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Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2 (2007)

Chapter: Appendix 5 Cadmium (Inorganic Salts)

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Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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5
Cadmium (Inorganic Salts)

Raghupathy Ramanathan, Ph.D. NASA-Johnson Space Center Toxicology Group Houston, Texas

OCCURRENCE AND USE

Cadmium (Cd) occurs naturally in the earth’s crust. In the environment, it exists as oxides or salts such as cadmium chloride, cadmium sulfate, or cadmium sulfide (see Table 5-1). It also exists as a complex with lead, zinc, and copper ores. In the industrial setting, cadmium is used extensively in smelting, batteries, plastics and metal plating, welding, fabric dyes, glass glazes, and the burning of fossil fuels. In the general population, the sources for cadmium exposure are food and water. There have been numerous reports of the contribution of cadmium to the indoor environment from cigarette smoke, the most important single source of exposure to the general population. Cigarettes and cadmium have been the subject of several investigations, especially using pregnant women who smoke. Depending upon the source of tobacco, a single cigarette may contain from 1 to 2 micrograms (µg) of cadmium (FDA 1993). The average daily intake of 10-20 µg per day (d) of cadmium by adults in the United States has been reported (Reeves and Chaney 2002). There are reports that among food sources, certain vegetables, rice, and meat (kidney and liver) contribute significant concentrations of cadmium. In an FDA survey of fresh clams and oysters from U.S. coastal areas, it was reported that they contain significant amounts of cadmium (Caper and Yess 1996). It has also been stated that the diets in which shellfish constitutes a significant portion contain twice as much cadmium as a more mixed diet. Usually the concentration of cadmium in drinking water in the United States is about 2 µg per liter (L) (below the regulatory level of 5 µg/L). At hazardous waste sites, where cadmium contamination of soil

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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TABLE 5-1 Physical Properties of Inorganic Cadmium and Cadmium Salts

Formula

Cda

CdCl2b

CdSO4c

CdCO3d

CdOe

CdSf

Chemical name

Cadmium

Cadmium chloride

Cadmium Sulfate

Cadmium carbonate

Cadmium oxide

Cadmium sulfide

Synonyms

Cadmium colloidal

Cadmium dichloride

Cadmium Sulfate

Otavite, cadmium monocarbonate

Cadmium fume; cadmium monoxide

Cadmium yellow; greenockite

CAS registry no.

7440–43–9

10108–64–2

10124–36–4

513–78–0

1306–19–0

1306–23–6

Molecular weight

112.41

183.32

208.47

172.42

128.41

144.47

Cadmium (mole %)

100%

61.2%

53.8%

65%

87.5%

77%

Solubility

Insoluble

140 g/dL

75.5 g/dL

Insoluble

Insoluble

Soluble at 1.3 mg/L

aData are from HSDB 2006a.

bData are from HSDB 2006b.

cData are from HSDB 2006c.

dData are from HSDB 2006d.

eData are from HSDB 2006e.

fData are from HSDB 2006f.

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

is very high because of the disposal of batteries, sewage sludge, and use of phosphate fertilizers, cadmium has the potential to contaminate the water supplies (Elinder 1985). Cadmium can also leach from copper piping in plumbing with nonlead-based solder joints into residential drinking water. A recent survey, the National Human Exposure Assessment Survey in Maryland (NHEXAS-MD), in which 381 water samples were taken from 73 households, indicated only 12 of the households had concentrations of cadmium higher than the method detection limit of 0.1 µg/L (Ryan et al. 2000).

Cadmium has been found in the humidity condensate samples collected from several Mir missions at a mean concentration of 27 µg/L, with a maximum concentration of 240 µg/L. In the water processed from humidity condensates, cadmium was not found above 1 µg/L. Once, up to 36 µg/L of cadmium was reported in the crew drinking water collected from the International Space Station (ISS) water-use port in the galley. The problem was isolated. Because cadmium is the most common ingredient in zinc coatings and because of the well-known toxicity of soluble cadmium, the National Aeronautics and Space Administration (NASA) needed to determine the spacecraft water exposure guidelines (SWEGs) for cadmium in case there is a malfunction of the multifiltration beds or other components of the ISS water reclamation system leading to the contamination of ISS crew potable water.

TOXICOKINETICS AND METABOLISM

The absorption, distribution, and elimination of cadmium have been extensively studied in animals. The route of exposure can greatly affect these parameters and thus the toxic effects. Our discussions will be limited to studies that describe exposure by ingestion of soluble cadmium salts through food and drinking water or gavages only. The data from inhalation exposures, or from intravenous (iv), subcutaneous (sc), or intraperitoneal (ip) injections, may be mentioned but will not be discussed in any detail. Almost all the studies pertaining to ingestion of cadmium have used cadmium chloride (CdCl2). Very few studies have used cadmium acetate, cadmium sulfate, or cadmium iodide.

Absorption

Whole-body counting after a single oral dose of radiolabeled cadmium has been used for the quantification of whole-body retention and

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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the estimation of intestinal cadmium uptake in humans (Newton et al. 1984). The intestinal absorption seems to take place in two steps: first, the trapping of cadmium by the mucosal epithelial cells—this is not considered true absorption; and second, clearance of this trapped cadmium into blood. A large portion of the ingested cadmium is not taken up by the mucosal cells and thus passes through the gastrointestinal (GI) tract without being absorbed, although some is trapped in the intestinal mucosa (Kjellström et al. 1978; Foulkes 1986). Most of the studies on the GI absorption of cadmium have compared the dose given with the amount retained shortly after the dose was administered. This has been measured as whole-body retention by counting a radioactive tracer (109Cd or 115Cd). Because excretion of absorbed cadmium is very slow, wholebody cadmium retention may not be an underestimation of cadmium absorption (at least in the short term). The total retention of cadmium in the bodies of humans has been measured after ingestion of radioactive cadmium. About 25% of a dose of cadmium administered mixed with food to five healthy adults was retained after 3-5 d, but retention decreased to about 6% after 20 d (Rahola et al. 1973 as cited in ATSDR 1999). Similar results were obtained with 14 healthy adults who after 1-2 weeks (wk) retained an average of 4.6% of a dose of CdCl2 in water taken with a meal (McLellan et al. 1978). In a related study, Flanagan et al. (1978) estimated that the average intestinal net uptake of cadmium was 2.6% in males and 7.5% in females. Foulkes (1991) inferred from studies using intestinal segments that mucosal cadmium uptake is a saturable process (see Lehman and Klaassen 1986). Once taken up by the mucosal cells, cadmium is generally believed to be partly bound to intestinal metallothionein (MT).

A number of studies indicate that the retention or overall absorption of CdCl2, cadmium nitrate, or cadmium sulfate given orally is 1-2%. Rats (Decker et al. 1958; Moore et al. 1973a, b) and mice (Cotzias et al. 1961; Nordberg 1972; Ogawa et al. 1972; Valberg et al. 1976) exposed to a single oral dose of radioactive CdCl2 retained about 1-2% of it. Nordberg et al. (1985) reported that in monkeys (Saimiri sciureus), the retention of 115CdCl2 administered by stomach tube depended on the dose: about 1% from cadmium at 1 µg per kilogram (kg) and 2.9-3.2% from cadmium at 0.17-1.7 mg/kg. Suzuki and Taguchi (1980), who administered 109Cd by stomach tube to Macaca irus monkeys, observed that after 19 d, 12% of the dose was retained and 50% of this was still in the GI mucosa. They reported a final retention of 6% of administered cadmium in the monkeys. The results of several studies on absorption of cadmium from single oral bolus studies show that monkeys and humans seem to absorb

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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(retain) more cadmium than rodents. Animal studies indicate that absorption of cadmium is complex and depends on the dose rate. Engstrom and Nordberg (1979a) observed that in mice, the absorption was 0.5% from a 1 µg/kg dose, 1.4% from 15 to 750 µg/kg, and 3.25% from 37.5 mg/kg (the highest dose tested). The highest dose caused morphologic changes in the GI mucosa.

In a study designed to determine the GI absorption of cadmium, rats were given one oral dose of cadmium (mixed with 109Cd) as CdCl2 (1 or 10,000 µg/kg) and the cadmium content was determined in organs 3 hours (h) later (Lehman and Klaassen 1986). The percent of the dose that was absorbed was dose-dependent (0.35 and 1% at 1 and 10,000 µg/kg, respectively). However, at 3 h, liver cadmium increased 80,000 times between the 1 and 10,000 µg/kg doses. Similar data were obtained for kidney, blood, pancreas, and bone. At the 1 µg/kg dose, 60% of cadmium in intestinal cytosol was bound to MT, whereas at the 10,000 µg/kg dose, 50% of the cadmium was bound to MT. It is also interesting to note that even when cadmium was iv injected into rats (at 0.1, 0.3, 1.0, or 3.0 mg/kg), the biliary excretion percentage of the injected dose measured 2 h after injection was dose dependent, increasing as the dose increased (Gregus and Klaassen 1986).

To evaluate the precise nature of cadmium absorption by the intestine and the role of MT in the intestinal absorption of cadmium in rats, a study was conducted by Goon and Klaassen (1989) using an isolated intestinal loop preparation in situ, which allowed direct measurement of intestinal absorption under nearly physiologic conditions. Cadmium (0.1, 10, 100, 1,000, or 10,000 µg/kg) was injected intraluminally into the isolated intestinal loop in situ and all mesenteric venous (portal) blood exiting from the loop was collected for 90 minutes (min). Absorption of cadmium into the portal circulation was low at all doses studied. At low doses (0.1 and 10 µg/kg), little difference was noted in the fractional absorption of cadmium (0.09% and 0.14% of the dose, respectively). However, in rats administered cadmium at 100 µg/kg, the fractional absorption of cadmium was 10-fold greater (1.1% of the dosage). Administration of higher doses of cadmium (1,000 and 10,000 µg/kg) further increased the percentage of the dose absorbed, a nonlinear absorption kinetics (1.8% and 3.4%, respectively) (Goon and Klaassen 1989). This dose-dependent increase in fractional absorption is not because of saturation of intestinal MT at high doses, because this phenomenon was seen even when the intestinal level of MT was experimentally increased (MT induction) by pretreatment of the rats with zinc injections (Goon and Klaassen 1989). In an experiment conducted by Liu et al. (2001) to clar-

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

ify the role of MT in Cd absorption and tissue distribution, single oral doses of 109Cd (1 or 300 micromol/kg) were administered to MT-null mice and their parental wild-type mice. Four hours after Cd administration about 0.15% of the lowest dose (1 micromol/kg) and 0.75% of the highest dose (300 micromol/kg) in the liver, and similarly about 0.05% of the lowest dose and 0.15% of the highest dose in kidneys were found in both MT-null and wild-type mice. This experiment indicated that the absorption and initial distribution of orally administered Cd was dose dependent but was not influenced by MT.

Differences between the rodent and human diets may be responsible for the reported differences in absorption rates. Rabar and Kostial (1981) found that retention was at least four times greater when rats were fed bread, meat, or milk that humans consume.

Cadmium absorption from the GI tract can be influenced by several factors (for instance, age and dietary constituents such as iron, calcium, zinc, and dietary fiber content [see Wing 1993]). When human volunteers consumed crabmeat into which cadmium was incorporated, the whole-body retention ranged from 1.2% to 7.6% with a mean of 2.7% (Newton et al. 1984). This was only slightly lower than the values of 4.6-6.0% when cadmium salt was ingested as a solution (McLellan et al. 1978). This seems to indicate that complexation of cadmium in the food did not influence the estimated absorption significantly.

Cadmium Absorption and Age

Consistent with data on absorption of other metals, several animal studies have indicated that in general, absorption of cadmium is higher at younger ages. This appears also partly because of slower excretion from younger animals (Kello and Kostial 1977; Kostial 1984). For example, Engstrom and Nordberg (1979b) reported that absorption from an oral dose of 109Cd in mice of different ages decreased from 5.2% in 1-month (mo)-old mice to 2.9% in 3-mo-olds and 2.1% in 6-mo-old mice. Similar data are not found for rats. No human data could be found. After a single oral administration of 115Cd to albino rats 1-26 wk old, the whole-body cadmium retention (measured 1 or 2 wk after dosing) was higher in sucklings than in weaned rats, and retention of cadmium in the kidneys was 5-7 times higher in the sucklings than in older rats (Kostial 1984).

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Cadmium and Iron

The body store of iron influences cadmium absorption. Subjects with low iron stores (assessed by serum ferritin concentrations) had an average absorption of 8.9%, and those with adequate iron stores had an average absorption of 2.3% (Flanagan et al. 1978). In 10 human subjects with low body iron stores (serum ferritin less than 20 nanogram (ng)/mL), the average absorption of cadmium labeled with 115mcadmium at 25 µg from a test meal was 8.9 ± 2.0% (mean ± SD), whereas, it was 2.3 ± 0.3% in 12 subjects with normal iron stores (serum ferritin greater than 23 ng/mL). The biologic half-life of 115mcadmium in three of the subjects ranged from 90 to 202 d. Thus, iron deficiency in both experimental animals and human subjects lead to the increased absorption of cadmium (Flanagan et al. 1978). Some of the gender differences in absorption arise from differences in iron status between men and women. Females may absorb a larger fraction of dietary cadmium than men because they have lower body stores of iron (Berglund et al. 1994; Vahter et al. 1996; Choudhury et al. 2001). Increased tissue cadmium concentration in iron deficient rats by increased intestinal absorption and 10-fold higher retention in the body has also been documented (Park et al. 2002). It was proposed that iron depletion upregulates the expression of divalent metal transporter protein (DMT1) in the intestine leading to the increased absorption and transport of cadmium.

Cadmium and Calcium

Low calcium intake has been shown to increase the whole-body retention of cadmium. Correspondingly, the uptake of calcium decreases when the ingestion of cadmium is high. Female rats on low-calcium diets exposed to cadmium as CdCl2 at 25 mg/L in drinking water for 1 or 2 mo had accumulated about 50% more cadmium than the rats on a high-calcium diet (Larsson and Piscator 1971). Washko and Cousins (1977) showed that when rats were exposed to cadmium as CdCl2 at 25 ppm in drinking water for 8 wk, the groups that were fed a low-calcium diet (0.1%) had enhanced cadmium retention and cadmium toxicity (for example, depressed packed-cell volume and the highest concentrations in lung, liver, and kidneys) compared with groups fed a high-calcium diet (0.6%). In another study, rats on a low-calcium diet or normal-calcium diet were given rice containing cadmium at 0.1-0.6 mg/kg for 74 wk. Liver and kidney cadmium concentrations in the low-calcium-diet group

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

were 1.5-5 times greater than in the normal-calcium-diet group (Kobayashi et al. 1971). Similarly, liver and kidney cadmium concentrations in rats on a low-calcium diet exposed to cadmium at 0-10 mg/L for 1 year (y), were at least two times higher than those on a normal-calcium diet (Piscator and Larsson 1972, as cited in Nordberg et al. 1985). Similar results have been reported by several investigators (Hamilton and Smith 1978). According to Brzoska and Moniuszko-Jakoniuk (1998), large intakes of calcium can protect against absorption, accumulation, and toxicity of cadmium.

Cadmium and Zinc

Several reports in the literature seem to clearly indicate that zinc plays a critical role in cadmium-induced toxicity and even carcinogenesis (see, for example, Petering et al. 1971; Goering and Klaassen 1984; Waalkes et al. 1989, 1992). Dietary zinc intake has an important effect on the absorption, accumulation, and toxicity of cadmium. Increased zinc supply reduced cadmium absorption. It is beyond the scope of this document to discuss the mechanism of competition between cadmium and zinc. Several studies have been carried out using in vitro systems and should be interpreted carefully because the result can vary depending on whether intraluminally perfused rat intestinal preparations were used or the vascularly perfused system was used. It also depends on the relative concentrations of zinc and cadmium in the perfusion medium (Foulkes and Voner 1981; Hoadley and Cousins 1985; Jaeger 1990).

Marginal nutritional status (not a deficient status) with respect to the minerals zinc, iron, or calcium can result from consuming one staple grain such as rice, wheat, sunflower kernels, or maize as a large proportion of the diet. To evaluate the effect of such a diet on the interactions of these minerals with cadmium, Reeves and Chaney (2002) conducted a study in female rats (SAS:VAF [SD] Charles River rats) that were fed a diet containing a high proportion of milled rice that was formulated to give only marginal concentrations of these metals. The diet was supplemented with cadmium (0.25 mg/kg diet), and retention of 109Cd (intrinsically labeled CdCl2) was measured. The rats consumed the rice diet, with or without cadmium, for 5 wk and then were fed 1 g of radiolabeled-cadmium diet for 2 wk. The results were compared with control whose diet contained adequate amounts of these previously mentioned minerals. The authors reported that whole-body retention of cadmium in rats consuming diets low in zinc, iron, or calcium was significantly more than

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

rats consuming a diet adequate in all these minerals. There was a significant interaction of zinc and iron with cadmium; thus, marginal zinc along with marginal iron resulted in greater whole-body retention of (radioactive) cadmium than it did in rats fed adequate zinc and marginal iron. Cadmium concentration in the duodenum was also 10-fold higher in rats fed diets marginally deficient in zinc and iron compared with rats fed diets containing adequate amounts of these minerals. Marginal intake of zinc led to higher concentrations of cadmium in the liver, without any change in concentrations of cadmium in the kidney (Reeves and Chaney 2002).

Cadmium and Low Dietary Protein

Suzuki et al. (1969) reported that in mice given a low-protein diet 24 h before an oral dose of 115CdCl2, the kidney and liver and the whole body had considerably higher concentrations of cadmium than in mice given a high-protein diet. Whole-body retention of cadmium was 9% (mean of 5-14%) in mice fed a low-protein diet and 4.5% (mean of 3-10%) in mice fed a high-protein diet. On the other hand, a refined diet high in fat and protein increased cadmium absorption in mice, partially because of increased GI-passage time (Schafer et al. 1986).

Cadmium and Fasting

The acute oral toxicity of cadmium (as CdCl2) was enhanced in rats fasted 24 h, as shown by a markedly decreased LD50 (the dose lethal to 50% of test subjects). Rats were administered cadmium at 75 mg/kg orally 24 h after fasting and euthanized after a further 4 or 24 h for various assays (Shimizu and Morita 1990). Cadmium uptake by the liver (both concentration and content) 24 h after cadmium treatment was higher in fasted rats than in fed rats. Fasting enhanced the focal degenerative and necrotic changes from the midlobular to the pericentral region in the livers. The authors also found changes and shifts in the distribution of liver glutathione (GSH) in the fasted and cadmium-treated rats different from that seen in the control group (Shimizu and Morita 1990, 1992).

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Metabolism and Transport

Evidence from studies with rats and mice has led investigators to propose a complex mechanism for the transport of cadmium in the intestinal epithelial cells. The mechanism involves the binding of cadmium to membrane proteins involved in the transport of essential metals, such as calcium, iron, and zinc, and endocytosis of the membrane proteins bound to cadmium (Cd-MT) by enterocytes in the small intestine. The transport proteins are DMT1, iron transporter protein (MTP1), and zinc transporter protein (ZTL1). These processes have been described in a recent review by Zalups and Ahmad (2003). Competition by Cd for essential metal transporters could explain the greater gastrointestinal Cd absorption when iron, zinc, and calcium dietary levels are low. Cadmium exists mostly as the Cd2+ ion and is not known to undergo any direct oxidation, reduction, or alkylation. It can avidly bind to sulfhydryl groups in proteins (especially albumin and MT) and other molecules (Nordberg et al. 1978, 1985). In plasma, cadmium is initially and predominantly bound to protein of high molecular weight (albumin) a short time after exposure (in the case of parenteral administration) or 1 d after single oral administration. The cadmium-protein complexes are taken up by the liver. After 2-3 d, when plasma cadmium concentrations are low, plasma cadmium is also bound to a low-molecular-weight protein, MT (Norberg et al. 1985; Foulkes and Blanck 1990). MT is very rich in cysteine and capable of binding as many as seven cadmium atoms per molecule. MT is inducible in most tissues by exposure to cadmium among other metals and agents (Waalkes and Goering 1990). Initially the albumin-bound cadmium is taken up by the liver. In the liver, cadmium induces the synthesis of MT, and a few days after exposure, MT-bound cadmium appears in the blood plasma. MT is ultrafiltrable and taken up by the tubules (Nordberg 1992). Thus, the binding is of interest in relation to kidney function, especially with respect to glomerular filtration and tubular reabsorption of MT-bound cadmium. MT is thought to be a carrier of cadmium from liver to kidney. MT concentrations in urine and plasma of cadmium-exposed workers and in urine samples from cadmium-exposed Japanese farmers and itai-itai disease (a disease resulting from consuming cadmium-contaminated rice in Japan) patients have been extensively reported (Chang et al. 1980; Nordberg et al. 1982; Tohyama et al. 1982; Falck et al. 1983).

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×
Distribution

Since we will restrict ourselves to discussing the oral route of cadmium exposure, the distribution of cadmium administered via iv, ip, or sc injection will not be discussed here. Upon ingestion of cadmium, a considerable quantity is retained in the intestinal walls. Once transported to blood, it is transported to all the tissues, with a large portion in liver, kidneys, muscle, and bones. The distribution depends on the exposure regimens and the amount of time after exposure. Initially most of the absorbed cadmium will go to the liver, with small amounts going to the kidneys. With increasing time after exposure, cadmium will be redistributed and concentrations in the kidneys will increase. The time-dependent changes in the distribution to kidneys and liver have been the subject of numerous investigations because these organs are considered storage organs (Kotsonis and Klaassen 1978; Weigel et al. 1984; Andersen et al. 1988; Jonah and Bhattacharya 1989). In the liver and kidneys of cadmium-exposed animals, more than 80% of the cadmium is bound to MT.

The concentration of cadmium is higher in the kidney cortex than in the medulla. Renal damage initially occurs in the proximal tubules located in the renal cortex. Livingston (1972) analyzed the concentrations in serial sections of the cortex and found that cadmium decreased from the outer layer to the inner medulla. A ratio of 2:1 between the outer cortex and inner medulla has been reported. In humans, 65-75% of the whole kidney is cortex and 25-35% is the medullar collection system, and this ratio is usually taken into consideration when calculating the cadmium concentration in cortex and the whole kidney concentration (Kjellström and Nordberg 1978; Kjellström et al. 1984; Svartengren et al. 1986). A number of studies have confirmed the selection distribution of cadmium to the cortex of the kidney in preference to the medulla for different routes of exposure, exposure types, and animal species. The cadmium concentration in kidney and liver tissues is very low at birth but markedly increases with age. In humans with normal exposures, liver accumulation reaches near steady-state at age 30, and kidney accumulation reaches a maximum at 40-50 y of age (Bernard and Lauwerys 1986). In muscles, accumulation of cadmium continues throughout life (Elinder 1985; Satarug et al. 2000).

Decker et al. (1958) gave 115Cd nitrate to rats (cadmium at 6.6 mg/kg) by gavage. After 8 h, the largest total amount was in the liver, although the highest concentration was in the kidney. The maximum concentration in both tissues was reached at 72 h after exposure. Kotsonis and Klaassen (1977) administered a single oral bolus dose of

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

radioactive cadmium chloride at 0, 25, 50, 100, and 150 mg/kg and reported that at the end of 2 d, the tissue cadmium concentration was highest in the liver, which contained most of the body burden. This was followed by the intestine > kidney > pancreas > spleen > heart > lung > muscle > other organs. After 2 wk, most tissue concentrations were decreased by 50%, but concentrations in the liver remained unchanged at the maximum, and in the kidney, the concentrations had increased threeto four-fold. In addition, in the kidney, the MT concentration was also increased several-fold at 2 wk, whereas in the liver, it remained at the 2-d level. Dorian et al. (1995) have shown in several investigations that cadmium eventually binds to the proximal tubules, where it is distributed equally to the convoluted and straight segments. While there are many studies of the distribution of cadmium after a single bolus dose or a range of doses, there are few reports on the distribution of cadmium after repeated administration of minimum amounts roughly equal to typical human exposure.

