III) than antimony(V). At 2 hours post-injection, over 95% of the antimony(III) in blood was incorporated into red blood cells, but 90% of antimony(V) was in the plasma (Edel et al. 1983). By 24 hours after inhalation exposure in hamsters, the ratios of antimony in red blood cells to serum were similar regardless of the valence (Felicetti et al. 1974a).
Reduction of antimony(V) to antimony(III) occurs in vitro, and perhaps also in cell cytoplasm or in lysosomes, by reaction with GSH, cysteine, or cysteinyl-glycine. Evidence for reduction of antimony(V) to antimony(III) in humans is based on detection of both antimony(III) and antimony(V) in the urine of people injected with meglumine antimoniate(V) (Glucantime) (Miekeley et al. 2002; Petit de Peña et al. 1990), consistent with release of anionic antimony(V) from the drug and possible reduction to antimony(III) in vivo. The kinetics of reduction of antimony(V) from the antileishmanial drug meglumine antimoniate to antimony(III) by L-cysteine in vitro indicate a peak rate constant at pH 4.7, which is consistent with the pH range of 4.5 to 5.0 within lysosomes, where the drug is believed to act (De Oliveira et al. 2006). Reduction of antimony(V) to antimony(III) in various types of human cells in vitro is consistent with this finding. Antimony(V) from sodium stibogluconate (Pentostam) was reduced to antimony(III) in the human macrophage cell line Mono Mac 6 (Hansen et al. 2011). Antimony(V) incubated with human blood in vitro was reduced to antimony(III) in the plasma and red-cell cytoplasm in the presence of GSH; however, antimony(III) could be re-oxidized to antimony(V) in the plasma (López et al. 2015). No conversion was detected when cultured human keratinocytes were incubated with antimony(V) as potassium hexahydroxy antimonate (Patterson et al. 2003).
Data for interconversion between antimony(III) and antimony(V) in experimental animals are generally limited, but one study in dogs injected s.c. with a single dose of meglumine antimoniate(V) reported systemic conversion of 23.62% of antimony(V) to antimony(III) in blood in 24 hours (de Ricciardi et al. 2008). In rhesus monkeys injected i.m. with meglumine antimoniate(V) daily for 21 days, the proportion of antimony(V) remained in the range of 11% to 20% of total antimony, while that of antimony(III) increased from 5% on day 1 to 50% on day 9, which could indicate reduction of antimony(V) to antimony(III) within cells (Friedrich et al. 2012). The authors did not report what form of antimony made up the balance of the total concentration.
The valence state also affects the distribution of antimony in tissues. Felicetti et al. (1974a) reported that hamsters exposed to radioactive antimony (124Sb) aerosols, one antimony(III) and one antimony(V), both with median aerodynamic diameters of 1.6 μm, had similar average body burdens on the day after exposure. However, slightly more antimony(III) than antimony(V) accumulated in the liver while more antimony(V) accumulated in the skeleton; reduction of antimony(V) to antimony(III) was not extensive. Antimony(III) tartrate inhaled as aerosols by mice (Thomas et al. 1973) or beagle dogs (Felicetti et al. 1974b) was distributed primarily to the lung, bone, liver, pelt, and thyroid gland.
Several recent studies have determined blood and tissue levels resulting from exposure to antimony(V) from drugs used to treat leishmaniasis, primarily meglumine antimoniate(V) (Glucantime) in rats (Coelho et al. 2014), mice (Borborema et al. 2013), and dogs (de Ricciardi et al. 2008; Ribeiro et al. 2010). In rats injected s.c., the highest levels of antimony were in the spleen, bone, thyroid, and kidney (Coelho et al. 2014) and a biphasic clearance was reported. Biphasic clearance was also reported for mice injected i.p. (Borborema et al. 2013). Dogs injected s.c. converted 23.62% of antimony(V) to antimony(III) by 24 hours after injection, and clearance of antimony(III) was not biphasic (de Ricciardi et al. 2008; Ribeiro et al. 2010). In hamsters (Al Jaser et al. 2006) injected intramuscularly (i.m.) with antimony(III) as sodium stibogluconate, antimony concentrations were highest in kidney and lowest in spleen, and clearance was linear from blood but biphasic from individual tissues.
The valence of antimony also affects the route and rate of excretion, which vary among species. Following injection of organic antimonials with different valences, antimony from the antimony(V) drug was excreted mainly in the urine, and that from the antimony(III) drug mainly in the feces (Otto et al. 1947; Tylenda and Fowler 2015). In mice injected s.c., i.p., or i.m. with either stibophen with antimony(III) or sodium antimony(V) gluconate, total urinary excretion after 48 hours was approximately 70%. Although the initial excretion rate was slower for antimony(III), the difference decreased over 48 hours. In hamsters, i.p. injection resulted in urinary excretion of 15% for antimony(III) and 65% for antimony(V), while fecal excretion was 50% for antimony(III) and <10% for antimony(V).
