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Barium and Compounds
CASRN 7440-39-3
01/21/1999
Contents
0010
Barium and Compounds
CASRN -- 7440-39-3; 1/21/1999
Health assessment information on a chemical substance is included in IRIS only after a
comprehensive review of chronic toxicity data by U.S. EPA health scientists from several
Program Offices, Regional Offices, and the Office of Research and Development. The
summaries presented in Sections I and II represent a consensus reached in the review process.
Background information and explanations of the methods used to derive the values given in IRIS
are provided in the Background Documents.
STATUS OF DATA FOR Barium and Compounds
File First On-Line 01/31/1987
| Category (section) | Status | Last Revised |
|---|
|
| Oral RfD Assessment (I.A.) | On-line | 1/21/1999 |
|
| Inhalation RfC Assessment (I.B.) | On-line | 3/30/1998 |
|
| Carcinogenicity Assessment (II.) | On-line | 3/30/1998 |
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_I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
__I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Barium and Compounds
CASRN -- 7440-39-3
Last Revised -3/30/98
The oral Reference Dose (RfD) is based on the assumption that thresholds exist for certain toxic
effects such as cellular necrosis. It is expressed in units of mg/kg-day. In general, the RfD is an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily exposure to the
human population (including sensitive subgroups) that is likely to be without an appreciable risk
of deleterious effects during a lifetime. Please refer to the Background Document for an
elaboration of these concepts. RfDs can also be derived for the noncarcinogenic health effects of
substances that are also carcinogens. Therefore, it is essential to refer to other sources of
information concerning the carcinogenicity of this substance. If the U.S. EPA has evaluated this
substance for potential human carcinogenicity, a summary of that evaluation will be contained in
Section II of this file.
___I.A.1. ORAL RfD SUMMARY
| Critical Effect | Experimental Doses* | UF | MF | RfD |
|---|
| No Adverse Effect** | NOAELs: 10 and 7.3 mg/L | 3 | 1 | 7E-2 |
| NOAEL (adjusted): | | | mg/kg-day |
Subchronic human study and
community exposure study
Wones et al., 1990;
Brenniman and Levy, 1984 | 0.21 mg/kg-day
LOAEL: None |
| Increased kidney weight | NOAEL: 65 mg/kg-day
LOAEL: 115 mg/kg-day |
Subchronic rat study
NTP, 1994 |
| Increased kidney weight*** | NOAEL: 45 mg/kg-day
LOAEL: 75 mg/kg-day |
Chronic rat study
NTP, 1994 |
*Conversion Factors and Assumptions: Wones et al. (1990): 10 mg Ba/L drinking water
concentration was multiplied by the actual water consumption rate of 1.5 L/day and divided by
the 70 kg reference body weight. NOAEL (adjusted) = 10 mg/L × 1.5 L/day × 1/70 kg = 0.21
mg/kg-day. Brenniman and Levy (1984): 7.3 mg Ba/L drinking water concentration was
multiplied by the reference water consumption rate of 2 L/day and divided by the 70 kg reference
body weight. NOAEL (adjusted) = 7.3 mg/L × 2 L/day × 1/70 kg = 0.21 mg/kg-day. NTP
(1994) subchronic and chronic studies: as estimated by authors.
**Previous investigations in reSEARCH animals (both acute and chronic) have demonstrated the
potential for hypertension to develop as a result of high barium exposures. Based on these
reports, lower dose human studies were conducted to examine potential effects on blood
pressure, electrocardiographic events, serum and urinary markers of toxicity following barium
exposure. Although no evidence of barium-induced toxicity was identified in humans, these
studies have identified a dose at which no adverse effects were observed. That dose, along with
the kidney effects in experimental animals, serves as the basis for derivation of the reference
dose and is consistent with EPA's RfD methodology.
***Based on 15-month interim evaluation.
___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD)
Brenniman, GR; Levy, PS. (1984) Epidemiological study of barium in Illinois drinking water
supplies. In: Advances in modern toxicology, Calabrese, EJ, ed. Princeton, NJ: Princeton
Scientific Publications, pp. 231-249.
National Toxicology Program (NTP). (1994) Technical report on the toxicology and
carcinogenesis studies of barium chloride dihydrate (CAS No. 10326-27-9) in F344/N rats and
B6C3F1 mice (Drinking Water Studies). NTP TR 432. National Toxicological Program,
Research Triangle Park, NC. NIH Pub. No. 94-3163. NTIS Pub PB94-214178.
Wones, RG; Stadler, BL; Frohman, LA. (1990) Lack of effect of drinking water barium on
cardiovascular risk factor. Environ Health Perspect 85:355-359.
No single study is appropriate as the basis for a lifetime RfD for barium. The RfD is
based on a weight-of-evidence approach that focuses on four co-principal studies: the Wones et
al. (1990) experimental study in humans, the Brenniman and Levy (1984) epidemiologic study,
and the subchronic and chronic rat studies that employed adequate diets and investigated both
cardiovascular and renal endpoints (NTP, 1994). The McCauley et al. (1985) study of
unilaterally nephrectomized rats was used to support the identification of the kidney as a co-critical target.
The identification of hypertension as a health endpoint of concern is supported by findings of hypertensive effects in humans who ingested acutely high doses of barium compounds, in workers who inhaled dusts of barium ores and barium carbonate, in experimental animals given barium intravenously, and in rats exposed to barium in drinking water while on restricted diets. Based on these findings, lower dose human studies were conducted to examine the potential effects on blood pressure in humans, and both blood pressure and kidney function in animals. Although the experimental study by Wones et al. (1990) together with the
epidemiological study by Brenniman and Levy (1984) did not report any significant effects on
blood pressure, they establish a NOAEL in humans of 0.21 mg Ba/kg-day. The animal data
suggest that the kidney may also be a sensitive target for ingested barium from low level
exposure (McCauley et al., 1985; NTP, 1984; Schroeder and Mitchener, 1975a); neither of the
human studies investigated sensitive renal endpoints. Therefore, 0.21 mg Ba/kg-day is used as
the basis to derive the RfD. The use of a NOAEL from human studies increases the confidence
in the Agency's judgement in the derivation of the RfD, which is defined as an estimate (with
uncertainty spanning perhaps an order of magnitude) of a daily exposure to human population
(including sensitive subgroups) that is likely to be without an appreciable risk of deleterious
effects during a life time.
Wones et al. (1990) administered barium (as barium chloride) in the drinking water of 11 healthy male volunteers (mean age of 39.5 years). None of the subjects was taking any medications and none had hypertension, diabetes, or cardiovascular disease. Barium
concentrations in the drinking water consumed by the subjects prior to the study were known to
be very low. The subjects were given 1.5 L/day of distilled water containing various levels of
barium chloride. No barium was added for the first 2 weeks, which served as a control period; 5 ppm barium (0.11 mg Ba/kg-day using 70 kg reference weight) was added for the next 4 weeks
and 10 ppm barium (0.21 mg Ba/kg-day) was added for the last 4 weeks of the study. Diets were
controlled in order to mimic American dietary practices (barium content of the diet was not
determined, but the authors mentioned that a typical hospital diet provides 0.75 mg Ba/day, or
0.011 mg Ba/kg-day using 70 kg reference weight). All beverages and food were provided, and
subjects were instructed to consume only what was provided. The subjects were instructed to
keep their level of exercise constant and to abstain from alcohol, and smokers were told to smoke
consistently throughout the study. Systolic and diastolic blood pressures (measured in the
morning and evening) were not significantly affected by barium exposure. Blood was collected
at the beginning and periodically, particularly as four consecutive daily samples at the end of
each of the three study periods. No significant alterations in serum calcium levels were observed
(9.11, 9.23, and 9.23 mg/dL at the 0, 5, and 10 ppm exposure levels, respectively). When the
serum calcium levels were "normalized" for differences in albumin levels, a significant increase
(p = 0.01) was observed (8.86, 9.03, and 9.01, respectively). This type of adjustment has been considered unreliable (Sutton and Dirks, 1986). The study authors attributed the increase in
adjusted serum calcium levels to a slight decrease in serum albumin. The increase in serum
calcium levels was considered borderline and not clinically significant. No significant changes
were observed in plasma total cholesterol, triglyceride, LDL or HDL cholesterol, LDL:HDL
ratio, and apolipoproteins A1, A2, and B; in serum glucose, albumin, and potassium levels; or in
urinary levels of sodium, potassium, vanillymandelic [sic] acid or metanephrines.
Electrocardiograms (measured for 24 h on 2 consecutive days at the end of each study period)
revealed no changes in cardiac cycle intervals including the QT interval; the study authors noted
that the lack of shortening of the QT interval provided evidence that the slight increase in serum
calcium was not clinically significant. In addition, no significant arrhythmias, increase in
ventricular irritability, or apparent conduction problems were seen with barium exposure. The
NOAEL of 0.21 mg Ba/kg-day can be determined from the 10 ppm barium exposure regime that
was used for the last 4 weeks of the study.
Brenniman and Levy (1984) reported a retrospective epidemiology study of two communities, McHenry and West Dundee, IL, which had similar demographic and
socioeconomic characteristics and a 70-fold difference in barium concentrations in drinking
water. The mean concentration in McHenry's drinking water was 0.1 mg Ba/L, whereas the
mean concentration in West Dundee's drinking water was 7.3 mg Ba/L. The levels of other
minerals in the drinking water of the two communities were stated to be similar. Subjects were
selected randomly from a pool that included every person 18 years of age or older in a random
sample of blocks within each community. All subjects underwent three blood pressure
measurements (taken over a 20-min period with a calibrated electronic blood pressure apparatus)
and responded to a health questionnaire that included such variables as sex, age, weight, height,
smoking habits, family history, occupation, medication, and physician-diagnosed heart disease,
stroke, and renal disease. Data were analyzed using the signed ranked test for age-specific rates,
the weighted Z test for prevalence rates, and analysis of variance for blood pressures. No
significant differences in mean systolic or diastolic blood pressures, or in rates of hypertension,
heart disease, stroke, or kidney disease were found for men or women of the two communities.
A more controlled study was conducted on a subpopulation of the McHenry and West Dundee
subjects who did not have home water softeners, were not taking medication for hypertension,
and had lived in the study community for more than 10 years. No significant differences were
observed between the mean systolic or diastolic blood pressures for men or women of these
subpopulations in the low-barium (0.1 mg Ba/L, 0.0029 mg Ba/kg-day assuming water ingestion
of 2 L/day and 70 kg weight) and elevated-barium communities (7.3 mg Ba/L, 0.21 mg Ba/kg-day). Thus, the dosage associated with the elevated barium levels, 0.21 mg Ba/kg-day, is a
NOAEL.