Ando et al. (1998) studied the pattern of accumulation of cadmium in the liver and kidney in female rats given a diet containing CdCl2 at 8, 40, 200, or 600 ppm for 2, 4, or 8 mo. The authors reported that although the tissue cadmium concentrations increased as a function of dose, there was a plateau in the kidney at a concentration of 250 µg/g. The highest-dose group reached the plateau at 2 mo and remained the same at 4 and 8 mo while the 200 ppm group took 8 mo. However, in the liver, it did not reach a plateau even with cadmium at 200 and 600 ppm. The decrease in the ratio of kidney to liver as the dose increased indicated that at low doses, cadmium accumulated preferentially in the kidney and that the converse is true for the high dose. Hiratsuka et al. (1999), from the same research group, reported the tissue distribution of cadmium in female rats given minimum amounts of cadmium-polluted rice or CdCl2 for 8 mo, indicated the absence of any hepatic or renal lesions at the end of the experiment regimen even at 40 ppm. In this study, CdCl2 was given at 5.08, 19.8, and 40.0 ppm in the diet (doses of 360, 1,438, or 2,883 µg/kg). After 1, 4, and 8 mo, the concentration of cadmium in the liver and kidneys had increased as a function of dose. The concentration of MT in the liver, kidney, serum, and urine had increased with dose at 4 and 8 mo. However, the distribution rates of cadmium (percent of administered dose) to the liver and kidney changed with the dose. In liver, it increased from 40% at the lower dose to 60% at the highest dose, whereas in the kidney, it decreased from 20% at lower dose to 10% in the high-dose group.

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

Liu et al. (2000) reported data from several studies examining the role of MT in cadmium absorption, tissue distribution, and elimination. Using MT-I/II Null mice and wild-type mice, the author and his colleagues also evaluated whether MT can protect against cadmium-induced renal toxicity. In wild-type mice, chronic oral consumption of cadmium via drinking water (30, 100, or 300 ppm) or feed (100 ppm cadmium) had no effect on body weight over the 6-mo exposure period (Liu et al. 2000). Immunohistochemical staining for MT showed that renal MT concentrations increased several-fold over those of controls. Kidney-to-body weight ratios were unaffected by up to 100 ppm either in water or in feed, although in the 300 ppm water group they were increased. Renal cadmium (µg/g kidney) increased with dose; at both highest doses (300 ppm water and 100 ppm diet), the tissue cadmium concentrations were 50 µg/g. Renal MT was induced in both the cytoplasm and nucleus. Consumption of cadmium in water (30, 100, or 300 ppm) or in feed (100 ppm) did not increase urinary excretion of gamma-glutamyl transferase (GGT), N-acetyl-β-D-glucosaminidase (a marker of renal tubular dysfunction), glucose, or protein, indicating a lack of nephrotoxic effects. Similarly, blood urea nitrogen (BUN), an indicator of renal dysfunction, was not increased in cadmium-treated groups. However, renal morphology in the 300 ppm water group showed degenerated proximal tubules and glomerular swelling. Mice exposed to cadmium in their feed (100 ppm) had glomerular swelling and severe tubular degeneration (Liu et al. 2000). Hepatotoxicity was not indicated, as measured by the activity of serum alanine aminotransferase under the conditions of this study. In this study the authors also documented that the lack of MT rendered the MT-null mice vulnerable to severe renal toxicity, even though the cadmium concentrations in the kidney of MT-null mice were much lower than in wild-type mice. MT protects against cadmium-induced liver injury as it increased MT binds cadmium in the cytosol, reducing cadmium content in the organelles. Thus, MT-null mice are highly susceptible to cadmium toxicity (Liu et al. 2000).

Excretion and Elimination

Most orally administered cadmium is not absorbed systemilcally and is therefore excreted in the feces. The amount that is truly absorbed, which is very low after oral exposures, is excreted very slowly, urinary and fecal excretion being equal (Kjellström and Nordberg 1978). After repeated exposures, excretion increases over time, and there is an asso-

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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ciation between body burden and urinary cadmium excretion. Especially after the kidney has accumulated excess cadmium and renal damage has set in, urinary excretion of cadmium increases significantly. There have been a number of studies designed to examine cadmium excretion rates after sc injections in rats, mice, and rabbits, but they will not be discussed here.

The normal rate of urinary cadmium excretion in humans is about 1 µg/d, and urinary cadmium concentration increases with age. In individuals exposed to cadmium, urinary cadmium excretion and concentration are signs of renal dysfunction. Animal experiments have shown that fecal excretion is contributed to by both direct excretion from the mucosa and by biliary excretion; intestinal excretion contributes the most.

Using isolated rat jejunal segments or everted jejunal sacs, Foulkes (1979, 1985, 2000) has extensively studied possible mechanisms of cadmium absorption, transfer, and transport, and their determinants. Andersen et al. (1988) conducted an experiment in which 7- to 8-wk-old mice were given a single oral bolus of various doses of CdCl2 (5, 70, 270, or 790 µmoles/kg or 15.7, 30.4, 59.6, and 88.8 mg/kg/d). The doses were labeled with 109Cd. Whole-body counting was done at 15 min and 1, 2, 3, 4, 7, and 10 d after dosing. On d 10, all animals were killed, and tissues, including the GI tract, were removed and counted (Andersen et al. 1988). It was estimated that in rats, the whole-body elimination of cadmium from a single oral bolus is biphasic, with a rapid phase in which about 95% of the dose is eliminated within 4 d (mainly fecal elimination) and another, much slower, phase representing loss from the rest of the body. In long-term studies in mice, the latter phase has been reported to be about 200 d. This latter phase seems to vary with the strain of mice between 66 and 245 d (Engstrom and Nordberg 1979a, b). These studies also indicate that the half-life depends on the dose. Kjellström and Nordberg (1986) estimated from their kinetic model, developed after collating the literature data, that the half-life of cadmium in liver is between 6 and 38 y, and for kidney it is about 4 to 19 y (see discussion below).

Recently, Liu and Klaassen (1996) reported that MT does not play a role in the initial distribution of cadmium to tissues but does play a major role in the retention of cadmium, especially from liver, kidney, and pancreas. They conclude that the persistence of cadmium in the body is at least partially because of cadmium binding to MT in tissues. These investigators studied the role of MT in the tissue distribution and retention of cadmium using MT-I and MT-II null (MT-null) mice. The elimination of cadmium was much faster in MT-null mice than in control mice. In control mice, about 40% of the cadmium administered was found in the

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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liver 24 h after administration, and the majority was bound to MT. In contrast, only 20% of the administered cadmium was found in the liver of MT-null mice. Cadmium concentrations in kidney, pancreas, and spleen were also lower in MT-null than in control mice 1 wk after administration. The cadmium concentration in kidneys of control mice continued to increase with time, but in MT-null mice, it did not increase, indicating that the binding of cadmium by MT is an important source of cadmium in the kidney.

Using experimental and epidemiologic studies, Kjellström and Nordberg (1986) developed an eight-compartment kinetic model (human cadmium toxicokinetic model) to describe absorption, distribution, and biotransformation of cadmium. From this model, half-lives of cadmium in the whole body of mice, rats, rabbits, and monkeys have been calculated to be from several months to several years. Half-life in the slowest phase was from 20% to 50% of the maximum life span of the animal (Kjellström and Nordberg 1986). In the human body, the main portion of the cadmium body burden is found in the liver and kidney and in other tissues (particularly muscle, skin, and bone). From their model, Kjellström and Nordberg estimated that half-time for elimination from the human kidney would be between 6 and 38 y, and for the human liver, between 4 and 19 y. Using assumptions that urinary excretion depends on blood concentration and kidney concentration and total excretion is assumed to equal daily intake at steady state, Kjellström and Nordberg (1978, 1986) estimated daily fecal and urinary excretion to be 0.007% and 0.009% of body burden, respectively.

Recently, Choudhury et al. (2001) developed the Cadmium Dietary Exposure Model (CDEM), basing it on modifications to the cadmium biokinetic model of Kjellström and Nordberg (KNM). The model predicts a mean peak kidney cadmium burden of about 3.5 mg in males (range of 2.2-5.1 mg) corresponding to a peak renal cortex concentration of 15 µg/g wet cortex (range of 10-22 µg/g). Predicted kidney cadmium concentrations of females were higher than those of males: 5.1 mg (3.3-7.6 mg) total kidney and 29 µg/g (19-43 µg/g) wet cortex. According to the authors, the predicted and observed urinary cadmium excretion rates in males and females agreed with empirical estimates based on the National Health and Nutritional Evaluation Survey, 1988-1994 (NHANES III), with females predicted and observed to excrete about twice as much cadmium in urine as males. The authors suggested that females may also absorb a larger fraction of ingested dietary cadmium than males, and this difference may be the result of lower body iron stores in females than in males.

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Urinary cadmium excretion (cadmium µg/g creatinine) in the United States as predicted by nonsmoking, non-occupationally exposed population subset of the NHANES III report indicated that for all age categories, mean urinary cadmium excretion was higher for females than males if only nonsmokers are taken into account. Urine cadmium (U-Cd), expressed either as uncorrected µg/L or creatinine corrected (µg/g creatinine) increased with age and with smoking. The CDEM results indicated that predicted and observed urinary cadmium in males and females agreed with empirical estimates based on NHANES III, with females predicted and observed to excrete approximately twice the amount of cadmium in urine as in males (Choudhury et al. 2001).

TOXICITY SUMMARY

A number of toxic effects in humans and animals resulting from cadmium exposures have been reported. This has been the subject of great interest and concern due to cadmium-induced itai-itai disease in Japan among people who were exposed to rice contaminated with cadmium. Itai-itai or “ouch-ouch” disease was a serious health problem in a rural area in north central Japan. Severe osteoporosis and osteomalacia (soft bone) with tubular changes in the kidney were considered to be associated with excess intake of cadmium. It is a painful disease that includes kidney damage and bone demineralization. The disease primarily affected elderly Japanese women who had multiple child deliveries and who were exposed to water and rice contaminated with cadmium.

In the cadmium toxicology literature, although renal dysfunction has been well documented as the primary effect in humans, reports of several animal studies have attributed death, GI distress, hepatic injury, testicular atrophy, renal dysfunction, hypertension, anemia, CNS effects, reproductive and developmental effects, and possible cancers of the prostate and testes to exposure to cadmium via water or food. Numerous reports exist, mostly from studies conducted in mice, on the effects on immune system parameters that result from exposure to cadmium through the oral route. Some of these effects have also been occasionally evaluated in humans occupationally exposed to cadmium (WHO 1984) where exposure to other metals such as nickel and arsenic cannot be ruled out. Cadmium-associated changes with confounding factors of smoking, drinking, and age have been difficult to delineate.

Cadmium ions have a high affinity for tissue thiols, induce the synthesis of a carrier cysteine-rich polypeptide called MT, and impair pro-

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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teoglycan metabolism. Significant renal effects include tubular nephropathy manifested by proteinuria, aminoaciduria, glucosuria, phosphaturia, and calcium wastage. Chronic sequelae include a decrease in the glomerular filtration rate and an increased risk of kidney stone disease. Biologic monitoring of cadmium absorption includes determination of U-Cd and of low-molecular-weight marker proteins, such as β-2-microglobulin (β-2m) (Nogawa and Kido 1993) and retinol binding protein, the tubular reabsorption of which is impaired before a frank proteinuria.

Acute Exposures

Death has been reported in two cases of humans who used cadmium in suicide attempts. In these cases, massive fluid loss, edema, and widespread organ destruction were noted. In one case, the death was because of the ingestion of cadmium iodide, and the dose was estimated to be 25 mg/kg as cadmium. Death occurred in 7 d (Wisniewska-Knypl et al. 1971). In another case, death occurred in 33 h because of the ingestion of CdCl2, and the cadmium dose was estimated to be 1,840 mg/kg (Buckler et al. 1986).

There have been several single oral bolus studies in mice and rats from which the LD50 has been derived. A short summary is presented in Table 5-2.

Specific Short-Term Oral Exposure Studies

Although no surveys of environmentally exposed populations have reported GI symptoms (Roels et al. 1981), numerous human and animal studies indicate that oral exposure to cadmium in high concentrations causes severe irritation to the GI epithelium, resulting in nausea, vomiting, salivation, abdominal pain, cramps, and diarrhea (Buckler et al. 1986; Andersen et al. 1988; Nordberg et al. 1973). GI symptoms have been reported in children who drank soft drinks containing cadmium. The estimated concentration was 16 mg/L (Nordberg et al. 1973). Nordberg et al. (1973) calculated the dose that induced vomiting as 0.07 mg/kg (assuming ingestion of 150 mL and body weight of 35 kg for the child). The emetic threshold doses for cadmium have been estimated to be 3-90 mg and concentrations of soluble cadmium salt solutions exceeding 15 mg/L (CEC 1978). In humans, if vomiting occurs, the risk of con-

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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TABLE 5-2 Oral LD50 Values for Few Inorganic Cadmium Compounds, as Stated in the Registry of Toxic Effects of Chemical Substances (RTECS)

Compound

Species

LD50 (mg/kg )

Cause of Death

Cadmium chloride

Rat

88

Gastrointestinal hypermotility, diarrhea

Mouse

60

Weight loss

Guinea pig

63

Not reported

Cadmium iodide

Rat

222

Not reported

Mouse

166

Not reported

Cadmium nitrate

Rat

300

Not reported

Mouse

47

Not reported

Cadmium acetate

Rat

333

Not reported

Source: Data from CCOHS 2006.

tinuous exposure to a higher dose is minimized. Frant and Kleeman (1941) reported on four outbreaks of cadmium poisoning. Three members of a family, two children and one adult, drank lemonade made from a yellow crystalline powder and became ill with nausea, abdominal cramps, and vomiting in 15 min. The drink had 300 ppm of cadmium. The authors also reported an incident in which seven subjects (five adults and two children) drank a punch containing cadmium at about 85 ppm and experienced GI symptoms as mentioned above. They also reported two other cases, one of five subjects consuming a gelatin dessert that contained cadmium at 530 ppm, and the other of eight subjects consuming tea that contained cadmium at 160 ppm. The authors also cited the cases from the department of health record of 29 children who had violent nausea after eating frozen ice pops. Each ice pop contained cadmium at 13-15 ppm. Although the exact total amount consumed that caused the GI effects was not reported, it appears that a concentration of 13 mg/L can cause these effects.

Single gavage doses of CdCl2 to mice induced toxic gastroenteritis and hepatic and renal lesions. Experiments were performed with 7- to 8-wk-old CBA/Bom mice, and the acute toxicity of CdCl2 was studied after single gavage doses of 0, 0.6, 3.9, 7.9, 15.7, 30.3, 59.6, and 88.8 mg/kg (Andersen et al. 1988). On day 10, all animals were sacrificed. In addition to determining mortality, tissue damage to gastric epithelium, intestinal epithelium, liver, kidney, and testes was also scored on groups dosed with cadmium at 30.3 mg/kg and above. The authors observed decreased peristalsis at doses of cadmium at 59.6 and 88.8 mg/kg and intes-

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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tinal atony leading to higher fractional absorption at these doses. This may have led to the systemic toxicity. At the 88.8 mg/kg dose, very severe necrosis of the stomach was observed. The damage to intestinal epithelial tissue was more pronounced in the proximal parts of the tract (Andersen et al. 1988). Tissue damage to stomach and duodenum were observed even at 30.3 mg/kg/d. Because histopathology was not done on mice treated at doses below 30.3 mg/kg, a no-observed-adverse-effect level (NOAEL) cannot be identified. Similar results were found by Basinger et al. (1988) who reported that a single oral gavage dose of cadmium as CdCl2 at 1 mmole/kg (112 mg/kg) given to mice induced gastric epithelial tissue damage and hepatic damage.

Kotsonis and Klaassen (1977) reported that in male Sprague-Dawley rats given single doses (gavage) of radioactive CdCl2 (cadmium at 0, 25, 50, 100, or 150 mg/kg), liver hexobarbital oxidase activity measured after 2 d was lower in 100 and 150 mg/kg dose groups, without any change in the levels of hepatic cytochrome P-450 or aniline hydroxylase activity. Testicular function, measured after 14 d in rats of the 100 and 150 mg/kg groups, was decreased. Protein excretion and urine flow was decreased for the first 2 d in these dose groups but returned to normal values. Daily motor activity was determined in a five-tier residential maze to measure locomotion. For 2-3 d, this activity (both nocturnal and diurnal) was lower in 50, 100, or 150 mg/kg groups, but after 3 d, the motor activity was comparable to that of untreated controls (Kotsonis and Klaassen 1977). Because normal motor activity is critical for spaceflight-related activities, these data can be used for a 1-d acceptable concentration (AC). A dose of cadmium at 50 mg/kg will be a lowest-observed-adverse-effect level (LOAEL), and 25 mg/kg will be a NOAEL.

Borzelleca et al. (1989) conducted short-term (a 1-d and a 10-d) gavage and drinking water toxicity studies. They will be described separately because the doses and concentrations are different.

For the gavage experiment protocol, male and female Sprague-Dawley-derived Wistar rats received CdCl2 solution in water as a gavage at 25, 51, 107, or 225 mg/kg/d (cadmium at 15, 31, 65, or 137 mg/kg/d) for 1-10 consecutive days. Several measurements were made that included mortality; organ and body weight and changes in their relative ratios; several clinical chemistry parameters such as serum enzymes, glucose, proteins, BUN, electrolytes, and hematologic parameters; and urinary parameters such as ketones, glucose, and protein. Gross pathologic examinations were also performed at necropsy (Borzelleca et al. 1989).

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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In the 1-d gavage dosage study, no significant effects on hematologic parameters, serum chemistries, or urinalysis parameters were reported. Three of 10 male rats died within 1 d in the two highest-dose groups, whereas among females, only 2/10 died at the highest dose. One day after the dose was given, the lung-to-body weight ratio in the highest-dose group was significantly higher only in males. However, necropsy of animals that died did not reveal any gross histopathologic lesions (Borzelleca et al. 1989).

In the 10-d gavage study, dose-dependent mortality was observed. All male and female rats of the highest-dose group died by day 7. Even at the lowest dose (CdCl2 at 25 mg/d), two animals died. Weights and organ-to-body weight ratios were decreased for most of the organs, including the testes in the males. In general, organ weights (as the percentage of body weight) decreased in all dosed groups. Testicular necrosis was noted in male rats receiving CdCl2 at 107 and 225 mg/kg. Atrophy or loss of spermatogenic elements were also noted in these groups. In the high-dose group of male rats, focal necrosis of hepatocytes was noted. In addition, in both male and female rats, mild focal necrotic changes in kidney tubular epithelium were observed occurring in all dosed groups in a dose-dependent manner (Borzelleca et al. 1989). Because of high mortality at the high dose and significant levels of mortality at other doses, it was decided not to use the data for AC calculations. In addition, the authors had also carried out a 10-d drinking water study (Borzelleca et al. 1989).

In the short-term drinking water exposure study (Borzelleca et al. 1989), male and female Sprague-Dawley-derived Wistar rats (10 each per dose) were exposed for 10 consecutive days to CdCl2, which was added in the drinking water at concentrations to give theoretical doses of CdCl2 at 2.5, 25, and 51 mg/kg/d. The authors observed decreases in water consumption as a function of concentration of cadmium in water. Exposure-dose calculations based on actual water consumption were reported as CdCl2 at 1.8, 12.8, and 18.2 mg/kg/d for males, and 1.8, 13.3, and 22.6 mg/kg/d for females, which corresponded to a mean for both males and females to cadmium at 1.1, 7.8, and 11.1 mg/kg/d. Except for some decreases in body and organ weight, no compound-related histopathologic effects were noted at the end of the study. Among several clinical chemistry parameter measures, only decreases (about 45%) in serum alkaline phosphatase (ALP), and serum protein were seen both in male and female rats, but the clinical relevance of decreases in serum is not easily interpretable. An increase in serum BUN was seen at the highest dose in male rats. Qualitative urine analysis (using only reagent strips)

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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indicated that a dose of cadmium at 7.8 mg/kg/d can be identified as a LOAEL and a dose of 1.1 mg/kg/d as a NOAEL for increased protein excretion in urine. Increased BUN in the 11.1 mg/kg/d group supports these data.

Exposure Duration > 10 d

Kotsonis and Klaassen (1978) conducted a study in which male Sprague-Dawley rats were exposed to cadmium via drinking water at concentrations of 10, 30, and 100 ppm for 24 wk. Several measurements that included hemoglobin, hematocrit, blood pressure, testicular function, drug-metabolizing enzyme activities, histopathology, and others were made after 3, 6, 12, and 24 wk. Food and water intake, urine flow, protein excretion, and motor activity were measured weekly. In the 30 ppm groups, the water intake was lower than that of controls only during weeks 1, 2, 8, 14, and 15; whereas in the 100 ppm groups, it was significantly lower throughout the study. From the mean water consumption data, the authors calculated the mean amount of cadmium to be 0.41, 1.09, and 2.82 mg/d for the 10, 30, and 100 ppm groups, respectively, resulting in exposure doses of 1.15, 2.92, and 8.51 mg/kg/d. In the 30 and 100 ppm groups, increased concentrations of protein in urine were observed after 6 wk of exposure, indicating nephrotoxicity. A slight focal tubular necrosis was also observed by week 24 (Kotsonis and Klaassen 1978).

In addition, for several weeks starting at week 3 and decreasing with time, daily motor activity in the 30 and 100 ppm groups was significantly lower than that of controls (Kotsonis and Klaassen 1978). Because changes in water consumption and motor activity were seen as early as 3 wk of exposure to cadmium, these data will be used for 10-d AC derivation.

In a rat study, a significant decrease in hemoglobin and a 50% decrease in water intake within 2 wk were reported after young male and female rats were exposed to cadmium at 50 ppm in drinking water (Decker et al. 1958). In this study, 34-d-old albino Sprague-Dawley rats (male and female) weighing about 100 g were given drinking water containing cadmium as CdCl2 at 0.1, 0.5, 2.5, 5.0, 10.0, or 50.0 ppm. The study was conducted for 1 y except that the 50 ppm group was terminated at 90 d. Based on the water consumption data recorded 2 wk after dosing, the estimated dose for 10 ppm was 0.7 mg/kg/d, and the dose for 50 ppm was 3 mg/kg/d. Microscopic observations indicated many micro-

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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cytic, hypochromic red blood cells and polychromasia (change of colors) with 8-10 nucleated red blood cells per 100 white blood cells. The authors reported that in groups treated with cadmium at 0.1-10.0 ppm in water for 1 y, changes in body weight gain and water and food intake were not different from those of controls, nor were any other pathologic changes noted. A NOAEL of 10 ppm (about 0.7 mg/kg/d) was thus identified.

However, the authors also stated that mortality because of respiratory infection occurred in all the groups, accompanied by pleuritis and emphysema. Because of the lack of confidence in the quality of the animal maintenance, the study will not be considered in the AC derivation for any duration.

Although data from the 3 mo of observations of the 50 ppm group can be used for a 10-d AC for hematologic changes and for a 100-d AC for both hematologic and water consumption effects, we have low confidence in the observations. Also, the results are not consistent with the reports of Kotsonis and Klaassen (1978), who found no change in hemoglobin and hematocrit concentrations in male Sprague-Dawley rats given cadmium at 10, 30, and 100 ppm in drinking water for 24 wk (6 mo).

Sakata et al. (1988) reported that oral administration of cadmium to Wistar rats at 100 mg/L in drinking water (estimated dose rate of cadmium at 12 mg/kg/d) for 12, 26, 50, and 100 d resulted in iron-deficiency anemia characterized by microcytic hypochromic red blood cells and in decreased plasma iron. In the bone marrow, the density of late erythroid progenitors steadily increased as plasma iron decreased because of cadmium administration, which reached a plateau after 50 d. Cadmium treatment inhibited the in vitro growth of erythroid progenitor cells in a dose-dependent manner. Although there were no changes in the red blood cell count, hemoglobin decreased as early as 26 d and hematocrit decreased as early as 12 d. This study was not used for AC calculation because of the lack of dose-response data, and a NOAEL could not be identified.

