3.2.1.1. Death

The only studies located regarding death in humans following inhalation exposure to stable strontium are related to strontium chromate. Strontium chromate has been implicated as a cause of increased deaths from lung cancer in occupational studies (Davies 1979, 1984) (see Section 3.2.1.7). The toxicity of strontium chromate is attributed to hexavalent chromium ion, which enters lung cells and is metabolized to a genotoxic agent. Strontium itself contributes to solubility of strontium chromate, but any associated health effect is expected to be masked by that of the chromate. No studies were located regarding death in animals following inhalation exposure to stable strontium.

3.2.1.2. Systemic Effects

No data are available regarding systemic effects following inhalation exposure to stable strontium for which the exposure levels are known. For that reason, no LSE table has been created for stable strontium. No studies were located that described gastrointestinal, hematological, hepatic, renal, body weight, metabolic, endocrine, dermal, or ocular effects in humans or animals following inhalation exposure to stable strontium.

Respiratory Effects. The only report of adverse respiratory effects in humans resulting from the inhalation of stable strontium is a case report of an anaphylactic reaction to smoke from an ignited roadside flare (Federman and Sachter 1997). The flare contained approximately 75% strontium nitrate (31% strontium), among other known irritating ingredients, and the exact contribution of strontium to the effect is uncertain. The anaphylactic reaction to the smoke included coughing, wheezing, and severe respiratory difficulties. This case report is discussed in Section 3.2.1.3 Immunological and Lymphoreticular Effects. No other reports were located describing longer-term respiratory effects following inhalation of stable strontium compounds by humans or animals.

Cardiovascular Effects. A single study documented adverse cardiovascular effects in humans resulting from the inhalation of stable strontium in smoke from an ignited roadside flare (Federman and Sachter 1997). Extreme tachycardia resulted as part of an anaphylactic reaction to the smoke, which contained ~31% strontium as strontium nitrate, in addition to other known irritants. The role of strontium in this reaction is not established. No other reports were located describing longer-term cardiovascular effects following inhalation of stable strontium compounds by humans or animals.

3.2.1.3. Immunological and Lymphoreticular Effects

The single located study of immunological effects in humans following inhalation exposure to stable strontium is a case report of an anaphylactic reaction to smoke from an emergency roadside flare (Federman and Sachter 1997). A 35-year-old female paramedic developed a sudden, severe reaction upon inhaling fumes from a flare that contained approximately 31% strontium as strontium nitrate. Initial symptoms included coughing, wheezing, and shortness of breath that was not responsive to albuterol, epinephrine, or steroids; recovery ultimately required sedation, intubation, and intensive care for several days. Although the paramedic had been unsymptomatic before the incident, her medical history included several significant contributory factors: rheumatic fever requiring penicillin prophylaxis until age 12, a severe anaphylactic reaction to a bee sting at age 23, and adult-onset asthma at age 32. The ingredients of the flare (Road Fusee®; Standard Fusee Corporation, Easton, Maryland) included ±75% strontium nitrate (~31% strontium), ±10% potassium perchlorate, ±10% sulfur, and ±10% sawdust/oil binder. Upon combustion, each of these would yield products known to be irritating to the respiratory tract: strontium oxide, nitrous oxide, potassium oxide, chlorine gas, sulfur dioxide, and particulates. Thus, the exact contribution of strontium to the development of anaphylaxis in this case is uncertain. However, see Section 3.6.2 for a possible mechanism by which strontium could contribute to an immunological effect. No studies were located regarding immunological effects in animals following inhalation exposure to stable forms of strontium.

No studies were located regarding the following effects in humans or animals following inhalation exposure to stable strontium:

3.2.1.4. Neurological Effects

3.2.1.5. Reproductive Effects

3.2.1.6. Developmental Effects

3.2.1.7. Cancer

There were no reports regarding cancer in humans or animals resulting from inhalation exposure to stable strontium compounds except for strontium chromate. In an epidemiological study, no excess risk for lung cancer was found among workers in two Japanese factories who were involved in the production of strontium chromate pigment (Kano et al. 1993). However, exposures to strontium chromate in the factories may have been low because of suitable industrial hygiene procedures. Another epidemiological study examined workers in British chromate pigment manufacturing plants (Davies 1979, 1984). In one factory, both lead and zinc chromate were produced until 1976, and strontium chromate was produced from 1950 to 1968. For lung cancer deaths in workers exposed to ‘high’ and ‘medium’ levels of chromates before 1961, when industrial hygiene improvements were introduced, the observed/expected ratio (O/E) was 6/1.61, with a standard mortality ratio (SMR) of 373 (p<0.01). For workers exposed to ‘high’ and medium’ levels from 1961 to 1967, the values were O/E=5/089, SMR=562 (p<0.01). The contribution of strontium to toxicity in these studies was not addressed.

No standard inhalation study of strontium chromate in animals was located. However, Levy et al. (1986) used an intrabronchial pellet implantation technique to evaluate the carcinogenicity of 23 different commercially available chromates, including two batches of strontium chromate. Metal pellets were coated with a mixture of cholesterol and strontium chromate and implanted into the left bronchus of male and female young rats (100 per group). Of 198 lungs treated with strontium chromate, 105 (53%) had a primary keratinizing squamous carcinoma of the bronchial epithelium. The authors indicated that carcinogenicity was associated with sparingly soluble hexavalent chromium compounds such as strontium, calcium, or zinc chromates.

3.2.2.1. Death

No deaths in healthy humans have been reported after oral exposure to stable strontium. Stable strontium caused death in laboratory animals only at doses that are very high compared to normal human exposure. In acute exposure studies in mice, the oral LD₅₀ for strontium nitrate was reported to be 2,350 mg strontium/kg in males (Llobet et al. 1991a). For strontium chloride administered by gavage, the acute oral LD₅₀ in albino mice was reported to be 2,900 mg strontium/kg for males and 2,700 mg strontium/kg for females (Ghosh et al. 1990).

In intermediate-duration animal studies, ingestion of excess stable strontium resulted in increased mortality. The premature death rate was 40% among weanling male Sprague-Dawley rats fed stable strontium (form not specified) at a dose level of 565 mg strontium/kg/day for 43 days (Johnson et al. 1968). Weanling male Wistar rats exposed to strontium phosphate in the diet at a dose level of 2,820 mg strontium/kg/day for 4–6 weeks had a mortality rate of 30%, but no mortality occurred at 580 or 1,270 mg strontium/kg/day (Kshirsagar 1976). From an analysis of a pair-fed group (food intake matched to the high-dose group), the author concluded that the increased mortality in the high-dose group was not related to reduced food intake, but rather to the ingestion of strontium. No studies were located regarding death in animals following chronic-duration oral administration of stable strontium.

All reliable LOAEL values for death from stable strontium in each species and duration category are recorded in Table 3-1 and plotted in Figure 3-1.

3.2.2.2. Systemic Effects

No studies were located regarding dermal or ocular effects in humans or animals following oral exposure to stable strontium. The highest reliable NOAEL and all LOAEL values for the systemic effects from oral exposure to stable strontium in each species and duration category are shown in Table 3-1 and plotted in Figure 3-1.

Respiratory Effects. No studies were located regarding respiratory effects in humans following oral exposure to stable strontium. No studies were located regarding acute or chronic respiratory effects in animals following exposure to stable forms of strontium. In one intermediate-duration study, respiratory difficulties were noted in rats following lethal ingestion of 565 mg strontium/kg/day of stable strontium (form unspecified) for 4–6 weeks (Johnson et al. 1968). No description of the respiratory effects or incidence data were reported.

Table 3-1

Levels of Significant Exposure to Strontium - Chemical Toxicity - Oral.

Figure 3-1

Levels of Significant Exposure to Strontium - Chemical Toxicity - Oral.

Cardiovascular Effects. No studies were located regarding cardiovascular effects in humans following acute- or intermediate-duration oral exposure to stable strontium.

One epidemiological study examined the relationship between trace metals, including strontium, in drinking water and the rates of various kinds of vascular disease in 24 communities in the lowest quartile of the economic scale in Texas (Dawson et al. 1978). The concentration of strontium was measured in samples of drinking water and 2,187 urine samples from subjects (aged 5–97 years) in families that had resided within their respective communities for at least 10 years. There was a significant correlation between mean strontium levels in drinking water and in the urine. However, the only statistically significant product-moment correlationship for strontium (in urine and in drinking water) was for a decreased community mortality rate (in people over 45 years old) for hypertension with heart disease. There was no correlation found between strontium and mortality from arteriosclerotic and degenerative heart disease, other heart diseases, hypertension, general arteriosclerosis, or vascular diseases of the central nervous system.

No studies were located regarding cardiovascular effects after acute- or chronic-duration oral exposure in animals. In male weanling Wistar rats (5–6 per group) given strontium as strontium phosphate in the diet for 4–6 weeks, hemorrhage (unspecified) occurred at 2,820 mg strontium/kg/day, possibly related to the increased mortality at this dose level, but not at or ≤1,270 mg strontium/kg/day (Kshirsagar 1976).

Gastrointestinal Effects. No studies were located regarding gastrointestinal effects in humans following oral exposure to stable strontium.

No studies were located regarding gastrointestinal effects in animals following chronic-duration oral exposure to various forms of stable strontium. Acute- and intermediate-duration oral studies in animals have examined gastrointestinal effects that would be likely to influence calcium and phosphorus metabolism. Decreases in acid and alkaline phosphatase activities were observed in the small intestine of 5–6 male weanling (21 days old) Wistar rats given 3,000 mg strontium/kg/day as strontium phosphate for 2 weeks (Kshirsagar 1976). These effects were reversed by giving the rats a normal low-strontium diet for 2 weeks. The biological significance of the decreased phosphatase activities is not known. Studies in chickens first demonstrated the relationship between strontium toxicity, calcium, and vitamin D. In male white Leghorn chickens raised on a diet deficient in vitamin D for the first 2 weeks of life, ingestion of >2,300 mg strontium/kg/day as strontium carbonate in a low-calcium, low-vitamin D diet for 11–14 days, affected calcium transport in the duodenum (Omdahl and DeLuca 1972). Strontium ingestion reduced the duodenal activation of vitamin D₃ (conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol), reduced the activity of calcium binding protein, and reduced the absorption of calcium by the duodenum. Similar effects were observed in chickens given excess strontium in a diet with adequate vitamin D, but deficient in calcium (0.01%) (Corradino and Wasserman 1970; Corradino et al. 1971a, 1971b). In addition, excess strontium ingestion significantly reduced the absorption of glucose, histidine, and alanine by the duodenum to levels typical of rachitic (vitamin D-deprived) chickens (Corradino et al. 1971b). The effects of strontium on calcium transport by the duodenum were reversed by transferring chickens to a normal low-strontium diet containing adequate amounts of vitamin D₃ and calcium. The chicken data are not included in Table 3-2, because the physiological rates are likely to be very different from mammals, and also because health risk assessment methodology is currently limited to mammals. However, these phenomena were confirmed in a recent study in rats (Armbrecht et al. 1998). Six days on a diet low in calcium, but containing 0.8% strontium, was sufficient to suppress the serum levels of activated vitamin D, the concentrations of calbindin D protein (two calcium-binding protein induced by vitamin D; see Sections 3.6.1 and 3.6.2), and the rates of calcium transport in the duodenum of young, adult, and old rats.

In male weanling (3 weeks old) Wistar rats (5–6 per group) given strontium phosphate in the diet for 6 weeks, a decrease in alkaline phosphatase activity in the small intestine occurred at 1,270 mg strontium/kg/day, but not at 580 mg strontium/kg/day (Kshirsagar 1976). This decrease in enzyme activity was partly reversed by feeding the rats a normal low-strontium diet for 2 weeks. As mentioned above, the biological significance of these changes in phosphatase activity is not known. In slightly older female juvenile Wistar rats (36 days old, 6–8 per group) that ingested 510 mg strontium/kg/day as strontium carbonate for 27 days, the net intestinal absorption of calcium was reduced by 20%, but no effects occurred at 100 mg strontium/kg/day (Morohashi et al. 1994). In male white Leghorn chickens fed 255 mg strontium/kg/day (probably as carbonate) in a diet low in vitamin D₃ for the first 16 days after hatching, the conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol and the transport of calcium were suppressed in the duodenum (Omhdahl and DeLuca 1971). This study is omitted from Table 3-1 because of probable differences in physiology.

Hematological Effects. No studies were located regarding hematological effects in humans following oral exposure to stable strontium.

No studies were located regarding hematological effects in animals following chronic-duration oral exposure to stable strontium. In adult Wistar rats given up to 110 mg strontium/kg/day as strontium chloride in the diet for 2 weeks, the total number of erythrocytes was slightly elevated in both sexes, and the leucocyte count was slightly elevated in males at the highest dose level at termination (Kroes et al. 1977). However, since the results were not reported quantitatively, the significance of this information is uncertain. No hematological changes were observed among weanling Wistar rats fed up to 166 mg strontium/kg/day as strontium chloride in the diet for 90 days (Kroes et al. 1977). However, the relatively high level of calcium (0.85%) in the diet given to these animals may have reduced absorption and therefore the effect of strontium.

Musculoskeletal Effects. No studies were located regarding musculoskeletal effects in humans after acute-duration oral exposure to stable strontium. The only long-term human exposure study is an epidemiological study that was carried out in the Ulaş Health Region of Sivas, Turkey (Özgür et al. 1996). This region has a high prevalence of childhood rickets, 32% compared to 4.4% nationally among children aged up to 5 years, and the study sought to determine whether higher levels of strontium in the soil might be a contributing factor. Soils surrounding 55 villages were characterized as to strontium concentration (Group 1, >350 ppm; Group 2, <350 ppm). A total of 2,140 children (ages 6–60 months) from these localities (613 in Group 1 and 1,527 in Group 2) were examined for one or more signs of rickets: craniotabes (localized craniomalacia or thinning of cranium), rachitic rosary (beadlike growths at the ends of ribs where they join cartilage), conspicuous bulging at the wrist, bony deformities of the legs (bowleg, knock-knee), and delayed closure of the fontanelles. A significantly higher proportion of Group 1 children had one or more rachitic signs than those in Group 2: 37.5 vs 19.5%. In addition, the severity of disease (number of rachitic signs per child) was proportionally higher in Group 1 (p<0.001). For each cohort, the incidence of rickets was higher in Group 1 than in Group 2 and the differences were statistically significant for ages 6–12, 13–18, 25–36, and 37–48 months (odds ratios 1.66–2.55). When the duration of breast feeding was considered, the incidence of rickets within the two groups did not differ for children breast fed for 24 months or longer. However, for shorter periods of breast feeding, between 0 and 24 months, the incidence of rickets was significantly higher in Group 1 (odds ratios 1.79–3.14). The implication of this study is that breast feeding may be protective against strontium toxicity in nursing infants, probably by providing both calcium and protein, both of which tend to reduce the incorporation of strontium into bone (see Sections 3.10, 3.11, and 3.12.2). The authors attributed the higher incidence of rickets in Group 1 children to their diet, which, after weaning, is mainly based on grains grown in strontium-rich soil.

No studies were located regarding musculoskeletal effects in animals after chronic-duration oral exposure to stable strontium. Acute- and intermediate-duration studies in animals documented significant adverse effects of strontium on bone that were especially severe in the young. In an acute-duration study, there was no effect on bone in groups of adult SPF Wistar rats that ingested up to 110 mg strontium/kg/day as strontium chloride in the diet for 2 weeks (Kroes et al. 1977). Strontium was detected in bone following ingestion of 11 or 110 mg/kg/day, but not at lower doses (0.1 or 1.0 mg/kg/day). Among male weanling (21 days old) Wistar rats that ingested 3,000 mg strontium/kg/day as strontium phosphate in the diet for 2 weeks, alkaline phosphatase activity was significantly increased in bone compared to controls (Kshirsagar 1976). The author speculated that the observed increase in alkaline phosphatase activity may have been related to a stimulation of osteoblasts, which secrete osteoid and have a high alkaline phosphatase content. In acute studies on young chickens fed 2,300–2,400 mg/kg/day of strontium, and an inadequate level of calcium, severe defects in bone organization and decreased mineralization were observed within 1 or 2 weeks (Corradino and Wasserman 1970; Corradino et al. 1971a, 1971b; Omdahl and DeLuca 1972): abnormally wide hypertrophic cartilaginous zone and impaired endochondral ossification (the removal of hypertrophic cartilage and its replacement by bone). As noted above, the chicken data are omitted from Table 3-1.

Numerous abnormalities of bone structure and bone mineralization were observed in weanling male Sprague-Dawley rats (100–125 g) that ingested 500 mg strontium/kg/day as strontium carbonate in the diet for 3 weeks (Neufeld and Boskey 1994). In strontium-fed rats, the ash weight (mineral content) of metaphyseal bone was reduced and the complexed acidic phospholipid content (lipid nucleator of bone mineral) was significantly higher than in controls. Large areas of nonmineralized bone (osteoid) were observed in epiphyseal bone and secondary spongiosa. The epiphyseal plates were abnormally wide and the metaphyses were abnormally long and dense. The diaphyses contained localized areas of decreased bone density. The primary spongiosa of the proximal tibia was longer and the trabeculae was disorganized and apparently disconnected from the overlying calcified cartilage. The authors suggested that since the levels of complexed acidic phospholipids were high and vitamin D deficiency is known to increase complexed acidic phospholipid levels, that the effect of strontium was probably not mediated through its effect on vitamin D. They suggested the binding of strontium to the surface of initial hydroxyapatite crystallites reduced their further proliferation, resulting in a smaller crystal size.

Similarly, significant abnormalities of bone organization occurred in five weanling (21 days old) male England Wright Y rats that ingested 1,850 mg strontium/kg/day (form unspecified) for 20 days in a diet sufficient in calcium, phosphorus, and vitamin D (Reinholt et al. 1984). In treated rats, the mean thickness of the epiphyseal growth plate was 70% larger than normal. In the epiphyseal regions of long bones, the volume of each zone was larger than its normal counterpart, and in addition, the relative sizes were altered; the proportional volumes of the resting, proliferative, and calcifying zones were significantly smaller and that of the hypertrophic zone was significantly larger than normal. There was an increase in the volume of extracellular matrix in bone, suggested to be associated with a reduced rate of extracellular matrix vesicle degradation. Another study from this laboratory examined the biochemistry of epiphyseal cartilage in rats treated as above (Reinholt et al. 1985). In strontium-treated rats, alterations were observed in the proteoglycan composition (slightly higher galactosamine content), chondroitin sulfate chain lengths (larger), regional distributions of large and small chondroitin sulfate peptides, and regional distributions of both non-sulfated chondroitin sulfate disaccharides and hyaluronic acid-disaccharides. The authors suggested that these strontium-induced alterations in cartilage matrix might affect the process of mineralization.