In subchronic and chronic studies conducted by NTP (1994), groups of male and female F344/N rats were exposed to barium chloride dihydrate in drinking water for 13 weeks or 2 years. The barium chloride concentrations tested were 0, 125, 500, 1,000, 2,000, and 4,000 ppm (0, 10, 65, 110, and 200 mg Ba/kg-day for males and 0, 10, 35, 65, 115, and 180 mg Ba/kg-day for females; the study authors estimated doses using water consumption and body weight data) in the subchronic study (10 rats/sex/group) and 0, 500, 1,250, and 2,500 ppm (0, 15, 30, and 60 mg Ba/kg-day for males and 0, 15, 45, and 75 mg Ba/kg-day for females) in the chronic study
(60/sex/group). The animals were fed an NIH-07 diet; barium content of the diet was not
reported. Neurobehavioral and cardiovascular assessments were conducted as part of the
subchronic study.
In the subchronic study, chemical-related deaths were limited to 3 males and 1 female in the 4,000 ppm group; the cause of death was not evident on histological examination. In rats receiving 4,000 ppm barium chloride, there were significant decreases in water consumption (30% relative to that of controls) and body weight gain (final body weights increased 13% in males and 8% in females). Toxicologically significant organ weight changes consisted of
increased absolute and relative kidney weights in female rats at 2,000 and 4,000 ppm and
increased relative kidney weights in male rats at 4,000 ppm. Serum phosphorus levels were
significantly elevated in female rats at  500 ppm and in male rats at 2,000 ppm, but the
increase did not appear to be dose-related. The NTP (1994) concluded that the elevated values
probably were due to an artifact from hemolysis of the collected blood samples. No other
chemical-related or biologically significant changes in serum electrolytes or hematology values
were seen. Minimal to mild focal to multifocal areas of dilatation of the renal proximal
convoluted tubules were observed in 3/10 male and 3/10 female rats exposed to 4,000 ppm;
crystals were not present in the kidney tubules. Lymphoid depletions in the spleen and thymus
were observed in the rats receiving 4,000 ppm that died during the study. No other histological
changes were observed.
Neurobehavioral assessments were conducted at days 0, 45, and 90. At day 90, statistically significant decreases in the magnitude of undifferentiated motor activity were observed in both sexes of rats receiving 4,000 ppm. Marginal decreases were observed in all other barium-exposed groups except the 1,000 ppm females. No significant or dose-related
changes were observed in the other neurobehavioral endpoints (thermal sensitivity judged by a
tail flick latency test, startle-response to acoustic and air-puff stimuli, forelimb or hindlimb grip strength, or hindlimb foot splay). The neurobehavioral effects were attributed to the general
condition of the high-dose animals (Dietz et al., 1992). Cardiovascular studies in the rats
revealed no barium-associated differences in heart rate, systolic blood pressure, or
electrocardiogram. Thus, 4,000 ppm of barium in the drinking water (200 mg Ba/kg-day for
males and 180 mg Ba/kg-day for females) constitutes a subchronic FEL for mortality in rats.
Renal histopathological lesions were seen at this dose level but were not severe. Detection of
glomerular effects, however, would have required electron microscopy or urinalysis, neither of
which was performed. Glomerular effects were seen during electron microscopic examination in
unilaterally nephrectomized rats given 1,000 ppm barium (150 mg Ba/kg-day) through the
drinking water in a study by McCauley et al. (1985). The next lower dose level in the NTP
(1994) study, 2,000 ppm (110 mg Ba/kg-day for males and 115 mg Ba/kg-day for females), may
be a subchronic LOAEL for renal effects in females based on the increased absolute and relative
kidney weight changes. The subchronic NOAEL would be 1,000 ppm (65 mg Ba/kg-day for
both sexes).
In the chronic portion of the NTP (1994) study, there were no significant increases in mortality in the barium-exposed rats. Mean body weights were slightly lower in male rats receiving 2,500 ppm (5% lower than controls) and in female rats receiving 1,250 or 2,500 ppm (6% and 11% lower, respectively, than controls). Water consumption was decreased in a dose-related manner; at 2,500 ppm consumption was 22% and 25% lower than controls in the males
and females, respectively. Barium exposure did not result in toxicologically significant
alterations in hematologic or clinical chemistry parameters (assessed after 15 mo of exposure).
Toxicologically significant alterations in organ weights (measured at the 15-mo interim
evaluation) were limited to a statistically significant (p 0.01) increase in relative kidney weights
in female rats at 2,500 ppm. Chemical-related kidney lesions were not observed in rats; the only
potential indication of renal toxicity was the increased relative kidney weight seen in the females
at 2,500 ppm. In addition, there were no chemical-related histological changes in any other
organs or tissues. Thus, the highest exposure level tested in this study, 2,500 ppm barium in
drinking water (60 mg Ba/kg-day for males and 75 mg Ba/kg-day for females), may be a chronic
NOAEL or LOAEL for rats, depending on interpretation of the increased relative kidney weight
in females. When considered together with the results in the 13-week NTP (1994) study in rats,
in which increased relative and absolute kidney weights were seen in female rats receiving 2,000
ppm barium in drinking water (115 mg Ba/kg-day), and kidney lesions and greater increases in
relative and absolute kidney weights were seen in female rats at 4,000 ppm (180 mg Ba/kg-day),
the increased relative kidney weight in females in the 2-year study is suggestive of potential renal
effects. Therefore, 2,500 ppm (75 mg Ba/kg-day) is designated a chronic LOAEL and 1,250
ppm (45 mg Ba/kg-day) a chronic NOAEL for female rats for renal effects in the NTP (1994)
study.
McCauley et al. (1985) reported histological, electron microscopic, electrocardiograph, and blood pressure studies in rats given barium in their drinking water for various durations and fed Purina rat chow (contributing significant barium intake) or Tekland rat chow (insignificant barium intake). In the histology studies, groups of 10-12 male or female CD Sprague-Dawley rats received 0, 1, 10, 100, or 250 ppm barium (as barium chloride) in drinking water and Purina rat chow containing 12 ppm barium for 36, 46, or 68 weeks (not all concentrations or both sexes tested for each duration). The authors reported that no significant differences in food or water intake or body weight were observed, but did not report the actual data. They stated that rats that received 10 ppm of barium in the drinking water ingested 1.5 mg Ba/kg-day from water and 1 mg Ba/kg-day from the Purina diet. This barium intake was used to estimate total barium intake for the other exposure levels. Thus, the estimated total barium intakes were 1, 1.15, 2.5, 16, and 38.5 mg/kg-day for the 0, 1, 10, 100, and 250 ppm concentrations for all exposure regimens. Histological evaluations of an extensive number of tissues, including gastrointestinal tract, liver, heart, adrenal gland, brain, respiratory tract, spleen, thymus, kidneys, ovaries, and testes, did not reveal barium-related lesions. No alterations in hematocrit levels were observed.
In the electrocardiographic study, CD Sprague-Dawley rats (10-11/group, sex not specified) were given drinking water containing 0 or 250 ppm of barium (as barium chloride) for 5 mo and Purina rat chow (estimated intakes of 1 and 38.5 mg Ba/kg-day, based on the estimates for the histology study). Data were obtained at 0, 4, and 60 min after an intravenous injection of 0.5 µg/kg of l-norepinephrine (NE). Barium induced a significant enhancement of NE-induced bradycardia compared with controls 4 min after NE administration, but by 60 min, the heart rates of controls were still depressed, whereas those of barium-exposed animals were approaching
normal. No significant alterations in the PR, QS, QT, and ST interval durations or peak
amplitudes were observed. The toxicological significance of these findings is uncertain.
In the blood pressure study, CD Sprague-Dawley rats (6/group, sex was not specified) were fed Tekland rat chow (0.5 µg Ba/kg-day) and administered barium in drinking water for 16 weeks. Normotensive rats received 0, 3, 10, 30, or 100 ppm barium in drinking water or in 0.9% sodium chloride solution as drinking water. Unilaterally nephrectomized rats received 1, 10, 100, or 1,000 ppm barium in regular drinking water or in 0.9% sodium chloride as
drinking water. Using data from the histology study, the doses corresponding to 0, 1, 3, 10, 30,
100, and 1,000 ppm were estimated to be 0, 0.15, 0.45, 1.5, 4.5, 15, and 150 mg Ba/kg-day,
respectively. All of these groups showed fluctuations of blood pressure but no hypertension.
Dahl salt-sensitive rats, exposed to 1, 10, 100, or 1,000 ppm barium in 0.9% sodium chloride for
16 weeks, had a transiently elevated blood pressure (approximately 150-160 mm Hg) during the
first 1-2 weeks of exposure to 1 or 10 ppm barium. This response was considered to be a normal
reaction to 0.9% sodium chloride in the drinking water for this strain of rat. Blood pressure
during the remaining period of exposure to 1 or 10 ppm barium or during the entire period of
exposure to 100 or 1,000 ppm barium was not indicative of hypertension. No hypertension was
seen in Dahl salt-resistant rats given the same exposures. Thus, there was no indication that
barium contributed to hypertension, but further interpretation of the results is problematic
because of the lack of 0 ppm barium/0.9% sodium chloride control groups.
Electron microscopic examination of kidneys in all the rats in the blood pressure studies demonstrated no histopathologic changes in arteriolar vessel walls or in tubules of the nephrons. However, structural changes in glomeruli (fused podocyte processes and thickening of the capillary basement membrane, and myelin figures in Bowman's space) were observed in the 1,000 ppm groups. These changes are indicative of damage to the glomerulus that would be
evidenced as inefficient glomerular filtration, including proteinuria. Two groups of unilaterally
nephrectomized rats (barium administered in drinking water or in 0.9% sodium chloride) and the
Dahl salt-sensitive and salt-resistant rats (barium administered in 0.9% sodium chloride) were
exposed to 1,000 ppm. Normal CD Sprague-Dawley rats were not tested at this exposure level.
No glomerular effects were seen at the next-lower exposure level, 100 ppm, in any group of rats,
including normal CD Sprague-Dawley rats that received barium in regular drinking water.
Thus, the study by McCauley et al. (1985) detected no adverse effect of barium on blood pressure at drinking water exposure levels up to 1,000 ppm (150 mg Ba/kg-day), the highest level tested. The only effect seen was glomerular damage in all groups of rats (unilaterally nephrectomized rats, Dahl salt-sensitive rats and Dahl salt-resistant rats) that received 1,000 ppm of barium in drinking water (150 mg Ba/kg-day). The NOAEL for glomerular effects in this study is 100 ppm (15 mg Ba/kg-day) in both unilaterally nephrectomized and intact rats. The
McCauley et al. (1985) study is the only study that examined the kidney for glomerular effects
and also measured blood pressure. The applicability of dose-response data from renal toxicity
studies in unilaterally nephrectomized rats to intact rats or humans is uncertain, however,
because removal of renal tissue may affect sensitivity of the remaining tissue to nephrotoxins. A
reduction in renal mass, such as that produced by partial nephrectomy, results in compensatory
adaptation of the remnant kidney tissue and associated changes in cellular metabolism and
function that may affect the sensitivity of the animal to nephrotoxicity. These changes include
cellular hypertrophy and increased transport activity in the proximal and distal tubule, changes in
renal metabolism, and increased renal plasma flow and glomerular filtration rate (Zalups et al.,
1987). Increased, decreased, or no change in susceptibility to nephrotoxicity has been
demonstrated in rats that have undergone unilateral or three-quarter nephrectomy, depending on
the chemical (Zalups and Lash, 1990; Zalups et al., 1988). At present, it is not possible to
reliably predict which chemicals are likely to be more or less toxic or to have no change in
toxicity to unilaterally nephrectomized rats.