Anemia was reported in rats fed diets containing cadmium as CdCl2 at 30 mg/kg diet (cadmium at 2.4 mg/kg/d) for 4 wk. The test diets contained cadmium at 30 mg/kg either as CdCl2 or as cadmium incorporated in pigs' livers; the control group was fed a diet containing liver from a pig not treated with cadmium. cadmium-treated groups showed increased plasma aspartate and alanine aminotransferase activities. In addition, their spleens showed decreased extramedullary hematopoiesis (Groten et al. 1990). In groups fed CdCl2, all of these effects were more pronounced than for the group fed cadmium incorporated in liver; the cadmium con-

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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centration in the livers paralleled this. However, there were no differences in kidney cadmium concentrations between groups fed the cadmium-incorporated meat or CdCl2 in the diet. This study lacked doseresponse data, and Kotsonis and Klaassen (1978), who used even higher doses in drinking water than used in this study in diet, did not observe any such effects. Hence, the data from this study were also not considered for AC derivation.

Horiguchi et al. (1996) proposed that cadmium-induced anemia is caused by the low production of erythropoietin in the kidneys following renal injury. Thus, anemia may be secondary to cadmium-induced renal injury.

Ogoshi et al. (1989) conducted a study on the effect of cadmium ingestion on mechanical strength of the bone using female young, adult, and older rats. Rats received cadmium as CdCl2.2½H2O in drinking water for 4 wk. Young rats (21 d old) received cadmium at 0, 5, and 10 ppm, adult rats (24 wk old) received cadmium at 0, 10, 20, 40, 80, and 160 ppm, and old rats (1.5 y old) received cadmium at 0, 80, and 160 ppm. Rat strain was not specified. Compression strength of the metaphysis and diaphysis and the bending strength of the diaphysis of the femur were measured. Cadmium content of the kidney, liver, and femur were measured. At the end of 4 wk, although a decrease in the mechanical strength of the bone of young rats was noted even at a dose of cadmium at 5 ppm, no changes were noted in the adult and old rats at cadmium doses up to 160 ppm. Young rats accumulated more cadmium, especially in the bones, than adult and old rats. In the young rats, the strength was negatively correlated with bone cadmium content but not correlated with kidney cadmium content. This may be because young rats absorb more cadmium than adult and older rats. Based on the results from adult rats, for 4 wk, a NOAEL of 160 ppm (or a dose rate of cadmium at 22 mg/kg/d) for bone effects can be identified.

In a related study, Gur et al. (1995) studied the influence of cadmium administered through drinking water on the repair of injured bone. Rats were given cadmium at 20 ppm and 200 ppm in water for 5 wk. Significant reductions (43%) in ALP and tartrate-resistant acid phosphatase (46% reduction) were seen in samples taken from the bone. No cadmium-related liver or kidney abnormal histology was seen. Calcium accumulation in the newly formed repair tissue at the site of injury was also significantly reduced (53%) in the cadmium-treated (200 ppm) rats in comparison to control rats. The authors concluded that exposure to 200 ppm of cadmium in water for 5 wk affects the bone-repair process (reduction in ALP in osteoblastic cells). Because the bone was already

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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damaged and these findings reflect bone repair, these data could not be used for AC derivation.

Young male Long Evans rats (40-50 g) were exposed to cadmium at 20 ppm and 40 ppm as CdCl2 (estimated dose rate of cadmium at 2.9 and 5.8 mg/kg/d) in drinking water for 14 wk (Pleasants et al. 1992). The body weight of the 20-ppm group was not different from that of the untreated controls; also, the relative kidney, liver, and testes weights were not affected. However, the 40-ppm groups showed increased kidney and testes weights, although body weights showed a significant decrease starting at 7 wk. The femurs of this group revealed an increase in water and a decrease in mineral content (ash) with cadmium exposure. These findings were considered symptomatic of osteoporosis. Although no changes in hematocrit or peripheral red blood cell counts were noted, rats exposed to cadmium at 40 ppm for 14 wk showed evidence of erythrocyte hypochromia with intracellular non-heme iron inclusions (Pleasants et al. 1992). In a follow-up study, the authors (Pleasants et al. 1993) exposed 40-50 g male weanling Long Evans rats to cadmium at 80 ppm as CdCl2 (11.6 mg/kg/d) in their drinking water for 14 wk. Cadmium-treated rats displayed smaller body weight gains and larger relative kidney and testis weights than controls. Exposure of rats to cadmium significantly depressed the hematocrit and erythrocyte counts. A dose rate of cadmium at 2.9 mg/kg/d appears to be a NOAEL for all these effects.

A study of adult male rats exposed to cadmium in the diet (100 ppm/kg diet or cadmium at 9 mg/kg body weight) for 60 d and then tested in a Digiscan activity monitor indicated that cadmium decreased movement and increased rest time (Nation et al. 1990). Kotsonis and Klaassen (1977, 1978) reported that both single-bolus (LOAEL of cadmium at 50 mg/kg) and intermediate-duration exposures (NOAEL of 1.1 and a LOAEL of 2.82 mg/kg/d) to cadmium affect neurologic behavior. Nation et al. (1984) also showed that intermediate-duration exposure to cadmium (5 mg/kg/d) induced anxiety in animals, as manifested by increased passive avoidance behavior; cadmium at 1 mg/kg/d was without any effect and thus is a NOAEL for 60 d.

The effect of cadmium on hypertension is equivocal. Studies in which a hypertensive effect of cadmium has been reported have had several drawbacks. Fowler et al. (1975) exposed rats to cadmium in drinking water at concentrations ranging from 0.2 to 200.0 mg/L for 12 wk. After 6 wk, the authors noticed morphologic changes in the vascular system of the kidneys in all treated rats. There was a thickening of small and median arteries and dilation of the large ones. Blood pressure was not measured in this study. Eakin et al. (1980) conducted a study on

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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weanling rats to assess effects of cadmium on hypertension. Rats (16 male OSU Brown rats) were fed a diet containing cadmium as cadmium acetate at 150 ppm for 16 wk. Body weight, blood pressure, and plasma renin were measured at week 2, 4, 8, and 12, and terminally at week 16. While the blood pressure of control rats increased with age during the experiment, the blood pressure of the cadmium group decreased from week 8 to week 16. There was no change in plasma renin concentrations. Eakin et al. (1980) also conducted a long-term experiment in which cadmium was administered in drinking water at 0, 10, and 20 ppm for 64 wk. Blood pressure was measured every 4th wk for 24 wk and then once every 8 wk until the 64th wk. No significant changes were observed in blood pressure.

Loeser and Lorke (1977b) conducted a study in which cadmium in the form of CdCl2 was administered with the feed in concentrations of 0, 1, 3, 10, and 30 ppm over a period of 3 mo to groups of 2 male and 2 female beagle dogs. The systolic and diastolic blood pressure of the treated animals of all groups up to 30 ppm was within the normal range.

Although cadmium accumulated in the liver and kidneys, liver function (as measured by glutamate dehydrogenase and lactate dehydrogenase [LDH]) and kidney function (as measured by para-aminohippuric acid and inulin clearance) were unaffected at the end of 3 mo. Hematology parameters measured at 1 and 3 mo (erythrocyte sedimentation rate, hemoglobin, hematocrit, and erythrocyte and leucocyte count) did not indicate any clinically significant results (Loeser and Lorke 1977b).

Loeser and Lorke (1977a) conducted very similar subchronic studies in male rats (SPF Wistar, n = 5/dose) ingesting a diet containing cadmium (1, 3, 10, or 30 ppm) for 3 mo. A vast array of hematologic (including hemoglobin, hematocrit, erythrocyte and leukocyte counts, and differential counts), liver function (serum ALP, aspartate transaminase, alanine transaminase, bilirubin, and serum proteins detected by electrophoresis), and renal function parameters (sugar, albumin, bile pigments, urinary proteins detected by electrophoresis, urinary leucine aminopeptidase (LAP), and aspartate transaminase)) were measured. In addition, blood pressure, blood sugar, and cholesterol were evaluated, as well as cadmium concentrations in liver and kidney for all the doses. The authors did not find any significant adverse effects as judged by the above parameters.

The National Academy of Sciences calculated a 7-d suggested noadverse-response level (SNARL) based on the Loeser and Lorke study (1977a) where rats were fed CdCl2 in their diets at 1 to 30 ppm of cadmium for 3 mo. With the assumption that rats consumed 20 g of diet per

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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d and their body weight was 250 g, the exposure dose was calculated to be cadmium at 2.4 mg/kg. For a 70 kg human consuming 2 L/d, after applying a factor of 1,000, the 7-d SNARL was calculated to be 0.08 mg/L (NAS 1980) as follows:



Exposure Duration > 100 d

Several epidemiologic studies in Japan have provided models for dose-response relationships for adverse health effects from exposure to cadmium. One such study was performed on inhabitants of the Kakehashi River basin in Ishikawa Prefecture in Japan (878 cadmium-exposed males and 972 cadmium-exposed females) (Nogawa et al. 1989; Kido and Nogawa 1993; Nakagawa et al. 1993; Nishijo et al. 1995; Nakashima et al. 1997). The subjects were followed for 9 y. Controls for this study were 133 males and 161 females without exposure to cadmium. β-2m in urine was used as an index of the effect of cadmium on health, and the average cadmium concentration in locally produced rice was used as an indicator of cadmium exposure. The range of length of residence of the subjects was 1-70 y (Nogawa et al. 1989), and the mean residence time in the polluted area was 57 y in the case of males and 53 y in the case of females. Cadmium exposure was found to affect health in a dose-related manner when the subjects were classified according to the average cadmium concentration in their village’s rice and their length of residence in the polluted area. Abnormal β-2m was defined as >1,000 µg/L or 1,000 µg/g urine creatinine. The concentration of cadmium in the rice from 22 hamlets varied from 0.63 to 0.87 µg/g in heavily polluted areas and from 0.48 to 0.72 µg/g in moderately polluted areas. From the available data, the total cadmium intake that produced an adverse effect on health was calculated as 2,000 mg for both men and women. The authors calculated that the daily cadmium intake corresponding to a 2,000 mg total dose for 50 y is 110 µg/d, or 0.0021 mg/kg/d, for men and women. This will be considered a LOAEL.

Buchet et al. (1990) conducted a cross-sectional population study from 1985 through 1989 in Belgium to assess environmental exposure to cadmium and renal dysfunction. Eligible subjects (n = 1,699) aged 20-80 y were studied as a random sample of four areas of Belgium with varying degrees of cadmium pollution, primarily from contaminated water and food. After standardization for several possible confounding factors, five

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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variables (urinary excretion of retinol-binding protein, N-acetyl-β-glucosaminidase, β-2m, amino acids, and calcium) were significantly associated with U-Cd (which was used as a marker of cadmium body burden), suggesting the presence of tubular dysfunction. There was a 10% probability of the values of these variables being abnormal when cadmium excretion exceeded 2-4 µg/24 h. There was also evidence from this study that diabetic subjects may be more susceptible than normal subjects to the toxic effect of cadmium on the renal proximal tubule. The subjects excreting cadmium in urine at more than 2 µg in 24 h were predominantly women. Using cadmium at 2 µg/24 h as an estimated threshold for adverse concentrations, and assuming oral absorption of 5% and a daily excretion rate of 0.005% of body burden, Buchet et al. (1990) concluded that about 50 ppm of oral intake of 1 µg/kg/d would be retained in the renal cortex for 50 y. Using a toxicokinetic model, Clewell et al. (1997) arrived at an LOAEL of 0.84 µg/kg/d if the entire intake is via the oral route, using a factor of 3 to get a minimal LOAEL and not applying any other factor. A minimal risk level (MRL) for the Agency for Toxic Substances and Disease Registry (ATSDR) was calculated as 0.84 µg/kg/d ÷ 3 = 0.30 µg/kg/d or 0.0003 mg/kg/d.

Animal Studies

Itokawa et al. (1974) administered cadmium as CdCl2 in drinking water (50 mg/L or 5.6 mg/kg/d) to male Wistar rats fed a diet sufficient or deficient in calcium and studied the renal and skeleton lesions by histology and biochemical measurements 120 d after exposure to cadmium. According to the authors, the daily mean cadmium intake was 0.9 mg/d. Only the effects of cadmium in rats fed a calcium-sufficient diet will be reported here. Significant reductions in the number of erythrocytes (about 30%), hematocrit (about 30%), and amounts of hemoglobin (about 25%) were observed. Light microscopic examination of the kidneys revealed considerable desquamation and vacuolization of the tubular epithelium; other remarkable changes noted were marked degeneration and necrosis of the glomeruli and hypertrophy of the kidneys. Histology indicated thinning of bone cortex in treated rats. Significant increases in serum urea and ALP were also noted. As the levels of hepatotoxic marker enzymes such as serum aspartate transaminase and serum alanine transaminase were not affected, the changes in the serum urea and ALP seem to be related to a dysfunction in bone metabolism. Because of a lack of dose-response data, a NOAEL could not be identified.

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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In a study designed to compare early signs of cadmium toxicity via oral and inhalation exposures, Prigge et al. (1978) conducted a study in female Wistar rats (170-190 g) that were exposed to cadmium in drinking water at 25, 50, and 100 ppm (estimated doses of 4, 8, and 16 mg/kg) for 90 d. There was a significant decrease in serum iron as a function of dose and a decrease in serum ALP. Although ALP is present in several tissues, the major contribution to serum ALP seems to come from bone. The reduction of ALP in this study is not completely interpretable with respect to the effect of cadmium on the bone, although a reduction in serum bone-specific ALP may reflect a reduced bone-repair process or osteoblastic process. For example, Itokawa et al. (1974) observed an increase in serum ALP along with skeletal changes in rats exposed to cadmium at 50 ppm in drinking water for 120 d (see above). Proteinuria is the most significant observation in this study. Although there was a 20% increase in proteinuria in the 4 mg/kg group, it was statistically significant only in groups dosed with cadmium at 8 mg/kg and higher. A NOAEL of 4 mg/kg/d and a LOAEL of 8 mg/kg/d were identified for nephrotoxic effects in this study.

Male Sprague-Dawley rats were exposed to cadmium in drinking water at 10, 30, or 100 ppm (1.15, 2.92, or 8.51 mg/kg/d) for 24 wk (Kotsonis and Klaassen 1978). Central nervous system function was assessed by motor activity, and the “hourly nocturnal” and “daily motor activities” had decreased with time for the 30 ppm and 100 ppm groups by week 24. Also, renal injury was evident 6 wk after dosing as judged by the increased protein in the urine in these groups. There was also a slight focal tubular necrosis. A LOAEL for these effects seems to be 30 ppm, and 10 ppm (1.15 mg/kg) seems to be a NOAEL for 24 wk. The daily water intake was significantly less in the 100 ppm group throughout the study. No significant changes were noted in hemoglobin or hematocrit concentrations. Histopathologic examination of several tissues at 3, 6, 12, and 24 wk indicated that the only significant change was slight focal tubular atrophy at week 24.

Several investigators have studied the effect of oral administration of cadmium on the respiratory system, but results are equivocal. Petering et al. (1979) reported a reduced static compliance and lung lesions (not specified) in male Sprague-Dawley rats exposed to cadmium at 1.2 mg/kg/d in water for 200 d. Rats exposed to cadmium as CdCl2 at 3.62 mg/kg/d in drinking water for 120 d developed emphysema (Petering et al. 1979). On the contrary, no respiratory system effects were observed in female SPF Wistar rats after 90 d of exposure to cadmium in drinking water at 16 mg/kg/d (Prigge 1978). Also, no histopathologic lesions of

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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the lung were found in male Sprague-Dawley rats after 24 wk of exposure to cadmium in drinking water at a maximum dose of 2.82 mg/kg/d (Kotsonis and Klaassen 1978). In the study by Prigge (1978), findings inconsistent with those of Petering et al. (1979) might be because of the insensitivity of the particular rat strain used to study emphysema and/or the short duration for which the rats were observed.

Sutou et al. (1980a) administered CdCl2 by gavage for 9 wk to male and female Sprague-Dawley rats at daily doses of 0, 0.1, 1.0, and 10.0 mg/kg. This study was a part of a fertility study, and the sample size of the nonpregnant female group was very low; hence, female rat data will not be discussed. In the male rats, a 9% increase seen in the number of red cells in the male 10 mg/kg group, without any observed change in hemoglobin and hematocrit concentrations, was not interpretable. Activities of hepatotoxicity marker enzymes (glutamic-pyruvic transaminase [GPT] and glutamic-oxaloacetic transaminase [GOT]) in serum were not altered even at the highest dose. Serum clinical chemistry indicated that a significant increase (about 10%) occurred in serum creatinine at 1 mg/kg and above. In general, increased serum creatinine is clinically used as an indicator of decreased kidney function (glomerular filtration). However, the authors reported decreased food intake and water intake at the higher doses; the importance of this increase is questionable. No change was observed in the BUN even at 10 mg/kg. No nephrotoxic markers were measured in the urine. Other serum parameters measured, ALP, LDH urea nitrogen, bilirubin remained at concentrations comparable to controls. A NOAEL of cadmium at 10 mg/kg for hepatotoxicity for male rats can be identified (Sutou et al. 1980a). The authors did not carry out any histopathology of the organs of the male rats. However, they reported focal necrosis of the liver in five out of eight nonpregnant female rats and slight atrophy of glomeruli in two of eight of these female rats (Sutou et al. 1980a).

In a subchronic study (Ogoshi et al. 1992), young female rats were exposed to cadmium at 0, 5, and 10 ppm in drinking water for 20 wk. Old rats (18 mo) received only 0 and 40 ppm in drinking water but were exposed for 7 mo. In this study, the authors observed decreased compression strength of the femur bone (metaphysis) in the 10 ppm group of the young rats and the 40 ppm group of the older rats. The bone cadmium content (ng/g dry weight of femur) of the older rats was about twice that of young rats (10 ppm group). Because of variation in the duration, direct comparison of the data is difficult. Conservatively, cadmium at 5 ppm can be identified as a NOAEL. Because the concentration of cadmium in the kidney was below the critical concentration and there was no indica-

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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tion of kidney damage at the times when the effects on bone were noted, it seems that the effects on bone are not secondary to any renal effects that might be present.

Female Sprague-Dawley rats were given cadmium at 200 ppm (30 mg/kg/d) in drinking water for 11 mo (Bernard et al. 1981). From the 8th mo of treatment, the cadmium concentration in the kidney cortex leveled off at a value of 250 µg/g wet weight, and this phenomenon coincided with the occurrence of proteinuria. The proteinuria was characterized by an increased urinary excretion of high-molecular-weight (HMW) proteins, particularly γ globulins. Aminoaciduria also increased, which suggested the existence of a slight tubular dysfunction (Bernard et al. 1981). In a later study, female Sprague-Dawley rats exposed to cadmium in drinking water at 200 ppm (or 30 mg/kg) for 2-10 mo showed an increase in albuminuria and at 10 mo developed slight tubular damage, as evidenced by increased urinary excretion of β-2m and β-N-acetylglucosaminidase (NAG) (Bernard et al. 1988).

Enzymes from different cellular compartments of the nephron were measured in male and female weanling Wistar rats that received cadmium (as CdCl2) in their diet at concentrations of 0, 10, 50, and 250 ppm [0.66, 3.33, and 16.66 mg/kg/d] for a total of 72 wk (Bomhard et al. 1999). At the end of the study period, histopathology of the kidneys was done. Concentrations up to and including 50 ppm did not induce any adverse effect (NOAEL). Beginning with week 13, in males and females receiving 250 ppm, increased excretion of cytosolic phosphohexose isomerase enzyme was seen. Several nephron-related enzymes were measured in 24-h urine-sample pools collected during study week 1, 4, 8, 13, 26, 32, 57, and 68. The brush border enzymes (GGT, ALP, and leucine arylamidase) were not changed in a time-dependent manner in female rats. GGT activity was lower during the entire study period in the 250 ppm male rats, and activities of ALP and LAP were significantly lower than the control values from week 1 to week 18. Excretion of the lysosomal enzymes aryl sulfatase A, β-galactosidase, and NAG seemed to be unaffected. In the kidneys of 250 ppm males and females, histopathology after 72 wk revealed chronic and acute degenerative changes.

Male Wistar rats were fed diets containing cadmium as CdCl2 at 0.3, 3, 30, or 90 mg/kg for 10 mo (Groten et al. 1994). In the highest-dose group, an increase in urinary LDH activity, a sign of renal injury, was seen first at 4 mo of treatment at 90 mg/kg. After 8 and 10 mo, the renal effect became more pronounced and urinary enzyme activities of LDH, NAG, and ALP were all higher (Groten et al. 1994).

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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A critical target organ for accumulation of cadmium was well demonstrated in an experiment by Mitsumori et al. (1998). Female Sprague-Dawley rats were fed a diet containing CdCl2 at 0, 8, 40, 200, or 600 ppm (0, 0.33, 1.6, 8, or 24 mg/kg/d) for 2, 4, and 8 mo from 5 wk of age. Hepatotoxicity was observed after 2 mo in the groups treated with ≥200 ppm. By 4 mo, the rats in the 600 ppm group had developed periportal liver cell necrosis. At 4 mo, surviving rats given cadmium at 600 ppm showed anemia and decreased hematopoiesis in the bone marrow, in addition to reduction of cancellous bone in their femurs. Renal toxicity, characterized by vacuolar degeneration of proximal tubular epithelia, was apparent in the groups treated with ≥200 ppm from 2 mo, becoming more prominent in the high-dose rats at 4 mo. Hepatic accumulation of cadmium increased linearly with the duration of treatment. The concentration of cadmium in the renal cortex of rats reached a plateau concentration of 250 µg/g within the first 2 mo. The renal concentration of cadmium in the 200 ppm group when renal toxic lesions were first detected at 2 mo ranged from 104 to 244 µg/g. Although no renal lesions were observed in the 40 ppm (1.6 mg/kg/d) group even after 8 mo, despite the presence of 91-183 µg/g amounts of CdCl2 for periods longer than 8 mo, accumulation of cadmium might gradually progress. Shibutani et al. (2000), in a later study from the same laboratory, used a concentration of cadmium lower than in the previous study (concentrations of 1.1, 5, 20, or 40 ppm/kg diet) for a longer time (up to 22 mo). The observed incidence or severity of nephropathy in the treated animals was not different from that in controls. No renal or hepatic lesions were noted in this long-term low-cadmium-dose study.

In CBA/H mice that drank water containing CdCl2 at 300 mg/L for 12 mo (45 mg/kg/d), bone marrow hypoplasia was noted, characterized by significant reduction of the totipotent stem cells, granulocytemonocyte progenitor cells (GM-CFUc), and erythroid progenitor cells (Hays and Margaretten 1985). The bone marrow cellularity and the proliferative capacity of GM-CFUc measured in vitro were decreased. Consistent with these changes, anemia with reticulocytopenia and neutropenia was also seen. Peripheral red blood cells were hypochromic, with diminished bone marrow iron. Because this study did not provide dose-or time-response data, it was not useful for AC derivation.

Bomhard et al. (1987) conducted a study to evaluate the chronic effects of single versus multiple oral cadmium administrations on the testes of mature male Wistar rats. Cadmium was administered as CdCl2 in water in a single bolus dose of 50 mg/kg or in 10 weekly oral doses of 5 mg/kg. Some of the animals were necropsied after 12 and 18 mo, re-

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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spectively; the remainders were kept in the study for up to 30 mo. In a supplementary study, male rats were treated once with 200 or 100 mg/kg po. This experiment was terminated after 6 mo. Animals having received 1 × 100 or 1 × 200 mg/kg po showed severe lesions of the entire testicular parenchyma with massive calcification. These testicular lesions were not seen in rats that received a single 50 mg/kg dose or in rats treated 10 times, once per wk for 10 wk at 5 mg/kg po.