No effects on bone histology were observed in young female rats (40–60 g) that were fed 140 mg strontium/kg/day as strontium carbonate for 20 days, but histological abnormalities were detected at doses between 550 and 4,975 mg/kg/day (Storey 1961). Alterations in the appearance of the cartilage plate (irregular, thicker, with areas of uncalcified bone matrix in the distal ends of the metaphyseal trabeculae and proximal end of the diaphysis) were observed at 550 mg strontium/kg/day. Irregularities in the organization of the cells of hypertrophic zone (distorting the usual parallel arrangement of intercellular matrix columns), in the pattern of calcification, and in deposition of osteoid were more conspicuous with increasing dose. At higher doses, bands of uncalcified cartilage matrix were isolated between areas of osteoid tissue. In tibias, the dry weight, ash weight, ash percentage, and calcium in ash were significantly reduced with increased strontium intake. In the same study, adult female rats given doses of 170–2,750 mg strontium/kg/day exhibited milder effects in bone. Histological changes in the tibia (thicker epiphyseal cartilage, increased width of metaphyseal osteoid seams) were noted at 1,370 or 2,750 mg strontium/kg/day only. Other significant effects seen only at 2,750 mg strontium/kg/day included the deposition of osteoid tissue near vascular canals, a reduction in the area of bone resorption, and reductions in the dry weight, ash weight, ash percentage, and calcium in ash of bone (Storey 1961).

A 24% reduction in bone formation rate, 28% reduction in bone resorption rate (based on ⁴⁵Ca uptake), and a significantly reduced calcium content in ashed femurs, but no change in ash weight were observed after female juvenile Wistar rats (36 days old) ingested 510 mg strontium/kg/day as strontium carbonate in the diet for 27 days (Morohashi et al. 1994). These rats were also significantly hypocalcemic. No effects were observed at 50 or 100 mg strontium/kg/day other than an unexplained increase in calcium content of bone at 50 mg strontium/kg/day (Morohashi et al. 1994). Minor bone effects occurred in 21-day-old male C57BL/6J mice after ingesting 350 mg strontium/kg/day as strontium chloride in the drinking water for 29 days (Marie and Hott 1986). Strontium had no significant effect on tibial length or bone mineral content (percent ash, calcium, or phosphorus). In vertebrae, strontium had no effect on the osteoblastic surface (percent endosteal surface showing plump osteoblasts), bone matrix apposition rate, osteoid seam thickness (average width of all endosteal osteoid seams), or calcified bone volume. However, exposure to strontium resulted in a 10% increase in osteoid surface (percent endosteal surface covered by an osteoid seam) and an 11% reduction in the number of active osteoclasts.

There was radiographic evidence of abnormally thickened epiphyseal cartilage plates in the long bones of weanling male Wistar rats exposed to strontium phosphate in the diet at a dose level of 2,820 mg strontium/kg/day for 4–6 weeks, but no effect at 580 mg strontium/kg/day and little effect at 1,270 mg strontium/kg/day (Kshirsagar 1976). Ingestion of 565 mg strontium/kg/day for 43 days resulted in several bone abnormalities in young Sprague-Dawley rats (Johnson et al. 1968). The level of sodium in bone was significantly lowered, and the level of potassium was significantly increased, and the overall index of bone mineralization (percent bone ash) was decreased. Unmineralized osteoid was visible in histological sections of vertebrae. Rats became rachitic and osteomalacic and exhibited paralysis of the hindlimbs.

Beneficial effects of a low dose of strontium were noted on bone mineralization, such as a 17% increase in mineral bone volume and a 70% increase in the number of bone forming sites, with no adverse effect on the hydroxyapatite mineral particle size in 28-day-old male Sprague-Dawley rats ingesting 168 mg strontium/kg/day in an unspecified form for 8 weeks (Grynpas et al. 1996) or in young SPF Wistar rats fed doses up to 166 mg strontium/kg/day as strontium chloride in the diet for 90 days (Kroes et al. 1977). Stimulation of calcified bone growth was noted among male weanling Sprague-Dawley rats ingesting between 316 and 524 mg strontium/kg/day as strontium chloride for 9 weeks, but reduced bone calcification was observed at 633 mg/kg/day (Marie et al. 1985). In male weanling Sprague-Dawley rats ingesting 1,520 mg strontium/kg/day for 26 days, epiphyseal growth plates had abnormally thick hypertrophic zones and impaired calcification and resorption at the metaphyseal side (Svensson et al. 1985, 1987). In addition, cartilage from strontium-treated rats contained 75% less calcium and had a 60% lower rate of synthesis of glycosaminoglycans and collagen. When 4-week-old male Wistar rats (50–60 kg body weight) were fed 1,970 mg strontium/kg/day as strontium carbonate in a diet low in calcium (0.04%), bone mineralization was significantly affected (Matsumoto 1976). This study is presented in detail in Section 3.2.2.6 Developmental Effects, as an example of skeletal anomalies in young animals resulting from strontium ingestion.

In another intermediate-duration animal study, young (50–70 g) rats ingested 2,160 mg strontium/kg/day and adult rats ingested 1,570 mg strontium/kg/day as strontium carbonate for 7 months (Storey 1962). At 3 weeks, young rats developed a rachitic gait, and subsequently, some rats (numbers not specified) developed spinal kyphosis, bent tibiae, and irregular discolored enamel on anterior teeth. Histological abnormalities in long bone differentiation included reduced calcification, excess growth of epiphyseal cartilage, abnormal deposition of osteoid (unmineralized bone) in the metaphysis, fragmentation of the epiphyseal plates, and isolated nodules of cartilage. Osteoid accumulation was observed in the skull. Adult rats were affected by strontium ingestion in the same way, but to a lesser degree than young animals. Abnormal depositions of osteoid in long bones and skull were not as extensive as in young rats. The epiphyseal plate did not become fragmented. Tooth enamel was abnormally white and pitted.

Hepatic Effects. No studies were located regarding hepatic effects in humans following oral exposure to stable strontium.

No studies were located regarding hepatic effects in animals after chronic-duration oral exposure to stable strontium. In acute- and intermediate-duration studies, in which the diet contained adequate amounts of calcium and vitamin D, few hepatic effects were reported. No histological changes were observed in the livers of adult Wistar rats given up to 110 mg strontium/kg/day as strontium chloride in the diet for 2 weeks (Kroes et al. 1977). Acid phosphatase activity decreased by about 8% in the livers of 5–6 male weanling (21 days old) Wistar rats given 3,000 mg strontium/kg/day as strontium phosphate for 2 weeks (Kshirsagar 1976). However, this effect was reversible by feeding the rats a normal, low-strontium diet for 2 weeks. In male weanling Wistar rats, ingestion of strontium phosphate in the diet for 4–6 weeks resulted in a >26% decrease in hepatic alkaline phosphatase activity at 2,820 mg strontium/kg/day, but no decrease at 1,270 mg strontium/kg/day (Kshirsagar 1976). The biological significance of these small, but statistically significant, changes in hepatic phosphatase activity is not known. Among weanling male and female Wistar rats fed strontium chloride in the diet for 90 days, the only hepatic effects were ‘slight histological changes’ (not described) and an ‘increase in peripheral glycogen’ in females at the highest dose (166 mg strontium/kg/day); no other hepatic effects were observed in either sex ≤146 mg strontium/kg/day (Kroes et al. 1977).

Renal Effects. No studies were located regarding renal effects in humans after oral exposure to stable strontium.

No studies were located regarding renal effects in animals after chronic-duration oral exposure to stable strontium. In acute- and intermediate-duration studies, in which the diet contained adequate amounts of calcium and vitamin D, no renal effects were reported. No organ weight or histological changes were observed in the kidneys of adult Wistar rats given up to 110 mg strontium/kg/day as strontium chloride in the diet for 2 weeks (Kroes et al. 1977). Similarly, no such changes were observed among weanling Wistar rats fed up to 166 mg strontium/kg/day as strontium chloride in the diet for 90 days (Kroes et al. 1977). In male white Leghorn chickens raised on a diet deficient in vitamin D for the first 2 weeks of life, ingestion of 2,350 mg strontium/kg/day in a low-calcium, low-vitamin D diet for 7 additional days, reduced the activation of vitamin D₃ in mitochondria of the kidney (Omdahl and DeLuca 1972). Because of physiological differences between birds and mammals, this study is omitted from Table 3-1.

Endocrine Effects. Few studies were located regarding endocrine effects in humans after oral exposure to stable strontium. Vezzoli et al. (1998) reported that strontium absorption was inversely correlated with parathyroid hormone levels.

No studies were located regarding endocrine effects in animals of acute- or chronic-duration oral exposure to stable forms of strontium. There were no histological changes in the parathyroid gland or alterations in parathyroid hormone levels observed in male weanling Sprague-Dawley rats given 1,520 mg strontium/kg/day in the diet for 26 days (Svensson et al. 1987). The authors cautioned that their biochemical methods could not distinguish between active and inactive forms of the hormone. A few organ weight changes were observed among weanling Wistar rats fed up to 166 mg strontium/kg/day as strontium chloride in the diet for 90 days (Kroes et al. 1977). The relative thyroid weight was significantly heavier in males at 36 and 146 mg strontium/kg/day and the relative pituitary weight was significantly decreased in females at 10 and 166 mg strontium/kg/day, but in neither case was there a clear dose-response. Slight histological changes in the thyroid were reported.

Body Weight Effects. No studies were located regarding body weight effects in humans after oral exposure to stable strontium.

No studies were located regarding body weight effects in animals after chronic-duration oral exposure to stable strontium. In acute- and intermediate-duration animal studies, the effective dose levels for body weight effects were relatively high and young animals were more sensitive than adults. In an acute-duration study, there was no effect on body weight in groups of adult SPF Wistar rats that ingested up to 110 mg strontium/kg/day as strontium chloride in the diet for 2 weeks (Kroes et al. 1977). Body weight gain was reduced by 62% among male weanling (21-day-old) Wistar rats that ingested 2,820 mg strontium/kg/day as strontium phosphate in the diet for 2 weeks, but this effect was reversible by feeding rats a diet low in strontium for 2 weeks (Kshirsagar 1976). From an analysis of a pair-fed control group (food intake matched to this high-dose group), the author concluded that the severe effects were a result of excess strontium, and not the reduced diet. Ingestion of 1,090 or 1,630 mg strontium/kg/day as strontium lactate reduced body weight gain in 5-week-old albino rats within several days (Teree et al. 1965). However, it seems likely that the reduced body weight gains resulted from an observed (but not measured) reduction in food intake, possibly because of reduced palatibility at the higher dose levels. Since the reduction appears not to be a systemic effect of strontium ingestion, this study is omitted from Table 3-1.

Most of the intermediate-duration oral exposure studies in weanling rodents have reported no effect on body weight for exposures <633 mg strontium/kg/day (rats: Grynpas et al. 1996; Kroes et al. 1977; Marie et al. 1985; Morohashi et al. 1994; Neufeld and Boskey 1994; Skoryna 1981a; and mice: Marie and Hott 1986). Intermediate-duration exposures to stable strontium at levels above 1,000 mg/kg/day adversely affected body weight. A 15% reduction in body weight gain was observed among weanling (21-day-old) male Wistar rats that ingested 1,270 mg strontium/kg/day as strontium phosphate for 4–6 weeks, but no reduction was observed at 580 mg strontium/kg/day (Kshirsagar 1976). The body weight gain was 28% lower than controls in weanling (21-day-old) male England Wright Y rats that ingested 1,850 mg strontium/kg/day (form unspecified) for 20 days (Reinholt et al. 1985). The terminal body weight was 16% lower than normal in male weanling Sprague-Dawley rats that ingested 1,520 mg strontium/kg/day (form not specified in this paper, but other publications from this lab used strontium chloride) for 26 days (Svensson et al. 1987).

A >30% loss in body weight occurred in young female rats (40–60 g) that were fed 4,975 mg strontium/kg/day as strontium carbonate for 20 days (Storey 1961); body weight gain was reduced by 24% at 2,220 mg, but was unaffected at 1,460 mg strontium/kg/day. Food intake was not reported, so it is uncertain to what extent these results are attributable to unpalatability. Similarly treated adult female rats exhibited no significant body weight changes at 2,750 mg strontium/kg/day (Storey 1961). Body weight gain was about a third lower than controls in young (50–70 g) rats that ingested 2,160 mg strontium/kg/day as strontium carbonate for 7 months (Storey 1962); no quantitative body weight data were reported for young or adult animals.

In acute- and intermediate-duration studies, strontium effects on body weight were more severe in animals on diets low in calcium. Reduced body weight gain was reported in young white Leghorn chicks following ingestion of a high strontium/low calcium diet for 1 or 2 weeks (Corradino and Wasserman 1970; Corradino et al. 1971a, 1971b). The body weight gain of male weanling Wistar rats was reduced by 60% after ingestion of strontium carbonate (1,960 mg strontium/kg/day) in a diet low in calcium (0.04%) for 4 weeks (Matsumoto 1976).

Metabolic Effects. No studies were located regarding metabolic effects in humans after oral exposure to stable strontium.

No studies were located regarding metabolic effects in animals after chronic-duration oral exposure to stable strontium. In animal studies, few metabolic effects resulted from acute- or intermediate-duration oral exposure to stable strontium. In chicks given a normal Vitamin D₃-containing diet for 2 weeks after hatching, ingestion of a diet containing excess strontium reduced the plasma concentration of calcium, probably a consequence of reduced calcium absorption by the duodenum (Corradino et al. 1971a). Intermediate-duration exposures to 150–1,850 mg strontium/kg/day as strontium carbonate or strontium chloride had no effects on the serum levels of calcium, phosphorus, or magnesium in young or adult rodents given adequate dietary calcium, phosphorus, and vitamin D (rats: Grynpas et al. 1996; Kroes et al. 1977; Marie et al. 1985; Neufeld and Boskey 1994; Svensson et al. 1985, 1987; Reinholt et al. 1984; Skoryna 1981a; and mice: Marie and Hott 1986). No effects on serum calcium levels were observed in young female rats (40–60 g) that were fed 4,975 mg strontium/kg/day as strontium carbonate for 20 days or in adult female rats similarly fed 2,750 mg strontium/kg/day (Storey 1961). At 4,975 mg strontium/kg/day in the young rats, the calcium/strontium ratio was 1, whereas the ratio at 2,750 mg strontium/kg/day in adult rats was 1.4. A 13% reduction in serum calcium was observed in female juvenile Wistar rats (36-day-old, 6–8 per group) that ingested 510 mg strontium/kg/day as strontium carbonate in the diet for 27 days, but no effect was observed at 100 mg strontium/kg/day (Morohashi et al. 1994).

3.2.2.3. Immunological and Lymphoreticular Effects

No studies were located that reported immunological or lymphoreticular effects in humans or animals following oral exposure to stable strontium.

3.2.2.4. Neurological Effects

No studies were located that reported neurological effects in humans following oral exposure to stable strontium. No behavioral effects were observed in rats that ingested strontium chloride at levels up to 110 mg strontium/kg/day for 2 weeks or 166 mg strontium/kg/day for 90 days (Kroes et al. 1977). Johnson et al. (1968) reported paralysis of the hindlimbs in weanling male Sprague-Dawley rats that were fed 565 mg/kg/day of stable strontium (form not specified) for 43 days. It is not clear whether the observed paralysis was neurological or muscular, but it could have been related to abnormal calcium signaling in muscle or nerve. It is unlikely that the paralysis was due to the deformation of the femora as severely rachitic and osteomalacic rodents are not generally paralyzed. The NOAEL and LOAEL are recorded in Table 3-1 and plotted in Figure 3-1.

3.2.2.5. Reproductive Effects

No studies were located regarding reproductive effects in humans or animals following oral exposure to stable strontium.

3.2.2.6. Developmental Effects

No studies were located regarding developmental effects in humans following acute- or intermediate-duration oral exposure to stable forms of strontium. The only chronic-duration study is the Turkish epidemiological analysis that found a relationship between the concentration of strontium in the local soil and the prevalence of rickets in children between the ages of 6 months and 5 years (Ögzur et al. 1996). A relatively short period of breast feeding, which presumably affected calcium intake, and soil levels of strontium higher than 350 ppm, which probably determined the level of strontium in dietary grains consumed after weaning, were associated with an increase in the prevalence and severity of rickets. This study is discussed above in Section 3.2.2.2 Musculoskeletal Effects.

No studies were located that examined the effect of exposure to stable strontium in utero following oral maternal exposure in animals. However, the studies discussed in Section 3.2.2.2 Musculoskeletal Effects address the effects of strontium on bone organogenesis, in particular, endochondral ossification, a developmental process that continues long after birth. For example, in a study in which 4-week-old male Wistar rats (50–60 g body weight) were fed 1,970 mg strontium/kg/day as strontium carbonate in a diet low in calcium (0.04%), bone mineralization was significantly affected (Matsumoto 1976). Tibial length was reduced by 33% and the tibial proximal and distal epiphyseal plates were both about 5 times wider than normal. Microradiographic and histological analyses of tibial proximal heads revealed that no mineralization was detectable, that the organization of chondroblasts was irregular, and that osteoid rather than mineralized bone was deposited. Other studies on weanlings were conducted for acute durations (rat: Kshirsagar 1976) and intermediate durations (rat: Grynpas et al. 1996; Kroes et al. 1977; Morohashi et al. 1994; Neufeld and Boskey 1994; Reinholt et al. 1984, 1985; Svensson et al. 1985, 1987; and mice: Marie and Hott 1986). Intermediate-duration studies on rats demonstrated that ingestion of strontium resulted in more severe skeletal effects in young animals than in adults (Storey 1961, 1962). These studies are described in Section 3.2.2.2 Musculoskeletal Effects and are listed in Table 3-1 and Figure 3-1 under that category.

3.2.2.7. Cancer

No studies were located that demonstrated cancer effects of stable strontium following oral exposure in humans or animals. In one case-control study, no association was found between the incidence of liver cancer in 1984 on Chongming Island in China and the levels of stable strontium detected in hair (Wang et al. 1990).

3.2.3.1. Death

3.2.3.2. Systemic Effects

3.2.3.3. Immunological and Lymphoreticular Effects

3.2.3.4. Neurological Effects

3.2.3.5. Reproductive Effects

3.2.3.6. Developmental Effects

3.2.3.7. Cancer

3.3.1.1. Death

No studies were located regarding death in humans following inhalation exposure to radioactive strontium. Information on the lethality of inhaled radioactive strontium is limited to acute exposure studies. Because of the bone-seeking behavior of strontium, an acute exposure to airborne ⁹⁰Sr results in chronic exposure to radiation from ⁹⁰Sr incorporated into bone. If insoluble radiostrontium compounds are inhaled, there could be long-term lung exposure (see discussion of the study by Willard and Snyder (1966) in Section 3.5.1.1).