___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD)
UF = 3. An uncertainty factor of 1 is assigned to account for some database deficiencies and 3 for lack of potential differences between adults and children and adequate developmental toxicity studies. The RfD for barium is based on four principal studies. Two human studies (Brenniman and Levy, 1984; Wones et al., 1990) identified no effects in adults. Two well-designed rat studies (NTP, 1994) identified NOAELs and LOAELs for renal effects following subchronic or chronic exposure. The results of the NTP (1994) subchronic study suggest that under these test conditions renal effects may be a sensitive endpoint. However, a similar relationship may not occur following chronic exposure or in humans. Animal studies (Perry et al., 1983, 1985, 1989) suggest that a marginally adequate diet, particularly one with inadequate calcium levels, may
increase sensitivity to barium-induced hypertension. The Brenniman and Levy (1984) study
examined more than 2,000 men and women; it is likely that a wide range of dietary variability,
including low calcium intakes, was represented in this population. Additionally, it is likely that
this population includes individuals who may be unusually susceptible to the toxicity of barium.
Dog and rat pharmacokinetic studies (Taylor et al., 1962; Cuddihy and Griffith, 1972) suggest
that gastrointestinal absorption of barium may be higher in young animals than in older animals.
Brenniman and Levy (1984) examined 18- to 75+-year-old residents living in the community for
more than 10 years. It is likely that this study included adult residents who were exposed to
elevated barium levels as young children, but it may not account for all of the uncertainty. The
barium database consists of subchronic and chronic toxicity studies in three species (humans,
rats, mice) and a marginally adequate one-generation reproductive/developmental toxicity study.
This rat and mouse study (Dietz et al., 1992) gave no indication that developmental or
reproductive endpoints are more sensitive than other endpoints; interpretation of the study results
is limited by very low pregnancy rates in all groups, including controls, and by examination of a
small number of developmental endpoints.
MF = 1
___I.A.4. ADDITIONAL STUDIES/COMMENTS (ORAL RfD)
The WHO (1990) reported several published estimates of dietary and drinking water intake of barium by humans. The range of daily dietary intake was 300-1,770 µg Ba/day, with wide variations. This is equivalent to 4-25 µg (0.004-0.025 mg) Ba/kg-day, assuming a 70 kg adult body weight. The WHO (1990) also reported levels of barium in U.S. drinking water of
1-20 µg/L. This is equivalent to an intake of 0.03-0.60 µg Ba/kg-day, assuming a consumption
rate of 2 L/day and 70 kg adult body weight. The range from these two sources combined is
0.004-0.026 mg Ba/kg-day.
NTP (1994) also examined the subchronic and chronic toxicity of barium in mice. In these studies, groups of male and female B6C3F1 mice received 0, 125, 500, 1,000, 2,000, or 4,000 ppm (13-week duration) or 0, 500, 1,250, or 2,500 ppm (2 years) barium (as barium chloride dihydrate) in the drinking water. The animals were fed a NIH-07 diet; barium content not reported. Increased mortality was observed in the subchronic and chronic studies at the
highest doses tested (4,000 or 2,500 ppm, respectively). Chemical-related nephropathy was also
observed at these doses. The nephropathy was characterized as tubule dilatation, renal tubule
atrophy, tubule cell regeneration, and the presence of crystals primarily in the lumen of the renal
tubules. Other adverse effects observed in the high-dose animals were attributed to debilitation
of the animals. Thus, these studies identify FELs for nephropathy and mortality of 4,000 ppm
(450 and 495 mg Ba/kg-day for males and females) and 2,500 ppm (160 and 200 mg Ba/kg-day)
in mice receiving barium in drinking water for a subchronic or chronic duration. The NOAELs
were 2,000 ppm (205 and 200 mg Ba/kg-day) and 1,250 ppm (75 and 90 mg Ba/kg-day),
respectively.
In a study by Tardiff et al. (1980), male and female Charles River rats were exposed to 0, 10, 50, or 250 ppm barium (as barium chloride) in drinking water for 4, 8, or 13 weeks. The rats were fed Tekland diet pellets (baseline dose of 0.5 µg Ba/kg-day). No significant alterations in survival, organ weights, hematologic and serum clinical chemistry parameters, and gross or histopathologic appearance of major tissues (liver, kidney, spleen, heart, brain, muscle, femur, and adrenal glands) were observed. This study identifies a subchronic NOAEL of 250 ppm (38.1 and 45.7 mg Ba/kg-day for males and females).
Perry et al. (1983, 1985, 1989) exposed female weanling Long-Evans rats to 0, 1, 10, or 100 ppm barium (as barium chloride) in drinking water for 1, 4, or 16 mo. The drinking water was fortified with five essential metals (molybdenum, cobalt, copper, manganese, and zinc). The rats were fed a rye-based diet with low trace metal content (1.5 ppm barium). After 8 mo of exposure to 10 ppm, there was a significant increase in systolic blood pressure (6 mm Hg), which remained significantly elevated (4 mm Hg) through 16 mo. In the 100 ppm group, systolic blood
pressure was elevated at 1 mo (12 mm Hg) and continued through 16 mo (16 mm Hg). No
effects were observed at 1 ppm. Exposure to 100 ppm also resulted in reductions in ATP and
phosphocreatinine levels in the myocardium, depressed cardiac contraction rates, and depressed
excitability. This study identifies a NOAEL of 1 ppm (0.17 mg Ba/kg-day) and LOAEL of 10
ppm (0.82 mg Ba/kg-day) for hypertension in rats maintained on low-mineral-content diets.
The differences in the cardiovascular outcome of the Perry et al. (1983, 1985, 1989) study as compared with the NTP (1994) and McCauley et al. (1985) studies may have been confounded by differences in diet composition. Rats in the Perry et al. (1983, 1985, 1989) study were maintained on a rye-based diet that contained low levels of several elements compared to standard laboratory chow (e.g., Purina chow), including calcium (3,800 vs. 12,000 ppm) and potassium (7,600 vs. 8,200 ppm). Animals maintained on diets low in calcium and/or potassium
may be more sensitive to the cardiovascular effects of barium. The calcium content of the above
rye-based diet is below the minimum requirement according to the NRC (1995); the potassium
content is not. Acute effects of barium on the cardiovascular system are modified by calcium
and potassium. Barium has been shown to be a calcium agonist (Perry et al., 1989; Brenniman et
al., 1981; Shanbaky et al., 1978; U.S. EPA, 1990; WHO, 1990). Potassium alleviates the cardiac
effects and skeletal muscle effects associated with acute barium poisoning (Gould et al., 1973;
Roza and Berman, 1971; Diengott et al., 1964; U.S. EPA, 1990; WHO, 1990). Perry and
Erlanger (1982) observed that rats maintained on the rye-based diet and exposed to cadmium
developed hypertension, whereas rats maintained on standard chow and exposed to cadmium did
not. In view of a possible association between the barium-induced cardiovascular effects and
calcium and potassium intake, the applicability of dose-response data from the Perry et al. (1983)
study to RfD derivation is not considered appropriate.
Schroeder and Mitchner (1975a,b) exposed groups of male and female Long-Evans rats and Charles River CD mice to 0 or 5 ppm barium (as barium acetate) in drinking water from weaning to natural death. No adverse alterations in lifespan, growth, or histopathology of the heart, lungs, kidneys, liver, and spleen were observed in either species. A significant reduction in longevity (defined as mean lifespan of the last surviving five animals) was observed in the male mice. The incidence of proteinuria in male rats exposed to barium for 152 days (173 days of age) was significantly higher than in controls; proteinuria was assessed by dipstick method and the magnitude was not reported. Other clinical chemistry alterations observed in the rats included an increase in serum cholesterol concentrations in females (measured at age 532 and
773 days) and a non-age-related alteration in serum glucose levels in males; the study authors
attached no toxicological significance to these serum chemistry results. Thus, these studies
identify a LOAEL of 5 ppm (0.61 mg Ba/kg-day) for renal glomerular damage, evidenced as
proteinuria in male rats maintained on low mineral diets, and a NOAEL of 5 ppm (1.2 mg Ba/kg-day) in similarly exposed mice.
A health survey of workers at a Sherwin Williams plant concluded that workers exposed to inhaled barium ores and barium carbonate during grinding and mixing operations for at least 5 years had a significantly higher incidence of hypertension (7/12 or 58%) as compared with workers who never worked in barium processes (5/25 or 20%) (NIOSH, 1982). Demographic characteristics and smoking histories for the two groups were similar. No statistically significant differences in mean beta2-microglobulin or prevalence of workers with elevated serum
creatinine, blood urea nitrogen (BUN) values, or urine protein levels were observed between the
two groups. No significant differences in mean blood lead levels or the number of workers with
blood lead levels of > 39 µg/dL were found. Although the results of this study suggest an
association between exposure to barium and hypertension, the results should be interpreted
cautiously because a small number of workers were examined, it appears that blood pressure was
only measured once, and the workers were exposed to a number of other chemicals, including
lead, which is associated with an increase in blood pressure. This study also compared the health
status of current workers exposed to barium ores with those in each of four other job areas; these
comparisons revealed no differences in blood pressure or renal parameters.
Intentional or accidental ingestion of barium compounds causes gastroenteritis, hypokalemia, hypertension, cardiac arrhythmias, and skeletal muscle paralysis. Potassium infusion is used clinically to reverse many of the toxic effects, but does not reverse the
hypertension (Diengott et al., 1964; Gould et al., 1973; U.S. EPA, 1990; WHO, 1990).
Intravenous infusion of barium chloride into anesthetized dogs or guinea pigs resulted in increased blood pressure and cardiac arrhythmias (Hicks et al., 1986; Roza and Berman, 1971). The study in dogs also reported skeletal muscle flaccidity and paralysis (Roza and Berman, 1971). In the dog study, determination of plasma potassium concentrations revealed severe hypokalemia, apparently resulting from enhanced movement of potassium into cells. The hypertension did not appear to be mediated through the renin-angiotensin system because it was
not prevented by bilateral nephrectomy of the dogs. Simultaneous infusion of potassium into the
dogs abolished the cardiac effects and the skeletal muscle flaccidity but did not affect
hypertension.