In a study that evaluated the relationships of certain urinary enzymes and various anatomical areas of the kidney (Gatta et al. 1989), 40 Wistar rats were exposed to CdCl2 at 16 ppm in drinking water for 4, 16, 40, or 60 wk. At the end of each period, all the cadmium-dosed rats and five controls were assessed for creatinine clearance, fractional excretion of GGT and α-glucosidase (indices of anatomical tubular damage), and fractional clearance of lysozyme (an index of functional tubular damage). Subsequently, the rats were sacrificed and their kidneys examined. No histologic impairment was seen for up to 16 wk of exposure according to light and electron microscopy. A widespread vesiculation of proximal tubular cells with mitochondrial and lysosomal alterations was found at 40 wk and was more evident at 60 wk. The brush border never showed any damage (normal excretion pattern of GGT, an enzyme situated in this structure). Urinary α-glucosidase was increased only at 60 wk and showed the most severe anatomic damage. Urinary lysozyme, an index of tubular function, was increased at 40 wk and 60 wk.

A pronounced increase in the mean duration of the estrous cycle, mainly because of the lengthening of diestrus, was noted in female rats that received an aqueous solution of CdCl2 for 14 wk, 5 d/wk by gavage at doses of 0.04, 0.4, 4.0, and 40.0 mg/kg/d. This was seen 6 wk after treatment only in rats in the 40 mg dose group (Baranski and Sitarek 1987).

Loeser (1980) conducted a long-term 2-y feeding study on cadmium with Wistar rats (50 male and female) ingesting a diet containing CdCl2 at 1, 3, 10, and 50 ppm. In this study, the author did not look at any parameters except food consumption, body weight changes, and extensive histopathology. Except for a significantly decreased growth rate in the 50 ppm dose group, the author did not find any cadmium dose-related change in benign or malignant neoplasia. In particular, there was not a single case of prostate tumors.

Ohta et al. (2000) conducted a study evaluating the relationship between renal dysfunction and bone metabolism (osteotoxicity) in 6-wk-old male rats after long-term oral cadmium administration of CdCl2 by gavage, 6 consecutive d/wk for 60 wk (360 doses) at doses of 2, 5,10, 20,

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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30, and 60 mg/kg for 60 wk. Hepatotoxicity was assessed by determining plasma hepatotoxic marker enzymes GOT (also called AST, L-aspartate aminotransferase), and GPT (also called ALT, alanine aminotransferase). Several urinary variables such as glucose, protein, creatinine, amino acids, and the excretion of urinary enzymes such as NAG, alanine aminopeptidase, and glutathione-s-transferase were measured as nephrotoxic indices. Nephrotoxicity was also confirmed by histopathologic examination of renal tissue especially by evaluating morphologic changes in the proximal tubular cells (Ohta et al. 2000). Bone metabolism and osteotoxicity were evaluated by measuring bone mineral density (by radiographic microdensitometry), urinary excretion of pyridinoline (Pyr, synonym pyridinium collagen crosslinks) and deoxypyridinoline (Dpyr), and plasma intact-osteocalcin. Usually Pyr and Dpyr provide rigidity and strength to the bone. During the bone resorption process, these are released into the circulation and are excreted unmetabolized in the urine (Ohta et al. 2000). Manifestations of enzymuria followed the dose and duration of exposure. From the 5th wk, both hepatotoxic and nephrotoxic markers were found to be higher in rats treated with cadmium at 30 and 60 mg/kg. In 10 mg/kg dose groups, GST increased as early as 5 wk after treatment. Proximal tubular regeneration, vacuolization, and eosinophilic bodies were mainly observed in the groups receiving 20, 30, and 60 mg/kg at this time. Such changes were noted at the 30th wk in rats administered 5 and 10 mg/kg and at the 60th wk in the lowest-dose group (2 mg/kg).

As far as osteotoxicity is concerned, dose groups of 5 and 10 mg/kg were studied only for 30 wk for bone mineral density and other markers of bone resorption. Bone mineral density measured at the midpoint of the femur decreased as the cadmium dose increased. In the high-dose groups (30 and 60 mg/kg), the decrease in bone mineral density was observed at about the same time or before increased excretion of aforementioned urinary enzymes were observed. No significant differences were noted in the 2 mg/kg group at the 5th wk. At 10 wk, bone mineral density was unaffected in both 5 and 10 mg/kg groups. The rats of the 10 mg/kg group showed changes in bone mineral density only at 30 wk. In rats of groups dosed with cadmium at 2-10 mg, a reduction in bone mineral density was seen after the onset of renal toxicity. Significant increases in Pyr and Dpyr—the bone resorption markers—were also observed in high-dose groups during the early part of the treatment regimen (Ohta et al. 2000). These data were not considered for AC derivations as the doses in this study were administered as single boluses (gavage) and data from drinking water studies were preferred.

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Cadmium and Immunotoxicity

Several studies on cadmium immunotoxicity have been extensively reviewed by Koller (1996, 1998) and others (Bernier et al. 1995). The reviews concluded that it can be demonstrated that cadmium, in vivo, can modulate certain immune responses with a tendency to induce various degrees of immunosuppression, although the results from numerous rodent studies on humoral immune responses and cell-mediated immune responses as a result of exposure to cadmium appear to be contradictory and human data from occupational settings (probably because of co-exposure to other metals) are inconsistent. However, the complex nature of the results and the direction of effects make the data difficult to interpret so as to be quantitatively useful for deriving ACs with any confidence. Some of the studies have been described here.

A few studies have measured changes in parameters of immunotoxicity because of cadmium exposure (mostly by inhalation) in an occupational setting, but the results are somewhat ambiguous (see Bernier et al. 1995). There are no human epidemiologic data demonstrating any immunotoxic effects of cadmium on populations exposed via an oral route.

Although little information is available from human studies, the effects of cadmium on the immune system have been studied extensively in animals, particularly in rodents. A review of the experimental literature indicates that the immunotoxic effects of cadmium are dependent upon dose, time between cadmium administration and exposure to antigen, and mode and length of exposure. In some instances, species-, strain-, and age-specific effects have been reported (Koller 1980; Malave and de Ruffino 1984; Fujimaki 1985, 1987; Thomas et al. 1985; Borgman et al. 1986; Exon et al. 1986; Blakley 1988; Cifone et al. 1989; Schulte et al. 1994; Bernier et al. 1995; Fawl et al. 1996).

Cadmium-induced immunotoxicity has been studied using various approaches such as host-resistance challenge assays that assess increased susceptibility against bacterial and/or viral pathogens; primary and secondary immune response against specific antigens (sheep red blood cells [sRBC]); antibody titers; proliferative response of peripheral lymphocytes to a particular mitogen; and shifts in lymphocyte subpopulations. Due to a vast amount of literature from studies employing a variety of exposure routes (which likely do not extrapolate well to ingestion), only results from oral exposures will be discussed in this section.

The effects of cadmium on the immune system of rodents exposed either by drinking water or gavage have been thoroughly reviewed by Koller (1998).

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Host Resistance and Exposure to Cadmium

In studies in which different strains of mice were exposed orally to a soluble cadmium salt and subsequently challenged with an infectious viral or bacterial pathogen, effects on host resistance were highly variable and ranged from no effect (Ilback et al. 1994) to increased host survival time and tumor regression rate (Kerkvliet et al. 1979).

Thomas et al. (1985) also studied the effects of cadmium (CdCl2) on host resistance against viral and bacterial agents. The investigators treated female B6C3F1 mice with CdCl2 at 10, 50, or 250 mg/L via drinking water for 90 d and then challenged on day 91 with various infectious agents such as influenza virus, herpes simplex virus type I (HSV-1) and type II (HSV-2), and Listeria monocytogens. Cadmium treatment did not alter the mortality or mean survival times (MST) following a primary infectious challenge or a secondary challenge (21 d after the primary challenge) of the survivors with HSV-1, influenza virus or L. monocytogens compared to controls. However, resistance to HSV-2 challenge in cadmium-treated animals decreased (not statistically significantly) as the dose of cadmium increased. Exon et al. (1986) reported that the incidence of viral-induced mortality was lower in male Swiss Webster mice exposed to cadmium sulfate, acetate, or chloride in the drinking water at 3, 30, or 300 mg/L for 10 wk followed by an inoculation of encephalomyocarditis virus (EMCV). When resistance to coxsackievirus B3 (CB3)-induced myocarditis in female Balb/c mice was investigated after a dose of cadmium at 2 millimolar (mM) (225 mg/L) in drinking water for 10 wk, no influence on mortality from the CB3 infection was found. The inflammatory and necrotic lesions in the myocardium were also not changed (Ilback et al. 1994). On the other hand, Kerkvliet et al. (1979) observed that male C57BL/6 mice exposed to cadmium as CdCl2 at 0, 3, 30, or 300 ppm in their drinking water for 21 wk had significantly inhibited in vivo growth of MSB-induced tumors and had enhanced manifestions of cell-mediated cytotoxicity in the tumor-bearing hosts and that the latter was inversely correlated to the dose.

Recently, Seth et al. (2003) pretreated CD-1 mice (either sex) and 6-wk-old C57BL/6 mice with a single oral dose of cadmium as CdCl2 by gavage at either 0.13 or 0.26 mg/kg. Subsequently, animals were inoculated with Venezuelan equine encephalitis virus (VEE), EMCV, or Semliki Forest virus (SFV). Increased severity of symptoms and mortality compared to untreated controls were noted in all cases. An early onset of virus infection was found in the brains of cadmium-treated animals. This indicated immunosuppression as a result of cadmium treatment.

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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From the above results, the extent of immunotoxic effects of cadmium when ingested via the oral route cannot be conclusively determined. The concentrations used in most of these studies are several-fold higher than those shown to result in nephrotoxicity.

Humoral Immunity and Exposure to Cadmium

Humoral immunity is conferred by B lymphocytes, but maximum responses in most cases require interactions with both the innate and cell-mediated arms of the immune response. Although data concerning the effects of cadmium on humoral immunity are conflicting and depend upon rodent species, strain, dose, and duration of exposure, mechanisms important in maintaining humoral-mediated immunity (B lymphocyte proliferation, antibody formation/response, and antibody-complement interactions) appear sensitive to the immunotoxic effects of cadmium.

For example, Koller et al. (1975) observed a significant decrease in the plaque-forming cell (PFC) response (immunoglobulin g [IgG]) to injected sRBC in Swiss Webster mice given CdCl2 orally at 3, 30, or 300 ppm for 10 wk. Although immunoglobulin M (IgM) was also depressed, it appeared to recover 14 d after the cessation of exposure. Blakley (1985) and Blakley and Tomar (1986) reported suppression of splenic antibody production against injected sRBC when 6-wk-old BDF1 or CD-1 female mice were exposed to CdCl2 in their drinking water at 5,10, or 50 mg/L for 3 wk. Borgman et al. (1986) exposed young mice to cadmium at 50 ppm via drinking water for 3 wk, and mice were killed at 0, 3, and 6 wk after the cessation of the dose (that is, at 3, 6, and 9 wk of the experiment). When sRBCs were injected immediately at the end of the experiment and splenic PFC response enumerated 5 d after immunization, suppression was observed; after 7 d, PFC response was similar to controls. Injection of sRBCs 3 wk after experiment cessation revealed no effect on the PFC response. Results demonstrate that effects on humoral immunity observed immediately following cadmium exposure were no longer visible 3 wk following the cessation of exposure. Blakley (1986) reported that in female albino Swiss mice exposed to cadmium in drinking water for 280 d at doses of 0, 5, 10, or 50 mg/L, deaths that normally occur from spontaneous murine lymphocytic leukemia in this mouse strain were increased by 33% in the 10 and 50 mg/L groups, indicating immunosuppressive effects. According to the authors, this effect was possibly because of the suppression of the T-lymphocyte-dependent antibody response. Also, albino Swiss mice exposed to cadmium as CdCl2 at

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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30, 100, or 300 ppm in drinking water for 35 d revealed significant decreases in IgM and IgG titers against sRBC and IgG titer against bovine serum albumin (BSA) in groups treated with cadmium at 100 and 300 ppm (Dan et al. 2000).

In contrast to the above findings, Ohsawa et al. (1988) reported that spleen cells of ICR mice administered cadmium as CdCl2 via drinking water at 3, 30, and 300 ppm for 10 wk showed enhanced antibody-forming ability in response to sRBC after exposure. In addition, Malave and de Ruffino (1984) observed that the PFC response to sRBC was moderately increased in C57BL/6 mice administered cadmium at 50 ppm in drinking water for either 3-4 wk or 9-11 wk; the antibody response to sRBC was depressed in the 300 ppm dose group exposed for 9-11 wk.

However, Thomas et al. (1985) did not find any effect on PFC numbers when B6C3F1 mice were administered cadmium as CdCl2 at 10, 50, or 250 ppm for 90 d in drinking water. Similarly, when female Balb/c mice were given cadmium as CdCl2 at 1, 10, or 100 ppm in drinking water for 7, 14, 21, 28, 60, or 90 d, the titer of antibodies in the blood (IgM and IgG) produced when immunized with the specific antigen dinitrophenyl-BSA were no different from the untreated control mice (Schulte et al. 1994).

Thus, the reports on antibody response to an administered antigen in rodents (particularly in mice) orally treated with cadmium vary from decreases, increases, and no changes reported.

Cell-Mediated Immunity

Several studies have measured cell-mediated immunity to cadmium exposure by determining splenic B and T lymphocyte blastogenesis in response to mitogens. T-cell function was measured using proliferative response to phytohemagglutinin (PHA) and concanavalin A (ConA) and B-cell mitogenic response to bacterial lipopolysaccharide (LPS) and, in some cases, to pokeweed mitogen (PWM). Mitogen stimulation assays per se are not a measure of immune function of these immunocyte cell populations (Koller 1998).

Cultured splenic cells from male Swiss Webster mice administered cadmium as CdCl2 at 160 ppm in drinking water for 30 d showed decreased proliferative response to PWM and PHA (Gaworski and Sharma 1978), whereas Muller et al. (1979) reported increased stimulation to ConA and PHA in mice exposed to CdCl2 orally at 30, 300, or 600 ppm for 10 wk. Malave and de Ruffino (1984) reported that in C57BL/6 mice

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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administered cadmium at either 50 or 200 ppm in their drinking water for either 3-4 wk or 9-11 wk, proliferative responses to PHA and ConA were increased. Chopra et al. (1984a) reported that when CdCl2 was given to male albino Wistar rats as a gavage (5 mg/kg/d) in water for 7 wk, cultured splenocytes showed an inhibition of proliferative response to ConA. However, cadmium increased the antibody-dependent, cell-mediated cytotoxic activity (ADCC) of the splenocytes (effector cells) against chicken red blood cells (cRBC) (target cells).

In another study, the authors (Chopra et al. 1984b) did not find any difference in stimulation by PHA, ConA, or PWM of peripheral lymphocytes recovered from rhesus monkeys (Macaca mulata) orally exposed to cadmium at 5 mg/kg (n = 3 to 4) for 2 and 6 mo. Based on the results, the authors suggested (albeit prematurely) that oral cadmium exposure does not produce immunosuppression. Given that only one cadmium dose was examined and that lymphocyte proliferation was the only end point examined, more studies are needed to support the author’s conclusion.

Thomas et al. (1985) treated adult female B6C3F1 mice with CdCl2 at 10, 50, or 250 mg/L of via drinking water for 90 d and determined splenic lymphocyte blastogenesis of T- and B-lymphocytes. T-cell mitogenic response to PHA and ConA and B-cell mitogenic response to Salmonella typhosa lipopolysccharide were both found to be significantly decreased in the 10 and 250 mg/L group, but the decrease was not statistically significant in the 50 mg/L group; effects on lymphoproliferation occurred in the absence of any change in the viability of splenic cells isolated from all three treatment groups. In the same study, the authors noted that delayed-type hypersensitivity response was unaffected by cadmium treatment (Thomas et al. 1985). Alternatively, Blakley (1985) reported that ConA-induced T-lymphocyte proliferation was unaffected in mice treated with cadmium at 5-50 mg/L in their drinking water for 3 wk; in contrast, a dose-dependent enhancement of B-lymphocyte proliferation to Escherichia coli lipopolysaccharide (LPS) mitogen was noted. Stacey et al. (1988) studied the effects on T- and B-cell blastogenesis of in vivo exposure to cadmium administered as a gavage at 2.5, 25, or 250 µg/kg for up to 6 wk or via drinking water at 5 ppm (400 µg/kg/d) for 6 wk. An effect of cadmium exposure by gavage on mitogen-stimulated splenocyte proliferation was not statistically different from controls at the end of 2 wk even at the highest dose (250 µg/kg). At the end of 6 wk, the observed increase in response to both mitogens was statistically significant but only at the highest dose. In the drinking water study, ingestion of cadmium at 5 ppm (400 µg/kg/d) for 6 wk increased the splenocyte proliferative responsiveness to ConA, but not to LPS. Thus, the

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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mode of oral exposure also makes a difference for cadmium responsiveness.

Ilback et al. (1994) reported that the observed increase in lymphoproliferation to LPS stimulation in BALB/c mice treated with cadmium at 2 mM (225 mg/L) in drinking water for 10 wk was not statistically significant compared to controls. Alternatively, delayed-type hypersensitivity (DTH) response to sRBC and splenic T-cell proliferative response to BSA were observed in albino Swiss mice exposed to CdCl2 at 100 or 300 ppm in drinking water for 35 d but not in the 30 ppm group (Dan et al. 2000).

Cadmium and Innate Immune Function

Thomas et al. (1985) reported that peritoneal macrophage phagocytosis of opsonized chromium (51Cr)-labeled cRBC in cadmium-treated groups was significantly increased in mice exposed to CdCl2 at 10, 50, or 250 ppm in their drinking water for 90 d. The authors also reported that natural killer (NK) cell activity to lyse YAC-1 lymphoma cells showed a nonsignificant increase in treated animals (Thomas et al. 1985). Ohsawa et al. (1983) reported no change in the numbers of B- or T-lymphocytes in the blood or spleen of ICR mice orally exposed to cadmium for 10 wk at 3, 30, or 300 ppm in drinking water. Cifone et al. (1989) reported that rats exposed to CdCl2 at 200 or 400 ppm in their drinking water for 6 mo demonstrated during the first month, a decrease in large granulocyte lymphocyte numbers (that is, NK cells) in the peripheral blood. This initial decrease was followed by a marked increase during the rest of the 5 mo of treatment. In a parallel manner, NK-cell cytotoxic activity of rat peripheral blood lymphocytes (PBL) or splenocytes against YAC-1 target cells (a A/Sn mouse T-lymphoma cell line) from treated groups was depressed during the first month of treatment followed by a persistent increase until the end of the treatment period (Cifone et al. 1989).

Stacey et al. (1988) studied the effects of in vivo exposure to cadmium as a gavage on NK cell and killer (K) cell functions at 2.5, 25, or 250 µg/kg for up to 6 wk or exposed to cadmium via drinking water at 5 ppm for 6 wk. Neither the NK- nor the K-cell activity was altered because of cadmium treatments by either exposure routes at the end of 2 or 6 wk. Ohsawa et al. (1988) reported induction of anti-nuclear antibodies (ANA) in ICR mice exposed to cadmium as CdCl2 in drinking water at 3, 30, and 300 ppm, whereas, in inbred BALB/c mice, the changes in ANA was seen only at the 300 ppm dose, demonstrating species specificity and

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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sensitivity. Recently, Leffel et al. (2003) reported that in New Zealand black-and-white F1 mice (a genetically predisposed model for spontaneous development of an autoimmune disease) exposed to cadmium at 0, 3, 30, 3,000, or 10,000 parts per billion (ppb) in tap water (much lower concentrations than those used in the Oshawa study) for 2, 4, 28, or 31 wk, there was an increased incidence of ANA and immune complex deposition in the kidney after 4 wk of exposure in all treated groups. Lafuente et al. (2003) observed that in adult male rats exposed for 1 mo to CdCl2 at 0, 5, 10, 25, 50, and 100 ppm in drinking water, the B-lymphocytes increased with doses of CdCl2 at 5 and 10 ppm in both spleen and thymus, although they decreased at doses greater than 25 ppm. In the high-dose groups, spleen-derived CD4+ cells were decreased, and at the lower doses, CD8+ cells were increased. The authors noted that although the concentration of cadmium in the spleen was lower than that in the thymus, the CD4+ and CD8+ T-cell subsets were altered only in the spleen and not in the thymus (Lafuente et al. 2003).

When female Balb/c mice were given cadmium as CdCl2 at 1, 10, and 100 ppm in drinking water for 7, 14, 21, 28, 60, or 90 d, there was a significant loss of thymus and spleen weight in the 100 ppm group (Schulte et al. 1994). This is inconsistent with the observations of Cifone et al. (1989) who demonstrated that thymus weight was unchanged even after 6 mo of exposure of 2-mo-old female CD rats to cadmium in drinking water at 200 or 400 ppm.

The apparently conflicting and complex nature of results, as evidenced from the descriptions of the effects of cadmium on the immune response, do not allow the use of the extensive data for AC calculation for cadmium based on immunotoxicity.

Genotoxicity

It is beyond the scope of this document to describe all the genotoxic studies on cadmium. This document will, as far as possible, be restricted to describing studies that pertain to genotoxic effects resulting from oral ingestion of cadmium.

Cytogenetic studies conducted in human populations exposed to cadmium compounds have been recently reviewed by Verougstraete et al. (2002). Conflicting results of genotoxicity studies have been reported for humans exposed to cadmium. Evidence concerning chromosomal aberrations (CAs) in humans following oral exposure to cadmium is equivocal (Shiraishi and Yoshida 1972; Bui et al. 1975; Tang et al.

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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1990). Shiraishi and Yoshida (1972) examined lymphocyte chromosomes in blood samples obtained from seven female patients suffering from itai-itai disease (exposed to cadmium through consumption of contaminated rice) and from a control group of seven similarly aged females unexposed to cadmium. The frequency of chromosomal abnormalities (various types) in the cells of the itai-itai patients was higher than that of controls. The mean percentage of cells with structural aberrations was 50.6% (range of 14-64%) in cadmium-exposed groups and 0.6% (range 0-2%) in the unexposed group. In addition, the frequency of aneuploid cells was higher in the exposed population than in controls. In an additional examination 3 y later (Shiraishi 1975) with 12 itai-itai patients and 9 controls, the author obtained similar results. However, Bui et al. (1975), who examined only four female itai-itai patients from the cadmium-contaminated area and four from a non-cadmium-contaminated area (three females and one male), did not find any difference in structural aberrations or prevalence of aneuploidy between these groups. Tang et al. (1990) examined cultured peripheral lymphocytes from 21 men and 19 women in China who had been environmentally exposed to cadmium (as judged by urinary cadmium and soil cadmium concentrations). Lymphocyte cultures from exposed subjects were significantly different with respect to chromosome aberration frequency from cultures from unexposed subjects. Furthermore, among cadmium-exposed subjects, ones with higher cadmium concentrations in their urine had higher chromosome-aberration frequencies and more severe aberration types (Tang et al. 1990), with a good correlation between U-Cd and the aberration frequency. In another study, Fu et al. (1999) reported a significant increase in the frequency of chromosome aberrations and micronuclei in peripheral lymphocytes from 56 people in China who were environmentally exposed to cadmium for up to 30 y. There was a significant correlation between the increased frequency of CA and MN and the levels of U-Cd.