In two different experiments briefly described in a report by the Lovelace Foundation (now known as the Lovelace Respiratory Research Institute), young male and female Holtzman rats were exposed once to ⁹⁰Sr by whole body inhalation for initial body burdens ranging from 170 to 1,660 µCi ⁹⁰Sr/kg (0.63–61.4 MBq/kg) of body weight and average skeletal radiation doses ranging from 12,600 to 19,000 rad (126–190 Gy) (Fission Product Inhalation Project 1967b). Survival was inversely proportional to dose, with rats receiving the lowest dose living for more than 700 days, and those receiving the highest dose living less than 200 days. In the two experiments, 77% of the rats that died and 47% of the rats that were killed in a moribund state were found to have osteosarcoma. Among rats dying with tumors, the average skeletal dose was 81 rad/day, compared to 62 rad/day for rats without tumors (0.81 vs 0.62 Gy/day). The small sample sizes in this study do not permit its inclusion in the LSE Table 3-2.

In acute inhalation studies in beagle dogs, high-dose radiation effects of inhaled ⁹⁰SrCl₂ on bone marrow resulted in death within days or weeks of exposure, whereas lower doses reduced long-term survival through carcinogenetic effects. For all exposed dogs, the mean survival time was 3,000 days, compared to 4,500 days for the controls (Gillett et al. 1987b). Among dogs receiving high or medium doses (long-term retained body burdens between 47 and 120 µCi ⁹⁰Sr/kg (1.74 and 4.44 MBq/kg), 6/22 died within 32 days from severe hypoplasia of the bone marrow (Gillett et al. 1987a; Muggenburg et al. 1979). Individual neutrophil counts were the most reliable predictors of lethality. Death from primary bone tumors occurred from 2 to 10 years after exposure to inhaled ⁹⁰SrCl₂ (Gillett et al. 1987b). Fibrosarcomas and metastasizing hemangiosarcomas occurred somewhat earlier than osteosarcomas and were the major contributors to shortened mean survival times for the dogs exposed to inhaled ⁹⁰SrCl₂ (Gillett et al. 1987b). Deaths from myelomonocytic leukemia and from bone-associated soft tissues of the skull were also concluded to be associated with radiostrontium; the long-term retained burdens were 9.2–27 µCi ⁹⁰Sr/kg (0.34–1.0 MBq/kg) and 21–35 µCi ⁹⁰Sr/kg (0.081–1.3 MBq/kg), respectively. These are extreme doses.

In beagle dogs exposed by acute inhalation to ⁹⁰Sr fused-clay particles, the pattern of mortality was different since the radioactive particles were initially embedded in the lung. No deaths occurred until the 5^th month postexposure. Of 36 dogs with initial lung burdens ≥25 µCi ⁹⁰Sr/kg (925 kBq/kg) of body weight, 35 died within the first 2 years, primarily of radiation pneumonitis and/or pulmonary fibrosis (Snipes et al. 1979). Subsequently, within the 2^nd to 7^th years after exposure, deaths from hemangiosarcoma and carcinoma of the lung were common. None of the control dogs died during the 9 years following exposure (Snipes et al. 1979), indicating that the observed mortality was not caused by inhalation of nonradioactive aluminum silicate particles alone. Among dogs dying prematurely from neoplasms of the lung, the initial lung burdens were between 3.7 and 94 µCi/kg (0.14–3.5 MBq/kg) and the doses to the lungs ranged from 43,000 to 67,000 rad (430–670 Gy) (Benjamin et al. 1975).

The percent mortality values for dogs from exposure to radioactive strontium by the inhalation route are presented in Table 3-2 and plotted in Figure 3-2.

3.3.1.2. Systemic Effects

No studies were located that described endocrine, dermal, or ocular effects in humans or animals following inhalation exposure to radioactive strontium. The highest NOAEL values and all reliable LOAEL values in each species and duration category for systemic effects from radiation exposure to strontium by the inhalation route are presented in Table 3-2 and plotted in Figure 3-2.

Respiratory Effects. The only respiratory effects reported for the study in which beagle dogs were exposed to soluble aerosols of ⁹⁰SrCl₂ (Boecker et al. 1969; Gillett et al. 1987b) were late primary cancers of the respiratory tract or tumors metastasizing to the lung. These effects are discussed in Section 3.2.1.7 Cancer.

Table 3-2

Levels of Significant Exposure to Strontium - Radiation Toxicity - Inhalation.

Figure 3-2

Levels of Significant Exposure to Strontium - Radiation Toxicity - Inhalation. Acute (≤14 days)

Respiratory effects were more pronounced in beagle dogs that were exposed to ⁹⁰Sr fused-clay particles by inhalation (Benjamin et al. 1976c; Snipes et al. 1979). The primary cause of early death among dogs exposed to initial lung burdens ≥25 µCi ⁹⁰Sr/kg (925 kBq/kg) was radiation pneumonitis and/or pulmonary fibrosis (Snipes et al. 1979). No such effects were reported in control dogs exposed to nonradioactive aluminosilicate-fused clay particles (Snipes et al. 1979). Clinical signs included an increased respiratory rate, dyspnea, cyanosis, and dry and moist rales (Benjamin et al. 1976c). Radiographically, the dogs showed increased focal or diffuse lung-field densities. The pneumonitis was characterized by acute and chronic inflammation with increased numbers of alveolar macrophages, hypertrophy and hyperplasia of alveolar lining cells, degeneration of the bronchiolar epithelium and alveolar ducts, focal emphysema, and edema. The fibrosis involved the alveolar septa, pleura, and perivascular regions, with substantial scarring. Vascular damage in the lungs was characterized by congestion, hemorrhage (possibly related to thrombocytopenia), fibrin exudation, and occasional vessels with fibrinoid necrosis or intimal proliferation.

Cardiovascular Effects. Acute inhalation of radiostrontium was reported to lead to adverse cardiovascular effects in dogs. Among beagles that died within 5–15 months following inhalation exposure to ⁹⁰Sr fused-clay particles, most exhibited myocardial necrosis or degeneration, and fibrosis, primarily of the right atrium (Hobbs et al. 1972); these animals had initial lung burdens between 33 and 100 µCi/kg (1.2–3.7 MBq/kg) and cumulative beta radiation doses to the lung of 34,000 to 82,000 rad (340–820 Gy). In a later report of the same study, acute and chronic vascular lesions, characterized as inflammatory or degenerative, affected the elastic and muscular pulmonary arteries in dogs with initial lung burdens between 16 and 94 µCi/kg (0.6–3.5 MBq/kg) and doses to the lung between 40,000 and 96,000 rad (400–960 Gy) at the time of death (Snipes et al. 1977). Vascular damage in the lungs was characterized by congestion, hemorrhage, fibrin exudation, and occasional vessels with fibrinoid necrosis or intimal proliferation (Benjamin et al. 1976c). These effects were attributed to the direct effect of beta radiation (from radiostrontium particles embedded in the lung) on adjacent tissue. In addition, presumably as a consequence of radiation damage to the pulmonary vasculature, the right ventricle became dilated and hypertrophic with congestive heart failure. Hemangiosarcomas resulting from radiostrontium exposure in this study are discussed in Section 3.3.1.7 Cancer.

Gastrointestinal Effects. Gastrointestinal effects were observed in beagle dogs receiving single high doses (long-term retained body burdens between 47 and 83 µCi/kg; 1.74 and 3.07 MBq/kg) of soluble aerosols containing ⁹⁰SrCl₂ (Gillett et al. 1987a). Anorexia and, 2 days before death, bloody diarrhea, developed in six dogs that died between 18 and 32 days after the extreme radiation dose rate induced acute radiation syndrome (Gillett et al. 1987a). It is likely that severe thrombopenia, one of the features of radiation-induced bone marrow hypoplasia, contributed to hemorrhage in the gastrointestinal tract as elsewhere in the body. In addition, some effects could have been due to inhaled ⁹⁰SrCl₂ droplets being transported from the mucoid, ciliated nasopharyngeal and tracheobronchial epithelia to the pharynx and then swallowed. The gastrointestinal epithelium then would have been exposed directly to beta emissions from radiostrontium for a day or two. Another report of the same study described three exposed dogs that died at age >11 years with a malabsorption syndrome (Muggenburg et al. 1977). All of the dogs exhibited chronic diarrhea with anorexia, and at necropsy, contained chronic degenerative and inflammatory lesions of the small intestines. Their long-term retained burdens were 1.9–9.6 µCi/kg (70.3–355.2 kBq/kg) and the absorbed doses to the skeleton were calculated to be 530–5,600 rad (5.3–56 Gy). Although the authors could not firmly establish whether the syndrome was a consequence of exposure or of age, the cumulative radiation dose to the digestive tract was likely to have been very low and this argues against ⁹⁰Sr as the cause.

One beagle dog that was exposed to ⁹⁰Sr fused-clay particles and had an initial lung burden of 4.1 µCi/kg (151.7 kBq/kg) and a cumulative radiation dose to the lung of 20,000 rad (200 Gy) died 9 years after exposure with anorexia and an ulcerative lesion to the pharynx (Snipes et al. 1979). Whether the pharyngeal lesion was related to exposure is uncertain, since the report was preliminary and no other response to radiation had been observed in this animal.

Hematological Effects. Profound hematological effects were observed in beagle dogs that were exposed once by inhalation either to soluble aerosols containing ⁹⁰SrCl₂, or to ⁹⁰Sr fused to aluminosilicate particles that produced extremely large radiation dose rates and doses in the affected tissues sufficient to induce acute radiation syndrome.

Significant dose-related pancytopenia developed in dogs that were exposed to ⁹⁰SrCl₂ aerosols and had long-term retained burdens >10 µCi (370 kBq) ⁹⁰Sr/kg (Gillett et al. 1987a). Profound decreases in platelet numbers were evident by 7 days and were maximal by 28 days. Drastic thrombocytopenia (platelets reduced >90%) probably contributed to widespread hemorrhaging and premature death in dogs with long-term retained burdens ≥47 µCi/kg (≥1.7 MBq/kg). Significant immediate reductions in platelet counts (>60%) occurred in surviving dogs with long-term retained burdens of ≥1.5 µCi/kg (≥0.56 MBq/kg). However, even dogs with the lowest long-term retained burdens (1–10 µCi/kg; 0.04–0.36 MBq/kg), which otherwise showed little immediate effect, exhibited long-term (>3 years) depression in platelet counts compared to controls. The pattern of neutropenia followed a similar exposure-response, and profound neutropenia was the most accurate predictor of death. In surviving dogs that were immediately affected by exposure, neutrophil counts recovered, but in these dogs, as well as those immediately unaffected, significant long-term (>3 years) suppression was observed compared to controls. Similarly, lymphocyte counts were drastically reduced (by 75%) in dogs dying within weeks of exposure with long-term retained burdens ≥47 µCi/kg (≥1.7 MBq/kg). Surviving dogs with long-term retained burdens >10 µCi (370 kBq) ⁹⁰Sr/kg exhibited a long-term (>3 years) suppression of lymphocyte counts (>30%). Dogs with long-term retained burdens between 6 and 10 µCi/kg (0.26–0.36 MBq/kg) exhibited normal lymphocyte counts that were normal over 1,400 days except for periods of significant depression at 60–120 and 900–1,000 days. Dogs with long-term retained burdens between 1 and 3 µCi/kg (0.04–0.12 MBq/kg) had lymphocyte counts that were not significantly different from controls. Reduced erythrocyte mass, as exemplified by decreases in hematocrit, red blood cell counts, and hemoglobin levels, occurred between 2 and 3 weeks after exposure (slightly later than the depression in platelet and white cell counts). In the most severely affected dogs, red blood cell counts fell to 70–80% of pre-exposure values, with maximal depression at 32 days. Prolonged depression of erythrocyte counts was observed in surviving dogs with long-term retained burdens ≥27 µCi/kg (≥1 MBq/kg).

Significant suppression of peripheral lymphocyte counts was observed in beagle dogs that were exposed by inhalation to ⁹⁰Sr fused-clay particles (Jones et al. 1976). Lymphocytes declined gradually over time in all exposed groups (initial lung burdens ≥5 µCi/kg; ≥185 kBq/kg), and remained more than 50% lower than controls after 2 years.

Hepatic Effects. No studies were located that described hepatic effects in humans following inhalation exposure to radioactive strontium. All beagle dogs that died from radiation pneumonitis following a single inhalation exposure to high concentrations of ⁹⁰Sr fused-clay particles (25 µCi ⁹⁰Sr/kg of body weight; 925 kBq/kg) exhibited chronic passive congestion of the liver, and one had mild centrilobular fibrosis (Benjamin et al. 1976c).

Renal Effects. No studies were located that described renal effects in humans following inhalation exposure to radioactive strontium isotopes. Some beagle dogs in the terminal stages of acute radiation syndrome following inhalation exposure to aerosols of ⁹⁰SrCl₂ (long-term retained burden 47–83 µCi ⁹⁰Sr/kg; 1.74–3.07 MBq/kg) had low urine output and elevated blood urea nitrogen (Gillett et al. 1987a).

Body Weight Effects No studies were located that described body weight effects in humans following inhalation of radiostrontium. Anorexia and reduced body weight were observed among beagle dogs with long-term retained burdens between 45 and 119 µCi/kg (1.7–4.4 MBq/kg) following inhalation of ⁹⁰SrCl₂ aerosols (Gillett et al. 1987a; Muggenburg et al. 1977) or initial lung burdens between 25 and 32 µCi/kg (0.93–1.2 MBq/kg) following inhalation of ⁹⁰Sr fused-clay particles (Benjamin et al. 1976c).

3.3.1.3. Immunological and Lymphoreticular Effects

No studies were located regarding immunological effects in humans following inhalation exposure to radioactive strontium isotopes. However, profound effects on the immune system were a consequence of acute inhalation exposure to radiostrontium in dog studies. Effects in dogs exposed to soluble aerosols of ⁹⁰SrCl₂ were sequelae of general irradiation of the bone marrow from ⁹⁰Sr incorporated into bone. Significant dose-related lymphopenia was observed in young adult beagle dogs (12–14 months old) after a single inhalation exposure to ⁹⁰SrCl₂ at long-term retained burdens >10 µCi ⁹⁰Sr/kg (370 kBq/kg; Gillett et al. 1987a). Furthermore, there was some evidence of immunosuppression in dogs with average initial body burdens of 35 µCi ⁹⁰Sr/kg (1.3 MBq/kg) (Fission Product Inhalation Project 1967a); titers for infectious canine hepatitis and leptospira vaccines were depressed more than 30% following exposure to ⁹⁰SrCl₂ aerosols. Effects in dogs exposed to relatively insoluble ⁹⁰Sr fused-clay particles were primarily a consequence of irradiation of the blood as it circulated through the lungs, although some damage to thoracic lymph nodes was observed. Among beagle dogs (17–20 months old) exposed by nose-only inhalation to ⁹⁰Sr fused clay particles (initial lung burdens 25–32 µCi ⁹⁰Sr/kg; 0.925–1.18 MBq/kg), the numbers of peripheral lymphocytes were depressed by more than 50% during the 12^th through 28^th weeks after exposure, although recovery was observed by week 44 (Benjamin et al. 1976c). The cumulative radiation dose to the lungs ranged from 35,000 to 43,000 rad (350–430 Gy). During the period of lymphocyte suppression, the immune response to phytohemagglutinin antigen tested in vitro was depressed 10-fold in the dog that had the highest initial lung burden (32 µCi/kg; 1.18 MBq/kg) and was the first to die. In this animal, the tracheobronchial and sternal lymph nodes, which received a significant radiation dose from ⁹⁰Sr, were depleted of lymphocytes, although peripheral nodes, which received much lower doses, were nearly normal. In the main study that employed 1-year-old beagles, the highest initial lung burdens of ⁹⁰Sr fused-clay particles resulted in severe atrophy and fibrosis of the tracheobronchial lymph nodes (Snipes et al. 1977). In other dogs, which had initial lung burdens averaging between 5 and 19 µCi/kg (185 and 703 kBq/kg), fluctuations in the peripheral lymphocyte numbers were observed, but the values remained depressed by 40% for 2 years following inhalation exposure (Jones et al. 1976).

Cumulative doses in these dogs ranged from 1,055 to 4,005 rad (10.5–40 Gy). None of the dog studies reported whether there was a NOAEL identified for immunological effects. Significant chronic suppression of the immune system is considered a serious effect because of the impaired resistance to infectious disease.

3.3.1.4. Neurological Effects

No studies were located that described neurological effects in humans following inhalation exposure to radioactive strontium. A beagle dog that was exposed to the highest concentration of ⁹⁰SrCl₂ aerosol (long-term retained burden of 119 µCi/kg or 4.4 MBq/kg) succumbed with epileptic seizures, but the authors deemed these to be unrelated to exposure (Gillett et al. 1987b). Serious neurological effects (convulsions, paralysis) were observed in several dogs that were in the terminal stages of cancer following inhalation of ⁹⁰Sr fused clay particles (Snipes et al. 1977, 1978). No other studies addressed neurological effects in animals following inhalation exposure to radioactive strontium isotopes.

The highest NOAEL values and all reliable LOAEL values in each species and duration category for neurological effects from exposure to radioactive strontium by the inhalation route are presented in Table 3-2 and plotted in Figure 3-2.

No studies were located regarding the following effects in humans or animals following inhalation exposure to radioactive strontium:

3.3.1.5. Reproductive Effects

3.3.1.6. Developmental Effects

3.3.1.7. Cancer

No studies were located regarding cancer in humans following inhalation exposure to radioactive strontium isotopes, but several studies reported carcinogenetic effects in animals. The types of cancers produced varied with the form of strontium administered. In studies using soluble forms of radioactive strontium, (e.g., ⁹⁰SrCl₂), bone-associated cancers were the predominant types, because absorbed strontium primarily incorporates into bone. Studies using relatively insoluble ⁹⁰Sr fused-clay particles reported lung-related cancers as the major initial types, since the particles were initially embedded in the lungs. As particles slowly dissolved (releasing ⁹⁰Sr) or were cleared from the lungs, tumors were induced in other tissues.

In two different experiments described in a report by the Lovelace Foundation (now known as the Lovelace Respiratory Research Institute), young male and female Holtzman rats were exposed once to an aerosol of ⁹⁰Sr in cesium chloride by whole body inhalation for initial body burdens ranging from 170 to 1,660 µCi ⁹⁰Sr/kg (6.3–61.4 MBq/kg) of body weight (Fission Product Inhalation Project 1967b). The average skeletal radiation doses over their remaining lifespans averaged from 12,600 to 25,900 rad (126–259 Gy). In the two experiments, 77 or 47% of the rats that died or were euthanized in a moribund state were found to have bone tumors (osteosarcomas). Among rats dying with tumors, the average skeletal dose rate was 81 rad/day, compared to 62 rad/day for rats without tumors (0.81 vs 0.62 Gy/day).