Data on the reproductive and developmental toxicity of barium compounds are limited. In a study by Dietz et al. (1992), no significant alterations in gestation length, pup survival, or occurrence of external abnormalities were observed in Fischer 344/N rats or B6C3F1 mice exposed to 0, 500 (mice only), 1,000, 2,000, or 4,000 (rats only) ppm barium (as barium chloride dihydrate) in drinking water for 60 (males) or 30 (females) days. Decreases in average litter sizes (not statistically significant in rats) were observed in the 4,000 ppm rat group and 1,000 ppm mouse group. No alterations in epididymal sperm counts, sperm motility, sperm morphology, testicular or epididymal weights, or vaginal cytology were observed in the F0 rats or mice. Low pregnancy rates were observed in all groups (40% in controls to 65% in 4,000 ppm in rats and 55% in controls to 55%-70% in barium-treated groups of mice). The results of this study suggest that oral exposure to barium chloride does not result in reproductive toxicity; however, the results should be interpreted cautiously because of the below-normal pregnancy rates in all groups. Tarasenko et al. (1977) conducted oral and inhalation developmental toxicity studies, but the poor reporting of the study design and results and the lack of statistical analysis of data limit the usefulness of these studies in assessing the developmental toxicity of barium.
___I.A.5. CONFIDENCE IN THE ORAL RfD
Study -- Medium
Database -- Medium.
RfD -- Medium.
The overall confidence in this RfD assessment is medium. Confidence in the principal studies is medium. In the human studies, LOAELs for cardiovascular effects and kidney disease were not identified. The subchronic and chronic animal studies using adequate diets (NTP, 1994; McCauley et al., 1985) provide information regarding NOAELs and LOAELs for renal effects of barium, but cardiovascular effects did not occur in these studies. The lack of cardiovascular measurements (heart rate, blood pressure, or electrocardiogram recordings) in the chronic animal studies that used adequate diets (NTP, 1994) reduces the confidence. Confidence in the database is medium because of the existence of subchronic and chronic human studies, subchronic and chronic animal studies in more than one species, and a reproductive/developmental study in rats
and mice. Medium confidence in the RfD follows.
___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD
Source Document -- U.S. EPA, 1998
This assessment was peer reviewed by external scientists. Their comments have been evaluated and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to U.S. EPA, 1998.
Other EPA Documentation -- None
Agency Consensus Date -- 2/18/1998
___I.A.7. EPA CONTACTS (ORAL RfD)
Please contact the Risk Information Hotline for all questions concerning this assessment or IRIS, in general, at (513) 569-7254 (phone), (513) 569-7159 (fax), or
RIH.IRIS@EPAMAIL.EPA.GOV (Internet address).
__I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
Barium and Compounds
CASRN --7440-39-3
Last Revised -- 3/30/1998
The inhalation Reference Concentration (RfC) is analogous to the oral RfD and is likewise based on the assumption that thresholds exist for certain toxic effects such as cellular necrosis. The inhalation RfC considers toxic effects for both the respiratory system (portal-of-entry) and for
effects peripheral to the respiratory system (extrarespiratory effects). It is expressed in units of mg/cu.m. In general, the RfC is an estimate (with uncertainty spanning perhaps an order of
magnitude) of a daily inhalation exposure of the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. Inhalation RfCs were derived according to the Interim Methods for Development of Inhalation Reference Doses (EPA/600/8-88/066F August 1989) and subsequently, according to Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry (EPA/600/8-90/066F October 1994). RfCs can also be derived for the noncarcinogenic health effects of substances that are carcinogens. Therefore, it is essential to refer to other sources of information concerning the carcinogenicity of this substance. If the U.S. EPA has evaluated this
substance for potential human carcinogenicity, a summary of that evaluation will be contained in
Section II of this file.
NOT VERIFIABLE status indicates that the available data do not meet the minimum database requirements according to the current Agency methods document for RfCs (U.S. EPA, 1994). This status does not preclude the use of information in cited references for assessment by others.
___I.B.1. INHALATION RfC SUMMARY
An RfC for barium is not recommended at this time. The human and animal inhalation and intratracheal studies suggest that the respiratory system is a target of barium toxicity. The data also suggest that systemic effects, such as hypertension, may occur following inhalation exposure. The human studies cannot be used to derive an RfC for barium because exposure concentrations were not reported. Although the NIOSH (1982) study measured barium breathing zone levels for some groups of workers, the barium exposure levels were not measured in the group of workers with the increased incidence of hypertension. The deficient reporting of the
methods and results (in particular, the lack of information on the aerosol generation, number of
animals tested, incidence data, and statistical analysis) of the only animal subchronic/chronic
inhalation study (Tarasenko et al., 1977) precludes deriving an RfC for barium from animal data.
___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC)
Several human studies have investigated the toxicity of inhaled barium compounds. Exposure to insoluble forms of barium such as barium sulfate and barite ore results in baritosis (Pendergrass and Greening, 1953; Seaton et al., 1986; Doig, 1976). Although profuse opacities are observed on the radiographs, no alterations in lung function, abnormal physical findings, or increases in the incidence of subjective symptoms have been reported. It appears that the accumulation of barium sulfate in the lungs will diminish upon termination of barium exposure. Barium exposure levels resulting in baritosis have not been reported. NIOSH (1982) reported an increased incidence of hypertension in workers exposed to an unspecified concentration of barium. Although the results of this study are consistent with the suggestion of hypertension following oral exposure to barium compounds, the results of the NIOSH (1982) study should be interpreted cautiously because it is likely that the workers were also exposed to other metals, including lead, which has a known hypertensive effect.
Inhalation toxicity data in animals are limited to inhalation exposure and intratracheal administration studies by Tarasenko et al. (1977) and an intratracheal administration study by Uchiyama et al. (1995). In the Tarasenko et al. (1977) inhalation study, a number of adverse effects were reported in rats exposed to 5.20 mg/m3 barium carbonate (3.6 mg/m3 barium) 4 h/day, 6 days/week for 4 mo. The effects included alterations in some hematological and serum chemistry parameters, perivascular and peribronchial sclerosis with collagenation in the lungs, and increases in arterial pressure. It does not appear that statistical analysis of the data was performed, and incidence data for the lung effects were not reported. No adverse effects were observed in the rats exposed to 1.15 mg/m3 barium carbonate (0.80 mg/m3 barium). The finding of lung lesions following exposure to barium carbonate was confirmed by an intratracheal administration study conducted by Tarasenko et al. (1977). In this study, fibrous pneumonia and necrosis of the mucous membrane of the large bronchi was observed 9 mo after animals received an intratracheal dose of 50 mg barium carbonate (35 mg barium). As with the
inhalation study, the results of this study were poorly reported. Uchiyama et al. (1995) also
found pulmonary effects (bronchopneumonia, bronchitis, or bronchiolitis) in rabbits
intratracheally administered a suspension containing 85% barium sulfate. Although studies
conducted by Tarasenko et al. (1977) suggest that inhalation exposure to barium carbonate may
result in reproductive effects, confidence in these studies is very low because of poor reporting of
study design and results. Thus, the potential of barium to induce developmental and/or
reproductive effects following inhalation exposure has not been adequately assessed.
Human Studies
The database on the toxicity of inhaled barium compounds in humans consists primarily of studies of occupational exposure to barium sulfate or barite ore or to unspecified soluble barium compounds. Several case reports (for example, Pendergrass and Greening, 1953; Seaton et al., 1986) and a prospective study conducted by Doig (1976) have reported baritosis in barium-exposed workers. Baritosis is considered a benign pneumoconiosis resulting from the inhalation of barite ore or barium sulfate. The most outstanding feature of baritosis is the intense radiopacity of the discrete opacities, which are usually profusely disseminated throughout the lung fields; in some cases the opacities may be so numerous that they appear confluent. The
Third Conference of Experts on Pneumoconiosis (ACGIH, 1992) noted that barium sulfate
produced a noncollagenous type of pneumoconiosis that has a minimal stromal reaction and
consists mainly of reticulin fibers, intact alveolar architecture, and potentially reversible lesions. The available human data on baritosis suggest that the accumulation of barium in the lungs does not result in medical disability or symptomatology. A decline in the profusion and opacity
density, suggesting a decrease in the amount of accumulated barium in the lung, has been
observed several years after termination of barium exposure. Studies by NIOSH (1982) and
Zschiesche et al. (1992) on soluble barium compounds did not include radiography; these studies
focused on the potential for barium to induce systemic effects (e.g., increases in blood pressure,
kidney effects, EKG alterations).
Doig (1976) conducted a prospective study on workers at a barite grinding facility. During the initial investigation in 1947, 5 workers employed for more than 3.5 years were examined. No evidence of baritosis was observed in any of the workers. In 1961, 8 workers (aged 26-45 years, mean of 32 years) employed for 3.5-18 years (mean of 9 years) were
examined (1 of these workers was also examined in 1947). Seven of the workers reported no
respiratory symptoms; 1 worker reported a slight occasional cough. No abnormal findings were
observed during the physical examination of 7 of the workers; crepitations dispelled by cough
were observed in 1 worker (not the same worker reporting an occasional cough).
Pneumoconiosis was detected in the radiographs of 7 workers. Three other workers employed
for 1 mo to 1 year were also examined in 1961. Two of these workers reported having slight
coughs, but no abnormal findings were observed during the physical examination and the chest
radiographs were normal. At this time, dust concentrations ranging from 2,734 to 11,365
particles per cubic mL were measured using a thermal precipitator; the concentration of barium
in the dust was not measured. Barite samples were analyzed for quartz, silica, and iron content.
No quartz was detected, and the total silica and total iron (as Fe2O3) concentrations were 0.07%-1.96% and 0.03%-0.89%, respectively.
Ten of the 11 workers examined in 1961 were reexamined in 1963 (18 mo later). Two new cases of pneumoconiosis were diagnosed. Thus, 9 of 10 workers exposed to barium sulfate for 1.5 to 19.5 years (mean of 8.2 years) had well-marked baritosis. Three of these workers reported a slight or occasional cough and none had dyspnea. Among the 9 workers with
baritosis, 3 did not smoke, 4 smoked 1 pack/day, and 2 smoked > 1 pack/day. In six of the seven workers with previously diagnosed baritosis, no significant changes in the degree of pneumoconiosis were observed; an increase in the number of opacities was observed in the seventh worker. Spirometric lung function tests (vital capacity, flow rate, and forced expiratory volume) were performed in five workers. For three of these workers, the results of the lung function tests were similar to predicted normal values (89%-119% of predicted values). Lung function was below normal in the other two workers (70%-85% of predicted values). It is questionable whether the impaired lung function was related to barium exposure. One of the two workers was an alcoholic and heavy smoker and the other had a fibrotic right middle lung lobe that probably resulted from a childhood illness.
In 1964, the barite grinding facility closed. Follow-up examinations were performed in 1966, 1969, and 1973 on five of the workers. Termination from barium exposure resulted in a decline in the profusion and density of opacities. In 1966, there was slight clearing of opacities; by 1973, there was a marked decrease in profusion and density. No significant changes in lung function were observed during this 10-year period.