Mutagenic effects of cadmium, as revealed by chromosome changes, have mainly been seen in cells exposed to cadmium sulfate, cadmium sulfide, and CdCl2. Shiraishi et al. (1972) observed a marked increase in the frequency of chromatid breaks, translocation, and dicentric chromosomes in human leukocytes cultured for 4-8 h in a medium containing cadmium sulfide at 62 µg/L. Rohr and Bauchinger (1976) studied fibroblast cell cultures from Chinese hamsters that had been exposed to cadmium sulfate at concentrations ranging from 1 µg/L to l0 mg/L. At concentrations exceeding 100 µg/L, the mitotic index was significantly reduced, and at concentrations exceeding 0.5 mg/L, chromosome damage was seen. Saplakoglu and Iscan (1998) reported that when

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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sister chromatid exchanges (SCE) were analyzed in PHA-stimulated peripheral lymphocyte cultures exposed to varying concentrations of CdCl2 (107 to 10−3 M) at two different stages of the cell cycle, G0 and early S phase, a statistically significant increase in SCE was observed only when cultures were exposed at S phase and not during G0. The authors suggested that the stage of the cell cycle in which the measurements are made may be a source of contradictory results published in the literature on the effect of CdCl2 on the induction of SCE in human lymphocyte cultures.

Cadmium induced DNA single-strand breaks and DNA-protein crosslinks in V79 Chinese hamster cells (Ochi and Ohsawa 1983). Amacher and Paillet (1980) and Oberly et al. (1982) observed an enhanced number of mutations at the thymidine kinase locus in mouse lymphoma L51784/TK+/ cells. A concentration-dependent increase in the frequency of 6-thioguanine-resistant mutations at the HPRT locus in V79 cells was observed by Ochi and Ohsawa (1983).

In spite of the fact that ip injections of CdCl2 at 0.42-6.75 mg/kg into mice have been shown to induce genotoxic damage (CAs, SCE, micronuclei, and sperm-head abnormalities) in somatic and germ cells (Mukherjee et al. 1988), data from humans are inconclusive.

Cadmium concentrations as CdCl2 ranging from 0.3 to 5.6 µg Cd/L (Paton and Allison 1972) or cadmium at 0.6 and 6 mg/L (Deknudt and Deminatti 1978) added to human lymphocytes and fibroblasts cultured for periods ranging from 24 to 72 h, did not produce any CAs. On the other hand, when human lymphocytes in culture were exposed to cadmium at 1.1 mg/L for 4 h (Andersen and Ronne 1983), reduced chromosome length, an indication of translocation, was observed.

Bruce and Heddle (1979) found that when hybrid mice (C57BL/6 × C3H/He) were injected ip with doses ranging up to 20 mg/kg, no changes were noted in the micronucleus test or in the sperm-head abnormality assay. On the contrary, Mukherjee et al. (1988) reported that when CdCl2 was injected ip into albino Swiss, 8- to 10-wk-old male mice at doses of 0, 0.42, 0.84, 1.68, 3.37, or 6.75 mg/kg, significant increases occurred in the frequency of SCE in bone marrow assayed 24 h after injection in all treatment groups above 0.42 mg/kg. The incidence of micronucleated cells per 500 polychromatic erythrocytes was found to be increased only at the highest dose. The authors also used the same doses to determine the effect of cadmium on the induction of sperm-head abnormalities, but the mice were injected with the doses daily for 5 consecutive d. After 35 d, 500 sperms isolated from the cauda epididymis were evaluated for abnormal sperm morphology, and significant increases in abnormal

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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sperm heads were observed in all treatment groups. Fahmy and Aly (2000) evaluated the in vivo and in vitro genotoxic effects of CdCl2 in the chromosomes of mice. After 24 h, a single ip injection of CdCl2 at 1.9, 5.7, or 7.6 mg/kg, induced a significant and dose-dependent increase in the percentage of polychromatic erythrocytes with micronuclei, and the last two dosed groups showed increased frequency (less than twofold that of controls) of SCE in the bone marrow. The changes at 48 h postinjection were less pronounced than those at 24 h. In germ cell (primary spermatocytes) samples taken 12 d after the single injection, CAs were observed at a dose of 5.7 mg/kg. There was also a pronounced reduction in the number of spermatocytes at all doses of CdCl2 (0.9, 1.9, and 5.7 mg/kg).

Cadmium and Cancer

Several epidemiologic studies have attempted to establish a link between occupational exposure to cadmium and the incidence of lung, prostate, and bladder cancer among workers in a variety of industries in various countries (Kjellström et al. 1979; IARC 1993; Sorahan and Lancashire 1994, 1997; Waalkes 2000; Sorahan and Esmen 2004). This has been well summarized in a recent review (Verougstraete et al. 2003). The results are conflicting or difficult to interpret because subjects were coexposed to other heavy metals such as nickel, arsenic, and lead (for example, battery plant workers were exposed to both nickel and cadmium, and workers in the cadmium-recovery industry were co-exposed to arsenic). The National Institute for Occupational Safety and Health (NIOSH) came to the following conclusions based on their evaluation of existing data several years ago and has not updated this information:


In a study of 292 cadmium production workers who had a minimum of 2 years of employment between 1940 and 1969, a statistically significant excess of deaths from all malignancies and from lung cancer was observed in the entire cohort. In addition, a statistically significant excess of deaths from prostate cancer was detected among workers who lived for at least 20 years after the date of first working in a cadmium production facility. Some of these workers had been hired before 1926, when arsenic (a known human lung carcinogen) was produced in the plant. NIOSH considered the body of toxicologic and epidemiologic evidence for carcinogenicity to be

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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inconclusive and recommended against basing a standard on potential human carcinogenicity.

However, the criteria document stated, “This recommendation should be reconsidered if additional data on these points that warrant such reconsideration are developed” (Current Intelligent Bulletin 42, September 27, 1984).

However, the International Agency for Research on Cancer (IARC) had concluded that sufficient evidence existed to classify cadmium and cadmium compounds as human carcinogens. IARC (1993) had identified seven cohort studies of multinational origin, and they were all occupational and case-control studies. According to IARC (1993), in several cohort studies of workers exposed to various cadmium compounds, the risk of death from lung cancer is increased. IARC did not find any excess prostatic cancer. Although excess prostate cancer was found initially in a U.S. cadmium-recovery plant, the relative risk was found to be nonsignificant later on. On evaluation of animal carcinogenicity data, IARC (1993) concluded that although cadmium and cadmium compounds have been tested by oral administration in several studies in mice and rats, most of the studies were inadequate for an evaluation of carcinogenicity. There have not been any updates or follow-ups released by IARC since 1993. IARC also evaluated several animal studies that tested carcinogenic action of cadmium and cadmium compounds via single or multiple injections (sc, intramuscular, or ip) and noted that in addition to local sarcomas in rats and mice, a variety of tumors such as malignant tumors of the peritoneal cavity, testicular tumors, and tumors of the prostate were reported in these studies. IARC concluded that there is sufficient evidence based on these studies that cadmium and cadmium compounds are carcinogenic to animals.

In a follow-up study of cancer incidence and mortality in Swedish factory workers exposed to cadmium and nickel, Jarup et al. (1998) concluded that there was no exposure relation between cumulative cadmium exposure and risk of lung cancer. The increase in incidence of prostate cancers was not statistically significant and could not be confirmed by some cohort studies. A population-based case-control study was carried out in Montreal, Canada, using 484 pathologically confirmed cases of bladder cancer. The odds ratios estimated by the logistic regression analyses indicated that only a weak association existed between bladder cancer and exposure to cadmium compounds from various occupations (Siemiatycki et al. 1994). The National Toxicology Program (NTP), in its 11th report on carcinogens (NTP 2005), stated that cadmium and

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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cadmium compounds are human carcinogens. This conclusion was based on “sufficient evidence of carcinogenicity in humans, including epidemiological and mechanistic information that indicate a causal relationship between exposure to cadmium and cadmium compounds and human cancer” (NTP 2005).

Very recently, Verougstraete et al. (2003) compiled all cancer data published since the IARC evaluation of 1993 and selected from them, under strict criteria for systematic analysis, all studies of cohorts exposed to cadmium and cadmium compounds that assessed the association between cadmium exposure and lung and/or prostate cancer. In total, the authors analyzed 17 plant cohort studies. The major finding was that increased mortality from lung cancer is of only borderline significance. The concentration versus response did not follow an expected trend. Only three studies had updates on prostate cancer. The authors concluded that, considering the results of the most recent updates, for lung cancer, the relative risk is lower than suggested earlier in the absence of nickel and arsenic and the association between cadmium exposure and prostate cancer was not confirmed. Furthermore, there is no increased risk of cancer for populations environmentally exposed to cadmium (Verougstraete et al. 2003).

These conclusions from data collected from occupational exposures of cadmium are not significantly relevant to cancer risk from exposure by oral ingestion. One of the reasons is that absorption of cadmium from the lung is much greater than that from the GI tract, and it is unrealistic to expect such high concentrations of cadmium absorption from space-flight potable water. Similarly, cancer data from animals receiving cadmium by iv, sc, or intramuscular injection (Waalkes 2003) are not very useful for assessing risk by the oral route, in addition to the fact that the doses are high. No definitive human data exist to indicate that long-duration exposure to low levels of cadmium by the oral route will result in an increased incidence of malignant tumors. A few available epidemiologic studies of cancer rates among humans exposed to cadmium orally, although relevant to our analysis, are limited in their usefulness because the exposures were not estimated.

Shigematsu (1984) conducted a retrospective mortality study for three areas of Japan, categorized on the basis of cadmium content of the polluted rice that was ingested. No significant differences were found in mortality or prostate cancer. No significant increase in cancer rates was found among residents of a cadmium-polluted village in England (Inskip et al. 1982) or in prostate, kidney, or urinary tract cancer among residents of a cadmium-polluted area of Belgium (Lauwerys and De Wals 1981).

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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However, in a Canadian study, prostate cancer incidence seemed to parallel increased cadmium concentrations in water, soil, or grain crops in Alberta, Canada. Incidence of prostate cancer per 100,000 individuals for all urban communities was 35.6, 10.6 in the low-cadmium community, and 53.2 in the high-cadmium community (Bako et al. 1982). Nakagawa et al. (1987, 1993) noted that mortality from malignant neoplasms in the inhabitants of cadmium-polluted areas of Japan with increased urinary excretion of retinal-binding protein was no different from that of inhabitants of unpolluted areas. Overall, there is little evidence of an association between oral exposure to cadmium and increased cancer rates in humans.

Several animal studies have been conducted to assess the carcinogenic risk from exposure to cadmium by oral route. Schroeder et al. (1965) exposed mice to cadmium acetate in drinking water (5 mg/L) for their whole lifetimes and did not find an excessive number of tumors of any type in males or females. When CdSO4 was administered to rats via stomach tube once weekly for 2 y (cadmium at 0.09, 0.18, and 0.35 mg/kg/wk), there was no evidence of increased incidence of prostate tumors or any increase in lung or liver tumors compared to controls. Similar results were observed in mice (n = 50) that received weekly gavage doses of cadmium at 0.44, 0.88, or 1.75 mg/kg/wk for 18 mo (Levy et al. 1973, 1975; Levy and Clark 1975).

Kanisawa and Schroeder (1969) reported seven malignant tumors in 47 cadmium-exposed rats (5 mg/L in drinking water) compared with two malignant tumors in 34 controls. The authors concluded that because the number of animals was low, the statistical power for the increased incidence of tumors was poor. Loeser (1980) did not find any change in the incidence of benign or malignant neoplasia in groups of 50 male and 50 female Wistar rats fed CdCl2 in their diet at 1, 3, 10, or 50 ppm for 2 y. A few additional animal studies designed to evaluate noncancer effects of chronic-duration oral cadmium exposure have indicated no dose-related increases in tumors (Fingerle et al. 1982; Watanabe et al. 1986) in rats or mice.

Waalkes and associates evaluated oral carcinogenic potency of cadmium in two separate studies. In one, cadmium was administered via the diet to male Wistar rats, and in the other, cadmium was given via drinking water to Noble rats. In the cadmium-diet study, Waalkes and Rehm (1992) evaluated the effect of chronic dietary zinc deficiency on the carcinogenic potential of dietary cadmium in groups of male Wistar (WF/NCr) rats fed diets adequate (60 ppm) or marginally deficient (7 ppm) in zinc and containing cadmium at various concentrations (0, 25,

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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50, 100, or 200 ppm). Lesions were assessed over the next 77 wk. The incidence of prostatic proliferative lesions and atrophy, the incidence of large granular leukocytic leukemia, and the incidence of interstitial cell tumors of the testes were evaluated. Only data from zinc-adequate groups will be mentioned here. In treated groups fed cadmium at 50 ppm, the incidence of prostatic proliferative lesions, both hyperplasias and adenomas, was higher than in controls (1.8%) and treated groups fed cadmium at 50 ppm (20%). However, in 100 and 200 ppm dose groups, the incidence was only 13% and 11.5%, respectively, showing a lack of clear dose response. This is above the concentration used in the rat study by Loeser (1980). Cadmium treatment also resulted in an increased incidence of large granular lymphocytic leukemia (maximum 4.8-fold over control). Only in rats receiving cadmium at 200 ppm were testicular interstitial tumors significantly increased (treated 6/27, controls 1/28). Up to and including a 100 ppm concentration, the incidences were comparable to controls. On the basis of these results for prostate tissue, testicular tumors, and leukemia, Vainio et al. (1994), at the IARC, emphasized that cadmium cannot be considered to be a noncarcinogen by the oral route. In a comment article, Collins et al. (1996) reconsidered all the data from the Waalkes and Rehm study and the comments from Vaino et al. (1994) and came to the conclusion that the cancer potency of low concentrations of ingested cadmium would be low relative to that of inhaled cadmium.

Waalkes (1999) studied the effects of oral doses of cadmium (in drinking water) in Noble (NBL/Cr) rats to characterize proliferative lesions of the prostate and the kidneys. This strain of rats is known to be susceptible to the induction of prostate tumors by chemicals (Noble 1982). Cadmium as CdCl2 was given ad libitum throughout the study in the drinking water at 0, 25, 50, 100, and 200 ppm to groups of male rats, and the rats were observed for up to 102 wk. The authors reported that cadmium did not affect water consumption. Taking body weight into consideration, the doses of cadmium can be calculated as 0, 0.37, 0.75, 1.5, and 3.5 mg/kg/d. The proliferative lesions seen in prostate were intraepithelial with multiple foci (Category A2, as the author calls it) with a prevalence in the dorsolateral lobe. At higher doses, the incidence of prostatic proliferative lesions was reduced to control levels. The loss of prostatic response at the higher doses was likely because of diminished testicular function (testicular atrophy) secondary to cadmium treatment.

In the testes, the total number of proliferative lesions and the severity of interstitial cell hyperplasia was significantly higher than in controls only at cadmium at 200 ppm. Renal tumors occurred only in groups treated with cadmium at 100 and 200 ppm, and only three of these oc-

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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curred. The incidence of pheochromocytomas of the adrenal was also increased by cadmium but only at the 50 ppm dose, and there were no significant trends based on cadmium dose. These results indicate that oral exposure to cadmium can induce proliferative lesions in the prostate and kidney of the Noble rat. The rat strain used (Noble) in the study is well known to be a sensitive strain for developing prostate tumors. Hence, use of data from this study will not be suitable for NASA.

Nishiyama et al. (2003) have shown that in C3H/HeN mice (who have a high frequency of spontaneous hepatocarcinogenesis) and A/J mice (who have a high frequency of spontaneous hepatitis), dietary supplementation with cadmium as CdCl2 at 50 ppm (daily dose of approximately 0.1 mg per animal) for 54 wk inhibits spontaneous carcinogenesis in C3H/HeN and spontaneous hepatitis in A/J mice. Control diets contributed only 0.02 µg/d per animal. According to the authors, this may be because of cadmium-induced increases in hepatic MT and hepatic zinc concentration noted in this study. Cadmium-induced nephrosis was not observed in this study.

Reproductive Toxicity

No human epidemiologic studies have documented any reproductive toxicity elicited exclusively by exposure to cadmium salts via oral ingestion. However, several animal studies in rats and mice have addressed the adverse effects of cadmium on the reproductive system, and a vast number of them involves studies where cadmium was administered by sc or ip injection; for example, Laskey et al. (1984) reported that weight of testes, seminal vesicles, and epididymides were reduced by at least 40% in male rats injected at doses of 1.8 or 3.66 mg/kg and observed 14 d later. Such data are difficult to extrapolate to oral ingestion.

Kotsonis and Klaassen (1978) did not find any adverse effect on testicular function, as assessed by the number of pregnancies and number of fetuses per pregnant rat when untreated female rats were mated with male Sprague-Dawley rats that received cadmium at 0, 10, 30, or 100 mg/L via drinking water for 24 wk. In rats exposed to cadmium at 0.001, 0.01, or 0.1 mg/L in drinking water for 30 d, Dixon et al. (1976) did not find any effect on several parameters assessed for adverse reproductive effects such as changes in weight of testes, prostate, and seminal vesicles, or on fertility (fertility indices measured by number of resorptions or number of viable fetuses). Male Long-Evans hooded rats, 100 d old, were exposed to cadmium in distilled water at 0, 17.2, 34.4, or 68.8 mg/L

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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for 70-80 d, and male reproductive system parameters (histology and a number of spermatogenesis parameters) and measures of fertility and pregnancy outcome were examined. Electron microscopic observation of the testes of the high-dose group indicated no difference in spermatogenesis, Leydig cell morphology, or testicular vessels between controls and the high-dose group. There were no differences in the weight of cauda or testes or in sperm morphology or sperm count (Zenick et al. 1982). Pregnant rats were given CdCl2 as a gavage at 2, 4, 8, 12, 20, and 40 mg/kg/d from day 7 to 16 of gestation (Baranski et al. 1982). On day 21, tissues were removed and weighed, and the number of corpora lutea was counted. The uterus was opened and the numbers of live and dead fetuses and early and late resorptions were recorded. Live fetuses were examined for crown-rump length and external malformations. The highest dose resulted in significant maternal toxicity (reduction in body weight, abnormal histopathology of liver and adrenals), placental injury, and increased fetal cadmium. A significant reduction of live fetuses and a significant increase of resorptions per litter were seen only in the 40 mg/kg dose group. Fetal development was retarded in groups dosed at 2-20 mg/kg. The skeletal morphology indicated delayed ossification, which was not dose dependent, and the authors concluded that it is more attributed to retarded development. No teratogenic effects were observed (Baranski et al. 1982). In a later experiment, Baranski (1987) exposed pregnant female rats to cadmium at 60 and 180 ppm (9 and 29 mg/kg/d, respectively) in their drinking water from day 1 to 20 of gestation. The average numbers of total implantations, corpora lutea, live and dead fetuses, resorptions, and postimplantation losses were not different from untreated control pregnant rats. External examination of fetuses did not reveal any gross malformations in the rats administered cadmium in drinking water at 60 and 180 ppm. There was, however, fetal growth retardation. There was a reduction of hematocrit in the fetal blood and not in the maternal blood in the 60 ppm group. The changes in fetal hematocrit did not follow a dose-response effect. A significant dose-dependent decrease in water consumption, which could cause hemoconcentration, might be the reason for not seeing a reduction of hematocrit and hemoglobin. No changes in resorptions or live fetuses/litter were seen. Fetal body weight and length were decreased in both groups, although litter size was not affected (Baranski 1987).

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Developmental Effects

The limited data on developmental effects in humans from exposure to cadmium indicate several confounding factors such as lead and nickel, and no data are available from exposures through oral ingestion (ATSDR 1999). There have been several reports in the literature of rodent studies aimed at assessing the adverse developmental effect of cadmium exposure via several routes (inhalation, subcutaneous injections, iv, oral ingestion via gavage, feed, and water), and the results are equivocal: reduced fetal weight, birth weight, skeletal malformations, and behavioral changes in the pups. Malformations or skeletal effects reported include fused lower limbs, absence of one or more limbs, and delayed ossification of the sternum and ribs (Baranski 1985); dysplasia of facial bones and rear limbs, edema, exenteration, cryptorchism, and palatoschisis (Machemer and Lorke 1981); and sharp angulation of the distal third of the tail (Schroeder and Mitchener 1971). Adverse effects of cadmium exposure prior to and during gestation on the neurobehavioral development in offspring have also been reported. CdCl2 was administered by gavage to female rats 5 d/wk for 5 wk and then during mating and gestation periods at doses of 0.04, 0.4, and 4.0 mg/kg/d. The exploratory locomotor activity of 2-mo-old males and females born to rats given 0.4 and 4 mg/kg/d was significantly reduced. The progeny of cadmium-treated females showed decreased performance in the rota-rod test. In general, the degree of behavioral impairment was dose-related (Baranski et al. 1983).

Cadmium and Effects on Bone

Numerous epidemiologic and experimental studies have been conducted on the effects of cadmium exposure on bone, particularly reduction in bone mineral density. Cadmium can cause osteoporosis (low bone mass and increase in bone fragility) and also osteomalacia (generalized bone pain, tenderness, decreased mineralization). Epidemiologic results from China, Europe, and Japan have been very consistent. For example, the high prevalence of bone damage in cadmium-exposed patients with itai-itai disease and the high cadmium concentrations in their skeletons are well recognized (Blainey et al. 1980; Friberg et al. 1985; Nogawa et al. 1987; Noda and Kitagawa 1990; Kido et al. 1991a, b; Tsuritani et al. 1996; Staessen et al. 1999; Alfven et al. 2000; Nordberg et al. 2002). In a

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Chinese epidemiology study, Nordberg et al. (2002) reported finding decreased bone mineral density in postmenopausal women with heightened U-Cd and blood cadmium (B-Cd) concentrations and in men with heightened cadmium concentrations resulting from environmental cadmium pollution.

Several experimental rodent studies on this effect of cadmium are available in the literature, some that used confounding conditions such as ovariectomy or some nutritional deficiency such as zinc and calcium. The reduction in bone mineral density has been attributed to the effect of cadmium on bone resorption in female mice (Bhattacharyya et al. 1988a, b). When bone G1 protein was used as an indicator of bone damage, its concentrations correlated positively with U-Cd, B-Cd and β-2m, and microdensitometry indicators for bone damage (Kido et al. 1991a, b). Rats administered cadmium for 60 wk by oral gavage had less bone mineral density in the femur and greater excretion of bone-specific markers in the urine than before they were exposed to cadmium (Ohta et al. 2000).

Although the effect of cadmium on bone may be direct (Ogoshi et al. 1989) or secondary to renal damage, one of the mechanisms suggested is the disturbance of vitamin D metabolism in the kidney by cadmium. Accumulated cadmium in the kidney reduces the generation of active vitamin D (1, 25,(OH)2D), the lack of which delays calcium uptake by the GI track and calcium reabsorption from the kidney proximal tubules. Under normal circumstances, 98% of the calcium is reabsorbed at the kidney proximal tubules, and tubular damage by cadmium leads to calciuria. Nogawa et al. (1987) found decreased serum 1-α-25-dihydroxy vitamin D concentrations in the serum of inhabitants environmentally exposed to cadmium; this indicated that vitamin D metabolism may be a key factor (also see Nogawa et al. 1990; Aoshima and Kasuya 1991; Chalkley et al. 1998). It has also been stated that serum ALP activity and the urinary excretion of calcium had a significantly positive correlation with U-Cd in both men and women (Staessen and Lauwerys 1993).

Epidemiologic studies have evaluated the possibility that renal dysfunction and osteoporosis are associated (Nogawa et al. 1987; Jin et al. 2004). As stated above, cadmium accumulated in the proximal renal tubules inhibits the generation of active vitamin D in renal tubular cells, which in turn inhibits the active reabsorption of calcium in the distal convoluted tubule (Nogawa et al. 1987; Kjellström 1992; Tsuritani et al. 1992; Tsuritani et al. 1996). Thus, the excretion of calcium would increase, which can lead to resorption of bone calcium to maintain circulating calcium. For example, on the basis of observations from 5 patients with itai-itai disease, 36 cadmium-exposed residents with renal tubular

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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damage, and 17 nonexposed individuals, Nogawa et al. (1987) showed that cadmium-induced bone effects were mainly attributable to a disturbance in vitamin D and parathyroid hormone metabolism that was caused by the cadmium-induced kidney damage. This cadmium-bone-mineral interaction and kidney damage has been reviewed by Berglund et al. (2000).