Primary bone cancer was the most frequent cause of death in beagle dogs (30/66) given a single inhalation exposure to ⁹⁰SrCl₂ aerosol and then observed for their lifespans (Benjamin et al. 1974a, 1976a, 1979; Gillett et al. 1987b; McClellan et al. 1973; Muggenburg et al. 1977, 1978, 1979). The cumulative absorbed doses of beta radiation to bone ranged from 12 to 1,200 rad (0.012–12 Gy) at 30 days and from 200 to 170,000 rad (2–1,700 Gy) at 1,000 days after exposure. In dogs with bone-related tumors, the long-term retained burdens ranged from 2 to 119 µCi ⁹⁰Sr/kg (0.081–4.4 MBq/kg) of body weight. Bone-tumor-related deaths occurred 759–3,472 days after exposure (median survival time of 1,702 days, compared to 4,500 days for controls). Twenty-seven tumors were classified as different subtypes of osteosarcoma, 14 as hemangiosarcomas, 3 as fibrosarcomas, and 1 as a myxosarcoma. Four additional animals developed carcinomas in soft tissues adjacent to the bones of the skull: invasive baso-squamous carcinoma, transitional carcinomas of the nasal cavity, and an adenocarcinoma in the maxilloturbinate region (Benjamin et al. 1979). In addition, two dogs died from myelomonocytic leukemia resulting from irradiation of bone marrow. Metastasis occurred from 21 tumors, in particular the hemangiosarcomas, with the lungs being the most frequent site of metastasis (76%).

Among 127 beagle dogs exposed by inhalation to ⁹⁰Sr fused-clay particles, deaths from primary pulmonary tumors were common: 19 dogs with hemangiosarcomas (one each also with bronchioalveolar carcinoma, nasal squamous cell carcinoma, or pulmonary epidermoid carcinoma), and one with pulmonary squamous cell carcinoma (Snipes et al. 1979). All 34 dogs exposed to ⁹⁰Sr fused clay particles with cumulative exposures of >29,000 rad (290 Gy) developed pulmonary hemangiosarcoma. The heart wall was the other primary location of hemangiosarcoma (11 dogs), the others being the mediastinum, spleen, rib, lung-associated lymph nodes, and liver (Snipes et al. 1979). Hemangiosarcomas were metastatic in all but one affected dog. Among dogs dying prematurely from neoplasms of the lung, the initial lung burdens were 3.7–94 µCi/kg (0.14–3.5 MBq/kg) and the estimated cumulative doses to the lungs ranged from 43,000 to 67,000 rad (430–670 Gy) (Benjamin et al. 1975). Considering all dogs with tumors, pulmonary carcinomas or sarcomas occurred in 3/12 dogs that received cumulative radiation doses of 17,000–25,000 rad (170–250 Gy), but no pulmonary tumors were reported for three dogs with cumulative exposure levels of 11,000–15,000 rad (110–150 Gy; Hahn et al. 1983a).

The highest NOAEL values and all reliable LOAEL values in each species and duration category for cancer effects from exposure to radioactive strontium by the inhalation route are presented in Table 3-2 and plotted in Figure 3-2.

3.3.2.1. Death

In the Techa River population that was exposed to radiostrontium and radiocesium in drinking water and food between 1949 and 1956, an increase in the number of deaths from leukemia and solid cancers was reported (Kossenko 1996). In the exposed group, the standardized mortality rate was 140 (95% CI: 131–150) per 100,000 compared to 105 (95% CI: 101–109) per 100,000 in the control group during the followup period (1950–1982). Absorbed doses to the red bone marrow in the study group were between 17.6 and 164 rad (0.176 and 1.64 Gy). No increase in cancer mortality was observed among offspring of exposed individuals. These data are omitted from Table 3-3 because the exposures were to multiple sources of radiation.

Oral exposure to radioactive strontium caused dose-related increases in mortality in animal studies. In general, younger animals were more sensitive to the effects of radiation than older animals. There was an increase in deaths in a small number (6 out of 7) of Rhesus monkeys given 100 µCi of ⁹⁰Sr per day (3.7 MBq/day) by gavage for 5 or 10 days (Casarett et al. 1962). One monkey given 11 µCi/kg/day (0.42 MBq/kg/day) for 5 days died 4 years after treatment from leukemia with a total skeletal dose of 4,300 rad (43 Gy). One monkey given a dose of 28 µCi/kg/day (1.0 MBq/kg/day) for 10 days died within 4 months of treatment from pancytopenia with an estimated skeletal dose of 4,500 rad (45 Gy). Two others exposed to an average of 18 µCi/kg/day (0.67 MBq/kg/day) for 10 days died from bone associated cancers within 36 months of treatment, and with estimated skeletal doses of 4,700–9,500 rad (47–95 Gy). Because of the small sample size and the fact that the animals were of different ages, this study serves as an indicator, but not as proof of dose-response effects of ingested radiostrontium.

In experiments in which weanling (30 days old) and adult Long-Evans rats were given ⁹⁰Sr in drinking water for 10 days, survival at 5 months was reduced by 80% in the weanlings consuming at least 297–386 µCi ⁹⁰Sr/kg/day (11 MBq/kg/day; total 464 µCi or 17 MBq), but was unaffected in adults consuming 64–194 µCi ⁹⁰Sr/kg/day (7.2 MBq/kg/day; total 650 µCi or 24.1 MBq; Casarett et al. 1962). The reduced survival of the weanlings was consistent with their higher skeletal burden at 5 months: >20 times higher than in the adults. In another acute study, six young female dairy cattle (three sets of twins from three different strains, ages 398 and 479 days and weighing 145–349 kg at the start of treatment) were given 44 µCi ⁹⁰Sr/kg/day (1.63 MBq/kg/day) ‘orally’ for 5 days (Cragle et al. 1969). The four youngest (398 days) and lightest heifers (145–212 kg), which were administered a total of 32–46 mCi (1.18–1.70 GBq), died of radiation sickness between 93 and 132 days after treatment was started, whereas the older and heavier animals (342–349 kg), which had received a total of 75–77 mCi of ⁹⁰Sr (2.78–2.85 GBq), were still alive 3 years after treatment. In addition to age-related differences, strain differences may have contributed to the results; the older cows were Holsteins, which have more massive skeletons than the Brown Swiss and Jersey strains. The authors suggested that the larger animals survived because of the wider diameter of the marrow cavity, which possibly shielded the central marrow from beta radiation released from ⁹⁰Sr (and its ⁹⁰Y decay product) deposited at the periphery of the bone shaft.

In an intermediate-duration experiment, young (87-day-old) Long-Evans rats were treated with up to 104 µCi of ⁹⁰Sr per kg of body weight per day (3.8 MBq/kg/day) for 30 days over a period of 37 days (Casarett et al. 1962; Hopkins et al. 1966); the total amount administered was 790 µCi (29.2 MBq). In these rats, the estimated skeletal activity of ⁹⁰Sr at 5 months was 11 µCi (407 kBq) and survival was reduced by about 36%. In the young rats treated for 30 days, skeletal activity was higher and survival was reduced accordingly compared to the adult rats treated for 10 days (see previous paragraph), but the differences were out of proportion to the total amounts of ⁹⁰Sr administered to the two sets of rats. The total amount given to adults was 18% less than to the juveniles, but the skeletal doses in the adults were 82% less, suggesting age-related differences in incorporation.

In a lifetime study, adult CF-1 mice that were exposed to ⁹⁰Sr beginning at ages 110–250 days were less vulnerable to continuous exposure than mice that had been exposed since conception (Finkel et al. 1960). The adult lifespan was shortened by 17% in mice given 31 µCi ⁹⁰Sr/kg/day (1.15 MBq/kg/day), but was unaffected by administration of up to 16 µCi ⁹⁰Sr/kg/day (592 kBq/kg/day). In mice exposed from conception, the lifetime was shortened by 40% when given 36 µCi ⁹⁰Sr/kg/day (1.33 MBq/kg/day), and by 26% when given between 4 and 19 µCi ⁹⁰Sr/kg/day (148 and 703 kBq/kg/day), but was unaffected by 0.05–0.4 µCi ⁹⁰Sr/kg/day (1.85–14.8 kBq/kg/day). In albino rats that were fed 0.5 or 2 µCi ⁹⁰Sr/kg/day (18.5 or 74 kBq/kg/day) for their postweaning lifetime, the lifespan was shortened, by about 18 or 30%, respectively, compared to controls (Zapol’skaya et al. 1974). The authors calculated that the lifespan was shortened by 0.09 day per rad. A plot of mortality against absorbed dose showed maximum mortality (40%) against a skeletal absorbed dose of 4,000 rad (40 Gy). In a study in which eight weanling Dutch rabbits were fed approximately 6 µCi/kg/day (218 kBq/kg/day) in pellets once a day for 31–280 days, some died within a few weeks with bone marrow that was slightly hypoplastic (Downie et al. 1959). The bone marrow was entirely atrophic in rabbits dying several months later with osteogenic sarcoma.

Two related long-term oral exposure studies demonstrated dose-related effects of ⁹⁰SrCl₂ on survival in beagle dogs. In the main study, groups of pregnant beagles were fed 0.002–3.6 µCi ⁹⁰Sr/kg/day (0.074–133.2 kBq/kg/day) from gestational day 21 through lactation to postnatal day 44, and the pups were fed the same doses from weaning at day 42 through day 540 (Raabe et al. 1983; White et al. 1993). Survival of the pups was reduced by 18, 64, and 85% at the three highest levels (0.4, 1.2, and 3.6 µCi/kg/day or 14.8, 44.4, and 133.2 kBq/kg/day, respectively). Survival was not significantly different from the controls for exposures of 0.002–0.13 µCi/kg/day (0.074–4.8 kBq/kg/day). Mean absorbed skeletal absorbed doses at or below 2,250 rad (22.5 Gy) had no effect on mortality, whereas increased mortality was observed at or above 5,040 rad (50.4 Gy). The secondary study had a similar protocol, except that the dogs were given doses of 0.13–1.2 µCi/day (4.81–44.4 kBq/day) from gestational day 21 throughout their entire lifetime (Book et al. 1982). The mean lifetime absorbed skeletal doses were 2,840–11,190 rad (28.4–111.9 Gy). The median lifespans were reduced by 11–65%, which was similar to the results of the main study. This implies that irradiation after day 540 did not significantly change the survival rate and that survival was shortened because of exposure at a young age. The two main radiation-related causes of death in these studies were myeloproliferative syndrome and skeletal sarcomas (see Section 3.3.2.7 Cancer).

In a multigenerational study of female Pitman-Moore miniature swine, there were dose-related effects on mortality following chronic ingestion of ⁹⁰Sr in the form of strontium chloride (Clarke et al. 1970; McClellan et al. 1963; Ragan et al. 1973). Sows ingesting 3,100 µCi ⁹⁰Sr/day (114.7 MBq/day) from age 9 months did not survive their first pregnancy, succumbing from the destruction of hemopoietic tissue in the bone marrow. The sows developed anemia, leukopenia, thrombocytopenia, and terminal hemorrhagic syndrome (Clarke et al. 1972). Exposure to 25, 125, or 625 µCi ⁹⁰Sr/day (0.925, 4.625, or 23.13 MBq/day) significantly increased mortality after 11, 5, and 1 year(s), respectively, whereas exposure to 1 or 5 µCi ⁹⁰Sr/day (37 or 185 kBq/day) had no effect on survival. Effects on the F1 females exposed from the time of conception were more severe, even though, after weaning, their administered dose level was only a fraction of the maternal level until the age of 6 months. None of the F1 females exposed to 625 µCi ⁹⁰Sr/day (23.13 MBq/day) survived to the age of 9 months, whereas that dose was not immediately fatal to the parental generation of sows. Furthermore, the F1 females receiving 25 µCi ⁹⁰Sr/day (925 kBq/day) showed a significant increase in cumulative mortality after 7 years, rather than 11. However, the 1 and 5 µCi ⁹⁰Sr/day levels (37 and 185 kBq/day), as in the parental generation, had no effect on survival. In this study, the average attained body burden was 10, 50, 250, 1,250, and 4,700 µCi (0.37, 1.85, 9.25, 46.25, and 173.9 MBq) for the 1, 5, 25, 125, and 625 µCi ⁹⁰Sr/day (0.037, 0.185, 0.925, 4.625, and 23.13 MBq/day) levels, respectively.

All reliable LOAEL values for death from oral exposure to radioactive strontium in each species and duration category are recorded in Table 3-3 and plotted in Figure 3-3.

3.3.2.2. Systemic Effects

No studies were located regarding endocrine, dermal, or metabolic effects in humans or animals after oral exposure to radioactive strontium. The highest reliable NOAEL and all LOAEL values for the systemic effects from oral exposure to radioactive strontium are shown in Table 3-3 and plotted in Figure 3-3.

Respiratory Effects. No studies were located regarding respiratory effects in humans following oral exposure to radioactive strontium isotopes. No studies were located regarding respiratory effects in animals following acute- or intermediate-duration exposure to radioactive strontium. In a chronic-duration beagle study, animals exposed to 0.4 or 1.2 µCi/kg/day (14.8 or 44.4 kBq/kg/day) of ⁹⁰Sr in utero from gestational day 21, throughout lactation, and from weaning on day 42 to day 540 exhibited only secondary respiratory effects (Dungworth et al. 1969); lungs showed varying degrees of myeloid infiltration (see Section 3.3.2.7 Cancer). Since this effect is not the direct result of the action of radiostrontium on lung tissue, but rather a secondary effect of myeloid proliferation induced by irradiation of bone marrow, it is not categorized under Systemic: Respiratory Effects in Table 3-3.

Cardiovascular Effects. No studies were located regarding cardiovascular effects in humans after oral exposure to radioactive strontium isotopes. No studies were located regarding cardiovascular effects in animals after acute- or intermediate-duration oral exposure to radioactive strontium isotopes. Petechiae, ecchymoses, and gastrointestinal bleeding were found postmortem in some beagles in a chronic-duration study, in which animals were exposed to 0.002–1.2 µCi ⁹⁰Sr/kg/day (0.074–44.4 kBq/kg/day) in utero from gestational day 21, throughout lactation, and from weaning on day 42 to day 540 (Dungworth et al. 1969). These findings, observed in high dose animals (0.4 and 1.2 µCi/kg/day; 14.8 and 44.4 kBq/kg/day), indicated the presence of a hemorrhagic disorder related to thrombocytopenia (see Hematological Effects below).

The highest reliable NOAEL and all LOAEL values for cardiovascular effects from oral exposure to radioactive strontium in each species and duration category are shown in Table 3-3 and plotted in Figure 3-3.

Table 3-3

Levels of Significant Exposure to Strontium - Radiation Toxicity - Oral.

Figure 3-3

Levels of Significant Exposure to Strontium - Radiation Toxicity - Oral.

Gastrointestinal Effects. No studies were located regarding gastrointestinal effects in humans after oral exposure to radioactive strontium. Intestinal hemorrhage occurred in cows succumbing to radiation sickness 3 months after ingesting 44 µCi ⁹⁰Sr/kg/day (1.63 MBq/kg/day) for 5 days (Cragle et al. 1969). It is likely that other reports of terminal hemorrhagic effects (see Hematological Effects below) following high doses of radiostrontium encompassed intestinal hemorrhage whether or not it was specifically mentioned.

Hematological Effects. In human and animal studies, adverse hematological affects were associated with beta radiation of bone marrow following incorporation of radiostrontium into bone.

The Techa River population exposed to chronic combined external gamma radiation and internal radiation due to ⁹⁰Sr and ¹³⁷Cs exhibited alterations in hematological parameters, including leukopenia, thrombocytopenia, and granulocytopenia (Akleyev et al. 1995). These effects were observed in a portion of the exposed population that received radiation doses to the bone marrow at rates in excess of 30–50 rem (0.3–0.5 Sv) per year. These data are omitted from Table 3-3 because exposures were to multiple sources of radiation.

Among Rhesus monkeys given 1,000 µCi (37 MBq) of ⁹⁰Sr over 10 days, the one with the highest dose on a kg body weight basis (28 µCi/kg/day; 1.0 MBq/kg/day) died from pancytopenia within 4 months of treatment (Casarett et al. 1962). Among young (30 days old) Long-Evans rats that were given >300 µCi ⁹⁰Sr/kg/day (11 MBq/kg/day) in drinking water for 10 days (total 460 µCi; 17 MBq), the bone marrow was extremely hypoplastic. Hypoplastic effects were slight among adult males given doses of 64 or 135 µCi/kg/day or adult females given 92 or 194 µCi/kg/day (total 330 or 650 µCi; total 12.2 or 24.1 MBq; Casarett et al. 1962). Skeletal radiation doses were about 15 times higher in the younger rats. In another acute study, six young female dairy cattle (three sets of twins, ages 398 and 479 days and weighing 145–349 kg at the start of treatment) were given 44 µCi ⁹⁰Sr/kg/day (1.63 MBq/kg/day) for 5 days (Cragle et al. 1969). All six heifers exhibited decreases in leukocyte and platelet counts by the first month. In surviving animals, the counts plateaued at about 60% of the normal value. In four animals, the youngest (398 days old) and lightest (145–212 kg) at the time of dosing, leukocyte and platelet counts dropped severely after 80 days, shortly before the onset of the terminal stages of radiation sickness.

In an intermediate-duration study in young Long-Evans rats, moderate hypoplasia of the bone marrow occurred among males (87 days old) given 74 µCi/kg/day and females given 104 µCi/kg/day (2.7 and 3.8 MBq/kg/day, respectively) of ⁹⁰Sr in drinking water for 30 days (total 790 µCi; 29.2 MBq) (Casarett et al. 1962). Hypoplasia of the bone marrow leading to anemia and thrombocytopenia developed in Dutch rabbits that were fed approximately 6 µCi ⁹⁰Sr/kg/day (218 kBq/kg/day) in pellets for 31–280 days (Downie et al. 1959).

Chronic-duration studies in several species reported suppression of hematopoiesis. In albino rats fed ≥0.5 µCi ⁹⁰Sr/kg/day (18.5 kBq/kg/day) for their post-weaning lifetime, hematopoiesis was significantly depressed (Zapol’skaya et al. 1974). Lymphocytes were the first cells affected, then neutrophils, thrombocytes, and after 1 year, erythrocytes. Morphological abnormalities included binucleation. At 0.5 µCi ⁹⁰Sr/kg/day (18.5 kBq/kg/day), leukocyte numbers remained 20% depressed by the end of the second year. The authors calculated that the minimal dose to induce leukopenia was 150–200 rad. The reduction in leucocytes plateaued at about 30–35% for absorbed doses between 400 and 2,000 rad. Hematological effects were reported in a chronic-duration beagle study, in which animals were exposed to 0.002–1.2 µCi/kg/day (0.074–44.4 kBq/kg/day) of ⁹⁰Sr in utero from gestational day 21, throughout lactation, and from weaning on day 42 to day 540 (Dungworth et al. 1969). Six years after exposure began, the following effects were observed at doses of 0.44 or 1.2 µCi/kg/day (14.8 or 44.4 kBq/kg/day): abnormal erythrocyte morphology (primarily poikilocytosis, anisocytosis, and hypochromasia, with some instances of macrocytosis), dose-related, radiation-induced leukopenia, an abnormal number of immature granulocytes, one case of unusual giant neutophils, a reduction in the number of platelets, anemia, and splenomegaly. Similarly, female Pitman-Moore miniature swine exposed to 3,100 µCi ⁹⁰Sr/day (114.7 MBq/day) as strontium chloride died within 3–4 months from destruction of hematopoietic tissue in bone marrow, which resulted in anemia, leukopenia, thrombocytopenia, and terminal hemorrhagic syndrome (Clarke et al. 1972). In addition, two animals in this group developed myeloid metaplasia.