NIOSH (1982) conducted a health survey of past and present workers at the Sherwin Williams Company's Coffeyville, KS, facility. Work performed at the facility included grinding, blending, and mixing of mineral ores. At the time of the study, four processes were in operation: "ozide process," which involved blending several grades of zinc oxide; "ozark process," which involved bagging very pure zinc oxide powder; "bayrite process;" which involved grinding and mixing several grades of barium-containing ores; and "sher-tone process," which involved mixing inert clays with animal tallow. A medical evaluation was performed on 61 current
workers (91% participation) and 35 laid-off or retired workers (27% participation). Information
on demographics, frequency of various symptoms occurring during the past 2 mo, chemical
exposure, occupational history, smoking history, and histories of renal disease, allergies, and
hypertension were obtained from directed questionnaires. In addition, spot urine and blood
samples and blood pressure measurements were taken. Exposures to barium, lead, cadmium, and
zinc were estimated from 27 personal samples collected over a 2-day period. In the seven
personal breathing zone samples collected from the bayrite area, the levels of soluble barium
ranged from 87.3 to 1,920.0 µg/m3 (mean of 1,068.5 µg/m3), lead levels ranged from not detected to 15.0 µg/m3 (mean of 12.2 µg/m3, excluding the two detect samples), zinc levels ranged from 22.4 to 132.0 µg/m3 (mean of 72 µg/m3), and all seven samples had no detectable levels of cadmium. Soluble barium was also detected in breathing zone samples in the ozark area (10.6-1,397.0 µg/m3; mean of 196.1 µg/m3), ozide area (11.6-99.5 µg/m3; mean of 46.8 µg/m3), and
sher-tone area (114.3-167.5 µg/m3; mean of 70.45 µg/m3).
Two approaches were used to analyze the results of the health survey. In the first approach, the workers were divided into five groups on the basis of current job assignments. Fourteen of the 61 current workers worked in the bayrite area. No statistically significant increases among the different groups of workers were observed in the incidence of subjective symptoms (e.g., headache, cough, nausea), or differences in mean blood lead levels, number of workers with blood lead levels of greater than 39 µg/dL, mean free erythrocyte protoporphyrin (FEP) levels, mean hematocrit levels, mean serum creatinine levels, number of workers with serum creatinine levels of greater than 1.5 mg/dL, number of workers with BUN levels of greater
than 20 mg/dL, blood pressure, or mean urine cadmium levels.
In the second approach, the workers were divided into seven groups on the basis of past job assignments. One group consisted of 12 workers working in barium process areas (bayrite process and other processes no longer in operation at the facility that involved exposure to barium ores and barium carbonate) for at least 5 years; barium exposure levels were not reported for this group. The results of the health survey for the barium-exposed workers were compared with 25 workers who stated that they had never worked in barium process areas. No statistically significant differences between the groups were observed in mean age, number of years
employed, number of current or past smokers, prevalence of subjective symptoms, mean FEP
levels, mean hematocrit levels, mean urine cadmium levels, mean beta2-microglobulin levels, or
the prevalence of workers with elevated serum creatinine, BUN, or urine protein levels. The
number of workers with elevated blood pressure (defined as systolic pressure 140 mm Hg or
diastolic pressure 90 mm Hg, or taking medication for hypertension) was significantly higher (p = 0.029) in the barium-exposed group (7/12, 58%) than in the comparison group (5/25, 20%). The number of workers in the barium group with blood lead levels of > 39 µg/dL was lower than in the comparison group (0% versus 28%); however, the authors determined the difference not to be statistically significant (p = 0.072). Additionally, there was no significant difference between mean blood lead levels in the barium-exposed workers (24 µg/dL) and the comparison group (32 µg/dL). Although the results of this study suggest an association between exposure to barium and hypertension, the results should be interpreted cautiously because only a small number of workers were examined, it appears that blood pressure was only measured once, and the workers were exposed to a number of other chemicals, including lead, which is associated with an increase in blood pressure.
The health effects associated with occupational exposure to barium during arc welding with barium-containing stick electrodes and flux-cored wires were investigated by Zschiesche et al. (1992). A group of 18 healthy welders not using barium-containing consumables in the past 10 days were divided into three groups: group A (n = 8, mean age of 30.4 years) performed arc welding with barium-containing stick electrodes, group B (n = 5, mean age of 43.6 years) performed arc welding with barium-containing self-shielded flux-cored wires, and group C (n = 5, mean age of 32.0 years) performed arc welding with barium-containing self-shielded flux-
cored wires using welding guns with built-in ventilation systems. All welders performed
welding with barium-free consumables on Thursday and Friday of the first week of the study.
Barium-containing consumables were used during week 2 of the study and on Monday of week
3. The subjects welded for an average of 4 h per day. The average barium concentrations in the
breathing zones were 4.4 (range of 0.1-22.7), 2.0 (0.3-6.0), and 0.3 (0.1-1.5) mg/m3 for groups A, B, and C, respectively. No exposure-related subjective symptoms of health or neurological signs were found. No significant differences between pre and postshift EKG, pulse rate, whole blood
pH, base excess and standard bicarbonate, and plasma concentrations of sodium, magnesium, and
total and ionized calcium were observed. During week 2, decreases in plasma potassium
concentrations were observed in groups A and C; the levels returned to the normal range under
continuation of barium exposure and were not statistically different from levels during week 1
(no barium exposure). This drop in serum potassium levels was not observed in group B, which
had a barium exposure level similar to group A.
Animal Studies
Data on the toxicity of barium compounds in animals following inhalation exposure is
limited to a subchronic study conducted by Tarasenko et al. (1977). In this study, male albino
rats (strain and number of animals per group not reported) were exposed to 0, 1.15, or 5.20
mg/m3 barium carbonate (0, 0.80, or 3.6 mg Ba/m3) 4 h/day, 6 days/week for 4 mo. No information on aerosol generation or the size distribution of the particles was reported. In the introduction section of the paper, the authors state, "we have demonstrated by electron
microscopy that the size of almost 80% of the dust particles is less than 2 µm"; however, it is not
known if this statement refers to the aerosols generated for this study. The following endpoints
were used to assess toxicity: body weight gain, arterial pressure, hematological (hemoglobin,
leukocytes, and thrombocytes) and serum chemistry (glucose, phosphorus, total protein, alkaline
phosphatase, and cholinesterase) parameters, urine calcium levels, bromosulfophthalein test of
liver function, electrocardiogram measurement, and histological examination (tissues examined
were not listed).
The authors noted that no alterations were observed in the rats exposed to 1.15 mg/m3 barium carbonate. In the 5.20 mg/m3 group, a number of alterations were reported; however, it does not appear that the data were statistically analyzed. The alterations included a 21% decrease in body weight gain, a 32% increase in arterial pressure, altered hematological parameters (decreases in hemoglobin and thrombocyte levels and increases in leukocyte levels), altered serum chemistry parameters (decreased sugar and total protein levels, increased phosphorus levels, decreased alkaline phosphatase activity, and increased cholinesterase
activity), increased calcium levels in the urine, impaired liver function, and histological
alterations in the heart, liver, kidneys, and lungs. No alterations in the EKG readings were
reported. However, when the rats were administered proserine, the EKG reading suggested
disturbances in heart conductivity. The authors noted that the heart, liver, and kidneys "had a
character of mild protein ('granular') dystrophy." In the lungs, the histological alterations
consisted of moderate perivascular and peribronchial sclerosis with focal thickening of the
intraalveolar septa and collagenation. No incidence data were provided.
In another study conducted by Tarasenko et al. (1977), animals (it appears that albino rats and rabbits were tested; number of animals not specified) were administered an intratracheal dose of 50 mg barium carbonate (35 mg barium). Three months after administration, sclerotic changes were observed in the lungs. The severity of the sclerosis progressed. At 9 mo, fibrous pneumonia with necrosis of mucous membranes of the large bronchi was observed.
Uchiyama et al. (1995) administered a single intratracheal dose of 0.015, 0.3, or 0.6 mL/kg of Ba147 to rabbits. Ba147 is a preparation containing 85% barium sulfate. No treatment-related effects on pulmonary ventilation (measured 1 day, 3 days, and 1, 2, and 4 weeks after dosing), levels of blood gases (measured at the same time as pulmonary
ventilation), or lung weights were observed. Soft X-rays of the lungs revealed dose-related
shadows. Bronchopneumonia, bronchitis, or bronchiolitis was observed in 28 of 36 animals
during the first week after dosing. Thereafter, the alterations were not observed. No further
details of this study were available because the study was published in a Japanese-language
journal; information on the study was obtained from an English abstract.
Information on the reproductive/developmental toxicity of inhaled barium compounds is limited to a series of studies conducted by Tarasenko et al. (1977). The results of these studies were described in general terms and no data were provided. The poor reporting of the study design and results and the lack of statistical analysis of the data limit the usefulness of the data for assessing the reproductive/developmental toxicity of barium.
Exposure of male rats to 22.6 mg/m3 barium carbonate (15.7 mg Ba/m3) for one cycle of spermatogenesis (daily exposure duration and frequency of exposure were not reported) resulted in decreases in the number of spermatozoids, percentage of motile forms and time of motility, osmotic resistance of spermatozoids, increases in the number of ducts with desquamated epithelium, and a reduced number of ducts with 12th stage meiosis (Tarasenko et al., 1977). Similar results were observed in rats exposed to 5.2 mg/m3 barium carbonate (3.6 mg Ba/m3) 4 h/day, 6 days/week for 4 mo.
Tarasenko et al. (1977) also reported that a shortening of the mean duration of estrous cycle and an alteration in the proportion of mature and dying ovarian follicles were observed in rats exposed to 13.4 mg/m3 barium carbonate (9.3 mg Ba/m3) for 4 mo (duration of daily exposure or frequency of exposure was not reported), as compared to a control group. These effects were not observed in rats exposed to 3.1 mg/m3 (2.2 mg Ba/m3). The authors also noted that rats in the 13.4 mg/m3 group gave birth to underdeveloped offspring that showed considerable mortality and slow increases in body weight during the first two months of life. The authors did not state whether the barium carbonate-exposed females were mated to exposed or unexposed males.
___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC)
Not applicable.
___I.B.4. ADDITIONAL STUDIES/COMMENTS (INHALATION RfC)
Not applicable.
___I.B.5. CONFIDENCE IN THE INHALATION RfC
Not applicable.
___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC
Source Document -- U.S. EPA, 1998.
This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to the Toxicological Review of Barium and Compounds (CAS No. 7440-39-3) in support of summary information on IRIS (U.S. EPA, 1998).
Agency Consensus Date -- 2/18/1998
___I.B.7. EPA CONTACTS (INHALATION RfC)
Please contact the Risk Information Hotline for all questions concerning this assessment or IRIS, in general, at (513) 569-7254 (phone), (513) 569-7159 (fax), or
RIH.IRIS@EPAMAIL.EPA.GOV (Internet address).