Jin et al. (2004) examined the relationship between cadmium nephropathy and its effect on bone in a population aged >35 y living in a cadmium-polluted area near a smelter in China. They concluded that the prevalence of renal dysfunction was significantly higher in persons who had osteoporosis than in those who did not. Furthermore, they found a significant correlation between the severity of tubular damage and osteoporosis: those without tubular damage did not have osteoporosis, whereas those with tubular damage did. However, glomerular dysfunction played a smaller role: osteoporosis was not related to the severity of glomerular damage (Jin et al. 2004).

In a cross-sectional study in Belgium of people exposed to cadmium (n = 1,700), cadmium dose was significantly associated with tubular renal dysfunction and urinary excretion of calcium (Staessen et al. 1999). The authors also suggested that cadmium exposures can promote skeletal demineralization, which can lead to bone fractures. Alfven et al. (2000) evaluated whether long-term low-level cadmium exposure, through environment or occupation, increased the risk of osteoporosis (decreased forearm bone mineral density) in a total of 1,753 subjects (520 men and 544 women) aged 16-80 y who resided in a community in southern Sweden where nickel-cadmium batteries and heat exchangers for cars were manufactured. The authors concluded that a dose-response relationship existed between cadmium dose (U-Cd concentrations used as dose estimates and protein-HC used as an index of tubular damage) and osteoporosis. Individuals, both men and women, with higher tubular proteinuria had a lower bone mineral density. The environment was substantially polluted with both lead and cadmium from both nickel-cadmium-battery plants and also lead-battery plants. Similar results were reported in another recent study by Hayashi et al. (2003) that evaluated urinary excretion rates of calcium and phosphorus among the inhabitants (n = 3,164) of the cadmium-polluted KaKehashi River basin of Japan. The rate of excretion of these minerals by inhabitants of the polluted area was significantly greater than that of people in a control area.

Wang et al. (2003) studied the effect of cadmium exposure on bone mineral density using a study population of 302 males and 488 females over age 35 who resided near a cadmium smelter in China. The average

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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cadmium concentration in rice produced in the residents’ own fields was 3.7 ± 1.8 mg/kg, which is 18-fold higher than the hygienic standard. They reported that for subjects of both sexes over age 60, the decline in bone mineral density in subjects from a heavily cadmium-polluted area was greater than that in subjects from control areas. A dose-effect relationship between cadmium dose and decline in bone mineral density was also evident.

Very recently, Alfven et al. (2004) reported results of analyzing the relationship between low-level cadmium exposure and forearm fractures in 479 men and 542 women who were either occupationally or environmentally exposed to cadmium. Fracture hazard ratio increased as a function of cadmium exposure. The exposure was estimated from U-Cd concentrations. The authors estimated the fracture hazard ratio increased by 18% per unit of U-Cd (nanomoles [nmole]/mmole creatinine) (Alfven et al. 2004).

In a rat study, Brzoska et al. (2001) reported that 12 wk of exposure to cadmium at 50 mg/L in drinking water resulted in a decrease in ash weight, concentration and amount of calcium, and the percentage of nonorganic-components content of tibial bone. Also very recently, Brzoska et al. (2004) used a rat model to study the mineral status, mechanical properties, and incidence of deformities and fractures of the lumbar spine (L1-L5 vertebrates) in young female Wistar rats exposed to cadmium at 1, 5, 50, or 100 mg/L in drinking water for 12 mo and determined the above-mentioned parameters at 3, 6, 9, and 12 mo. It was reported that a dose- and time-dependent decrease was observed in bone mineral content (BMC) and density as well as ash weight. At 50 and 100 mg/L dose concentrations, deformities and fractures of the lumbar vertebral body were severely affected.

Cadmium Exposure and Renal Stones

Increased prevalence of kidney stones in workers occupationally exposed to cadmium has been reported in several studies (see Friberg et al. 1986). Jarup and Elinder (1993) conducted a study on a group of 902 male workers who were employed for at least 1 y in a Swedish cadmium battery factory between 1931 and 1982. They sent a questionnaire about the occurrence of kidney stones to 601 living workers and 267 relatives of deceased workers. Seventy-three workers reported that renal calculi appeared after their employment. Cumulative exposure for each employee was computed from the cadmium concentrations monitored in the

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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air and their years of employment. Smoking habits were also taken into account. The data from living workers were also correlated with U-Cd and urinary β-2m data that were collected. The rate of incidence of kidney stones was computed for three cumulative exposure categories: less than 250, 250-5,000, and greater than 5,000 µg per cubic centimenter (cm3); cumulative exposure to 250 µg/m3 was considered an internal control. All biologic data indicated that the higher the internal cadmium dose, the greater the degree of tubular damage; and the higher the degree of tubular damage, the higher the rate of incidence of kidney stones. For example, 13 of 33 workers (about 39%) who had a β-2m concentration greater than 34 µg/mmole of creatinine had kidney stones (Jarup and Elinder 1993).

Rationale for Spaceflight Safety Factor for Bone Effects

Microgravity induces adverse changes in the musculoskeletal system. Because of skeletal unloading, bone tissue is lost during space missions, and this has been the subject of numerous in-flight and groundbased microgravity (weightlessness) simulation studies (see LeBlanc 1998; Smith et al. 1999; Smith and Heer 2002). Urinary excretion rates of several biochemical markers, especially some bone-specific ones such as deoxypyridinoline, provide evidence for bone loss (Smith et al. 1998). For example, crewmembers (cosmonauts) who spent 4-12 mo on the Russian Mir space station lost areal bone mineral density at an average monthly rate of 0.3% from the total skeleton (97% of which was from the pelvis and legs) (LeBlanc et al. 2000; also see review by Smith and Heer 2002). Regional bone mineral density measurements made using dualenergy x-ray absorptiometry showed a loss of 1.06% per mo from the spine and 1.15-1.56% per mo from the hip (LeBlanc et al. 2000). Very recently, Lang et al. (2004) used volumetric quantitative computed tomography (vQCT) and dual-energy x-ray absorptiometry to measure cortical and trabecular bone loss in 14 astronauts (13 men and 1 woman) who spent 4-6 mo on the ISS. Bone mineral density -loss rates of 0.9% per mo at the spine and 1.4-1.5% at the hip were noted. The authors also measured losses from individual areas of the hip (Lang et al. 2004).

As described earlier, cadmium exposure has been reported in several investigations to affect bone mineral density. To protect against cadmium potentiating the spaceflight-induced bone changes, an estimated spaceflight safety factor of 3 is needed in cases where an AC is derived using bone effects as adverse end points.

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Spaceflight and Renal-Stone Risk

Negative calcium balance through increased excretion in feces and urine was observed during Skylab (28, 59, and 84 d) and Mir missions. Increased calcium in urine because of bone shedding has been proposed. Factors that increase the risk of renal stone formation are increased urinary calcium concentration; supersaturation of calcium oxalate (with subsequent formation of calcium oxalate crystals in renal epithelial cells) and brushite (calcium phosphate) uric acid saturation and decreased urine volume, magnesium, and citrate (Whitson et al. 2001b). It was suggested that urinary calcium may be a parameter critical for the increased risk of renal stone formation during and after spaceflight (Whitson et al. 1993; 1997; 1999; 2001a,b), because the majority of renal stones formed are composed of calcium phosphate and calcium oxalate. Hence, a safety factor of 3 should be applied to adverse end points that relate to bone damage by cadmium.

Why Spaceflight Safety Factor for Nephrotoxicity Is Not Needed

In several areas in this document, results have been described from human epidemiologic studies that showed that a relationship seems to exist between tubular damage and osteoporosis or bone damage; the most well-known example is the subjects suffering from itai-itai disease in Japan. One of the mechanisms proposed was that the accumulation of cadmium in the kidney directly inhibits the activation of vitamin D; this may lead to bone resorption, as described above. Hence, one would be tempted to apply a spaceflight safety factor for nephrotoxicity because it will lead to bone resorption, which is a well-known problem for astronauts. However, many of the human epidemiology studies involve long-term exposures to high concentrations of environmental cadmium. Although links were established, quantitative estimates could not be gathered. Ohta et al. (2000) conducted a study designed to simultaneously measure bone resorption parameters and nephrotoxic parameters to clearly show dose and duration of exposure and the relationship between renal dysfunction and bone disorder in male rats after long-term oral administration of cadmium by gavage. The study is described in detail elsewhere in this document. The important conclusion from the study is that a decrease in bone mineral density can be observed both before and after the manifestation of renal dysfunction or damage, but the amount of decrease depends on the dose and duration of exposure to cadmium. In

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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this study, as indicated by bone mineral density and the urinary excretion of pyridinoline and deoxypyridinoline, the bone damage occurred only at doses of 20, 30, and 60 mg/kg, as early as 3 wk after exposure. However, when kidney tubular damage was seen as early as 10 wk in the 5 mg/kg dose group, no change in bone mineral density or in the excretion of bone markers in the urine was seen, even at 60 wk. It is unrealistic to expect high cadmium concentrations in ISS water, and, at the cadmium concentrations that will be established as ACs for 1,000 d (or more), changes in the kidney, if any, will not be a driver for bone resorption. Hence, no additional safety factor would need to be applied to an AC determined using nephrotoxicity as the adverse end point.

Gender Differences and Cadmium Metabolism

The cadmium toxicology literature includes numerous studies containing data that indicate gender differences in cadmium toxicity. It is far beyond the scope of this document to discuss these individually. Only a summary of such observations can be included. In the cross-sectional study in Belgium, for the same degree of environmental exposure, the cadmium body burden was higher in women than men. Buchet et al. (1990) reported that women had higher blood and urinary concentrations of cadmium. Higher fractional absorption of cadmium in adults who have low iron stores have been reported (Flanagan et al. 1978; Shaikh and Smith 1980). Women have been found to have a higher incidence of low body stores of iron (nonoccupational, nonsmoker exposure subset of NHANES III data plotted by Choudhury et al. [2001]). A Thai study by Satarug et al. (2004) reported that the prevalence of low iron stores (serum ferritin < 20 µg/L) were 16% in nonsmoking women (n = 99) and only 2% in men; those women with low iron stores showed a 3.4-fold greater cadmium burden than women with normal iron stores (Satarug et al. 2004). A Swedish farm study with 48 women and 57 men indicated that when men and women who had never smoked were compared, women had 1.8-fold higher B-Cd and 1.4 times higher U-Cd, even though on a per-body-weight basis, women consumed less cadmium (Olsson et al. 2002). Various rodent studies have shown a higher body burden in females than in males with similar concentrations of cadmium exposure (Buhler et al. 1981; Bhattacharyya et al. 1982; Foulkes 1986). For example, when rats were provided water or food containing cadmium as 109CdCl2 in the range of 1-1,000 ng/g and tissue cadmium concentrations determined at 1, 2, 4, 8, and 12 wk, it was found that female

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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rats accumulated cadmium at a higher rate and retained a greater percentage of the ingested CD than male rats (Buhler et al. 1981). The cadmium Dietary Exposure Model (CDEM) predicts that to obtain a kidney burden of cadmium at 10 mg, the drinking water concentrations of cadmium for males should be 50 µg/L and for females 20 µg /L. This indicates that women have a higher rate of systemic uptake (Choudhury et al. 2001). It is well known that almost all itai-itai disease patients in the cadmium-polluted areas of Japan are women. Sex-related differences in vitamin D metabolism because of environmental cadmium exposure have been proposed as a reason for the vulnerability of women to bone damage (Tsuritani et al. 1992). In the Tsuritani et al. study, the authors reported decreased serum 1, 25-dihydroxy vitamin D, and an increase in parathyroid hormone that was more pronounced in women than in men who had similar degrees of renal dysfunction. This difference may be related to differences in calcium metabolism. It is well known that a significant dose-response relationship exists between the prevalence of hypercalciuria and the excretion of urinary cadmium, and a significantly increased prevalence of calciuria was found when excretion of urinary cadmium exceeded 2 µg/g creatinine (Wu et al. 2001).

A list of studies on the toxicity of cadmium from oral ingestion described here is summarized in Table 5-3.

RATIONALE

The following paragraphs provide a rationale for proposing guideline values for cadmium in drinking water for 1 d, 10 d, 100 d, and 1,000 d for NASA’s spacecraft water (see Table 5-4). The values listed were based on ACs for each duration according to Methods for Developing Spacecraft Water Exposure Guidelines (NRC 2000).

A review of studies of cadmium exposure via ingestion indicates that there are several toxicity end points such as GI effects/GI mucosal injury, hepatic necrosis, nephrotoxicity, skeletal-muscular system toxicity (osteotoxicity), reproductive toxicity, neurotoxicity, immunotoxicity, and hematotoxicity. Some of the effects can be considered local effects that develop rapidly, and/or systemic effects that are documented after absorption and accumulation in target tissues.

Nordberg et al. (1973) and Buchet et al. (1980) were selected for the derivation of the 1-day and 1000-day ACs, respectively, because both studies are based on human data and derive the lowest concentrations at which adverse effects are observed.

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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TABLE 5-3 Toxicity Summary

Chemical Form and Dose

Expected Duration

Species

Adverse Effects

Reference

CdCl2; cadmium at 5 mg/L

Consumed a contaminated beverage (acute)

Human child

Nausea, vomiting, abdominal distress, and diarrhea; LOAEL = 0.43 mg/L

Nordberg et al. 1973; CEC 1978; Elinder 1986

Cadmium iodide; Cadmium at 25 mg/kg/d

Oral ingestion, single dose (acute)

Human

Fatal dose; died in 7 d; necropsy revealed damage to the heart, liver, kidney, and GI tract

Wisniewska-Knypt et al. 1971

CdCl2; cadmium at 1.9 g/kg

Oral ingestion, single dose (acute)

Human

Death in 30 h; hemorrhagic necrosis of the stomach and GI tract; pulmonary edema; focal hepatic necrosis; pancreatic hemorrhage; normal kidney

Buckler et al. 1986

CdCl2; cadmium at 29 mg/kg/d

Gavage, single bolus

Rat

50% died in 8 d

Kostial et al. 1978

CdCl2; 25, 51, 107, and 225 mg/kg

Gavage, single bolus

Sprague-Dawley rats, male and female

Males: 3/10 died at 107, 225 mg/kg; no abnormal gross pathology; no changes in hematology, serum chemistry, or urine analysis; serum ALP decreased in both sexes; absolute and relative lung weights increased

Borzelleca et al. 1989

CdCl2; cadmium at 75 mg/kg/d

Gavage, single bolus

Sprague-Dawley rat

Necrosis of liver cells and focal degeneration

Shimizu and Morita 1990

CdCl2; cadmium at 15.7, 30.4, 59.6, and 88.8 mg/kg/d

Gavage, single bolus

MBA mouse

Gastritis and enteritis; necrosis of GI tract; fatty infiltration of liver cells; hepatic necrosis; tubular necrosis; hyaline casts

Andersen et al. 1988

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Chemical Form and Dose

Expected Duration

Species

Adverse Effects

Reference

CdCl2; 0, 25, 50, 100, and 150 mg/kg/d

Gavage (once); data collected at 2 and 14 d

Sprague-Dawley rats, male

Lower hexobarbital oxidase activity; decreased motor activity; testicular necrosis; decreased spermatogenesis; decreased urine flow and increased protein excretion at 3 d, followed by a recovery; focal tubular necrosis

Kotsonis and Klaassen 1977

CdCl2;50 mg/kg once or 5 mg/kg once/wk for 10 wk

Gavage; evaluated at 12, 18, and 30 mo

Wistar rat, male

Food and water consumption and general appearance and behavior were comparable to controls; no testicular lesions

Bomhard et al. 1987

CdCl2; single dose of cadmium at 100 or 200 mg/kg

Gavage; terminated At 6 mo

Wistar rats, male

Several deaths within 3 d; severe testicular necrosis and fibrosis; hemorrhages in testes and epididymides

Bomhard et al. 1987

CdCl2; cadmium at 112 mg/kg/d

Gavage (once)

ICR mouse

Epithelial necrosis of the stomach; hepatocellular coagulate necrosis

Basinger et al. 1988

CdCl2; 25, 51,107 and 225 mg/kg/d (or cadmium at 12.25, 25, 52, and 110 mg/kg/d)

Gavage; 1/d for 10 d

Sprague-Dawley rats, male and female

All died at high dose; 30-40% death in next two lower doses; mild hepatic focal necrosis at the high dose; abnormal kidney histopathology in both male and female; varied as a function of dose

Borzelleca et al. 1989

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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CdCl2; calculated mean doses of cadmium at 1.1, 7.8, and 11.1 mg/kg/d

Drinking water, 10 d

Sprague-Dawley rats, male and female

No deaths; in male and female high-dose rats, increase in BUN, decreases in serum ALP and serum protein; no dose dependent changes in hematology; increased protein in urine at middose; decreased organ weights and ratios in males and not in females; reduced water consumption

Borzelleca et al. 1989

CdCl2 at 1.8; cadmium at 6.13, 18.4, and 61.3 mg/kg/d (0, 3, 10, or 100 ppm)

Feed, 10 d

Rat, pregnant

100 ppm in the feed did not affect embryogenesis

Machemer and Lorke 1981

CdCl2; cadmium at 1.8, 6.13, 18.4, or 61.3 mg/kg/d (0, 3, 10, and 100 ppm)

Gavage, 1/d for 10 d

Rat, pregnant

25% decrease in body weight; intestinal necrosis, hemorrhage, and ulcers; decreased fertility; maternal toxicity; teratogenic effect (by gavages)

Machemer and Lorke 1981

CdCl2; cadmium at 12 mg/kg/d

Drinking water, 12 d

Wistar rat

Anemia

Sakata et al. 1988

CdCl2; cadmium at 1.1, 5, 20, and 40 ppm/kg

Feed, 12, 18, and 22 mo

Rat, female

No renal or hepatic lesions; incidence and severity of spontaneous nephropathy was not different from controls

Shibutani et al. 2000

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Chemical Form and Dose

Expected Duration

Species

Adverse Effects

Reference

CdCl2; 0, 8, 40, 200, and 600 ppm/kg/d

Feed; data collected at 2, 4, 8 mo

Sprague-Dawley rats, male and female

Hepatotoxicity (liver-cell necrosis) at 2 mo in ≥200 ppm group; renal toxicity at 4 mo and anemia and decreased hematopoiesis at 8 mo; reduction of cancellous bone in the femur; renal tubular degeneration in ≥200 ppm group from 2 mo; no renal lesions at 8 mo in 40 ppm group

Mitsumori et al. 1988

CdCl2; cadmium at 30 mg/kg/d

Drinking water, 2-10 mo

Sprague-Dawley rat

Urinary excretion of β-2m

Bernard et al. 1988

CdCl2; cadmium at 0.04, 0.4, and 4.0 mg/kg/d

Gavage, 5 d/wk for 5 wk

Rat, female

In offspring, decreased locomotor activity and behavioral impairment

Baranski et al. 1983

CdCl2; cadmium at 0.1, 1.0, and 10.0 mg/kg

Gavage, 6 wk and 3 wk during mating for a total of 9 wk

Sprague-Dawley rats, male and female

Number of total implantations and live fetuses decreased significantly at 10 mg/kg group as well as the number of pregnant females; increased number of resorbed fetuses and growth retardation of fetuses; dominant lethal tests by crossing cadmium-treated males and untreated females suggested cadmium did not affect male sterility, the females were affected most

Sutou et al. 1980b

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Cadmium sulfate; cadmium at 20 mg/kg

Gavage, gestation Day 6 to 14 (during embryogenesis)

Rats, pregnant

Reproductive performance and teratogenic effects studied: no reproductive effects (change in the number of implantation sites, resorption, live fetuses/litter, fetal weight, number of corpora lutea); changes in teratogenic parameters: induced external malformations, skeletal anomalies, and visceral anomalies

Salvatori et al. 2004

CdCl2; cadmium at 25, 50, and 100 ppm (or 4, 8 and 16 mg/kg/d

Drinking water, 90 d

SPF Wistar rats, female

No change in hematocrit or hemoglobin; decreased serum iron and serum ALP at 25 ppm and higher; 30% increase in protein at 50 ppm and higher

Prigge 1978

Cd+2 (salt not specified); 20, 40, and 80 ppm (cadmium at 2.9, 5.8, and 11.6 mg/kg/d)

Drinking water, 14 wk

Rat, young

Increased kidney and testes weights; increased femur weight with increased water content and decreased minerals; symptomatic osteoporosis; hematotoxicity including depressed erythrocytes and hematocrit

Pleasants et al. 1992, 1993

CdCl2; 250-500 mg/kg (cadmium as CdCl2 at0, 0.0031, 0.0062, 0.0125, 0.025, and 0.05%)

Feed, 100 d

Rat, male albino

Growth retardation; even 0.0031% of cadmium produced severe anemia as early as 2 mo; morphologic changes such as focal necrosis were seen; kidneys of two highest doses showed swelling and granulation of epithelium of convoluted tubules; marked atrophy and inflammation of the pancreas were noted

Wilson 1941

CdCl2; cadmium at 12 mg/kg/d

Drinking water, 12, 26, 50, or 100 d

Wistar rat,1 male

Iron-deficient anemia

Sakata et al. 1988

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Chemical Form and Dose

Expected Duration

Species

Adverse Effects

Reference

CdCl2; cadmium at 50 ppm (3.6 mg/kg/d)

Drinking water, 120 d

Wistar rat

Reductions in hematocrit and hemoglobin; marked degeneration and necrosis of the glomeruli and hypertrophy of the kidneys; thinning of bone cortex; increased serum urea and ALP

Itokawa et al. 1974

CdCl2; 10, 30, and 100 ppm (0, 1.15, 2.92, and 8.51 mg/kg/d)

Drinking water, 24 wk; data collected throughout the duration

Sprague-Dawley rats, male

Decreased water consumption in 30 and 100 ppm group at week 1; decreased motor activity at 3 wk; increased protein excretion from week 6 in 30 and 100 ppm group; focal tubular necrosis by week 24

Kotsonis and Klaassen 1978

CdCl2; cadmium at 2.5 mg/kg

Drinking water, 6 mo

CD mouse

Reproductive failure

Schroeder and Mitchener 1971

CdCl2; 0, 8, 40, 200, and 600 ppm

Feed, 2, 4, and 8 mo; 600 ppm group killed at 4 mo

Sprague-Dawley rat, female

In the 600 ppm group, at 4 mo, anemia and decreased hematopoiesis in the bone marrow and reduction of cancellous bone in their femurs seen in addition to periportal liver-cell necrosis; in 200 ppm and high-dosed grouped, renal toxicity (degeneration of proximal tubular epithelia and hepatotoxicity such as vacuolar degeneration with apoptotic cells) were seen as easily as 2 mo

Mitsumori et al. 1998

CdCl2; 57 mg/kg/d

Drinking water, 12 mo

Mice

Hematotoxic; decreased erythroid cells in bone marrow

Hays and Margaretten 1985

CdCl2; 13 mg/kg

Drinking water, 18 mo

Rats

Proteinuria

Bernard et al. 1992

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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CdCl2; 3.5 and 17.5 mg/kg

Feed, 72 wk

Rats

Increase in LDH and GST starting at 13 wk (hepatotoxic)

Bomhard et al. 1984

CdCl2; cadmium at 0.1, 0.5, 2.5, 5, 10, and 50 ppm

Drinking water, for up to 1 y; 50 ppm only for 90 d.