Musculoskeletal Effects. Skeletal effects following oral exposure to radioactive strontium have been reported in humans and animals. Dystrophic lesions of the skeleton, primarily affecting articular and periarticular tissues, were observed in the Techa River populations that were chronically exposed to radiostrontium and other radionuclides in contaminated food and water (Akleyev et al. 1995). The incidence of skeletal lesions was significantly higher for mean radiation doses to the surface of bone in excess of 200 rem (2 Sv).

In an acute uptake, chronic radiation study, male and female 30-day-old Long-Evans rats that were given 300 or 390 µCi ⁹⁰Sr/kg/day, respectively (11 or 14.4 MBq/kg/day) in drinking water for 5–10 days (total 460 µCi; 17 MBq) exhibited signs of abnormal osteogenesis more than 10 months after administration (Casarett et al. 1962). As marrow failed to invade into metaphyseal cartilage, the cartilage resumed active proliferation. Resorption failed to occur in metaphyseal cartilage and metaphyseal spongiosa failed to transform to lamellar bone. Often, cartilage and fibrous marrow were incorporated into cortical bone, sometimes causing fracture and deformation.

In an intermediate uptake, chronic radiation study on young (87 days old) Long-Evans rats, ingestion of 74 (males) or 104 (females) µCi ⁹⁰Sr /kg/day (2.7 or 3.8 MBq/kg/day) in drinking water for 30 days (total 790 µCi; 28.9 MBq) adversely affected the vasculature of the bone, which interfered with the normal transformation of cartilage into bone (Casarett et al. 1962). At the end of the long bones, the cartilage discs were damaged, with detachment of primary spongiosa and failure of resorption. In another intermediate-duration study, numbers of osteocytes (bone cells surrounded by a mineralized matrix and connected by a mesh-work of processes) were reduced in Dutch rabbits that ingested approximately 6 µCi ⁹⁰Sr/kg/day (218 kBq/kg/day) in pellets for 48 days (Downie et al. 1959).

Bone damage was a notable effect of chronic-duration oral exposure to radioactive strontium in dogs (Momeni et al. 1976). Groups of pregnant beagles were fed 0.002–3.6 µCi ⁹⁰Sr/kg/day (0.074–133.2 kBq/kg/day) from gestational day 21 through lactation to PND 44, and the pups were fed the same doses from weaning at day 42 through day 540 (Raabe et al. 1983; White et al. 1993). Ten years from the start of the study, dose-related skeletal effects included mild trabecular osteopenia, endosteal and periosteal cortical changes (sclerosis and thickening), and mottling or focal osteolytic lesions (Momeni et al. 1976). These occurred in all the dogs in the 3.6 µCi/kg/day group and also in the 1.2 and 0.4 µCi/kg/day groups (133.2, 44.4, and 14.8 kBq/kg/day, respectively). Radiation-induced osteodystrophy was noted in three out of four beagle dogs that received 1.2 µCi ⁹⁰Sr/kg/day (44.4 kBq/kg/day) for life beginning at midgestion (Book et al. 1982); the average dose rate (cumulative dose divided by lifespan) for these dogs was 4 rad/day (0.04 Gy/day). Radiation osteonecrosis was said to be a common finding among female Pitman-Moore miniature swine that died with hematopoietic disorders or bone marrow hypoplasia after ingesting ⁹⁰SrCl₂ at levels between 1 and 3,100 µCi/day (0.37–114.7 MBq/day) until death (Clarke et al. 1972). The incidence of osteonecrosis at each dose level was not reported. Bone cancers that were reported in these chronic studies are discussed below in Section 3.3.2.7.

Hepatic Effects. No studies were located regarding hepatic effects in humans after oral exposure to radioactive strontium isotopes. No studies were located regarding hepatic effects in animals after acute- or intermediate-duration oral exposure to radioactive strontium isotopes. In a chronic-duration beagle study, animals exposed to 0.4 or 1.2 µCi ⁹⁰Sr/kg/day (14.8 or 44.4 kBq/kg/day) in utero from gestational day 21, throughout lactation, and from weaning on day 42 to day 540 exhibited only secondary hepatic effects (Dungworth et al. 1969). Livers were sometimes enlarged from myeloid infiltration and periacinar lipidosis, sometimes with terminal necrosis, in dogs with severe anemia. Since the observed myeloid infilitration was a secondary effect resulting from irradiation of the bone marrow, it is not categorized under Systemic: Hepatic Effects in Table 3-3.

Renal Effects. No studies were located regarding renal effects in humans after oral exposure to radioactive strontium isotopes. Approximately 19% of adult Long-Evans rats ingesting 65 µCi ⁹⁰Sr/day (2.41 MBq/day; 135 or 194 µCi/kg/day, 5 or 7.2 MBq/kg/day for males and females, respectively) of in drinking water for 10 days developed chronic interstitial nephritis, a common disease in older rats, during their remaining lifespan (Casarett et al. 1962). It is very unlikely that the ingestion of radiostrontium was related to the occurrence of nephritis.

Ocular Effects. No studies were located regarding ocular effects in humans after oral exposure to radioactive strontium isotopes.

No studies were located regarding ocular effects in animals after acute- or intermediate-duration oral exposure to radioactive strontium isotopes. In one chronic-duration study, 2 out of 403 beagles that had been exposed to ⁹⁰Sr in utero from gestational day 21, during lactation, and from weaning on day 42 to day 540, developed a benign melanoma of the eye, but the dose-level was not reported (Raabe et al. 1994). Statistical analysis showed that these tumors (not found in controls, but also found in dogs irradiated through other exposure routes, or with other radionuclides) were significantly related to exposure to ionizing radiation. According to a 6-year report from the same chronic-duration beagle study, animals exposed to 0.4 or 1.2 µCi ⁹⁰Sr/kg/day (14.8 or 44.4 kBq/kg/day) in utero from gestational day 21, throughout lactation, and from weaning on day 42 to day 540 exhibited only indirect ocular effects (Dungworth et al. 1969). The eyes of dogs with a myeloproliferative disorder exhibited some slight degree of myeloid infiltration (see Section 3.3.2.7 Cancer). Since this was a secondary effect resulting from irradiation of bone marrow and not the direct response of the eye tissues to radiostrontium, it is not categorized under Ocular Effects in Table 3-3.

Body Weight Effects. No studies were located regarding body weight effects in humans after oral exposure to radioactive strontium isotopes. No studies were located regarding body weight effects in animals after acute- or intermediate oral exposure to radioactive strontium. No effect on body weight was observed among female CF-1 mice that had been exposed to ⁹⁰Sr in utero, during lactation, and up to day 414 at doses of up to 36 µCi of ⁹⁰Sr/kg/day (1.33 MBq/day) (Finkel et al. 1960). Progressive weight loss was observed among beagle dogs that developed anemia after having been exposed to 0.4–1.2 µCi of ⁹⁰Sr/kg/day (148–444 kBq/kg/day) from mid-gestation to age 1.5 years (Dungworth et al. 1969).

3.3.2.3. Immunological and Lymphoreticular Effects

Immunological changes were reported in the Techa River population that was exposed to chronic combined external gamma radiation and internal radiation from ⁹⁰Sr and ¹³⁷Cs between 1949 and 1956 (Akleyev et al. 1995). Immunological disorders persisted for 30 years and included decreased expression of antigens of differentiating T-lymphocytes, decreased T-lymphoblast transformation, and reduced counts of large granulocytic lymphocytes. Granulocytopenia developed in a portion of the exposed population that received radiation to the bone marrow at rates in excess of 30–50 rem (0.3–0.5 Sv) per year. Akleyev et al. (1995) suggested that radiation-induced immunodeficiency may have contributed to the higher incidence of leukemia in the exposed population (see Section 3.3.2.7 Cancer). Clinical manifestations of immune insufficiency in exposed cancer patients included 3-fold increases in the incidences of infectious diseases (chronic pneumonia, chronic bronchitis, pulmonary tuberculosis, and osteomyelitis) compared to a nontumor-bearing group. These data are omitted from Table 3-3 because of the mixed exposures.

No animal studies were located that described immunological effects following acute oral uptake of radiostrontium. Intermediate-to-chronic-duration exposures to radiostrontium resulted in impaired immune function in animals. In Pitman-Moore miniature pigs that were fed 625 µCi ⁹⁰Sr/day (23.13 MBq/day) as strontium chloride for 9 months, the antibody response to inoculated Brucella abortus (strain 19) antigen was determined by the plate agglutination test to be less than half that of controls (Howard 1970). In another test, peripheral leukocyte cultures were prepared from these same animals at monthly intervals, in medium containing phytohemagglutinin (PHA). In pigs that were fed 625 µCi ⁹⁰Sr/day (23.13 MBq/day) for 4–5 months, peripheral lymphocytes lost the ability to respond to PHA stimulation; this adverse effect was sustained for at least 6 months. The author attributed these immunological effects to exposure to ⁹⁰Sr. Myeloid metaplasia also afflicted female Pitman-Moore miniature swine that were fed 3,100 µCi ⁹⁰Sr/day (114.7 MBq/day) until the end of life at age 3–4 months (Howard and Clarke 1970). The cumulative doses at the time of death ranged from 40 to 10,000 rad (0.4–100 Gy).

In a 6-year status report of a chronic uptake study in which beagle dogs were exposed to ⁹⁰Sr from midgestion to age 1.5 years, 1.3% of dogs receiving 0.4 µCi ⁹⁰Sr/kg/day (14.8 kBq/kg/day) and 3.7% of dogs receiving 1.2 µCi ⁹⁰Sr/kg/day (44.4 kBq/kg/day) developed myeloid metaplasia of the spleen (Dungworth et al. 1969).

The highest reliable NOAEL values and all LOAEL values for immunological and lymphoreticular effects from oral exposure to radioactive strontium in each species and duration category are recorded in Table 3-3 and plotted in Figure 3-3.

3.3.2.4. Neurological Effects

Nervous system disorders (weakness, apathy, fatigue) were reported in the Techa River population that was chronically exposed to combined external gamma radiation and internal radiation from ⁹⁰Sr and ¹³⁷Cs (Akleyev et al. 1995). Neurological effects were observed at chronic dose rates in excess of 40–50 rad (0.4–0.5 Gy) per year and persisted for 14–20 years in the exposed population. However, it is not clear to what extent strontium-derived radiation contributed to neurological effects, compared to external gamma radiation. These data are omitted from Table 3-3 because of the mixed exposures.

No studies were located that reported neurological effects in animals following oral exposure to radioactive strontium isotopes.

3.3.2.5. Reproductive Effects

No significant reproductive effects were reported in the Techa River population that was exposed to combined external gamma radiation and internal radiation from ⁹⁰Sr and ¹³⁷Cs between 1949 and 1956 (Kossenko et al. 1994). Exposure had no effect on birth rate, fertility, or the incidence of spontaneous abortions in the study group that had received average doses to the gonads of up to 74 rem (0.74 Sv), primarily from external gamma radiation (Akleyev et al. 1995). An increase in the incidence of ectopic pregnancies was not dose-associated. These data are omitted from Table 3-3 because exposures were to multiple sources and it is probable that radiostrontium had a minor effect on the gonadal radiation dose.

In one acute study, female rats were given a single dose of 400 µCi ⁹⁰Sr/kg by gavage 1–10 days before impregnation (Moskalev et al. 1969). At the time of conception, the maternal skeletal dose was 800 rad (8 Gy) and soft tissue dose was 10 rad (0.1 Gy). Fetuses received skeletal doses of 20 rad (0.2 Gy). Under these conditions, 22% of fetuses died. In an intermediate-duration study, groups of 230–339 female CF-1 mice were fed ⁹⁰Sr in the diet at doses between 0.03 and 31 µCi/kg/day (1.11 and 1,147 kBq/day; Finkel et al. 1960). Dams and males bred while on the radiostrontium diet, and dams were maintained on diet throughout gestation and lactation. Radiostrontium feeding had no effect on fertility, the number of live offspring, or the number of female offspring surviving at PND 35.

In a multigenerational study, 9-month-old female Pitman-Moore miniature swine were fed a diet containing between 1 and 3,100 µCi ⁹⁰Sr/day (0.037 and 114.7 MBq/day) and then were bred with males that were only exposed to ⁹⁰Sr during the period of mating (Clarke et al. 1970, 1972; McClellan et al. 1963). Ingestion of radioactive strontium had no effect on fertility or fecundity. Pregnant sows receiving 3,100 µCi ⁹⁰Sr/day (114.7 MBq/day) did not survive to the end of the period of gestation because of bone marrow hypoplasia, but their fetuses were apparently normal (McClellan et al. 1963). For doses between 1 and 625 µCi ⁹⁰Sr/day (0.037 and 23.13 MBq/day), there was no significant effect on litter size, percentage of stillborn, or birth weight. Exposure had no effect on frequency and duration of the estrus cycle or in the number of repeat breedings. However, the F1 offspring of the sows ingesting 625 µCi ⁹⁰Sr/day (23.13 MBq/day) did not survive to adulthood. Survival of the F2 offspring was apparently similar to the F1 generation, but their reproductive capacity was not reported, since later studies focused on cancer effects.

The highest reliable NOAEL values and all LOAEL values for reproductive effects from oral exposure to radioactive strontium in each species and duration category are recorded in Table 3-3 and plotted in Figure 3-3.

3.3.2.6. Developmental Effects

Few developmental effects were reported in the progeny of the Techa River population that was exposed to combined external gamma radiation and internal radiation from ⁹⁰Sr and ¹³⁷Cs between 1949 and 1956 (Kossenko et al. 1994). The cohort of women in the study received radiation doses to the gonads of up to 74 rem (0.74 Sv), primarily from external gamma radiation (Akleyev et al. 1995); the proportion of the dose attributable to radiostrontium was not specified, but is likely to have been relatively small. No increase in the incidences of spontaneous abortion, miscarriages, or stillbirths was observed. However, there were slight increases in child mortality from chromosomal defects and from congenital anomalies of the nervous system, circulatory system, and other unspecified anomalies in the progeny of the exposed group compared to controls. Considering deaths from these anomalies, from labor complications, or from unspecified perinatal causes, the mortality coefficient of the offspring of parents with gonadal doses of 11 rem (0.11 Sv) was double that of the unexposed control group. Kossenko et al. (1994) calculated that the gonadal doses required to double the incidences of stillbirths, miscarriages, early neonatal mortality, or lethal developmental effects were rather high, ranging from 20 to 480 rem (0.2–4.8 Sv) for the different end points. These data are omitted from Table 3-3 because of the combined internal and external radiation exposures.

In one animal study, CF-1 mice were exposed to ⁹⁰Sr from the time of conception; breeding adults were fed a diet containing 0.03–31 µCi ⁹⁰Sr/kg/day (1.11–1,147 kBq/kg/day), and the dams were fed the same diet throughout gestation and lactation (Finkel et al. 1960). The offspring were fed the same diet throughout their lifetimes. Gestational exposure to radiostrontium did not affect litter size or early survival of offspring, and no teratogenic effects were noted. However, survival of the offspring was shortened at doses of 3 µCi ⁹⁰Sr/kg/day (111 kBq/kg/day) or higher, which was related to the higher incidence of bone-related cancer (see Section 3.3.2.7 Cancer). Autoradiographs demonstrated the uniform distribution of ⁹⁰Sr in the skeleton, which probably contributed to these effects.

In a large multigenerational study, 9-month-old female Pitman-Moore miniature swine were fed a diet containing between 1 and 3,100 µCi ⁹⁰Sr/day (0.037 and 114.7 MBq/day) and then were bred with males that were only exposed to ⁹⁰Sr during the period of mating (Clarke et al. 1970, 1972; McClellan et al. 1963). Ingestion of radioactive strontium had no effect on fertility or fecundity. Fetuses were apparently unaffected, even those of sows that died during pregnancy from bone marrow hypoplasia after ingesting 3,100 µCi ⁹⁰Sr/day (114.7 MBq/day; McClellan et al. 1963). For doses between 1 and 625 µCi ⁹⁰Sr/day (0.037 and 23.13 MBq/day), there was no significant effect on litter size, percentage of stillborn, or birth weight. In offspring of sows ingesting 625 µCi ⁹⁰Sr/day (23.13 MBq/day), the weaning weight was reduced because radiation-induced hematopoietic effects reduced the output of milk (Clarke et al. 1970). After weaning, the F1 offspring were fed ⁹⁰Sr in the diet at graded levels that, by 6 months, equaled the maternal level, 1–625 µCi ⁹⁰Sr/day (0.037–23.13 MBq/day). The 625 µCi ⁹⁰Sr/day (23.13 MBq/day) F1 females did not survive to be bred at 9 months. These results indicate an age-related vulnerability to ⁹⁰Sr, since the 625 µCi ⁹⁰Sr/day (23.13 MBq/day) dosage was not lethal to the parental generation (pigs exposed from age 9 months).

The highest reliable NOAEL values and all LOAEL values for developmental effects from oral exposure to radioactive strontium in each species and duration category are recorded in Table 3-3 and plotted in Figure 3-3.

3.3.2.7. Cancer

Epidemiological studies have found little or no association between oral exposure to radioactive strontium from fallout and cancer effects in humans. In an epidemiological study using the Danish cancer registry, no association was found between the incidence of thyroid cancer in Denmark between 1943 and 1988 and the levels of skeletal incorporation of ⁹⁰Sr from fallout (Sala and Olsen 1993). In another epidemiological study, data collected between 1959 and 1970 in a ⁹⁰Sr monitoring program in Glasgow, Scotland, were used to identify three cohorts with respect to the hypothetical risk for leukemia and non-Hodgkin’s lymphoma, acute myeloid leukemia, all childhood cancers combined, and bone tumors (Hole et al. 1993). The three cohorts were a high risk group born in 1963–1966 (exposed to high levels of fallout, i.e., ⁹⁰Sr, at a young age), a medium risk group born in 1959–1962 (exposed to high levels at an older age), and a low risk group born after 1966. Cumulative incidences for all cancers, leukemia and non-Hodgkin’s lymphoma, and acute myeloid leukemia all showed a secular (progressive, noncyclical) increasing trend for children born before 1982. However, the study found no evidence for increased risks of total cancers, leukemia and Non-Hodgkin’s lymphoma, or acute myeloid leukemia for cohorts born during the period of highest fallout (radiostrontium) exposure. The few cases of bone tumors showed a statistically nonsignificant increase for children born during the ‘high risk’ period.