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Barium and Compounds
CASRN -- 7440-39-3
Last Revised -- 3/30/1998
Section II provides information on three aspects of the carcinogenic assessment for the substance in question, the weight-of-evidence judgment of the likelihood that the substance is a human carcinogen, and quantitative estimates of risk from oral exposure and from inhalation exposure. The quantitative risk estimates are presented in three ways. The slope factor is the result of application of a low-dose extrapolation procedure and is presented as the risk per (mg/kg)/day. The unit risk is the quantitative estimate in terms of either risk per µg/L drinking water or risk per µg/m3 air breathed. The third form in which risk is presented is a concentration of the chemical in drinking water or air providing cancer risks of 1 in 10,000, 1 in 100,000, or 1 in 1,000,000. The rationale and methods used to develop the carcinogenicity information in IRIS are described in The Risk Assessment Guidelines of 1986 (EPA/600/8-87/045) and in the IRIS Background Document. IRIS summaries developed since the publication of EPA's more recent Proposed Guidelines for Carcinogen Risk Assessment also utilize those Guidelines where
indicated (Federal Register 61[79]:17960-18011, April 23, 1996). Users are referred to Section I of this IRIS file for information on long-term toxic effects other than carcinogenicity.
__II.A. EVIDENCE FOR HUMAN CARCINOGENICITY
___II.A.1. WEIGHT-OF-EVIDENCE CHARACTERIZATION
Under EPA's 1986 Guidelines for Carcinogen Risk Assessment, barium would be classified as Group D, not classifiable as to human carcinogenicity. Although adequate chronic oral exposure studies in rats and mice have not demonstrated carcinogenic effects, the lack of adequate inhalation studies precludes assessing the carcinogenic potential of inhaled barium.
Under the Proposed Guidelines for Carcinogenic Risk Assessment (U.S. EPA, 1996), barium is considered not likely to be carcinogenic to humans following oral exposure and its carcinogenic potential cannot be determined following inhalation exposure.
Basis -- Oral exposure studies in rats and mice (NTP, 1994; McCauley et al., 1985; Schroeder and Mitchener, 1975a,b) did not find significant increases in tumor incidence following chronic exposure. In the NTP (1994) rat study, statistically significant negative trends in the incidence of leukemia, adrenal tumors, and mammary gland tumors were observed. The design of the rat and mouse NTP (1994) studies was adequate to assess carcinogenicity. These studies used an adequate number of animals per group, exposed animals for 2 years, tested several dosage levels, and examined an extensive number of tissues.
The inhalation exposure and intratracheal studies conducted by Tarasenko et al. (1977) are inadequate for carcinogenicity evaluation because of several deficiencies in the design and reporting, including single or subchronic exposure duration, inadequate reporting of aerosol generation methodology, inferior reporting of study results (including the apparent lack of statistical analysis), and the use of only one sex (males). These studies were designed to be toxicity studies, and it is not known if the investigators looked for tumors.
___II.A.2. HUMAN CARCINOGENICITY DATA
Inadequate. The only available human carcinogenicity data are two topical application studies conducted by Ayre (1966) and Ayre and LeGuerrier (1967). These studies involved a single topical application of barium chloride to the cervix of one woman.
In a study to determine the safety of components of intrauterine contraceptive devices, a single topical application of 1.25 mM barium chloride was applied to the squamocolumnar junctional area of the cervix of a woman with no known history of abnormal cervical cytology results (Ayre, 1966; Ayre and LeGuerrier, 1967). A cervical cell scraping was performed 48 h after application. The topical application of barium chloride and cervical cell scraping was
repeated four times at intervals of 4-6 weeks. A number of cell transformations resembling
severe premalignant dysplasia were observed; the transformed cells were described as bizarre,
multinucleated cells with profoundly altered nuclear chromatin. One to three weeks after barium
chloride application, these cellular alterations were no longer observed.
In another study (Ayre, 1966; Ayre and LeGuerrier, 1967), 1.25 mM barium chloride was mixed with equal amounts of 70% DMSO and a single topical application of the mixture was applied to the squamocolumnar junctional area of the cervix. It is assumed that only one subject was used, and it was not reported whether this was the same woman previously tested. Cervical scrapings were performed after 48 h, 72 h, and twice weekly for an unspecified amount of time. The cell transformations were similar to extreme dysplasia; in addition, spindle cells and cells with marked hyperchromatism with multiple chromatin bundles and enlarged irregular nucleated
forms were observed. Cell transformations were also observed in deeper layers of the squamous
epithelium. The authors noted that the transformed cells resembled cell findings of cancer in
situ. Sixteen days after topical application, the cell transformations were not observed in the deeper layers of the epithelium, but were still present in superficial and intermediate areas.
___II.A.3. ANIMAL CARCINOGENICITY DATA
Oral Exposure. Sufficient. Four animal studies evaluated the carcinogenicity of barium (NTP, 1994; McCauley et al., 1985; Schroeder and Mitchener, 1975a,b) in rats and mice. The design of NTP (1994) rat and mouse studies was adequate for carcinogenicity evaluation.
In a chronic study conducted by NTP (1994), male and female B6C3F1 mice (60 animals/dose group/sex) received barium chloride dihydrate in drinking water at concentrations of 0, 500, 1,250, or 2,500 ppm for 103 weeks (males) and 104 weeks (females). The authors estimated the daily doses for the treated groups using measured water consumption and body
weights as 30, 75, and 160 mg Ba/kg-day for males, and 40, 90, and 200 mg Ba/kg-day for females. The animals were fed an NIH-07 mash diet; the barium content of the diet was not reported. At the 15-mo interim evaluation, venous blood was collected from all mice for hematology and clinical chemistry. In addition, a limited number of mice (9, 10, 10, and 10 males and 10, 7, 10, and 6 females from the 0, 500, 1,250, and 2,500 ppm groups, respectively) were sacrificed at 15 mo. The remaining animals continued on the study until they were moribund, died naturally, or were sacrificed at the end of the study. Necropsy and complete histopathological examinations were performed on all animals. Body weights were monitored and organ weights were determined at 15 mo.
At 2,500 ppm, the percent probabilities of survival for mice at the end of study (65% for males and 26% for females) were significantly lower than those of the controls (89% males; 76% females). The reduction in survival became apparent in females at week 15 and in males at week 65, and was attributed to chemical-related renal lesions. Survival was not significantly lower relative to controls at the lower dosage levels. In male and female high-dose mice, the final mean body weights were 8% and 12% lower, respectively, than those of the corresponding control groups. Water consumption was not affected by barium.
At the 15-mo interim evaluation, the absolute and relative spleen weights of the female mice that received 2,500 ppm were significantly lower than those of the controls, and the absolute and relative thymus weights of high-dose male mice that received 2,500 ppm were marginally lower than those of the controls. Determination of hematology and clinical chemistry parameters (e.g., phosphorus, calcium, and urea nitrogen) at the 15-mo interim evaluation
showed no significant differences between control and exposed mice.
The incidence of nephropathy at the end of the study was significantly increased in mice receiving 2,500 ppm. There were no other chemical-related noncarcinogenic histological changes. The incidence of neoplasms in the barium-exposed mice was not significantly higher than in control mice. In the 2,500 ppm female mice, the incidence of several neoplasms was significantly lower than in the controls; the authors attributed this finding to the marked reduction in survival in the barium-exposed animals.
In the same chronic study (NTP, 1994), male and female F344/N rats (60 animals/dose group/sex) received drinking water containing 0, 500, 1,250, or 2,500 ppm barium chloride dihydrate for 104 weeks (males) or 105 weeks (females). The authors estimated daily doses for the treated groups using measured water consumption and body weights as 15, 30, and 60 mg
Ba/kg-day for males, and 15, 45, and 75 mg Ba/kg-day for females. The animals were fed an NIH-07 mash diet; the barium content of the diet was not reported. For a 15-mo interim evaluation, venous blood was collected from all rats for hematology and clinical chemistry. In addition, a limited number of rats (10 from each group) were sacrificed at 15 mo. The remaining animals stayed on the study until they were moribund, died naturally, or were terminally sacrificed. Necropsy and complete histopathological examinations were performed on all animals. Body weights were monitored throughout the study, and organ weights were determined in the animals killed at 15 mo.
A marginally increased survival of exposed male groups (percent probability of survival: 62%, 58%, and 67% for the 500, 1,250, and 2,500 ppm groups, respectively) compared with that of the male controls (44%) was observed. Survival of the females was not significantly affected. For male rats receiving 2,500 ppm the final mean body weights were 5% lower than for controls. The final mean body weights of females receiving 1,250 and 2,500 ppm were 6% and 11% lower, respectively, than those of controls. Water consumption was decreased in a dose-related
manner; at the highest exposure level the decrease, relative to controls, was 22% in males and
25% in females.
Absolute and relative organ weights, determined only at the 15-mo interim evaluation, were not affected in the males. In the females, a decrease in the absolute liver weight and an increase in the relative kidney weights occurred at 2,500 ppm. Body weights in the females at 15 mo were decreased by 9% at 2,500 ppm in comparison with controls, whereas kidney weights in this group were slightly increased relative to those of controls. Determination of hematology values and clinical chemistry values (e.g., phosphorus, calcium, and urea nitrogen) at the 15-mo interim evaluation showed no significant differences between control and exposed rats.
No chemical-related noncarcinogenic histological changes were observed in any organs or tissues. No statistically significant increases in the incidence of neoplasms were observed in the barium-exposed rats. Significant negative trends were observed in the incidence of mononuclear cell leukemia in male rats (35/50, 25/50, 26/50, and 15/50 in 0, 500, 1,250, and 2,500 ppm groups, respectively), benign and malignant adrenal medulla pheochromocytoma in
male rats (13/49, 11/50, 12/49, and 6/50, respectively), and mammary gland neoplasms (fibroadenoma, adenoma, or carcinoma) in female rats (17/50, 21/50, 13/50, 11/50, respectively). Additionally, the incidences of mononuclear cell leukemia in the male rats exposed to 500, 1,250, and 2,500 ppm and adrenal medulla pheochromocytoma in male rats exposed to 2,500 ppm were significantly lower than the incidences in the controls.
In a study by McCauley et al. (1985), CD Sprague-Dawley rats were fed Purina rat chow containing 12 ppm barium. The three exposure regimens were as follows: (1) male CD Sprague-Dawley rats (12/group) were exposed to 0, 1, 10, 100, or 250 ppm barium (barium
chloride) in drinking water for 36 weeks; (2) female CD Sprague-Dawley rats (12/group) were
exposed to 0 or 250 ppm for 46 weeks; and (3) male CD Sprague-Dawley rats (10/group) were
exposed to 0, 1, 10, or 100 ppm barium in drinking water for 68 weeks. The authors reported
that no significant differences in food or water intake or body weight were observed, but did not
report the actual data. They stated that rats that received 10 ppm of barium in the drinking water
ingested 1.5 mg Ba/kg-day from water and 1 mg Ba/kg-day from the Purina diet. This barium
intake was used to estimate total barium intake for the other exposure levels. Thus, the estimated
total barium intakes were 1, 1.15, 2.5, 16, and 38.5 mg/kg-day for the 0, 1, 10, 100, and 250 ppm
concentrations for all exposure regimens.