Sprague-Dawley rats

High-dose rats developed anemia in 2 wk; continued to 3 mo; 50% reduction in water consumption in 2 wk; 10 ppm a NOAEL for various effects for 90 d

Decker et al. 1958

CdCl2; cadmium at 0, 25, 50,100, and 200 ppm

Feed, 77 wk

Wistar WF/NCr rats

At 50 ppm, prostatic proliferative lesions, both hyperplasia and adenomas, were increased without a clear dose response; cadmium also increased leukemia and testicular tumors in 50 and 100 ppm but not in 200 ppm group; benign interstitial tumors of the testes increased at 200 ppm group

Waalkes and Rehm 1992

CdCl2; 4 mg/kg/d

Feed, 90 wk

Monkey

Clinical signs of anemia; pale feces

Masaoka et al. 1994

CdCl2; 0.12, 0.4, and 4.0 mg/kg

Feed, 9 y

Rhesus monkey

Decreased food consumption, body weight, and growth rate; anemia, proteinuria, and glucosuria,

Masaoka et al. 1994

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

Chemical Form and Dose

Expected Duration

Species

Adverse Effects

Reference

CdCl2; cadmium at 10 mg/L

Drinking water, three-generation study

Mice

Toxic effects on the first generation (infantile death and runts); F2 generation same as F1 and also congenital abnormalities; F3: 3/5 pairs failed to breed (reproductive toxicity)

Schroeder and Mitchener 1971

CdCl2; cadmium at 0.3, 3, 30, and 90 mg/kg

Feed, 10 mo

Wistar rats, male

At 4 mo, only LDH excretion was found to be increased in the 90 mg group; however, at 8 and 10 mo, not only was there an increase in LDH, other renal enzymes such as NAG and ALP were also found to be increased, which indicates the nephrotoxic effects of cadmium progressed (or became more pronounced) as a function of time; at 10 mo, both 30 and 90 mg/kg dose groups indicated abnormal histopathology; however, there were no increase in urinary enzyme excretions even at 10 mo for doses up to and including 30 mg/kg

Groten et al. 1994

CdCl2; cadmium at 0, 25, 50, 100, and 200 ppm

Drinking water, 102 wk

Noble (NBL/Cr) rat, male

Prostatic lesions; testicular lesions, hyperplasia, pheochromocytomas of the adrenal; renal tumors; no significant trend in some

Waalkes et al. 1999

CdCl2; cadmium at 2, 4, 8, 12, 20, and 40 mg/kg/d

Gavages, gestation day 7-16

Rats, pregnant

Reduction of live fetuses in the 40 mg/kg dose group; increased number of resorptions per litter; fetal development was retarded in groups dosed at 2-20 mg/kg; no teratogenic effects

Baranski et al. 1982

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

CdCl2; cadmium at 60 and 180 ppm

Drinking water, gestation day 1-20

Rats, pregnant

No change in total implantations, corpora lutea, live and dead fetuses, resorptions and postimplantation losses; no gross malformations; there was fetal growth retardation and decreased fetal body weight and length, but litter size was not affected

Baranski 1987

CdCl2; 200 ppm

Drinking water, 11 mo

Sprague-Dawley rats,female

At 8 mo, proteinuria was seen; kidney cortex level off at a value of 250 µg/g wet weight; increased urinary excretion of gamma-globulins; aminoaciduria; slight tubular dysfunction

Bernard et al. 1981

Cadmium-polluted rice (cadmium at 0. 02, 0.04, 0.12, and 1.01 ppm) or CdCl2 (cadmium at 5.08, 19.8, and 40.0 ppm)

Feed, 1, 4, and 8 mo

Sprague-Dawley rats, female (n = 14)

No cadmium-related toxic changes; cadmium in the liver and kidneys at any time point at 4 and 8 mo increased dose dependently

Hiratsuka et al. 1999

CdCl2; 0, 10, 50, and 250 ppm

Feed, 72 wk (18 mo)

Wistar rats, male and female

No kidney-related adverse effects up to and including 50 ppm groups; increased urinary excretion of cytosolic phosphohexose isomerase, LDH, and GST in 250 ppm group; histopathology at 72 wk revealed chronic and acute degenerative changes in the kidney

Bomhard et al. 1999

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

Chemical Form and Dose

Expected Duration

Species

Adverse Effects

Reference

CdCl2; cadmium at 0, 0.1, 1.0, and 10.0 mg/kg.

Gavages, 9 wk

Sprague-Dawley rats, male and female

Decreased food and water consumption; 10 mg/kg was a NOAEL for hematologic effects; a 10% increases in serum creatinine in 1 and 10 mg/kg male rats; no hepatotoxicity even at the high dose in male rats (NOAEL for hepatotoxicity = 10 mg/kg/d)

Sutou et al. 1980a

CdCl2; 5 and 10 ppm; also used 10, 20, 40, 80, and 160 ppm for adults and older rats

Drinking water, 4 wk

Rats, young, adult, and old

Mechanical strength of bone decreased only in young rats and not in older rats

Ogoshi et al. 1989

CdCl2; cadmium at 2, 5, 10, 20, 30, and 60 mg/kg

Gavage, 6 d/wk for 60 wk

Wistar rats, female

Renal dysfunction and osteotoxicity; proximal tubular degeneration; also decreased bone mineral density even at 2 mg/kg; in 30 and 60 mg dose groups, effects seen as early as 5 wk-the effects were time and dose dependent; renal and bone effects occurred at different times

Ohta et al. 2000

CdCl2; 16 ppm (1.18 mg/kg/d as Cd)

Drinking water, 4, 16, 40, and 60 wk

Wistar rats

Pattern of nephropathy studied; a widespread vesiculation of proximal tubular cells with mitochondrial and lysosomal alterations; increased α-glucosidase indicated severe anatomical tubular damage; no damage to brush border even after 64 wk. Tubular damage seen as early as 16 wk.

Gatta et al. 1989

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

CdCl2; cadmium at 0, 3, 10, 30, and 100 ppm

Feed

Rhesus monkeys

The 100 ppm group had glucose in the urine after 48 wk, elevated urinary proteins at 98 wk, and markedly increased urine volume at week 102; no abnormalities in renal functions were noted in the 3 or 10 ppm groups; no aggravated renal dysfunction or renal failure during the 9-y study

Masaoka et al. 1994

CdCl2; 0.5 or 100 ppm

Feed; Cadmium supplemented in zinc deficient (0 ppm) and adequate in zinc (30 ppm); up to 5 mo

Sprague-Dawley rats, (3-wk-old) males

In the proximal convoluted tubules of the kidneys, degenerative changes, mitochondrial swelling, and coagulative necrosis and cytoplasmic vacuolation seen in rats fed the zinc-deficient diet containing cadmium at 100 ppm; also, diminished bone growth and cortical thinning of the femur without osteomalacia seen in this group

Tanaka et al. 1995

Abbreviations: ALP, alkaline phosphate; β-2m, β-2-microglobulin; BUN, blood urea nitrogen; GI, gastrointestinal; GST, glutathione-s-transferase; LDH, lactate dehydrogenase; LOAEL, lowest-observed-adverse-effect level; NAG, β-N-acetylglucosaminidase; NOAEL, no-observed-adverse-effect level.

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

TABLE 5-4 Spacecraft Water Exposure Guidelines for Soluble Cadmium (Salts)

Duration

SWEG (mg/L)

Toxicity End Point

Reference

1 d

1.6

Emetic effect

Nordberg et al.1973

10 d

0.7

Effect on water intake

Kotsonis and Klaassen 1978

100 d

0.6

Osteotoxicity

Ogoshi et al. 1989, 1992

1,000 da

0.022

Nephrotoxicity

Buchet et al. 1990

aThis level will provide protection from continuous exposure to cadmium beyond 1,000 d.

In general, we have applied a spaceflight factor of 3 for certain effects that are known to be exacerbated by microgravity such as adverse changes of hematocrit or hemoglobin, effects on bone indicative of bone resorption, and dehydration or reduction in water consumption. Low fluid consumption will lead to low urine volume, which will promote renal stone formation (Whitson et al. 2001b). Usually, an intraspecies uncertainly factor (UF) is not used because astronauts come from a homogenous, healthy population and there is no evidence of a group of healthy persons having excess susceptibility to cadmium. Our search of the literature indicates there are no known hypersusceptibility factors related to cadmium except anemia or diabetes, which have no relevance to the astronaut population.

Approaches by Other Organizations

EPA (1985) determined an oral reference dose (RfD) for inorganic cadmium based on renal toxicity. They determined that the highest renal cortical concentration of cadmium that is not associated with significant proteinuria is 200 µg/g wet human renal cortex, a critical concentration for renal dysfunction. Using a toxicokinetic model, Friberg et al. (1974) estimated that a daily intake of cadmium at 0.352 mg/d (or 0.005 mg/kg) for 50 y would result in a renal cortex concentration of 200 µg/g wet tissue. This model assumed absorption of 4.5% of the daily oral dose and an excretion rate of 0.01% of the cadmium body burden. Thus, based on an estimated NOAEL of cadmium at 0.005 mg/kg/d in drinking water, and after applying a UF of 10, an RfD of 0.0005 mg/kg/d (water) was calculated; an equivalent RfD for cadmium from food is 0.001 mg/kg/d,

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

assuming that the absorption from food is only half of that from water (EPA 1985; IRIS 1994).

Although no minimal risk levels (MRLs) for acute and intermediate durations of exposure to cadmium were derived by ATSDR, the chronic MRL derived was based on the report by Nogawa et al. (1989) of a dose response for renal effects of cadmium exposure of residents to cadmiumpolluted rice in Japan. Urinary β-2m was used as the index of renal damage, and an abnormal β-2m was defined as a concentration greater than 1,000 µg/L, or 1,000 µg/g of creatinine, in the morning urine. From the total lifetime intake of 2,000 mg from dietary sources, or 110 µg/g/d, and using a body weight of 53 kg for Japanese adults, the acceptable intake was calculated to be 0.0021 mg/kg/d (110 µg/g/d ÷ 53 kg = 2.1 µg/kg). After applying a safety factor of 10 for human variability, ATSDR arrived at a value of 0.0002 mg/kg/d as a chronic MRL (see Table 5-5).

ATSDR also obtained permissible concentrations by using physiologically based pharmacokinetic modeling (PBPK) and benchmark dose (BMD) calculation methods carried out by the K.S. Crump Group (Clewell et al. 1997) using the Nogawa et al. (1989) data. A BMDL10 was derived, which is defined as the 95% lower bound on the estimates of the doses predicted to correspond to 10% extra risk; that is, BMDL10 is the lower bound on the dose BMD10. Polynomial and Weibull models were used to model the data from males and females separately. The doses based on a benchmark dose approach gave a cumulative exposure of 28.2-33.4 mg/kg for males (for Weibull and polynomial model, respectively) and 19.2-23.1 mg/kg for females (for Weibull and polynomial model, respectively). Cumulative exposure was calculated for 70 y of exposure. Daily dose was calculated based on a value for 70 y of exposures and 365 d/y (total number of d = 25,550).

The resulting MRLs of 0.000075-0.00013 mg/kg/d for males and females, respectively, are 1.5-3 times lower than the current MRL by ATSDR (see Table 5-6). Because NASA would not apply an intersubject variability factor, the resulting values will be 10 times higher, and the 1,000-d AC determined is not far from values when adjusted (see section on 1,000-d AC for ingestion).

Furthermore, Clewell et al. (1997) also derived an MRL from the PBPK model based on a modified Oberdorster (1990) model that used data from Butchet et al. (1990). In this PBPK modeling approach, it was concluded that a daily oral intake of 0.84 µg/kg/d would correspond to a urinary cadmium excretion of 2.7 µg/d, assuming an excretion half-life of 20 y. After a factor of 3 was applied to reduce the LOAEL, a chronic MRL of 0.3 µg/kg/d was derived (0.84 µg/kg/d ÷ 3).

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

TABLE 5-5 Current Regulatory and Guideline Levels from Other Organizations

Standards

Exposure Limit

Reference

EPA

MCLG

0.005 mg/L

 

MCL

0.005 mg/L

 

1-d HA (child)

0.04 mg/L

EPA 2004

10-d HA (child)

0.04 mg/L

EPA 2004

RfD

0.0005 mg/kg/d (water)a

IRIS 1994

RfDa

0.001 mg/kg/d (food)a

IRIS 1994

Life-term HA

.005 mg/L

EPA 2004

Cancer grouping

Group B1b

IRIS 2006

Cancer grouping

Group 1c carcinogen

IARC 1993

ATSDR

Acute MRL (1-14 d)

None derived

 

Intermediate MRL (15-365 d)

None derived

 

Chronic MRL (>365 d)

0.0002 mg/kg/d

 

BMD method

0.000075-0.00013 mg/kg/dd

Clewell et al. 1997

PBPK approach

0.0003 mg/kg/d

Clewell et al. 1997

aA factor of 2 is used to account for increased absorption from water.

bGroup B1: probable human carcinogen.

cGroup 1: carcinogenic to humans.

dThe values are from two types of models used.

Abbreviations: BMD, benchmark dose; HA, health advisory; IARC, International Agency for Research on Cancer; MCL, maximum contaminant level; MCLG, maximum contaminant level goal; PBPK, physiologically based pharmacokinetic; RfD, reference dose.

TABLE 5-6 Derivation of MRL Using Benchmark Dose Modeling

Gender

Model

Cumulative Exposure (mg/kg)

Daily Exposure (mg/kg/d)

With Human Variability Factor of 10 ([mg/kg/d] = [MRL])

Extrapolated Concentration in Water (µg/L)a

Males

Weibull

28.2

0.0011

0.00011

2.75

Males

Polynomial

33.4

0.00131

0.000131

3.275

Females

Weibull

19.2

0.00075

0.000075

1.875

Females

Polynomial

23.1

0.0009

0.00009

2.25

aMultiplying the MRLs with 70 kg nominal human body weight and divide by 2.8 L/d, the NASA nominal water volume, and converting mg to µg.

Source: Data from Clewell et al. 1997.

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

To compare the relative bioavailability of cadmium from water and food, Ruoff et al. (1994) compiled and analyzed the published studies in which rats were exposed to CdCl2 in standard chow or drinking water. Relative bioavailability was assessed from estimates of the rate of accumulation of cadmium in kidney cortex or liver. The data were subjected to a linear regression analysis, with dose as the independent variable and tissue accumulation rate as the dependent variable, to determine whether bioavailability of cadmium was significantly different for different routes of administration. They concluded that in rats receiving food and drinking water ad libitum, the bioavailability of cadmium in drinking water was not significantly different (P > 0.05) from the bioavailability of cadmium in food when doses were less than 4 mg/kg/d. The authors also emphasized the fact that changes in food or water consumption should be taken into consideration in the exposure estimates. Studies of the effect of total diet composition on the bioavailability of cadmium may be more relevant than are studies of the effect of the exposure medium. Therefore, they recommend that distinct RfDs for cadmium in food and drinking water should not be based on the assumption that the bioavailability of cadmium in drinking water is greater than that of cadmium in food. EPA has used a factor of 2 when deriving an RfD for cadmium from water (IRIS 1994). One important consideration is that, in chronic-exposure protocols in which animals access food and water ad libitum, the compound being tested will mix with the components of the diet in the GI tract irrespective of whether it comes from water or diet. Therefore, for chronic durations, it may not be necessary to distinguish between the two routes.

There is no acceptable daily intake (ADI) for cadmium, but the World Health Organization (WHO) proposed a provisional tolerable weekly intake (PTWI), the dietary exposure level that can be ingested weekly over a lifetime without appreciable health risk (WHO 1993, 2001). From the human epidemiologic data, the 33rd Joint FAO/WHO Expert Committee on Food Additives (JECFA) in 1988 proposed that in the renal cortex, the critical concentration of cadmium that produces renal tubular dysfunction in 10% of the population is about 200 µg/g kidney. The JECFA committee also pointed out that a regular dietary intake of cadmium at 175 µg/man/d (2.9 µg/kg/d) would cause the concentration of cadmium in the renal cortex to reach a concentration of 200 µg/g in 50 y. Assuming absorption of 5% and a daily excretion rate of 0.005% of body burden, they recommended that the total intake should not exceed 1 µg/kg/d continuously for 50 y or 7 µg/kg/wk (PTWI). At the 55th

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

JECPA meeting in 2000 and at the 61st meeting in 2003, the committee did not find a need to revise these values (WHO 2001).

Derivation of AC for Various Durations of Exposures Through the Oral Route

Numerous studies in the literature have reported toxicity of orally administered cadmium in several animal experiments, but the medium of administration has been quite diverse. Cadmium had been administered by gavage, added to the diet, or added to the drinking water, so that a meaningful comparison between studies are confounded. Few studies have used multiple concentrations of cadmium that could provide dose-response data, and some have used only one concentration. The data that provided a dose-response effect have been preferentially considered in deriving ACs. Human exposure data for the oral route of exposure to cadmium were for only chronic-duration exposures, and most of the data are from people who were exposed to cadmium through their diet.

1-d AC for Ingestion

For acute toxicity studies, the only data that are available are the gavage studies. Drinking water regimen for acute toxicity studies is not customary. The following studies were considered for determining the 1-d AC.

Nordberg et al. (1973) reported that children who drank a soft drink contaminated with cadmium vomited. The concentration of cadmium was estimated to be 16 mg/L. Using 16 mg/L as the LOAEL and applying a factor of 10 for LOAEL to NOAEL, the 1-d AC can be calculated as follows:



where

16 mg/L = LOAEL; and

10 = LOAEL to NOAEL extrapolation factor.


Thus, the 1-d AC = 1.6 mg/L.

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

This concentration was derived based on the concentration of cadmium that determines the emetic effect and was not based on the dose. This is well below the emetic threshold range for cadmium, which has been estimated to be in the range of 3 to 90 mg. It is equivalent to a concentration exceeding 15 mg/L for soluble cadmium salt solutions (CEC 1978), assuming a fluid volume of 200 mL per drink and using the lowest value of the emetic threshold (3 mg) as the no-effect threshold.

A 1-d AC can also be derived from the study by Kotsonis and Klaassen (1977), who measured urine flow and hematologic parameters for 14 d after a single oral administration of various doses of radioactive CdCl2 (cadmium at 0, 25, 50, 100, and 150 mg/kg) to male Sprague-Dawley rats and observed that urine flow was significantly decreased during the first 2 d in all the treated groups. However, hematocrit and blood hemoglobin concentrations measured at 2 and 14 d remained unchanged by exposure to cadmium. Daily motor activity for the initial 2-3 d was lower in the 50, 100, and 150 mg/kg groups (Kotsonis and Klaassen 1977). Considering the importance of motor activity for spaceflight, the 1-d AC was derived from a NOAEL of 25 mg/kg for this end point.

Thus, a 1-d AC for motor activity can be calculated as follows:



where

25 mg/kg/d = NOAEL;

70 kg = nominal body weight;

10 = species extrapolation factor; and

2.8 L/d = nominal water consumption.


A significant reduction in urine flow noted during the first 2 d after dosing may be because of reduced water intake. Reduced body weight noted may be because of reduced food intake. A NOAEL could not be identified for this effect. A LOAEL of cadmium at 25 mg/kg was identified. A 1-d AC can be calculated using reduced urine flow with a LOAEL of 25 mg/kg as follows:



where

25 mg/kg/d = LOAEL;

70 kg = nominal body weight;

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

10 = LOAEL to NOAEL extrapolation factor;

10 = species extrapolation factor; and

2.8 L/d = nominal water consumption/d.


Acute toxicity of CdCl2 was studied after single gavage doses of 0, 0.6, 3.9, 7.9, 15.7, 30.3, 59.6, and 88.8 mg/kg (Andersen et al. 1988) in 7- to 8-wk-old CBA/Bom mice. On day 10, tissue damage to stomach and duodenum was observed at 30.3 mg/kg/d. At doses higher than 30.3 mg/kg, gastric necrosis was observed. The data could not be used for a 1-d AC because histopathology was not done on mice treated at doses below 30.3 mg/kg. This dose produced a serious adverse effect, making it difficult to identify a definitive LOAEL and a NOAEL although several doses had been used.

10-d AC for Ingestion

Male Sprague-Dawley rats were exposed to cadmium at concentrations of 10, 30, and 100 ppm in drinking water for 24 wk (Kotsonis and Klaassen 1978). Several measurements were made at 3, 6, 12, and 24 wk. Food and water intake, urine flow and protein excretion, and motor activity were measured weekly. The hourly nocturnal and daily motor activities decreased with time for the 30 and 100 ppm groups. Also in these groups, nephrotoxicity indicated by increased protein concentration (mg/100 mL of urine) was seen only after week 6 of treatment. The daily water consumption was significantly lower after week 1 for the 30 ppm and 100 ppm dose groups. The motor activity decrements were seen as early as 3 wk and at as low a dose as 30 ppm. This drinking water study thus indicates that 10 ppm is the NOAEL for these effects (motor activity and reduction in water consumption). Based on water consumption and the daily mean cadmium intake per day, the dose rates were calculated as 1.15, 2.92, and 8.51 mg/kg/d for 10, 30, and 100 ppm groups, respectively.

As the effect on motor activity was seen from week 3, the data were used for the 10-d AC without any time factor. A decrease in water consumption was seen as early as 1 wk at the dose of 2.92 mg/kg. This can be used to calculate a 10-d AC after applying a time factor from 7 to 10 d.

Thus, a 10-d AC based on reduced motor activity can be calculated as follows:

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

and a 10-d AC based on reduced water consumption can be calculated as follows:



where

1.15 mg/kg/d = NOAEL;

70 kg = nominal body weight;

10 = species extrapolation factor;

2.8 L/d = nominal water consumption/d;

3 = spaceflight factor for decreased water consumption; and

10/7 = factor to extrapolate time from 7 to 10 d.


Borzelleca et al. (1989) conducted a 10-d short-term exposure study in which male and female rats were administered CdCl2 by gavage or via drinking water for 10 consecutive d at various concentrations. Because data from the drinking water study are more appropriate and applicable for determining AC for drinking water, only the data from the drinking water protocol were used for deriving the AC for 10 d.

Male and female Sprague-Dawley-derived Wistar rats (10 each per dose) were exposed for 10 consecutive days to CdCl2, which was added to the drinking water at concentrations to give theoretical doses of 2.5, 25, and 51 mg/kg/d. Exposure dose calculations based on actual water consumption resulted in actual doses of CdCl2 at 1.8, 12.8, and 18.2 mg/kg/d for males and 1.8, 13.3, and 22.6 mg/kg/d for females (equivalent of cadmium at 1.1, 7.8, and 11.1 mg/kg/d). Except for some decreases in body weights and organ weights, no compound-related histopathologic effects were noted at the end of the study. Among several clinical chemistry parameters measured, only decreases (about 45%) in ALP and serum protein were seen in both male and female rats. However, the clinical relevance of these decreases in serum is not clear. An increase in serum BUN was seen at the highest dose in male rats. Qualitative urine analysis for protein (using reagent strips) indicated that a dose of cadmium at 7.8 mg/kg/d could be identified as a LOAEL and a dose of 1.1 mg/kg/d as a NOAEL for increased protein excretion in urine. The observation of increased BUN, a marker for renal dysfunction,

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

in the 11.1 mg/kg/d group supports use of these data for nephrotoxic effect.

Thus, a 10-d AC for nephrotoxicity can thus be calculated as follows:



where

1.1 mg/kg/d = NOAEL;

70 = nominal body weight;

10 = species extrapolation factor; and

2.8 L/d = nominal water consumption.


Ogoshi et al. (1989) studied the effect of cadmium added to drinking water on the mechanical strength of bones of young, adult, and old rats after administering the dose for 4 wk. Young rats were exposed at 5 and 10 ppm, and adult rats and older rats to cadmium at 10, 20, 40, 80, and 160 ppm. A decrease in bone strength was seen only in young rats; when exposed to cadmium at 160 ppm, the adult and older rats did not show any effect at the end of 4 wk of treatment. The authors reported that the amount of cadmium accumulation in the bone correlated well with the sensitivity of the rats to effects on bone. Using a NOAEL of 160 ppm (estimated dose rate of 22 mg/kg/d) for adult and old rats for 4 wk, a 10-d AC for effects on bone can be derived as follows:



where

22 mg/kg/d = NOAEL for 4 wk;

70 kg = nominal body weight;

10 = species extrapolation factor;

2.8 L/d = nominal water consumption; and

3 = spaceflight factor for bone effects.

(No time factor is needed; 4-wk data can be applied directly for 10 d.)