The quantification of antimony(III) and antimony(V) in human erythrocytes (Quiroz et al. 2013), in rhesus monkey plasma (Friedrich et al. 2012), and in urine (Miekeley et al. 2002) described above was based on ion chromatography for separation of antimony(III) and antimony(V). Miekeley et al. also determined the different valence states in human blood and hair, and Friedrich et al. examined thyroid, liver, spleen, kidneys, and other tissues from rhesus monkeys. However, no studies reporting additional data based on these methods were identified.
3.4. Toxicokinetics
The available information on the toxicokinetics of antimony is from Newton et al. (1994) and a recent NTP (2017a) report on lung accumulation and clearance in rats and mice exposed to antimony(III) trioxide via inhalation. No studies on the toxicokinetics of antimony in humans were identified.
Newton et al. (1994) exposed F344 male and female rats to antimony(III) trioxide for either 13 weeks followed by 27 weeks of observation (0.0, 0.25, 1.08, 4.92, or 23.46 mg/m3) or 1-year exposure followed by 1-year observation (0.0, 0.055, 0.51, or 4.5 mg/m3) with intermediate sample collection at 6 months for each period. The authors reported near steady-state lung burdens by 6 months of exposure for the 12-month exposure period (see Table 3-1). Semilogarithmic plots of clearance data (μg antimony(III) trioxide concentration per g of tissue plotted against time) indicated a lung-burden-dependent effect on the clearance rate. At a lung burden of approximately 2 mg antimony(III) trioxide per lung, the rate of lung clearance decreased by approximately 80% with a resulting increase in the clearance half-time from 2 months to 10 months.
Kinetic parameters were determined for inhaled antimony(III) trioxide in female rats and mice exposed at 0.0, 3.75, 7.5, 15, 30, or 60 mg/m3 for 2 weeks followed by recovery for 4 weeks (NTP 2017a). Clearance half-lives in lung ranged from 73 to 122 days in rats and 47 to 62 days in mice. The shortest half-life was for the lowest exposure concentration, but no clear concentration-response trend was seen. Deposition rates (micrograms of antimony(III) trioxide per day) were approximately proportional or slightly less than proportional to exposure concentrations; deposition rates increased 15-fold in rats and 13-fold in mice when exposure increased 16-fold. Steady-state lung burdens were not reached during the 2-week exposure, but half-lives to steady state were estimated to be 365 to 610 days in rats and 235 to 310 days in mice.
Lung burdens were expressed as mass rather than concentration because lung weights increased in exposed animals. NTP also reported that normalized antimony(III) trioxide lung burdens increased in approximate proportion to exposure concentration and with exposure duration during the 2-year bioassay in rats and mice. The lung burden in female rats increased steadily over time. The 3 mg/m3 and 10 mg/m3 exposure groups nearly reached steady state, but the 30 mg/m3 exposure group did not. The results in rats were consistent with the clearance rates from the lungs progressively decreasing.
NTP (2017a) also attempted to fit a lung-burden model to data for rats and mice based on assumptions of a zero-order (constant) deposition rate and a first-order (with respect to lung burden) clearance rate. Model-predicted values are shown in Table 3-2 and lung burdens are shown in Figure 3-2 and Figure 3-3. In rats, the predicted deposition rates were consistent with the measured lung-burden data. In mice, the data showed a poor fit, and meaningful deposition and clearance parameters could not be calculated for any of the exposure concentrations. In rats, approximately five half-lives would be required to reach steady state, and the durations for the two higher concentrations would exceed the normal life span of this rat strain.
Table 3-2
Model-Predicted Values for Wistar Han Rats Exposed to Antimony(III) Trioxide via Inhalation for Two Years.
Figure 3-2
Lung Antimony(III) Trioxide Burdens in Female Rats in the Two-year Inhalation Study
Figure 3-3
Lung Antimony(III) Trioxide Burdens in Female Mice in the Two-year Inhalation Study
Based on relatively longer clearance half-lives at the higher doses and an unexpectedly high lung burden in mice after 551 days of exposure, NTP (2017a) concluded that the reduced pulmonary clearance was associated with lung overload at 10 mg/m3 and 30 mg/m3, but not 3 mg/m3. Two theories to explain overload in relation to inhalation exposure to particulates have been proposed, one based on particle volume and the second on particle surface area. Volumetric overload is initiated when individual alveolar macrophages accumulate a particulate volume exceeding 60 μm3 per macrophage (Morrow 1988; 1992). When the particulate volume per macrophage exceeds 600 μm3, all macrophage-mediated clearance ceases, and the dust accumulates linearly with continued inhalation. Tran et al. (2000) proposed a second hypothesis for clearance impairment based on the total particle surface area of ultrafine particulates. This particle surface area hypothesis proposes that ultrafine particles with high surface area will cause macrophages to release proinflammatory mediators (chemokines), such as tumor necrosis factor, that attract macrophages and could prevent their migration. NTP concluded that volume-based overload occurred at 10 mg/m3 by day 418 in rats and day 369 in mice and at 30 mg/m3 by day 94 in rats and day 124 in mice.