The authors did not comment on whether there were any effects on survival. Histological evaluations of an extensive number of tissues, including gastrointestinal tract, liver, heart, adrenal gland, brain, respiratory tract, spleen, thymus, kidneys, ovaries, and testes, did not reveal barium-related lesions. No alterations in hematocrit levels were observed. A retinal lesion (focal absence of the outer layers of the retina) was observed in 5/12 males exposed to 100 ppm but 0/11 males exposed to 250 ppm for 36 weeks, 7/12 females exposed to 250 ppm for 46 weeks, 1/10 male controls exposed for 68 weeks, and 2/10 males in each of the 1, 10, and 100 ppm groups exposed for 68 weeks. Because this lesion does not appear to be dose or duration-related, its relationship to barium exposure is uncertain. No significant increases in the incidence of neoplasms were observed in the barium-exposed rats, but the study is shorter than lifetime and would have missed late-developing tumors.
Schroeder and Mitchener (1975a) exposed Long-Evans rats (52/sex/group) to 0 or 5 ppm barium (barium acetate) in drinking water from weaning to natural death. Dosages from drinking water were 0.61 mg Ba/kg-day for males and 0.67 mg Ba/kg-day for females based on reference body weights and water intake from U.S. EPA (1988). The diet was characterized as a "low- metal" diet and included 60% rye flour, 30% dried skim milk, 9% corn oil, 1% iodized chloride, and assorted vitamins; the barium content was not reported. Barium had no significant effect on the growth of males, but increased the growth of older females. The life span of the rats was not significantly affected. The incidence of proteinuria in males exposed to barium for approximately 152 days (at 173 days of age) was significantly (p < 0.05) higher than in controls; proteinuria was assessed by a dipstick method and the magnitude was not reported. Female rats at 532 and 773 days of age had higher (p < 0.001) serum cholesterol concentrations than did controls tested at 516 and 769 days of age. Serum glucose levels for males at these ages were also different from controls but did not follow an age-related pattern. The authors attached no biological or toxicological significance to these serum chemistry results. Histopathology of heart, lung, kidney, liver, and spleen did not reveal alterations. No significant increases in the number of gross tumors were observed in the barium-exposed male (8/30) or female (15/33) rats as compared to the controls (4/26 and 17/24 for males and females, respectively).
Schroeder and Mitchener (1975b) exposed white mice of the Charles River CD strain (36-54/sex) to 0 or 5 ppm of barium (as barium acetate) in drinking water for their lifetimes. Dosages from drinking water were 1.18 mg Ba/kg-day for males and 1.20 mg Ba/kg-day for females (U.S. EPA, 1988). The diet was characterized as a "low metal" diet and included 60%
rye flour, 30% dried skim milk, 9% corn oil, 1% iodized chloride, and assorted vitamins; the
barium content of the diet was not reported. Growth and body weights were not affected by the
barium treatment. Histology of the heart, lung, liver, kidney, and spleen was normal. In males,
longevity (defined as the mean life span of the last surviving 5 animals of each sex in each
treatment group) was significantly (p 0.025) reduced; longevity of the barium-treated males was 815 days as compared with 920 days for the controls. The mean life span, however, was not
affected. The incidences of lymphoma leukemia and lung tumors in the male (7/37 and 4/37,
respectively) and female (5/21 and 3/21) mice exposed to barium were not significantly different
from the incidences in the control mice (3/38 and 3/47 for lymphoma leukemia in males and
females, respectively, and 5/38 and 9/47 for lung tumors).
Inhalation Studies. Inadequate. The carcinogenic potential of barium following inhalation exposure has not been adequately tested. The inhalation toxicity/carcinogenicity database is limited to a single subchronic inhalation study conducted by Tarasenko et al. (1977). This study was not designed to assess carcinogenicity; the duration was too short (4 mo) and the study design and results were poorly reported. Tarasenko et al. (1977) also conducted an intratracheal administration study. Although this single-exposure study was not designed to assess carcinogenicity, it provides some information on the progression of lesions 3, 6, and 9 mo postexposure.
In the Tarasenko et al. (1977) inhalation study, male albino rats (strain and number of animals per group not reported) were exposed to 0, 1.15, or 5.20 mg/m3 barium carbonate (0, 0.80, or 3.6 mg Ba/m3) 4 h/day, 6 days/week for 4 mo. No information on aerosol generation or the size distribution of the particles was reported. In the introduction section of the paper, the authors state, "we have demonstrated by electron microscopy that the size of almost 80% of the dust particles is less than 2 µm"; however, it is not known if this statement refers to the aerosols generated for this study. The following endpoints were used to assess toxicity: body weight gain, arterial pressure, hematological (hemoglobin, leukocytes, and thrombocytes) and serum chemistry (glucose, phosphorus, total protein, alkaline phosphatase, and cholinesterase) parameters, urine calcium levels, bromosulfophthalein test of liver function, electrocardiogram measurement, and histological examination (tissues examined were not listed).
The authors noted that no alterations were observed in the rats exposed to 1.15 mg/m3 barium carbonate. In the 5.20 mg/m3 group, a number of alterations were reported; however, it does not appear that the data were statistically analyzed. The alterations included a 21% decrease in body weight gain, a 32% increase in arterial pressure, altered hematological parameters (decreases in hemoglobin and thrombocyte levels and increases in leukocyte levels), altered serum chemistry parameters (decreased sugar and total protein levels, increased phosphorus levels, decreased alkaline phosphatase activity, and increased cholinesterase
activity), increased calcium levels in the urine, impaired liver function, and histological
alterations in the heart, liver, kidneys, and lungs. No alterations in the EKG readings were
reported. However, when the rats were administered proserine, the EKG reading suggested
disturbances in heart conductivity. The authors noted that the heart, liver, and kidneys "had a
character of mild protein ('granular') dystrophy." In the lungs, the histological alterations
consisted of moderate perivascular and peribronchial sclerosis with focal thickening of the
intraalveolar septa and collagenation. No incidence data were provided. The presence of
neoplasms was not reported; it is unclear whether the investigators looked for neoplasms. This
study was not designed to assess carcinogenicity; in particular, the exposure duration was too
short.
In another study conducted by Tarasenko et al. (1977), animals (species and number not specified) were administered an intratracheal dose of 50 mg barium carbonate (35 mg barium). Three months after administration, sclerotic changes were observed in the lungs. The severity of the sclerosis progressed. At 9 mo, fibrous pneumonia with necrosis of mucous membranes of the large bronchi was observed. Although this study was not designed to assess carcinogenicity, the findings of the study suggest that the fibrogenic lesions progress over time.
___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
There is a limited amount of information available on the genotoxicity of barium compounds. No in vivo studies have been conducted. Most in vitro studies have found that barium chloride and barium nitrate did not induce gene mutations in bacterial assays with or without metabolic activation. Ames assays with Salmonella typhimurium strains TA1535, TA1538, TA1537, TA97, TA98, and TA100 with or without metabolic activation (Monaco et al.,
1990, 1991; NTP, 1994), rec assays with Bacillus subtilis strains H17 and H45 (Nishioka, 1975; Kanematsu et al., 1980), and a microscreen assay with Escherichia coli (Rossman et al., 1991) with metabolic activation have produced negative results with barium chloride. Negative results have also been observed for barium nitrate in the rec assay using B. subtilis strains H17 and H45 (Kanematsu et al., 1980). Barium chloride induced gene mutations in L5178Y mouse lymphoma cells with metabolic activation, but not in the absence of metabolic activation (NTP, 1994). Neither barium acetate nor barium chloride decreased the fidelity of DNA synthesis in avian
myeloblastosis virus DNA polymerase (Sirover and Loeb, 1976). In mammalian cells, barium
chloride did not induce sister chromatid exchanges or chromosomal aberrations in cultured
Chinese hamster ovary cells, with or without activation (NTP, 1994).
__II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL
EXPOSURE
Not applicable. The results of the oral carcinogenicity study suggest that barium is not likely to be carcinogenic to humans.
___II.B.1. SUMMARY OF RISK ESTIMATES
Not applicable.
___II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE)
Not applicable.
___II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE)
Not applicable.
___II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE)
Not applicable.
__II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION
EXPOSURE
Not applicable. The inhalation database is inadequate to determine the qualitative and quantitative cancer risk for barium.
___II.C.1. SUMMARY OF RISK ESTIMATES
Not applicable.
___II.C.2. DOSE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION
EXPOSURE
Not applicable.
___II.C.3. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION EXPOSURE)
Not applicable.
___II.C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION
EXPOSURE)
Not applicable.
__II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY
ASSESSMENT)
___II.D.1. EPA DOCUMENTATION
Source Document -- U.S. EPA, 1998
This assessment was peer reviewed by external scientists. Their comments have been evaluated and incorporated in finalization of this IRIS summary. A record of these comments in included as an appendix to the Toxicological Review of Barium and Compounds (CAS No. 7440-39-3) in support of summary information on IRIS (U.S. EPA, 1998).
___II.D.2. EPA REVIEW (CARCINOGENICITY ASSESSMENT)
Agency Consensus Date -- 2/18/1998
___II.D.3. EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
Please contact the Risk Information Hotline for all questions concerning this assessment or IRIS, in general, at (513) 569-7254 (phone), (513) 569-7159 (fax), or
RIH.IRIS@EPAMAIL.EPA.GOV (Internet address).
_III. [reserved]
_IV. [reserved]
_V. [reserved]
_VI. BIBLIOGRAPHY
Barium and Compounds
CASRN -- 7440-39-3
Last Revised -- 3/30/1998
__VI.A. ORAL RfD REFERENCES
Brenniman, GR; Levy, PS. (1984) Epidemiological study of barium in Illinois drinking water supplies. In: Advances in modern toxicology, Calabrese, EJ, ed. Princeton, NJ: Princeton Scientific Publications, pp. 231-249.
Brenniman, GR; Kojola, WH; Levy, PS; et al. (1981) High barium levels in public drinking water and its association with elevated blood pressure. Arch Environ Health 36(1):28-32.
Cuddihy, RG; Griffith, WC. (1972) A biological model describing tissue distribution and whole-body retention of barium and lanthanum in beagle dogs after inhalation and gavage. Health Phys 23:621-633.
Diengott, D; Rozsa, O; Levy, N; et al. (1964) Hypokalemia in barium poisoning. Lancet 2:343-344.
Dietz, DD; Elwell, MR; Davis, WE, Jr.; et al. (1992) Subchronic toxicity of barium chloride dihydrate administered to rats and mice in the drinking water. Fundam Appl Toxicol 19:527-537.
Gould, DB; Sorrell, MR; Lupariello, AD. (1973) Barium sulfide poisoning, some factors contributing to survival. Arch Intern Med 132(6):891-894.
Hicks, R; Caldas, LQ; Dare, PR; et al. (1986) Cardiotoxic and bronchoconstrictor effects of industrial metal fumes containing barium. Arch Toxicol Suppl 9:416-420.
McCauley, PT; Douglas, BH; Laurie, RD; et al. (1985) Investigations into the effect of drinking water barium on rats. In: Inorganics in drinking water and cardiovascular disease, Calabrese, EJ, ed. Princeton, NJ: Princeton Scientific Publications, pp. 197-210.
National Institute for Occupational Safety and Health (NIOSH). (1982) Health hazard evaluation report: Sherwin Williams Company, Coffeyville, Kansas. National Institute for Occupational Safety and Health, Centers for Disease Control, Cincinnati, OH. NIOSH Report No. HETA/81-356-1183.