In contrast, the Techa River population that was exposed to contaminated water and food as a result of releases from a nuclear weapons facility exhibited a significant increase in the incidence of leukemia (Kossenko 1996; Kossenko et al. 1997, 2000, 2002). An excess of leukemia cases (0.85 excess cases per 10,000 person-year Gy (95% CI: 0.2; 1.5) was observed in groups of individuals with estimated bone marrow doses in excess of 10 rem (0.1 Sv), and the risk of mortality from leukemia increased with increasing dose (Kossenko, 1997, 2002). This finding can be related to the body burdens of ⁹⁰Sr, which in the Techa River cohort, have been >100 times higher than fallout-related exposures during the same period (Shagina et al. 2000). No increase in cancer rates has been observed in the progeny of the Techa River cohort (Kossenko 1996).

As shown in numerous animal studies, oral exposure to radioactive strontium may increase the incidence of cancers of bone and bone marrow. In a small study in which young monkeys were given ⁹⁰Sr by gavage, one given 11.2 µCi ⁹⁰Sr/kg/day (0.42 MBq/kg/day) for 5 days died of leukemia, with a final skeletal dose of 4,300 rad (43 Gy) 4 years after treatment (Casarett et al. 1962). Two others exposed to an average of 18 µCi ⁹⁰Sr/kg/day (0.67 MBq/kg/day) for 10 days died from bone-associated cancers (chondrosarcoma, osteosarcoma) within 36 months of treatment, with estimated skeletal doses of 4,700–9,500 rad (47–95 Gy).

Acute-duration experiments using Long-Evans rats demonstrated that weanlings, with their relatively higher rate of incorporation of strontium into the skeleton, were more vulnerable than adults to the carcinogenetic effects of ⁹⁰Sr (Casarett et al. 1962). Weanlings (30 days old) were given 46 µCi ⁹⁰Sr/day (1.7 MBq/day) and adults were given 33 or 65 µCi ⁹⁰Sr/day (1.2 or 2.4 MBq/day) in drinking water for 10 days; on a body weight basis, the amounts given were >300 µCi/kg/day (11 MBq/kg/day) for weanlings, 64 or 135 µCi/kg/day for adult males, or 92 or 194 µCi/kg/day for adult females. After 5 months, 33 µCi (1.2 MBq) of radioisotope were detected in the skeletons of weanlings that received 460 µCi (17 MBq), but only 1 or 2 µCi (37 or 74 kBq) were detected in the skeletons of adults that received 330 or 650 µCi (12.2 or 24.1 MBq), respectively. The differences in incorporation of ⁹⁰Sr probably accounted for the age-related differences in the incidence of osteosarcoma; 17.5% of weanlings developed osteosarcoma compared to none of the adults. However, in the high dose adults, the overall incidence of malignancy (leukemia, squamous cell carcinoma of the skin, various other carcinomas) was more than doubled, compared to controls. At the lower dose, the overall rate of malignancies in adults was lower than in controls (6.25% compared to 16.2%). In an intermediate-duration experiment, in which male 87-day-old Long-Evans rats were given 74 µCi ⁹⁰Sr/kg/day (2.7 MBq/kg/day) and females were given 104 µCi ⁹⁰Sr/kg/day (3.8 MBq/kg/day) in drinking water for 30 days (total 790 µCi; 29.2 MBq), the incidence of osteosarcomas was 27.5% compared to none in the controls. Overall, the incidence of malignancy in the treated group was more than double that of controls; other neoplasms included 11.25% skin carcinoma (facial) and 6.25% leukemia. The 87-day-old rats treated for 30 days had a 5-month skeletal burden of about 11µCi (407 kBq), which, on a kg body weight basis, was less than one quarter that of weanlings treated for 10 days. This discrepancy reflects differences in rates of absorption and osteogenesis, which are higher in the younger rats. The older rats had a higher incidence of osteosarcoma than the weanlings because they survived beyond the latency period for the cancer. In another intermediate-duration rat study, oral exposure to ⁹⁰Sr for 37 days (total dose of 790 µCi; 29.2 MBq) increased the incidence of osteolysis and osteogenic sarcoma by 21% (Hopkins et al. 1966). The radiation dose to the skeleton after 150 days was 4,000 rad (40 Gy). Young rabbits (~52 days old) that were fed an average of 6 µCi ⁹⁰Sr/kg/day (218 kBq/kg/day) ⁹⁰Sr in pellets for 224–280 days developed multiple osteogenic sarcomas in the skull and at the rapidly growing ends of the long bones within 6–8 months (Downie et al. 1959).

Relatively large studies in rats, mice, dogs, and pigs demonstrated increased tumor induction following chronic ingestion of ⁹⁰Sr. In the rat study, albino rats were fed between 0.05 and 2 µCi ⁹⁰Sr/kg/day for their post-weaning lifetime, resulting in exposures between 0.01 and 0.4 µCi/day (Zapol’skaya et al. 1974). In rats consuming 2 µCi ⁹⁰Sr/kg/day, the number of rats with malignant tumors was 18.7%, compared to 1.3% for controls. At 0.5 ⁹⁰Sr/kg/day, the tumor incidence was 3–6 times lower (not specified numerically), but the outcome at 0.05 ⁹⁰Sr/kg/day was not reported. The most common malignancies were lymphosarcoma (8%), osteosarcoma (6.7%), and “leukosis” (4%). The latency periods were 300–540 days for lymphosarcomas and 450–660 days for “leukosis” and osteosarcoma. The cumulative absorbed doses averaged 1,350 rad (13.5 Gy) just before the onset of lymphosarcoma, 2,200 rad (22 Gy) just before the onset of ‘leukosis’, and 2,400 rad (24 Gy) just before the onset of osteosarcoma.

In the mouse study, mice were exposed either as adults (beginning at age 110–250 days) or from conception to 0.05–36 µCi ⁹⁰Sr/kg/day (Finkel et al. 1960). There was a higher incidence of reticular tumors in blood-forming tissues, but no evidence of osteogenic sarcoma in all adult exposed groups. Possibly because of the experimental design-groups were not exposed simultaneously and were subjected to environmental differences-tumor incidence in adults did not show a clear dose-response. However, the tumor incidence was significantly elevated in mice exposed to ⁹⁰Sr from conception. The highest dose level resulted in the early appearance of reticular tumors, especially lymphomas; 24% of mice at this level died with reticular-tissue tumors by 525 days, compared to 6% in controls. Other tumors unique to the high-dose level included six osteogenic sarcomas, four osteolytic tumors, and two epidermoid carcinomas of the oral cavity. Radiography demonstrated that radioactive strontium was ubiquitously distributed throughout the skeleton of mice exposed from conception.

In the dog study, groups of pregnant beagles were fed between 0.002 and 3.6 µCi ⁹⁰Sr/kg/day (0.074 and 133.2 kBq/kg/day) from day 21 of gestation to postnatal day 42 (White et al. 1993). The pups were weaned and then fed a diet containing the same ⁹⁰Sr/calcium ratio as the dam until day 540. Bone sarcoma deaths occurred in dogs ingesting between 0.13 and 3.6 µCi ⁹⁰Sr/kg/day (4.8–133.2 kBq/kg/day) resulting in bone doses at death of 5,000–10,700 rad (50–107 Gy), but not at 0.002–0.043 µCi ⁹⁰Sr/kg/day (0.1–1.6 kBq/kg/day) with doses to death of 100–2,300 rad (1–23 Gy). The higher the amount of ⁹⁰Sr given, the earlier the age of onset of sarcomas and the more likely they were to be osteosarcomas. Of 66 sarcomas, 75% were osteosarcomas; other types were chondrosarcoma, hemangiosarcoma, fibrosarcoma, and undifferentiated sarcoma. Multiple tumors occurred only at the two highest doses. Other cancer deaths occurred at high doses: radiation-induced myeloid leukemia (43 deaths), oral or nasal carcinoma (29 deaths), and periodontal carcinoma (16 deaths). The leukemic animals (average age at death 1,156 days) were not at risk for osteosarcoma, which had an average age of onset of 2,864 days. The mean cumulative skeletal doses at the time of onset in the four highest exposure groups for dogs with tumors were between 3,100 and 11,600 rad (31–116 Gy). The authors indicated that of the exposures that did not give rise to tumors, the lowest exposure (8 mrad/day; 0.08 mGy/day) was 25 times higher than background and the highest (146 mrad/day; 1.46 mGy/day) was 500 times higher than background. Therefore, lifetime chronic exposure to low linear energy transfer (LET) beta particle radiation up to 500 times background showed no apparent carcinogenic potential in dogs.

Stage-specific differences in carcinogenetic effects were reported in a large multigenerational study of female Pitman-Moore miniature swine that were fed between 1 and 3,100 µCi ⁹⁰Sr/day (0.037–114.7 MBq/day) for life (Clarke et al. 1972; Howard 1970; Howard and Clarke 1970). In the parental generation, which was started on the regimen at age 9 months of age, myeloid metaplasia was observed at nearly all levels, and lymphoid or myeloid neoplasms were observed when between 1 and 125 µCi ⁹⁰Sr/day were ingested. The average doses to the skeleton for the parental females were between 40 and 10,000 rad. No bone cancer occurred in the parental generation, whereas osteosarcomas occurred in F1 or F2 offspring exposed from conception to 125 or 625 µCi/day with average skeletal doses higher than 9,000 rad (90 Gy). Osteosarcoma had a longer latency period and occurred at higher exposure levels. Myeloid metaplasia and myeloid and lymphoid neoplasms developed sooner and more frequently in the F1 and F2 generations than in the parental generation.

The cancer effect levels (CELs) resulting from oral exposure to radioactive strontium in each species and duration category are recorded in Table 3-3 and plotted in Figure 3-3.

3.3.3.1. Death

No studies were located regarding death in humans or animals after external exposure to radioactive strontium.

3.3.3.2. Systemic Effects

No studies were located regarding respiratory, gastrointestinal, hematological, musculoskeletal, hepatic, renal, or endocrine effects in humans or animals after external exposure to radioactive strontium isotopes.

Cardiovascular Effects. Exposure to excessive ionizing radiation is known to affect the integrity of the vasculature of the skin, increasing the permeability of the vasculature to plasma protein. A study by Song et al. (1968) examined the ability of several anti-inflammatory agents to suppress this radiation-induced increase in vascular permeability. Albino male guinea pigs were exposed to 3,000 rep (Roentgen equivalent, physical) (3,230 rad; 1 rep.0.93 rad) of particles (800 rad/min; 8.0 Gy/min) from a ⁹⁰Sr/⁹⁰Y source. Immediately after irradiation, ¹²⁵I-labeled guinea pig serum albumin was injected into the heart as a tracer. The peak increase in vascular permeability, as measured by the ratio of accumulation of labeled plasma protein in the nonirradiated control and beta-irradiated skin, was determined to occur at 18 hours. In the group receiving no anti-inflammatory drug, the irradiated epidermis and dermis exhibited approximately 3- and 1.6-fold increases in the peak accumulation of plasma protein, respectively.

The highest reliable NOAEL values and all LOAEL values for cardiovascular effects from external exposure to radioactive strontium in each species and duration category are recorded in Table 3-4.

Dermal Effects. Several studies in humans and animals have reported damage to the skin following external exposure to radioactive strontium. Beta radiation from ⁹⁰strontium has been used to treat hemangiomas in children and adults. One study described some delayed effects of this radiation treatment within patients in one medical practice in Belgrad, Yugoslavia (now Serbia; Bekerus 1970). The beta source was a 50 mCi ⁹⁰Sr plate with a diameter of 9.9 mm. Adults were treated with an initial dose of 1,600 rad (16 Gy) and subsequent doses of 1,080–1,600 rad (10.8–16 Gy) in succeeding months, not exceeding a total of 7,530 rad (75.3 Gy). Children were treated with an initial dose of 200–300 rad (2–3 Gy) and additional treatments over 6–16 months, for a total exposure of 2,420–6,130 rad (24.2–61.3 Gy) in some cases. Eight or 10 years after treatment, about a third of the patients developed delayed reactions to radiation: achromia, excess pigmentation, slight atrophy, and telangiectasis. The author did not specify the exposure levels that resulted in these effects.

Table 3-4

Levels of Significant Exposure to Strontium - Radiation Toxicity - External Radiation.

Acute dermal reactions to ⁹⁰Sr have been described for depilated skin in mice, guinea pigs, and pigs. In mice, skin exposed to a single 2,000–5,000 rad (20–50 Gy) dose of beta radiation from a ⁹⁰Sr-⁹⁰Y source sustained an acute reaction (Hoshino and Tanooka 1975; Randall and Coggle 1995). For example, all mice exposed once to 5,000 rad (50 Gy) from a 1 mm diameter source developed an acute skin reaction with the following characteristics (Randall and Coggle 1995). After an asymptomatic period of 3 or 4 days, the skin exhibited increasing erythema and pigmentation changes, leading to dry desquamation by day 10. Within a few days, exposed skin entered a period of moist desquamation, during which a serum scab was formed that was prevalent between days 15 and 25. Re-growth of the epithelium commenced at the edges of the irradiated field and from surviving hair follicles. By 1 month postirradiation, the epidermis was overtly normal, although histologically hyperplastic. Chronic fibrosis was a delayed skin reaction that was not apparent until 3–6 months postirradiation.

Dose-related effects were noted in guinea pig skin that was treated with a 25×25 mm square ⁹⁰Sr source (Etoh et al. 1977). At 1,000 rad, there was a transient 25% reduction in the number of basal epithelial cells by day 10, which approached normality by day 15. At 2,200 rad, the epithelial basal cell population dropped by about 60% at day 12, but was slightly above normal by day 20. At 3,000 and 5,000 rad, the basal epithelial cell population was reduced 75%, but hyperplasia was also detected at the margin of the field. Hyperplasia was maintained for the 50-day observation period following exposure to 2,200–5,000 rad. At 3,000 rad, erythema was noted by day 14, followed by dry desquamation and complete hair loss by day 21. A similar pattern, with ulceration at 1 month, was seen at 5,000 rad.

Within certain ranges, field-size effects for acute, localized external exposures to radioactive strontium have been demonstrated in mice and pigs. Hopewell et al. (1986) exposed young SAS/4 male mice to different levels of radiation from ⁹⁰Sr sources varying in diameter between 1 and 22.5 mm. The ED₅₀ values for moist desquamation were 2,200–2,750 rad (22–27.5 Gy) for the 22.5-mm source and 7,500–9,000 rad for the 5-mm source. Acute tissue breakdown was only achieved in mouse skin by very high doses (ED₅₀ ≥14,000 rad) when the smallest sources were employed (≤2 mm in diameter). In a parallel study in pigs, moist desquamation occurred at 2,250–7,500 rad (22.5–75 Gy) and acute tissue necrosis occurred at doses of ≥14,000 rad (140 Gy) (Hopewell et al. 1985, 1986). Peel et al. (1984) compared the effect on pigskin of acute exposure to ⁹⁰Sr sources with diameters between 1 and 40 mm. The effects of acute beta radiation included epithelial cell death within the first 16 weeks, and subsequently, dermal necrosis that was attributed to vascular damage. The rate of repair was dependent on the size of the exposed area, since repair was dependent upon the migration of healthy cells into the wound. Transient moist desquamation associated with bright red erythema was observed between 4 and 6 weeks. At ‘high’ doses, this intensified and the dermis became ulcerated, but healed with scarring. After doses ≥4,000 rad (22.5-mm source), 6,600 rad (11-mm source), or 12,500 rad (5-mm source), a dusky red or mauve erythema followed by dermal necrosis occurred between weeks 10 and 16. In pigs that were acutely exposed to the same range of ⁹⁰Sr sources at the age of 3 months, dose-dependent dermal atrophy was detected in the irradiated field 2 years later, reaching a maximal 55% reduction in dermal thickness for all doses above 4,500 rad (45 Gy; Hamlet et al. 1986). Dermal atrophy was produced by doses below the threshold required to induce moist desquamation. The threshold dose for moist desquamation following irradiation by the 22.5 mm source (2,250 rad) produced a 38% thinning of the dermis. Irradiation from the 1-mm source produced 30% dermal thinning at the threshold (7,250 rad). Irradiation from the 5-mm source (2,000 rad) reduced the thickness of the dermis by 35%. For the 11–22.5-mm sources, above doses that caused maximal thinning (in the range of 12,000–6,250 rad, respectively), the relative dermal thickness increased slightly, but remained 30–40% thinner than normal.

The highest reliable NOAEL values and all LOAEL values for dermal effects from external exposure to radioactive strontium in each species and duration category are recorded in Table 3-4.

Ocular Effects. Beta radiation has been employed medically to treat pterygium, an alteration in the conjunctival connective tissue that results in the penetration of the superficial corneal stroma by vascular connective tissue (Tong et al. 1969; Wesberry and Wesberry 1993). As an adjunct to surgical removal of the pterygium, a solid ⁹⁰Sr source is apposed to the site in order to reduce neovascularization. Several clinical studies reported complications resulting from this procedure. Serious effects (radiation cataracts, keratinization and telangiectasis of the conjunctiva) resulted from the high dose levels used when the technique was first employed using other beta-emitting radionuclides (Merriam 1955). Atrophy of the sclera occurred after a dose of 1,600 rad from ⁹⁰Sr. In a later study, 78 eyes in 62 patients were treated with 1,080 rad (10.8 Gy) of beta radiation from a ⁹⁰Sr source repeated at weekly intervals (total dose 3,200 rad; 32 Gy; Tong et al. 1969). Because pterygia recurred within 2–18 months, six patients were re-treated as before, two were given a single dose of 2,100 rad (21 Gy), and one of these two received a third dose of 2,100 rad (21 Gy). One eye, which had received treatments of 5,380 rad (53.8 Gy) each to two adjacent fields, developed keratitis of the cornea. Other complications noted were telangiectasis of the conjunctiva (27%), scarring of the conjunctiva (14%), and scarring of the cornea (3%); the authors did not specify the exposure levels at which these side effects occurred. A more recent study described results for 171 eyes that had been treated with single doses of 1,700–1,800 rad (17–18 Gy) (Wesberry and Wesberry 1993). During follow-up periods lasting between 1 and 19 years, the only complications noted were one case each of corneal scarring, iritis, conjunctivitis, mild irritation, and, in a diabetic patient, scleral thinning. A complication rate of 1.8% was reported for a study of 490 eyes (399 patients) that received doses between 31 and 42 Gy (3,100–4,200 rad) in four or five fractions over 29 days (Nishimura et al. 2000). Scleral thinning, not severe enough to require treatment, was reported for four eyes in three patients 0.5, 2, and 9 years after treatment. Infectious scleral ulcer occurred within weeks of treatment in one male. Ischemic necrosis of the sclera in one male and adhesion of the eyelid and eyeball in one female occurred several years after repeat treatments for recurring pterygia; adhesive scarring of the eyelid occurred in one female 7 years after treatment.