100-d AC for Ingestion

Itokawa et al. (1974) reported that 112 d (16 wk) after exposure to cadmium, significant reductions in the concentrations of erythrocytes

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

(about 30%), hematocrit (about 30%), and hemoglobin (about 25%) were seen in male Wistar rats exposed to cadmium as CdCl2 in drinking water (cadmium at 50 mg/L or 3.6 mg/kg/d). Although this is a drinking water study, no NOAEL was identified and there was no dose-response data. Other studies with dose-response data were preferred over this study. Data from this study were not considered for AC derivation.

Prigge (1978) exposed 12 female SPF Wistar rats (between 170 and 190 g body weight) to cadmium in drinking water at 25, 50, and 100 ppm (estimated dose rates of cadmium at 4, 8, or 16 mg/kg/d) for 90 d. Hemoglobin and hematocrit concentrations were unaltered by cadmium administration. Coincident with the higher B-Cd concentrations, proteinuria (about a 30% increase in urinary protein excretion) was observed. The 4 mg group exhibited reduced serum iron (about 30%). There was a dose-dependent increase in urinary protein excretion, which was statistically significant at doses of 8 mg/kg/d and higher. The significant reduction in serum iron may have been because of the adverse effect of cadmium on iron absorption. However, the proteinuria noted in this study is a more critical effect. Even though there was a 20% increase in protein excretion in the urine in the 4 mg/kg group, it was not statistically significant and thus was considered a NOAEL for this effect. A time extrapolation factor of 90-100 d will be used.

Thus, a 100-d AC based on renal effects can be derived from this study as follows:



where

4 mg/kg/d = NOAEL;

70 kg = nominal body weight;

10 = species extrapolation factor;

2.8 L/d = nominal water consumption; and

100 d/90 d = time extrapolation factor.


The other study considered for 100-d-AC derivation is the 24-wk drinking water study. Kotsonis and Klaassen (1978) exposed rats to cadmium at concentrations of 10, 30, and 100 ppm (or cadmium at 1.15, 2.92, and 8.51 mg/kg/d, based on the amount calculated by the author) in drinking water for 24 wk. While hematocrit and hemoglobin concentrations, blood glucose concentration, liver aniline hydroxylase activity, cytochrome P-450, and hexobarbital oxidase activity were not signifi-

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

cantly different from those of control animals throughout the study, the concentration of protein in the urine of the 30 and 100 ppm rats (2.92 and 8.51 mg/kg/d) was unchanged until 6 wk but was significantly higher from week 9 (after 6 wk). Slight and focal tubular necrosis was observed in these treated groups by week 24. A LOAEL of 2.92 mg/kg/d and a NOAEL of 1.15 mg/kg/d for proteinuria and tubular necrosis were identified. Renal tubular atrophy was slight and focal. Bone calcification measured (bone ash) remained unchanged. In the same study, the authors also identified cadmium at 1.15 mg/kg/d as a NOAEL for decreased motor activity (rat locomotion), which was used to assess CNS function. Beginning with week 9, motor activity of cadmium-treated animals was consistently less than those of controls. Because the rats exposed to cadmium at 1.15 mg/kg/d were unaffected, at least up to 24 wk, no time factor was applied.

An AC for decreased motor activity effects can be derived as follows:

where

1.15 mg/kg/d = NOAEL;

70 kg = nominal body weight;

10 = species extrapolation factor; and

2.8 L/d = nominal water consumption.


A 100-d AC based on proteinuria (nephrotoxicity) can be calculated as follows:



where

1.15 mg/kg/d = NOAEL;

70 kg = nominal body weight;

10 = species extrapolation factor; and

2.8 L/d = nominal water consumption.


Two studies by Pleasants et al. (1992, 1993) were evaluated for calculating a 100-d AC. In the 1992 study, male Long Evans rats were exposed to cadmium at 20 ppm and 40 ppm (2.9 and 5.8 mg/kg/d) in drinking water for 14 wk. Significant increases in the weights (g/100 g body weight) of both kidney (20%) and testes (28%) were observed. The min-

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

eral content (ash, mg/100 g body weight) of the femurs decreased as a result of exposure to both doses of cadmium. This could be an indication of bone resorption, which has been reported in several cadmium-exposure studies (Kjellström 1986b; Berglund et al. 2000; Ohta et al. 2000). Although no changes in hematocrit or peripheral red blood cell counts were noted, rats exposed to cadmium at 40 ppm for 14 wk showed evidence of erythrocyte hypochromia with intracellular non-heme iron inclusions (Pleasants et al. 1992).

In the follow-up study (Pleasants et al. 1993), young Long-Evans rats (male weanling rats, 40-50 g initial body weight) were first exposed to cadmium at 40 ppm for 1 wk and then later on were exposed at 80 ppm (11.6 mg/kg/d) in their drinking water for a total of 14 wk. Cadmium-exposed rats showed significantly depressed hematocrit and erythrocyte counts. Combining the results from both studies, cadmium at 2.9 mg/kg/d seems to be a NOAEL for critical effects on the hematologic and skeletal systems. Since 14 wk is close to 100 d, no time extrapolation factor was used.

A 100-d AC for hematotoxicity and for effects on bone can be calculated as follows:



where

2.9 mg/kg/d = NOAEL;

70 kg = nominal body weight;

10 = species extrapolation factor;

2.8 L/d = nominal water consumption; and

3 = spaceflight factor for hematologic effects and for bone resorption.


The effects on bone are also supported by studies by Ogoshi et al. (1989, 1992). Young (3-wk-old) rats exposed to cadmium in drinking water at 5 and 10 ppm and old rats (18 mo old) that received 40 ppm showed significantly decreased compression strength (13-20%) of the femur at the distal end. The young rats were exposed for 20 wk (140 d), and older rats for 7 mo (215 d). In this study, a NOAEL of 5 ppm (0.7 mg/kg/d) was identified. A 100-d AC to protect bone effects using this value can be calculated as follows:


Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

where

0.7 mg/kg/d = NOAEL for 20 wk;

70 kg = nominal body weight;

10 = species extrapolation factor;

2.8 L/d = nominal water consumption; and

3 = spaceflight factor for hematologic effects and bone resorption.


Groten et al. (1994) studied renal toxicity after long-term administration of oral CdCl2 for 10 mo in male Wistar rats fed diets containing CdCl2 at 0, 0.3, 3, 30, and 90 mg/kg of diet. The doses were estimated to be 0, 0.027, 0.27, 2.7, and 8.1 mg/kg/d. The first sign of renal injury— increased excretion of urinary LDH activity—was seen at 120 d in rats fed cadmium at 8.1 mg/kg (90 mg/kg diet group). More pronounced proteinuria was seen after 8 and 10 mo, as indicated by increased excretion of urinary LDH, ALP (a brush-border enzyme), and NAG. No effects were seen in the 2.7 mg/kg group at 120 d. However, kidneys from the 2.7 mg/kg dose group showed an increased number of basophilic tubules at 10 mo, indicating slight nephrotoxicity. No abnormalities were detected in liver in any of the groups, nor were there any changes in the hepatotoxicity marker enzymes plasma aspartate amino transferase and alanine amino transferase. Therefore, for the sake of being conservative, the next lower dose of 0.27 mg/kg/d was identified as a NOAEL for 10 mo. This could be used for 100 d without any time extrapolation factor.

Thus, a 100-d AC can be calculated for nephrotoxicity as follows:



where

0.27 mg/kg/d = NOAEL;

70 kg = nominal body weight;

10 = species extrapolation factor; and

2.8 L/d = nominal water consumption.


Wilson et al. (1941) reported that rats fed cadmium in the diet at a dose rate of 2.79 mg/kg/d for 100 d suffered several serious effects such as muscle atrophy, focal kidney necrosis, tubular swelling and casts, atrophy of the pancreas, and anemia. At a higher dose, cadmium at 5.5 mg/kg/d, very significant body weight reductions were seen. In this study, 2.79 mg/kg/d was identified as a LOAEL; a NOAEL was not identified. Because this study was done several years ago and the results of

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

more recent studies are available, and because a NOAEL was not identified, the data were not used for AC derivation.

1,000-d AC for Ingestion

Bomhard et al. (1999) evaluated the time course of chronic renal toxicity by cadmium in male and female Wistar rats (n = 12/group) that were fed cadmium as CdCl2 in their diet at 0, 10, 50, and 250 ppm (cadmium at 0, 0.66, 3.33, or 16.7 mg/kg/d) for 72 wk. They were evaluated by measuring several urinary enzyme activities that represent different cellular compartments of the nephron, after 1, 4, 8, 13, 18, 26, 32, 45, 57, and 68 wk. The brush-border enzymes GGT, ALP, and leucine arylamidase, and lysosomal enzymes arylsulfatase A, β-galactosidase, and NAG were among those that were evaluated. At the end of the study period, the kidneys were examined histopathologically. Groups up to and including the 50 ppm group did not show any significant alterations (NOAEL). All nephrotoxic-marker enzymes clearly revealed renal damage at 250 ppm. Histopathology after 72 wk revealed not only chronic but also acute degenerative changes in the kidneys of the 250 ppm group of male and female rats, including some irregularities of the brush border lining. Thus, a NOAEL of 50 ppm or 3.33 mg/kg was identified for nephrotoxic effects.

A 1,000-d AC for nephrotoxic effects can be calculated as follows:



where

3.33 mg/kg/d = NOAEL;

70 kg = nominal body weight;

10 = species extrapolation factor;

1,000 d/504 d = time extrapolation factor from 72 wk to 1,000 d.


Another set of data that were evaluated for the 1,000-d AC for renal-effects calculation is from the Bernard et al. (1981) study. Although the authors had used only one dose, they had monitored the changes from 2 to 10 mo. In this study, 2-mo-old female Sprague-Dawley rats exposed to cadmium at 200 ppm (30 mg/kg/d) in their drinking water for 11 mo had proteinuria from month 8 of treatment. A slight tubular dysfunction was also evident from aminoaciduria. Because a NOAEL cannot be iden-

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

tified, the dose of 30 mg/kg/d is considered a LOAEL. This was confirmed by the authors in another study later (Bernard et al. 1988) in which female Sprague-Dawley rats exposed to cadmium in drinking water at a concentration of 200 ppm (30 mg/kg) for 2-10 mo showed an increase in albuminuria. At 10 mo, the rats developed slight tubular damage as evidenced by increased urinary excretion of β-2m and NAG (Bernard et al. 1988). Because the initial adverse renal effect was seen at 8 mo, the 1,000-d AC will be calculated from the results of the first study as follows:



where

30 mg/kg/d = LOAEL;

70 kg = nominal body weight;

10 = LOAEL to NOAEL;

10 = species extrapolation factor;

2.8 L/d = nominal water consumption; and

1,000 d/240 d = time extrapolation factor.


The third and fourth studies that were considered for 1,000-d AC derivation were that of Mitsumori et al. (1998) and Shibutani et al. (2000).

In the Mitsumori et al. (1998) study, female Sprague-Dawley rats were fed a diet containing CdCl2 at concentrations of 0, 8, 40, 200, and 600 ppm (0, 0.33, 1.6, 8, and 24 mg/kg/d) for 2, 4, and 8 mo from 5 wk of age. Hepatotoxicity was observed after 2 mo in the groups treated with ≥200 ppm (8 mg/kg/d). By 4 mo, the rats in the 600 ppm group had developed periportal liver cell necrosis. Renal toxicity characterized by degeneration of proximal tubular epithelia with vacuolar degeneration was apparent in the groups treated with ≥200 ppm (8 mg/kg/d) from 2 mo, becoming more prominent in the high-dose rats at 4 mo. No renal lesions were observed in the 40 ppm (1.6 mg/kg/d) group even after 8 mo. Similarly, the bile duct hyperplasia seen at 8 mo in the 200 ppm group was not seen in the group treated with 40 ppm. Therefore, 40 ppm (1.6 mg/kg/d) is also identified as a NOAEL for hepatotoxicity for 8 mo.

However, in a later study, Shibutani et al. (2000) reported that low-dose oral administration of cadmium in the diet even up to 22 mo (660 d) (at 1.1, 5, 20, or 40 ppm/kg of diet [0, 0.04, 0.2, 0.8, or 1.6 mg/kg/d]), produced only spontaneous nephropathy and no renal lesions as seen at

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

short-term high-dose exposures (Shibutani et al. 2000). The results demonstrated that, in contrast to high-dose cadmium administration, treatment with 40 ppm or less for 22 mo (660 d) did not influence tubular regeneration as a component of nonspecific chronic nephropathy, suggesting that long-term administration of low levels of cadmium orally does not injure renal tubules in female rats.

Thus, taking both studies together, 40 ppm is a NOAEL for both 240 d and 660 d. As the latter one is closer to 1,000 d, it was used for deriving the 1,000-d AC.

Thus, a 1,000-d AC for nephrotoxic and hepatotoxic effects can be calculated as follows:



where

1.6 mg/kg/d = NOAEL;

70 kg = nominal body weight;

10 = species extrapolation factor;

2.8 L/d = nominal water consumption; and

1,000 d/660 d = time extrapolation factor from 22 mo to 1,000 d.


Hiratsuka et al. (1999) studied rats given minimum amounts of cadmium-polluted rice or CdCl2 for 8 mo. The doses used for CdCl2 were cadmium at 0, 0.32, 1.28, or 2.56 mg/kg (as calculated by the author) in the diet. Biochemical and histopathologic measurements were made at 1, 4, and 8 mo. Urinary enzymes such as □-glutamyl transpeptidase, LDH, and N-acetyl-β-d-glucosaminidase were measured as markers of adverse renal effects. Histopathology was performed on liver, kidneys, lungs, sternum, and femur. The authors concluded that at any time or at any dose, there were no signs of renal tubular damage, either chemically or histopathologically. So on the basis of these results, a NOAEL of cadmium at 2.56 mg/kg for rats can be identified.

Thus, a 1,000-d AC for nephrotoxicity can be calculated as follows:



where

2.56 mg/kg/d = NOAEL;

70 kg = nominal body weight;

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

10 = species extrapolation factor;

2.8 L/d = nominal water consumption; and

1,000 d/240 d = time extrapolation factor.


Another animal study that was considered was that of Gatta et al. (1989), in which changes in certain urinary enzymes specific to various anatomic areas of the kidney were evaluated. Forty Wistar rats were exposed to CdCl2 at 16 ppm in drinking water for 4, 16, 40, and 60 wk (estimated dose of 0.75 mg/kg/d). No abnormal histology was seen by light or electron microscopy after 4 or 16 wk. A widespread vesiculation of proximal tubular cells with mitochondrial and lysosomal alterations was found at 40 wk and was more evident at 60 wk. The brush border never showed any damage (normal excretion pattern of GGT, an enzyme situated in this structure). Urinary α-glucosidase was increased only at 60 wk and showed the most severe anatomic damage to the proximal tubule. Urinary lysozyme, an index of tubular function, was increased at 40 and 60 wk. Having only one exposure dose, an insufficient number of controls, and a lack of paired controls for the group exposed for 60 wk made it difficult to assess spontaneous changes in the kidney of controls at 60 wk, and in general, because of poor design, this study could not be considered for AC derivation.

An epidemiologic study was conducted by Nogawa et al. (1989) on the dose-response relationship of cadmium ingestion to cadmium-induced health effects, especially to renal damage of the residents of the Kakehashi River basin in Ishikawa Prefecture in Japan, whose intake of cadmium came from food (polluted rice). β-2m was used as an index of adverse health (effect on renal cortex), and the average concentration of cadmium in the locally produced rice was used as an indicator of exposure assessment. The subjects were classified according to the average cadmium concentration in the rice in their village and the number of years of residency in that polluted area. Subjects were male and female— 878 males and 972 females. Subjects from a nonpolluted neighboring area were used as controls (294 total, 133 males and 161 females). Subjects over 50 y of age were included in the study. Levels of urinary excretion that exceeded 1,000 µg/L or 1,000 µg/g creatinine were considered abnormal. The prevalence of β-2m in the males of the unpolluted area was 5.3%, and its prevalence in females was 3.1%. The subjects were divided into 12 subgroups on the basis of their length of residence. The prevalence of β-2m in each group was then calculated. A regression equation relating total cadmium intake and prevalence of β-2m was derived separately for males and females. There was a highly significant

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

correlation in each of the groups between total exposure concentration and urinary β-2m. The authors concluded that a total lifetime intake of cadmium that would be comparable to that of controls (background renal excretion of β-2m) would be 2,000 mg. The authors calculated this as 110 µg/d by dividing 2,000 mg by 50 y of exposure, assuming accumulation in the renal cortex.

If NASA were to use this value of 110 µg/d, a 1,000-d AC would be derived as follows:



where

110 µg/d = total acceptable cadmium intake;

10 µg/d = average daily dietary contribution; and

2.8 L/d = nominal water consumption.


The original study had a large population that included sensitive individuals (such as persons with diabetes, aged subjects, and women in menopause); therefore, no additional factors are needed.

A large-scale epidemiology study was conducted by Buchet et al. (1990) from 1985 to 1989 to assess whether environmental exposure to cadmium is associated with renal dysfunction. A total of 1,699 subjects aged 20-80 y were studied as a random sample of four areas of Belgium that had varying degrees of cadmium pollution. After standardization for several possible confounding factors, five variables (urinary excretion of retinol-binding protein, N-acetyl-β-glucosaminidase, β-2m, amino acids, and calcium) were significantly associated with the urinary excretion of cadmium (as a marker of cadmium body burden), suggesting the presence of tubular dysfunction. Cadmium excretion was correlated with changes in measures of proximal tubular function. The authors used multiple regressions and logistic models to study the relationship between the frequency of abnormal values of the renal parameters and the derived exposure estimates based on excretion of cadmium in the urine. There was a 10% probability that values of these variables would be abnormal when cadmium excretion exceeded 2-4 µg/24 h (range for all the nephrotoxic markers). Excretion reached this threshold in 10% of nonsmokers. There was also evidence that diabetic patients may be more susceptible to the toxic effect of cadmium on the renal proximal tubule.

The authors used a cut-off level of renal cadmium excretion of 2 µg/24 h urine sample, below which the occurrence of renal damage remains low. Buchet et al. (1990) calculated that this cadmium concentra-

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

tion in the urine corresponded to 50 ppm in the renal cortex (wet weight of renal cortex) or 50 µg/g of the renal cortex, an amount of cadmium in the renal cortex that will be obtained in 50 y of daily intake of 1 µg/kg. Estimated average daily intake of cadmium in the diet by adults in the United States has been stated to be in the range of 10-20 µg/d (Pennington et al. 1986; FDA 1993).

This value of 1 µg/kg was considered for the 1,000-d AC with a background daily dietary intake of 10 µg/d (the lower end of the range of 10-20 µg/d) or 0.14 µg/kg/d.

So, daily acceptable intake is (1 µg/kg/d 0.14 µg/kg/d) = 0.86 µg/kg/d in water.

This is equivalent to



The Buchet et al. (1990) study did not exclude unhealthy populations and considered both genders and various ages. Therefore, no other safety factor is needed for deriving the 1,000-d AC.

Thus, the 1,000-d AC for cadmium in water is 22 µg/L or 0.022 mg/L.

Another study that was evaluated for the 1,000-d AC was that of Waalkes et al. (1999) in which male Noble (NBL/Cr) rats were exposed to cadmium (in drinking water) and proliferative lesions of the prostate and the kidneys were characterized. Cadmium as CdCl2 was given ad libitum in the drinking water at 0, 25, 50, 100, and 200 ppm, and rats were observed for up to 102 wk. NASA evaluated the data on renal-tumor incidence reported in the study to attempt to derive a 1,000-d AC. These data are summarized in the table below (Table 5-7).

The authors had stated that a strong trend was seen between cadmium dose and incidence of renal tumors, but they had added that a statistical significance can be seen only when these tumors of differing histogenesis are combined. Hence, the link between cadmium and renal tumors noted in the study is tenuous. NASA also discussed these data with Dr. Waalkes, the primary author of the paper, to obtain his opinion about the significance and robustness of these findings. According to the author, the incidence of renal tumors even in the 200-ppm group (3 tumors/29), should not be considered significantly different from the incidence in controls (0 tumors/29). Therefore, NASA decided that the use of the data from this study to provide a NOAEL and assess cancer risk associated with oral cadmium exposure was not warranted.

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

TABLE 5-7 Effect of Cadmium Exposure via Drinking Water on the Incidence of Renal Tumors in Noble Rats

Cadmium in Water (ppm)

Group Size

Incidence of Renal Tumorsa

0

29

0 (0%)

25

29

0 (0%)

50

29

0 (0%)

100

30

2 (7%)

200

29

3 (10%)

aTumors include two mesenchymal tumors in the 100 ppm group, and one lipoma, one mesenchymal tumor, and one transitional cell carcinoma in 200 ppmgroup.

Source: Data from Waalkes et al. 1999.

ACs derived for 1, 10, 100, and 1,000 d, the factors used for deriving the ACs, the critical effects, and the studies used have been summarized in Table 5-8. A SWEG for each duration is also listed by taking into considerations the AC values derived for that particular duration. These final SWEG values, the critical effect, and the key study have been summarized in the Rationale section (Table 5-4).

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

TABLE 5-8 Summary of Acceptable Concentrations (ACs) for Cadmium in Drinking Water

Toxicity End Point

NOAEL/LOAEL (mg/kg/d)

Species

Uncertainty Factors

Acceptable Concentration (mg/L)

Reference

To NOAEL

Species Factor

Time Factor

Spaceflight Factor

1 d

10 d

100 d

1,000 d

Induction of vomiting; emetic stimulus

LOAEL = 16

Human

10

1

1

1

1.6

a

Nordberg et al. 1973

Motor activity

NOAEL = 25

Rat

1

10

1

 

62.5

Kotsonis and Klaassen 1977

Reduced urine flow

LOAEL = 25

Rat

10

10

1

1

6

Kotsonis and Klaassen 1977

Neurotoxicity: motor activity

NOAEL = 1.15

Rat

1

10

1

1

3

Kotsonis and Klaassen 1977

Reduced water consumption

NOAEL = 1.15

Rat

1

10

1

3

0.7

Kotsonis and Klaassen 1977

Nephrotoxicity

NOAEL = 1.1

Rat

1

10

1

1

3

Borzelleca et al. 1989

Bone strength

NOAEL = 4

Rat

1

10

100/90

9

Prigge et al. 1978

CNS effect: decreased motor activity

NOAEL = 1.15

Rat

1

10

1

1

2.9

Kotsonis and Klaassen 1977

Nephrotoxicity

NOAEL = 1.15

Rat

1

10

1

2.9

Kotsonis and Klaassen 1977

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

Hematologic and bone effects

NOAEL = 2.90

Rat

1

10

1

3

2.5

Pleasants et al. 1992, 1993

Bone strength

NOAEL = 0.70

Rat

1

10

1

3

0.6

Ogoshi et al. 1989

Nephrotoxicity

NOAEL = 0.27

Rat

1

10

1

1

0.7

Groten et al. 1994

Nephrotoxicity

NOAEL = 0.66

Rat

1

10

1,000/504

1

4

Bomhard et al. 1999

Nephrotoxicity

LOAEL = 30

Rat

10

10

1,000/240

1

1.8

Bernard et al. 1988

Nephrotoxicity and hepatoxicity

NOAEL = 1.60

Rat

1

10

1,000/660

1

3

Shibutani et al. 2000

Nephrotoxicity

NOAEL = 2.56

Rat

1

10

1,000/240

1

1.5

Hiratsuka et al. 1999

Nephrotoxicity

NOAEL, see text

Human epidemiology

1

1

1

1

0.04

Nogawa et al. 1989

Nephrotoxicity

NOAEL, see text

Human epidemiology

1

1

1

1

0.022b

Buchet et al. 1990

SWEG

 

 

 

 

 

 

1.6

0.7

0.6

0.022

 

a—, Not derived.

bAt this concentration of cadmium, there would be protection with continued exposure beyond 1,000 d to a nominal lifetime.

Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

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Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 5 Cadmium (Inorganic Salts)." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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