National Research Council (NRC). (1995) Nutrient requirements of laboratory animals. Washington, DC: National Academy Press, p. 13.
National Toxicology Program (NTP). (1994) Technical report on the toxicology and carcinogenesis studies of barium chloride dihydrate (CAS No. 10326-27-9) in F344/N rats and B6C3F1 mice (drinking water studies). NTP TR 432. National Toxicological Program, Research
Triangle Park, NC. NIH Pub. No. 94-3163. NTIS Pub PB94-214178.
Perry, Jr., HM; Erlanger, MW. (1982) Effect of diet on increases in systolic pressure induced in rats by chronic cadmium feeding. J Nutr 112(10):1983-1989.
Perry, HM; Kopp, SJ; Erlanger, MW; et al. (1983) Cardiovascular effects of chronic barium ingestion. In: Trace substances in environmental health, XVII, Hemphill, DD, ed. Proc. Univ. Missouri's 17th Ann. Conf. on Trace Substances in Environmental Health. University of Missouri Press, Columbia, MO. pp. 155-164.
Perry, HM; Perry, EF; Erlanger, MW; et al. (1985) Barium-induced hypertension. In: Inorganic in drinking water and cardiovascular disease. Ch. XX. Adv Mod Environ Toxicol 9:221-279.
Perry, HM, Jr.; Koop, SJ; Perry, EF; et al. (1989) Hypertension and associated cardiovascular abnormalities induced by chronic barium feeding. J Toxicol Environ Health 28(3):373-388.
Roza, O; Berman, LB. (1971) The pathophysiology of barium: hypokalemic and cardiovascular effects. J Pharmacol Exp Ther 177(2):433-439.
Schroeder, H; Mitchener, M. (1975a) Life-term studies in rats: effects of aluminum, barium, beryllium and tungsten. J Nutr 105:421-427.
Schroeder, H; Mitchener, M. (1975b) Life-term effects of mercury, methyl mercury and nine other trace metals on mice. J Nutr 105:452-458.
Shanbaky, IO; Borowitz, JL; Kessler, WV. (1978) Mechanisms of cadmium- and barium-induced adrenal catecholamine release. Toxicol Appl Pharmacol 44(1):99-105.
Sutton, RAL; Dirks, JH. (1986) Calcium and magnesium: renal handling and disorders of metabolism. In: The kidney, third ed. Brenner, BM; Rector, Jr., FC, eds. Philadelphia: W.B. Saunders Company, pp. 551-552.
Tarasenko, NY; Pronin, OA; Silayev, AA. (1977) Barium compounds as industrial poisons (an experimental study). J Hyg Epid Microbiol Immun 21(4):361-373.
Tardiff, RG; Robinson, M; Ulmer, NS. (1980) Subchronic oral toxicity of BaCl2 in rats. J Environ Pathol Toxicol 4:267-275.
Taylor, DM; Pligh, PH; Duggan, MH. (1962) The absorption of calcium, strontium, barium and radium from the gastrointestinal tract of the rat. Biochem J 83:25-29.
U.S. Environmental Protection Agency. (1990) Drinking water criteria document on barium. Criteria and Standards Division, Office of Drinking Water, Washington, DC. NTIS PB 91-142869.
U.S. Environmental Protection Agency. (1998) Toxicological review of barium and compounds in support of summary information on the Integrated Risk Information System (IRIS). Available online from National Center for Environmental Assessment, http://www.epa.gov/iris.
Wones, RG; Stadler, BL; Frohman, LA. (1990) Lack of effect of drinking water barium on cardiovascular risk factor. Environ Health Perspect 85:355-359.
World Health Organization (WHO). (1990) Environmental Health Criteria 107: Barium. Sponsored by United Nations Environment Programme, International Labour Organisation, and World Health Organization.
Zalups, RK; Lash, LH. (1990) Advances in understanding the renal transport and toxicity of mercury. J Toxicol Environ Health 42(1):1-44.
Zalups, RK; Klotzbach, JM; Diamond, GL. (1987) Enhanced accumulation of injected inorganic mercury in renal outer medulla after unilateral nephrectomy. Toxicol Appl Pharmacol 89(2):226-236.
Zalups, RK; Gelein, RM; Morrow, PE; et al. (1988) Nephrotoxicity of uranyl fluoride in uninephrectomized and sham-operated rats. Toxicol Appl Pharmacol 94(1):11-22.
__VI.B. INHALATION RfC REFERENCES
American Conference of Governmental Industrial Hygienists (ACGIH). (1992) Documentation of threshold limit values for chemical substances. ACGIH, Cincinnati, OH.
Doig, AT. (1976) Baritosis: a benign pneumoconiosis. Thorax 31:30-39.
National Institute for Occupational Safety and Health (NIOSH). (1982) Health hazard evaluation report No. 81-356-1183, Sherwin Williams Company, Coffeyville, Kansas. U.S. Department of Health and Human Services, NIOSH, Health Evaluation and Technical Assistance Branch, Cincinnati, OH.
Pendergrass, EP; Greening, RR. (1953) Baritosis: report of a case. Arch Indust Hyg Occup Med 7:44-48.
Seaton, A; Ruckley, VA; Addison, J, et al. (1986) Silicosis in barium miners. Thorax 41:591-595.
Tarasenko, NYu; Pronin, OA; Silayev, AA. (1977) Barium compounds as industrial poisons (an experimental study). J Hyg Epidemol Microbiol Immunol 21:361-373.
Uchiyama, K; Nakajima, I; Hayashi, T, et al. (1995) Influence of a barium sulfate preparation (BA147) on lungs of rabbits following single dose intratracheal administration. Oyo Yakuri. 50(2):123-134. [Japanese; English abstract from TOXLINE database].
U.S. Environmental Protection Agency. (1994) Methods for derivation of inhalation reference concentrations and application of inhalation dosimetry. Prepared by the Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Office of Research and Development, Research Triangle Park, NC. EPA/600/8-90/066F.
Zschiesche, W; Schaller, KH; Weltle, D. (1992) Exposure to soluble barium compounds: an interventional study in arc welders. Int Arch Occup Environ Health 64(1):13-23.
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
Ayre, JE. (1966) Human cell-dysplasia following barium. Industr Med Surg 35(5):393-399.
Ayre, JE; Le Guerrier, J. (1967) Some (regressive) effects of DMSO dexamethasone upon cervical cells in cervical dysplasia and carcinoma in situ. Ann NY Acad Sci 141:414-422.
Kanematsu, N; Hara, M; Kada, T. (1980) Rec assay and mutagenicity studies on metal compounds. Mutat Res 77(2):109-116.
McCauley, PT; Douglas, BH; Laurie, RD; et al. (1985) Investigations into the effect of drinking water barium on rats. In: Inorganics in drinking water and cardiovascular disease, Calabrese, EJ, ed. Princeton, NJ: Princeton Scientific Publications, pp. 197-210.
Monaco, M; Dominici, R; Barisano, P; et al. (1990) Studio dell'attivata mutagena del bario cloruro in Salmonella typhimurium. Med Lav 81(1):54-64. [Italian with English abstract].
Monaco, M; Dominici, R; Barisano, P; et al. (1991) Valutazione della presunta attivita mutagena del bario nitrato. Med Lav 82(5):439-445. [Italian with English abstract].
National Toxicology Program (NTP). (1994) Technical report on the toxicology and carcinogenesis studies of barium chloride dihydrate (CAS No. 10326-27-9) in F344/N rats and B6C3F1 mice (drinking water studies). NTP TR 432. National Toxicological Program, Research
Triangle Park, NC. NIH Pub. No. 94-3163. NTIS Pub PB94-214178.
Nishioka, H. (1975) Mutagenic activities of metal compounds in bacteria. Mutat Res 31(3):185-190.
Rossman, TG; Molina, M; Meyer, L; et al. (1991) Performance of 133 compounds in the lambda prophage induction endpoint of the Microscreen assay and a comparison with S. typhimurium mutagenicity and rodent carcinogenicity assays. Mutat Res 260(4):349-367.
Schroeder, H; Mitchener, M. (1975a) Life-term studies in rats: effects of aluminum, barium, beryllium and tungsten. J Nutr 105:421-427.
Schroeder, H; Mitchener, M. (1975b) Life-term effects of mercury, methyl mercury and nine other trace metals on mice. J Nutr 105:452-458.
Sirover, MA; Loeb, LA. (1976) Infidelity of DNA synthesis in vitro: screening for potential metal mutagens or carcinogens. Science 194:1434-1436.
Tarasenko, NYu; Pronin, OA; Silayev, AA. (1977) Barium compounds as industrial poisons (an experimental study). J Hyg Epid Microbiol Immunol 21:361-373.
U.S. Environmental Protection Agency. (1986) Guidelines for carcinogen risk assessment. Federal Register 51(185):33992-34003.
U.S. Environmental Protection Agency. (1988) Recommendations for and documentation of biological values for use in risk assessment. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. EPA/600/6-87/008; NTIS PB88-179874.
U.S. Environmental Protection Agency. (1996) Proposed guidelines for carcinogen risk assessment. Federal Register 61(79):17959-18011.
U.S. Environmental Protection Agency. (1998) Toxicological review of barium and compounds in support of summary information on the Integrated Risk Information System (IRIS). Available online from National Center for Environmental Assessment, http://www.epa.gov/iris.
_VII. REVISION HISTORY
Barium and Compounds
CASRN -- 7440-39-3
| Date | Section | Description |
|---|
| 09/30/1987 | IV. | Regulatory Action section added |
| 03/01/1988 | I.A.1. | Dose conversion clarified |
| 03/01/1988 | I.A.3. | Text changed |
| 03/01/1988 | I.A.7. | Secondary contact changed |
| 06/30/1988 | I.A.7. | Contacts switched |
| 08/01/1989 | VI. | Bibliography on-line |
| 06/01/1990 | IV.F.1. | EPA contact changed |
| 07/01/1990 | I.A. | Withdrawn; new RfD verified (in preparation) |
| 07/01/1990 | VI. | Bibliography withdrawn |
| 08/01/1990 | I.A. | Oral RfD summary replaced; RfD changed |
| 08/01/1990 | VI. | Bibliography replaced |
| 12/01/1991 | I.B. | Inhalation RfC now under review |
| 01/01/1992 | IV. | Regulatory actions updated |
| 3/30/1998 | I.A. | Oral RfD Assessment |
| 3/30/1998 | I.B. | Inhalation RfC Assessment |
| 3/30/1998 | II. | Carcinogenicity Assessment |
| 1/21/1999 | I.A. | Minor revisions to RfD Assessment, revised critical effect |
_VIII. SYNONYMS
Barium and Compounds
CASRN -- 7440-39-3
Last Revised -- 3/30/1998
7440-39-3
BARIUM
UN 1399
UN 1400
UN 1854
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Last updated: January 21, 1999
URL: http://www.epa.gov/iris/SUBST/0010.HTM
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