No studies were located regarding ocular effects in animals after external exposure to radioactive strontium isotopes.

The highest reliable NOAEL values and all LOAEL values for ocular effects in humans from external exposure to radioactive strontium in each duration category are recorded in Table 3-4.

No studies were located regarding the following effects in humans or animals after external exposure to radioactive strontium isotopes:

3.3.3.3. Immunological and Lymphoreticular Effects

3.3.3.4. Neurological Effects

3.3.3.5. Reproductive Effects

3.3.3.6. Developmental Effects

3.3.3.7. Cancer

Development of skin cancers in mice following localized exposure to beta radiation from a solid ⁹⁰Sr-⁹⁰Y source depended on the dose and on strain susceptibilities (Hoshino and Tanooka 1975). In experiments using a 40 mCi (1.48×10⁹ Bq) ⁹⁰Sr-⁹⁰Y source that delivered doses of 290 rad/min (2.9 Gy/min) to the skin, ICR mice exposed to a single localized dose of 2,700 rad (27 Gy) developed an acute skin reaction within the first month (see Section 3.3.3 Dermal Effects), but did not develop skin cancer during a 23-month observation period (Hoshino and Tanooka 1975). When the exposure was repeated 7 times for a total dose of 17,800 rad (178 Gy), one fibrosarcoma of the skin appeared after 10 months among five mice. Even extending the duration of the repeated 17,800 rad treatment for 43 weeks did not increase the incidence of malignant skin tumor; a single reticulocyte sarcoma developed in one out of five mice. Mice from a different strain, Japanese ddN, exposed to single doses of up to 17,400 rad (174 Gy) did not develop skin tumors during a 1-year observation period (Hoshino and Tanooka 1975). In the acute dermal toxicity experiments described above, Randall and Coggle (1995) selected the exposure level of 5,000 rad (50 Gy) for their mouse studies since it is known to be a critical dose for carcinogenetic effects in humans exposed to ionizing radiation.

Ootsuyama and Tanooka (1988, 1989) exposed the backs of female ICR mice to beta radiation from a 40,000 µCi (1,500 MBq) source of ⁹⁰Sr–⁹⁰Y, which delivered a surface dose rate of 228 rad/minute (2.28 Gy/minute) and a 20–80% lower dose rate to the top of the vertebrae. Mice were irradiated 3 times weekly at skin entrance doses per exposure of 135–1,180 rad (1.35–11.8 Gy), and irradiation was continued until a palpable tumor appeared (up to 86 weeks). Tumors arising included squamous cell carcinomas, basal cell carcinomas, fibrosarcomas, and osteosarcomas. No skin tumors arose in mice receiving 135 rad/day (1.35 Gy/day). The total number of irradiations (and total dose) needed to induce 50% incidence of skin tumors ranged from 252 sessions for a total of 37,800 rad (378 Gy) for the 150 rad/day level and 156 sessions for a total of 192,300 rad (1,923 Gy) for the 1,180 rad/day level. Osteosarcomas were induced at lower doses, most frequently with skin surface doses of 250–350 rad (2.5–3.5 Gy) per exposure. In time, 100% of mice developed tumors in groups receiving 250–1,180 rad per exposure. Ootsuyama and Tanooka (1988) suggested that the 135 rad/day dose might represent a threshold dose, since no tumors formed. However, in their experimental design, they arbitrarily terminated exposures at this dose level on day 300, which conceivably could be shorter than the latency period for tumor development at that dose.

The CELs resulting from external exposure to radioactive strontium in each species and duration category are recorded in Table 3-4.

3.5.1.1. Inhalation Exposure

Evidence for absorption of inhaled strontium in humans is provided by several cases of accidental exposure of workers to airborne radiostrontium (Navarro and López 1998; Petkau and Pleskach 1972; Rundo and Williams 1961). Although these cases do not provide a complete quantitative description of the absorption of inhaled strontium in humans, they demonstrate clearly that inhaled aerosols of strontium compounds (e.g., SrCl₂, SrTiO₃) can be absorbed, as indicated by the detection of radiostrontium in urine and feces.

In one case, a worker accidentally inspired an unknown quantity of ⁹⁰SrCl₂ (physical form unknown) and over the subsequent 800 days, ⁹⁰Sr was excreted in the urine with half-times of 3.3 (52%), 17 (7%), and 347 days (18%) (Petkau and Pleskach 1972). The urinary:fecal excretion ratio was 3:1. In a second case, a worker was exposed to ⁹⁰SrCO₃ (physical form unknown) with deposition within the nasal tract as well as the hands, face, and hair. The actual inhaled dose could not be determined; however, based on the excretion kinetics of ⁹⁰Sr over the subsequent 300 days, the reconstructed internal dose was estimated to have been approximately 300–400 nCi (11.1–14.8 kBq) (Rundo and Williams 1961). Excretion in urine occurred with half-times of 2.2 (>90%), 15, and 175 days, and the urinary:fecal excretion ratio over the first 24 days was 0.71. In a third case, two workers accidentally inhaled ⁹⁰SrTiO₃ (physical form unknown), and ⁹⁰Sr was detected in urine over a period of 225 days (Navarro and López 1998).

Studies conducted in animals have shown that the rate of absorption depends on the chemical form of the inhaled strontium aerosol. Compounds of greater solubility are, in general, more rapidly cleared from the lung. For example, strontium is rapidly cleared from the lung after inhalation of SrCl₂. In dogs that received a 2–22-minute nose-only exposure to an aerosol of ⁸⁵SrCl₂ (activity median aerodynamic diameter [AMAD] 1.4–2.7 µm, geometric standard deviation [GSD] 2.0), <1% of the initial lung burden remained in the lung 12 hours after the exposure; 37% of the body burden was distributed to the skeleton within 12 hours after the exposure, and 84% was in the skeleton 4 days after the exposure (Fission Product Inhalation Project 1967a). In contrast to the relatively rapid absorption of inhaled SrCl₂, after exposures to strontium in particles of fused clay, absorption is much slower. In dogs that received a noseonly exposure to ⁹⁰Sr in fused montmorillonite clay particles (AMAD 2.2 µm, GSD 1.7), the average half-time of elimination of strontium from the lung was 490 days (Snipes et al. 1974a, 1974b). Thus, strontium compounds of lower solubility are more slowly absorbed from the lung. Support for this also comes from studies in which the rates of absorption of various compounds of strontium were compared in rats. Rats were exposed to aerosols of ⁸⁵Sr carbonate, phosphate, fluoride, oxide, or titanate (particle sizes and doses not specified) (Willard and Snyder 1966). Greater than 99% of the initial lung burden of ⁸⁵Sr was cleared from the lung 5 days after inhalation of the carbonate, phosphate, fluoride, or oxide, whereas 60% of the ⁸⁵Sr remained in the lung after inhalation of the more insoluble strontium titanate.

In rats exposed to airborne fly ash (sieved to have a particle diameter of distribution of 90% less than 20 µm) for 6 hours, strontium was eliminated from the lung with a half-time of 23 days (observations were made for 30 days) (Srivastava et al. 1984b). One day after the exposure, the tissue:plasma strontium concentration ratios were 0.3–0.5 in the liver, kidney, small intestine, and heart. The report of this study does not indicate whether whole-body or nose-only exposures were utilized in the study; therefore, it is not possible to know for certain how much of the absorption may have resulted from ingestion of fly ash deposited on the animals. Furthermore, given the relatively large particle size of the fly ash, it is likely that deposition in the respiratory tract was largely in the tracheobronchial and nasopharyngeal region, from which the strontium may have been cleared mechanically to the esophagus and swallowed. Nevertheless, studies in which ⁸⁹Sr-enriched fly ash was instilled into the trachea of rats indicate that strontium in this form was partly absorbed and appeared in plasma and other tissues within days of the exposure (Srivastava et al. 1984a).

Although intratracheal instillation does not precisely replicate inhalation exposure, these studies provide additional evidence that strontium compounds of greater solubility are absorbed more rapidly from the lung. Strontium was cleared relatively rapidly from the lungs of rats that received an intratracheal dose of SrCl₂ (half-times <1 day) and was eliminated from the body in the urine (4–6% of the initial body burden) and in the feces (10–18%) (Naményi et al. 1986). By contrast, in rats that received an intratracheal dose of 360–760 µg Sr as SrTiO₃, strontium was eliminated from the lung with half-times of 0.4 days (85%) and 130 days (15%); the long retention phase reflects the slow absorption of the insoluble SrTiO₃ deposited in the lung, whereas the rapid phase reflects the mechanical clearance from the tracheobronchial region (Anderson et al. 1999b).

Strontium has been shown to be absorbed from the nasopharyngeal region of the respiratory tract. In hamsters administered ⁸⁵SrCl₂ (in saline solution) directly into the nasal tract, 67% of the ⁸⁵Sr was absorbed in 4 hours and 63% was estimated to have been absorbed directly from the nasopharynx region of the respiratory tract (Cuddihy and Ozog 1973).

3.5.1.2. Oral Exposure

The fractional absorption of ingested strontium has been estimated in healthy human subjects or hospital patients who received an oral dose of strontium chloride (SrCl₂) or ingested strontium in the diet (Table 3-7). Absorption was quantified in these studies from measurements of plasma strontium concentration-time profiles for ingested and intravenously injected strontium (bioavailability), or from measurements of the difference between the amount ingested and excreted in feces (balance). Collectively, the results of these studies indicate that approximately 20% (range, 11–28%) of ingested strontium is absorbed from the gastrointestinal tract. Balance measurements can be expected to yield underestimates of absorption as a result of excretion of absorbed strontium in the feces (see Section 3.5.4); nevertheless, the two methods have yielded similar estimates of absorption.

Vezzoli et al. (1998) compared the area under the plasma strontium concentration-time curves in adult males and females and found no significant difference (males, 10.6±0.6 mmol/L-minute; females, 9.3±0.6 mmol/L-minute). The subjects included groups of healthy age-matched men and women (15 males, 12 females) and groups of normocalcuric patients (29 males, 18 females) who had calcium-oxalate urinary tract stones. Although the fraction absorbed could not be estimated in this study because the area under the curve for an intravenous dose was not measured, the results suggest that there were no substantive differences in absorption between males and females. This conclusion may not be valid for physiologic states in which there is an increased demand for calcium such as pregnancy and lactation. Calcium absorption is higher in these states, and studies in animals suggest that strontium absorption may also be higher (Kostial et al. 1969b). In general, strontium absorption appears to be a good indicator of calcium absorption in adult humans as both elements appear to share common mechanisms of absorption (Bianchi et al. 1999; Blumsohn et al. 1994; Milsom et al. 1987; Reid et al. 1986; Sips et al. 1994) (see Section 3.6.1).

Studies conducted in infants and children indicate that approximately 15–30% of dietary strontium is absorbed, similar to estimates in adults (Alexander et al. 1974; Harrison et al. 1965; Kahn et al. 1969a; Sutton et al. 1971a). Although age-related changes in strontium absorption cannot be discerned from the studies in humans, age-related changes in absorption of strontium have been observed in rats, suggesting the possibility of increased absorption of strontium during the neonatal period in humans. Adult male rats that received a single oral dose of 1.4 mg Sr as SrCl₂ absorbed 19% (±5 standard deviation [SD]) of the dose (Sips et al. 1997); this value is similar to that reported for humans (Sips et al. 1995, 1996).

Table 3-7

Summary of Estimates of Absorption of Ingested Strontium in Humans.

However, when absorption was estimated at various ages, absorption was found to decrease from 85% of the dose at 15 days of age to 8% of the dose at ages older than 89 days (Forbes and Reina 1972). The differences between the adult estimates in these two studies may reflect the different methodologies; in the Sips et al. (1997) study, absorption was estimated from the area under the plasma strontium concentration-time curve for orally and intravenously administered strontium, whereas in the Forbes and Reina (1972) study, the absorption estimate was based on the measurements of 8-hour body burdens of strontium minus strontium in the gastrointestinal tract.

The fractional absorption of strontium appears to increase in rats during lactation. Rats that received a tracer dose of ⁸⁵Sr as SrCl₂ in drinking water between 14 and 16 days after the start of lactation absorbed twice as much strontium as control rats that were not lactating and received the same oral dose of strontium; 11% of the dose was absorbed in lactating rats compared to 5% in controls (Kostial et al. 1969b). Absorption was estimated in this study as the fraction of the dose in the skeleton, urine, and pups 3 days after the start of exposure.

The exact site of absorption of strontium in the gastrointestinal tract is not known; however, studies in hamsters suggest the possibility of absorption in both the stomach and small intestine. In hamsters that received a gavage tracer dose of ⁸⁵SrCl₂, 37% was absorbed, whereas 20% was absorbed when the dose was administered to hamsters that had their pyloric sphincter ligated (Cuddihy and Ozog 1973). Studies in preparations of in vitro and in situ isolated intestine of the rat provide direct evidence for strontium absorption in the small intestine (see Section 3.6.1).

3.5.1.3. Dermal Exposure

There is little evidence for systemic toxicity following dermal exposure to strontium compounds, which would suggest that they are not readily absorbed across the skin of humans. Ilyin et al. (1975) estimated absorption rates for solutions of strontium chloride across intact or abraded skin of human subjects. Three groups of three male volunteers received topical applications of ⁸⁵Sr as strontium chloride in aqueous solution (pH 7.0) without a carrier. In the first group, intact forearm skin (average area 8 cm²) was exposed for 6 hours. In the second and third groups, the skin of the forearm was abraded with a metal grater just before the solution was applied; exposures were 6.1 cm² for 30 minutes and 6.9 cm² for 6 hours, respectively. For comparison, a fourth group received an intravenous injection of ⁸⁵SrCl₂. After exposure and decontamination of the skin, radioactivity measurements were taken over 40 days of the ⁸⁵Sr present in the whole body, the patella, the right unexposed forearm, and, during the first 20 days, in daily urine samples. Absorption of strontium was estimated from whole body or partial body ⁸⁵Sr burdens, or urinary excretion of ⁸⁵Sr in comparison to the same end points after an intravenous dose of ⁸⁵SrCl₂. The absorption of radiostrontium through intact skin over 6 hours was estimated to be 0.26% (range, 0.14–0.37%) of the applied dose, indicating that undamaged skin is a relatively effective barrier to penetration by strontium. Strontium absorption was greater through scratched and abraded skin. An average of 38% (range, 25.5–45.8%) of the applied dose was absorbed after 30 minutes and an average of 57.4% (range of coefficients, 55.7–65.3%) was absorbed after 6 hours. No other studies were located regarding dermal absorption of strontium compounds in humans.

An in vitro study evaluated penetration of ⁹⁰Sr through abdominal skin removed from 5- or 9-day-old Wistar rats and arranged in vertical penetration cells (Bauerová et al. 2001). The radionuclide in a chloride carrier solution (0.01–1.0% strontium chloride w/v) was applied to the epidermal surface; radioactivity of the permeated ⁹⁰Sr in the receptor chamber solution was measured by liquid scintillation spectrometry. Penetration was inversely related to concentration of the carrier solution. Penetration of the radiostrontium through the hairless skin of 5-day-old rats over 24 hours was 4 times lower than through the hairy skin of 9-day-old rats: at a carrier concentration of 0.1%, penetration was 0.5% for hairless skin of 5-day old rats compared to 2% for 9-day old rats. The authors attributed this difference to the barrier provided by the intact stratum corneum in 5-day skin, indicating that hair follicles in skin of 9-day-old rats increase the permeability of skin to strontium. In experiments in which epidermal layers were stripped (by the 20× repeated application of adhesive tape) or entirely removed from skin of 5-day-old rats, penetration was approximately 25% over 24 hours.

3.5.2.1. Inhalation Exposure

Information on the distribution of inhaled strontium in humans is not available; however, it is reasonable to assume that the distribution of strontium absorbed into the systemic circulation after deposition in the respiratory tract would be similar to that absorbed after ingestion (see Section 3.5.2.2).

Studies in animals have shown that strontium that is absorbed after an initial deposition in the respiratory tract ultimately distributes primarily to the skeleton. In dogs that received a 2–22-minute nose-only exposure to aerosols of ⁸⁵SrCl₂ (AMAD 1.4–2.7 µm, GSD 2.0), 37% of the body burden was distributed to the skeleton within 12 hours after the exposure and 84% was in the skeleton 4 days after the exposure (Fission Product Inhalation Project 1967a). Four to 6 days after a 30-minute inhalation exposure of rats to aerosols of ⁸⁵Sr carbonate, phosphate, fluoride, or oxide (particle sizes and doses not specified), >99% of the body burden of ⁸⁵Sr was in the skeleton (Willard and Snyder 1966). Two days after rats received a 10-minute head-only exposure to tracer levels of ⁸⁵Sr or a mixture of ⁸⁵Sr and ⁹⁰Sr aerosols (AMAD 1.8–2.8), at which time radioactive strontium could no longer be detected in the lung, the concentration in bone was 100–2,000 times that in soft tissues (Fission Product Inhalation Project 1967b). The rank order of soft tissue concentrations (highest to lowest) was muscle > skin > liver > kidney. In rats exposed to airborne fly ash (sieved to have a particle diameter of distribution of 90% less than 20 µm) for 6 hours, strontium was detected in various tissues; 1 day after the exposure, the tissue:plasma strontium concentration ratios were 0.3–0.5 in the liver, kidney, small intestine, and heart (Srivastava et al. 1984b).

Information on the distribution of strontium absorbed after deposition in the respiratory tract can be derived from studies in which strontium compounds were instilled directly into the trachea. Although intratracheal instillation does not precisely replicate inhalation exposure, the distribution of the absorbed strontium is likely to be similar to that which would be absorbed after inhalation. In rats that received an intratracheal dose of ⁸⁹Sr-enriched fly ash (sieved to have a particle diameter of distribution of 90% less than 20 µm), radioactivity was eliminated from the lung and appeared in plasma and other tissues within days of the exposure; tissue:plasma concentration ratios were >1 (1.5–2) in the liver, kidney, stomach, and small intestine, and <1 (0.7–0.9) in the spleen, heart, and brain (Srivastava et al. 1984a). The relatively high concentrations of strontium in the gastrointestinal tract may reflect the mechanical clearance of strontium from the airways to the esophagus.