3.5. Summary
3.5.1. Absorption and Distribution
Humans exposed occupationally to antimony(III) trioxide by inhalation excreted more antimony in urine, which increased with increasing levels in the air, and some workers were shown to retain antimony in their lungs for months or years. Rats and mice exposed to antimony(III) trioxide by inhalation showed increased concentrations of antimony in blood and in the lung. Absorption of antimony was greater in rats than in mice. Inhalation exposure can also result in gastrointestinal absorption if larger particles of antimony are cleared from the lung by mucociliary transport and then swallowed. Absorption is estimated to be low or very low for both inhalation and oral exposure, and limited data indicate similar absorption of antimony(III) and antimony(V).
Information from studies with exposure to antimony(III) trioxide and other forms of antimony indicated that this element is distributed through the body via the blood, and distribution to tissues is generally similar for different routes of exposure. Both antimony(III) and antimony(V) forms tend to accumulate mainly in red blood cells, although antimony(V) is initially present in plasma during the first few hours after exposure. The highest levels of antimony are generally in organs rich in reticuloendothelial cells, such as the spleen, liver, and bone marrow. In rats, dogs, and some studies in humans, high levels have also been reported in the thyroid. However, the relative accumulation of inhaled antimony in liver and skeleton differs by valence; antimony(III) is distributed more rapidly than antimony(V) to the liver, while antimony(V) is delivered more rapidly than antimony(III) to the skeleton. Both forms were also found in the kidneys and other organs. In humans exposed to radioactive antimony, it was still detected in tissues, particularly the liver, weeks or months after exposure ended. During pregnancy and lactation, both humans and rats passed antimony to the fetus via the placenta and to infants via milk.
3.5.2. Metabolism
Mammalian metabolism of antimony consists of interconversion of the valence state between +3 and +5. The valence state and electrical charge affect the distribution of antimony between blood and cells and its excretion. Reduction of antimony(V) to antimony(III) has been shown to occur in the presence of glutathione, cysteine, or cysteinyl-glycine in vitro. Although methylated forms of antimony have been reported in the environment, no convincing evidence was found for methylation in mammals.
3.5.3. Excretion
Studies of workers exposed to antimony by inhalation showed generally higher urinary excretion with higher levels of exposure in air. Both antimony(III) and antimony(V) are excreted mainly in the urine, but excretion occurs over a relatively long period after exposure, and the pattern of excretion can vary with exposure route and species. The data generally support slower excretion of antimony(III) than antimony(V). Some studies have reported greater excretion of antimony(III) than antimony(V) in feces, but generally at lower levels for both compared with their excretion in urine. Antimony excreted in bile undergoes enterohepatic recycling, which likely depends on binding to GSH.
3.5.4. Toxicokinetics
Toxicokinetics data for antimony are mainly from the NTP (2017a) report on studies in rats and mice exposed to antimony(III) trioxide by inhalation for 2 weeks plus 4 weeks’ recovery or for 2 years. Clearance half-lives from lung were calculated from 2-week exposure data as 73 to 122 days for rats and 47 to 62 days for mice. The models that NTP used fit the data for rats relatively well, but not those for mice. Model-estimated clearance half-lives for 2-year exposure data in rats increased with exposure concentration with durations of 136 for 3 mg/m3, 203 days for 10 mg/m3, and 262 days for 30 mg/m3. (Data for mice could not be modeled.) NTP also considered the question of lung overload during the 2-year exposure, concluding that lung overload was not reached at the lowest concentration tested (3 mg/m3), but was reached in both rats and mice at the middle (10 mg/m3) and high concentrations (30 mg/m3).
- Disposition and Toxicokinetics - Report on Carcinogens Monograph on Antimony Tri...Disposition and Toxicokinetics - Report on Carcinogens Monograph on Antimony Trioxide
- Chain BV, Ribosomal Protein L23Chain BV, Ribosomal Protein L23gi|1995665845|pdb|4V61|BVProtein
- Chain BN, Ribosomal Protein L15Chain BN, Ribosomal Protein L15gi|1995665837|pdb|4V61|BNProtein
- Chain BA, 23S rRNAChain BA, 23S rRNAgi|1995665824|pdb|4V61|BANucleotide
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