Although placental transfer of strontium has been demonstrated in humans and animals exposed to strontium by other routes of exposure (see Section 3.5.2.2), only one study has examined placental transfer after a dose to the respiratory tract. Pregnant rats received an intratracheal dose of ⁸⁹Sr-enriched fly ash (sieved to have a particle diameter of distribution of 90% less than 20 µm) on days 14–18 of gestation. The concentrations of strontium in whole fetus, liver, lung, heart, and kidney were not significantly different from controls that received an instillation of saline (Srivastava et al. 1990).

3.5.2.2. Oral Exposure

The distribution of absorbed strontium in the human body is similar to that of calcium, with approximately 99% of the total body burden in the skeleton (ICRP 1993). The skeletal burden of stable strontium has been estimated from analyses of bone samples from human autopsies (Herring and Keefer 1971a; O’Connor et al. 1980; Papworth and Vennart 1984; Tanaka et al. 1981). Skeletal burden was estimated in Japanese adult males to be approximately 440 mg compared to 850 g of calcium (Tanaka et al. 1981).

Papworth and Vennart (1984) analyzed published data on ⁹⁰Sr and calcium concentrations in human bone tissues and diets of people in the United Kingdom during the period from 1955 to 1970 and concluded that approximately 4.75% of the dietary intake of ⁹⁰Sr was taken up by the adult skeleton. Approximately 7.5% of the cortical bone ⁹⁰Sr burden was eliminated from bone each year (equivalent to elimination half-times of approximately 9.2 years). The rate of elimination from trabecular bone was approximately 4 times this value. The same analysis yielded estimates of skeletal uptakes of strontium that varied with age, being highest, approximately 10%, in infants and during adolescence, ages in which bone growth rates are high relative to other ages.

Strontium distributes relatively uniformly within the bone volume where it exchanges with calcium in hydroxyapatite (see Section 3.6.1), although small differences in the calcium and strontium distributions within bone have been reported. The Sr:Ca concentration ratio in bone increases with age from approximately 0.3 mg strontium/g Ca at birth to a value of 0.5 in adults (Papworth and Vannart 1984; Tanaka et al. 1981). The Sr:Ca ratio in bone also has been shown to vary with the bone type; ratios in cortical bone were approximately 10–20% higher than in trabecular bone (Tanaka et al. 1981).

Information on the distribution of strontium in soft tissue is extremely limited. In rats that were exposed to 3.4 mg strontium/L (as SrCl₂) in drinking water for 3 months, the serum concentration of strontium was 8.7 mg/L and tissue:serum strontium concentration ratios (based on the latter mean serum concentration) were as follows: liver, 0.7; heart, 1.2; muscle, 1.1; adrenal, 1.3; brain, 1.2; and bone, 1,300 (Skoryna 1981b). Strontium:calcium ratios in these tissues were approximately 0.05–0.1. Tissue:plasma strontium concentration ratios in rats 1–5 hours after they received an intraperitoneal injection of strontium revealed ratios <1 in the fat, spleen, liver, ovary, testis, skeletal muscle, and heart; and values of 1.2–1.7 in the lung, small intestine, salivary gland, kidney, and skin (Brues et al. 1969). Tissue:plasma concentration ratios of seminal vesicles in mice increased to values exceeding 2 several days after an intraperitoneal dose of strontium (Brues et al. 1967).

Information on the subcellular location of strontium in soft tissues is also extremely limited. In rats that were exposed to 1.9 mg strontium/L (as SrCl₂) in drinking water for 3 months, the strontium concentrations (per mg protein) in the mitochondrial, lysosomal, and microsomal fractions of liver were approximately 5 times that of cytosol (Skoryna 1981b). A major fraction of the strontium in tissues, possibly as much as 50–80% appears to be bound to protein (Kshirsagar 1977).

The partitioning of strontium in blood has not been extensively explored. The concentrations of strontium in the erythrocyte and plasma fractions of human blood obtained from blood banks were 7.2 µg/L in the erythrocyte fraction and 44 µg/L in the plasma fraction, suggesting that most of the strontium in blood resides in the plasma (Olehy et al. 1966). The strontium concentration in serum from 100 human subjects (health status not reported) was 53 µg/L, similar to the value reported for blood bank serum (Skoryna 1981b). Strontium binds to proteins in human serum; however, the specific proteins to which strontium binds have not been characterized. Alda and Escanero (1985) found that 45% of the strontium incubated with human serum at a concentration of 10 mg/L was ultrafilterable. Harrison et al. (1955) reported a value of 60% for the ultrafilterable fraction of plasma at a plasma concentration of 3.5 mg/L in two subjects who received an intravenous dose of 20 or 100 mg strontium chlorides. Note that this concentration is 300–1,000 times that reported for serum concentrations in subjects that were not receiving strontium supplements (Olehy et al. 1966; Skoryna 1981b); at lower concentrations, a larger fraction of the serum strontium may be bound, as binding appears to be saturable (Alda and Escanero 1985; Berg et al. 1973). Values of 40–60% bound to protein have been reported for guinea pig and rabbit plasma or serum, respectively (Lloyd 1968; Twardock et al. 1971).

Strontium in the maternal skeleton can be transferred to the fetus during pregnancy. Studies of residents of the Techa River who were exposed to strontium as result of releases from a plutonium production plant provide evidence for fetal transfer of strontium (Tolstykh et al. 1998, 2001). The fetal:maternal transfer coefficient—the ratio of ⁹⁰Sr concentrations in the fetal and maternal skeletons (expressed in becquerels per gram of calcium)—was determined for six subjects who were exposed prior to pregnancy and their seven stillborn infants (Tolstykh et al. 1998). The transfer coefficients varied from 0.012 to 0.24, with the higher values associated with maternal exposures that occurred during adulthood and lower values associated with maternal exposures during childhood or adolescence. The difference was not related to the maternal strontium burden at pregnancy and may reflect a lower availability of strontium deposited in cortical bone during periods of active bone growth.

Studies in animals provide additional evidence for transfer of strontium through the placenta to the fetus. The fetus begins to accumulate strontium as the fetal skeleton develops. In mice, ossification of the fetal skeleton begins on approximately the 14^th day of gestation, at which point, the fetal strontium burden begins to increase (Olsen and Jonsen 1979). In pregnant mice that received an injection of strontium at different stages of pregnancy, fetal strontium burden was 4.5% of the maternal dose administered on the 18^th day of pregnancy compared to 0.7% of the maternal dose administered on the 14^th day of pregnancy (Rönnbäck 1986). Thus, fetal transfer was highest when the maternal dose occurred at the time of greatest skeletal growth. A similar observation has been made in rats; uptake of strontium by the fetus is highest (1–2% of an injected maternal dose) if the maternal dose is given on or after the 16^th day of gestation when ossification of the fetal skeleton begins (Hartsook and Hershberger 1973; Wykoff 1971). The distribution of strontium in the fetus at the end of gestation is similar to that of the mother with most of the strontium burden in the skeleton. In mice, the skeletal (long bones):soft tissue concentration ratio was approximately 40 in both the fetuses and dams (Jacobsen et al. 1978).

Strontium enters mammary milk in humans and can be transferred to newborns during breast feeding (Harrison et al. 1965). The concentration of strontium in breast milk of 12 healthy women was estimated to be 74 µg/L (range, 39–93) and the Sr:Ca concentration ratio was 0.24 µg strontium/mg Ca (Harrison et al. 1965). In a study of the transport of trace elements, the concentration of strontium in colostrum samples collected from 29 healthy women during the first 3 days after delivery was found to be comparable to that in serum from venous blood samples taken 20 minutes before delivery (Rossipal et al. 2000). In contrast, the concentration of calcium in colostrum was significantly increased over the level in maternal serum, which was indicative of active transport. The authors concluded that the transfer of strontium was based primarily on a concentration gradient mode of action. Numerous studies in animals provide additional evidence for transfer of strontium from breast milk to newborns during lactation (Hopkins 1967; Jacobsen et al. 1978; Kostial et al. 1969b; Rönnbäck et al. 1968). In lactating rats that received an oral exposure to tracer concentrations ⁸⁵Sr in drinking water during the 14^th through 16^th days of lactation, approximately 5% of the ingested dose was recovered in the nursing pups 24 hours after the end of the 2-day exposure (Kostial et al. 1969b). In a study in which lactating mice received an intraperitoneal injection of radioactive strontium, strontium levels of the nursing pups was approximately 20% of that of the dams (Rönnbäck et al. 1968). These results are consistent with the oral exposure study (Kostial et al. 1969b), if one assumes that approximately 25% of the oral dose was absorbed by the dam. The tissue distribution of strontium in lactating mice and their offspring was found to be similar after an intraperitoneal dose to the dams during lactation; concentrations in bone were approximately 1,000 times higher than liver and kidney (Jacobsen et al. 1978). The strontium concentration in calvaria of the lactating pups, after 5 days of lactation, was approximately 3 times that of the dams, whereas the concentration in long bones of pups and dams were similar (Jacobsen et al. 1978). The difference in the bone concentrations in the dams and pups may reflect the relatively higher rate of bone formation in the pups and associated incorporation of strontium into the new bone.

3.5.2.3. Dermal Exposure

In volunteers who were exposed to dermally applied ⁸⁵SrCl₂ in the left forearm, ⁸⁵Sr was detected by external counting of the patella and right forearm 3 and 6 hours after the exposure was initiated, suggesting that the absorbed strontium had been taken up by bone (Ilyin et al. 1975). Although no other studies were located regarding the distribution of dermally absorbed strontium, it is likely that the distribution would be similar to that absorbed from the oral route, with the most of the body burden in the skeleton (see Section 3.5.2.2).

3.5.3.1. Inhalation Exposure

3.5.3.2. Oral Exposure

3.5.3.3. Dermal Exposure

3.5.4.1. Inhalation Exposure

Whole body elimination times have been measured in dogs and rats that received inhalation exposures to SrCl₂. In dogs that were exposed to aerosols of ⁸⁵SrCl₂ (AMAD 1.4–2.7 µm, GSD 2.0), elimination half-times were 0.6 (59%), 9 (12%), and 300 days (29%) (Fission Product Inhalation Project 1967a). The rapid early phase of elimination reflects the mechanical clearance of strontium deposited in the tracheobronchial region of the respiratory tract and transfer to the gastrointestinal tract and feces, whereas the slower elimination component reflects the elimination from the skeleton. A similar pattern of elimination has been observed in rats. In rats that were exposed to tracer levels of ⁸⁵Sr or a mixture of ⁸⁵Sr and ⁹⁰Sr aerosols (AMAD 1.8–2.8), the long-term whole-body elimination half-time, measured 5–230 days after exposure, was 330 days (Fission Product Inhalation Project 1967b).

Strontium that is absorbed after an initial deposition in the respiratory tract is excreted in feces and urine. Evidence for this comes from accidental exposures to radioactive strontium. In one case, a worker accidentally inspired an unknown quantity of ⁹⁰SrCl₂ (physical form unknown) and, over the subsequent 800 days, the urinary:fecal excretion ratio was 3:1 (Petkau and Pleskach 1972). The urinary:fecal excretion ratio of 3 is consistent with observations of long-term urinary:fecal excretion ratios observed in people who ingested radioactive strontium or short-term ratios in people who received an intravenous dose of radioactive strontium (see Section 3.5.4.2). In a second case, a worker was exposed to ⁹⁰SrCO₃ with deposition within the nasal tract as well as the hands, face, and hair and the urinary:fecal excretion ratio over the first 24 days was 0.71 (Rundo and Williams 1961). The lower ratio in this case probably reflects the fecal contribution of strontium that was mechanically cleared from the respiratory tract over the shorter observation period (24 days compared to 800 days). Similar observations have been made in animals. In dogs that received a 2–22-minute nose-only exposure to aerosols of ⁸⁵SrCl₂ (AMAD 1.4–2.7 µm, GSD 2.0), an initially large fecal component of excretion was followed by urinary:fecal excretion ratios of 1.0–1.4 (Fission Product Inhalation Project 1967a). An increase over time in the urinary:fecal excretion ratios from values <1 to 2–4 has also been observed after intratracheal instillation of SrCl₂ in rats (Fission Product Inhalation Project 1967b; Namenyi et al. 1986).

3.5.4.2. Oral Exposure

The long-term (decades) elimination of strontium has been studied in people who were exposed to strontium in the Techa River area of Russia after fission products from a plutonium production process were released in the area. Whole-body elimination half-times were estimated in a study population of 361 males and 356 females to be 28 years in males and 16 years in females (Tolstykh et al. 1997). Most of the difference in the elimination rate estimated for males and females resulted from a pronounced increase in the elimination rate in females after age 50 years. The increase most likely reflects the increase in bone resorption that tends to occur in females after menopause. Müller et al. (1966) estimated a similar value, 25 years, for the long-term elimination half-time of strontium in 56 radium dial painters. In two dial painters, long-term elimination half-times were estimated to be 9 years (Wenger and Soucas 1975). Estimates of the long-term elimination half-times of strontium reflect primarily the storage and release of strontium in bone. Over shorter time periods after exposure, faster elimination rates are observed that reflect soft-tissue elimination as well as elimination from a more rapidly exchangeable pool of strontium in bone. When whole-body elimination of a tracer dose of ⁸⁵Sr was measured for periods of 42–108 days in nine subjects, the mean elimination half-time was 91 days (±32, SD) (Likhtarev et al. 1975). In three healthy subjects that received a single oral dose of SrCl₂, the estimated average whole-body elimination half-times, estimated over 13 days, were 2 (30%) and 59 days (70%) (Uchiyama et al. 1973). Similar short-term rates of elimination have been observed within days to a few weeks after an intravenous injection of SrCl₂ (MacDonald et al. 1965; Newton et al. 1990).

Strontium that has been absorbed from the gastrointestinal tract is excreted primarily in urine and feces. In two dial painters, rates of urinary and fecal excretion of radium approximately 10 years after the exposure were approximately 0.03 and 0.01% of the body burden per 24 hours, respectively (Wenger and Soucas 1975). The urine:fecal excretion ratio of 3 that was observed in the radium dial workers is consistent with ratios of 2–6 observed several days to weeks after subjects received an intravenous injection of SrCl₂ (Bishop et al. 1960; Blake et al. 1989a, 1989b; Likhtarev et al. 1975; Newton et al. 1990; Samachson 1966; Snyder et al. 1964; Uchiyama et al. 1973). Thus, urine appears to be the major route of excretion of absorbed strontium. The observation of fecal excretion of radioactive strontium weeks to decades after an oral exposure or over shorter time periods after an intravenous exposure suggests the existence of a mechanism for transfer of absorbed strontium into gastrointestinal tract, either from the bile or directly from the plasma. Evidence for direct secretion of strontium from the plasma into the intestine is provided by studies in animals (see Section 3.5.1). The available information does not address the extent to which biliary excretion may also contribute to fecal excretion of strontium.

As discussed in Section 3.5.2.2, absorbed strontium is eliminated in breast milk during lactation. The concentration of strontium in breast milk of 12 healthy women was estimated to be 74 µg/L (range, 39–93) and the Sr:Ca concentration ratio was 0.24 µg strontium/mg Ca (Harrison et al. 1965).

Strontium has been detected in human saliva and seminal fluid. In healthy subjects who received a single intravenous injection of SrCl₂, the saliva:plasma concentration ratio was 0.9 and the semen:plasma ratio was 0.6 (Harrison et al. 1967a).

3.5.4.3. Dermal Exposure

In volunteers who were exposed to dermally applied ⁸⁵SrCl₂ in the left forearm, ⁸⁵Sr was excreted in urine (fecal excretion was not measured in this study) (Ilyin et al. 1975). Although no other studies were located regarding the excretion of dermally absorbed strontium, it is likely that the excretion would be similar to that absorbed from the oral route, with urinary excretion being approximately 2–3 times greater than fecal excretion (see Section 3.5.4.2).

ICRP (1993) Strontium Biokinetics Model

Description of the model. ICRP (1993) developed a compartmental model of the kinetics of alkaline earth elements, including strontium, in humans that is applicable to infants, children, adolescents, and adults. The model is based on a nearly identical model developed by Leggett (1992). The fraction of ingested strontium that is absorbed (uptake to blood) is assumed to vary with age and have values of 0.6 in infants up to 12 months of age, 0.4 from 12 months of age through 15 years, and 0.3 from age 15 years through adulthood. Absorbed strontium that enters the blood plasma is assumed to distribute to the skeleton, liver, and other tissues (Figure 3-8). Excretion pathways included in the model are plasma to urine, plasma to feces, and liver to feces. Transfer rate coefficients between compartments are age-specific and, depending on the specific coefficient, values can change at ages 3 months, 1 year, 5 years, 10 years, 15 years, and adult (>15 years). The model assumes that 99% of the strontium that enters the body and is not excreted is ultimately transferred to the skeleton and 1% is in soft tissues. Skeletal deposition is assumed to distribute initially to the bone surface of either cortical or trabecular bone, from which it can exchange relatively rapidly with calcium in plasma or more slowly with calcium in the bone volume. Two pools are assumed to exist within the bone volume, an exchangeable pool that communicates with surface bone, and a nonexchangeable pool from which strontium can be returned to plasma as a result of bone resorption. Approximately 55% of the transfer from plasma to bone in adults is to the trabecular bone surface and 45% to the cortical bone surface.

Figure 3-8

ICRP (1993) Model of Strontium Biokinetics.

Validation of the model. The extent to which the ICRP model has been validated is not described in ICRP (1993).

Risk assessment. The model has been used to establish radiation dose equivalents (Sv/Bq) of ingested ⁸⁹Sr and ⁹⁰Sr for ages 3 months to 70 years (ICRP 1993). The model has also been applied by the ICRP to calculate limits on inhalation for ⁸⁹Sr and ⁹⁰Sr (ICRP 1995) and limits on inhalation or ingestion for ⁸⁰Sr, ⁸¹Sr, ⁸²Sr, ⁸³Sr, ⁸⁵Sr, ^85mSr, ^87mSr, ⁹¹Sr, and ⁹²Sr (ICRP 1994b). It was used in the U.S. Federal Guidance Report No. 13 (EPA 2000e) to calculate inhalation risk coefficients and ingestion risk coefficients (separately for food and water) for the following radionuclides: ⁸⁰Sr, ⁸¹Sr, ⁸²Sr, ⁸³Sr, ⁸⁵Sr, ^85mSr, ^87mSr, ⁸⁹Sr, ⁹⁰Sr, ⁹¹Sr, and ⁹²Sr.

Target tissues. The model is designed to calculate ⁸⁹Sr and ⁹⁰Sr intake limits, based on radiation dose to all major organs, including the bone surfaces, bone marrow, and liver, to which the highest doses would be expected.

Species extrapolation. The model is designed for applications to human dosimetry and cannot be applied to other species without modification.

Interroute extrapolation. The model is intended for application to strontium reaching blood by absorption from lungs, gastrointestinal tract, or wound, or by injection.