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 Carcinogen Risk Assessment (U.S. EPA, 1996b),
barium is considered not likely to be carcinogenic to humans following oral exposure, and its
carcinogenic potential cannot be determined following inhalation exposure.
4.7. SUSCEPTIBLE POPULATIONS
4.7.1. Possible Childhood Susceptibility
Limited data exist on which to make an assessment of possible childhood susceptibility.
Gastrointestinal absorption data suggest that barium absorption may be higher in children than in
adults. Studies in rats (Taylor et al., 1962) and dogs (Cuddihy and Griffith, 1972) indicate that
absorption in the younger animals is approximately 10-fold higher than absorption in the older
animals. The mechanism behind this apparent increase in absorption efficiency among younger
animals is not known, and it is not known if similar findings would be observed in humans.
There are no human data examining age-related differences in susceptibility to barium toxicity.
4.7.2. Possible Gender Differences
Gender-based susceptibility to barium toxicity has not been documented.
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5. DOSE-RESPONSE ASSESSMENTS
5.1. ORAL REFERENCE DOSE (RfD)
5.1.1. Choice of Principal Study and Critical Effect—With Rationale and Justification
The NTP (1994) 2-year drinking water study in B6C3F1 mice was selected as the
principal study, and chemical-related nephropathy was identified as the critical effect for
deriving an RfD for barium and its soluble salts. The principal study and critical effect were
selected after careful evaluation of all the available toxicity studies. The primary reason for
selecting this study and critical effect was that the nephropathy data provide the best evidence of
a dose-response relationship.
The kidney appears to be the most sensitive target of toxicity resulting from repeated
ingestion of soluble barium salts. NTP (1994) observed renal toxicity in F-344/N rats and
B6C3F1 mice following chronic and subchronic drinking water exposures to barium chloride
(see Table 5–1). A significant number of chronically exposed mice in the high dose group,
19/60 males and 37/60 females, had mild to severe cases of nephropathy. A significant increase
in mortality among animals in this dose group was attributed to the chemical-related renal
lesions. One female and two male mice in the intermediate dose group had mild to moderate
cases of chemical-related nephropathy. There was a statistically significant trend for increasing
incidence of nephropathy with increasing exposure level (p<0.01). Chemical-related
nephropathy was not detected in the chronic rat study because of the prevalence of spontaneous
nephropathy in both the control and treatment groups. In the subchronic studies, chemical-
related nephropathy was observed in 10/10 male and 9/10 female mice and 3/10 male and 3/10
female rats in the high dose groups.
McCauley et al. (1985) detected glomerular damage in unilaterally nephrectomized rats
that received 1000 ppm barium in drinking water (150 mg/kg-day). However, the applicability
of dose-response data from unilaterally nephrectomized rats to intact rats or to humans is not
clear because removal of renal tissue may affect sensitivity of the remaining tissue to
nephrotoxins. Glomerular damage was also observed in Dahl salt-sensitive and salt-resistant
rats, but the relevance of these findings to humans is also uncertain.
Schroeder and Mitchener (1975b) found evidence of glomerular damage (i.e., proteinuria)
in mice exposed to a much lower concentration of barium (5 ppm or 0.61 mg/kg-day). The
proteinuria was not accompanied by an increased incidence of renal lesions, and, unfortunately,
40
this study only employed one exposure concentration. As with other studies that used the low-
metal rye-based diet, there is some uncertainty about the potential association with the reduced
calcium and potassium concentrations in the diet.
Increased kidney weight in rats was used as a co-critical effect for deriving the previous
RfD for barium (see Section 5.1.4). However, the effect of barium on kidney weights was
variable and not observed in the treatment groups with the greatest incidences of chemical-
related renal lesions (Table 5–1). Increased kidney weights were predominantly observed in the
subchronic studies. Female rats were the only chronically exposed animals with significantly
increased kidney weights. Researchers from NTP concluded the effects on kidney weight were
most likely associated with the treatment-related depression in weight gain rather than renal
toxicity (Dietz et al., 1992). For these reasons, increased kidney weight is not considered a co-
critical effect in this assessment.
Hypertensive effects have also been noted following barium exposure; however, the
reports are conflicting. An investigation of anesthetized dogs (n=24) infused with barium
chloride at a rate of 2
:
mol/kg/min reported an increase in mean blood pressure from 138/86 to
204/103 (Roza and Berman, 1971). In a series of subchronic and chronic drinking water studies,
Perry et al. (1989, 1985) observed a hypertensive effect in rats receiving as little as 6 mg/kg-day
barium. The animals in these studies were maintained on a low metal diet with lower
concentrations of calcium and other minerals than standard rat chow. However, NTP (1994)
found no association between subchronic barium exposure and cardiovascular toxicity in rats at
the highest level tested (200 mg/kg-day). Likewise, McCauley et al. (1985) observed no adverse
effect on blood pressure following subchronic exposure to barium in drinking water at the
highest level tested (150 mg/kg-day).
The reduced concentrations of calcium and other minerals in the low metal diet
have been identified as a possible reason for the discrepancy between the findings of Perry et al.
(1989, 1985) and other animal studies that did not observe hypertension in barium-treated
animals (NTP, 1994; McCauley et al.,1985). The calcium concentration of the low metal diet
was 3.8 g/kg, and the nutritional requirement for maintenance, growth, and reproduction of rats
is 5 g/kg (NRC, 1995). Perry has stated that the concentration of calcium in the diet was
adequate for normal growth and development (Perry, 1984). It is, however, unclear if the
reduced dietary concentrations of calcium may have contributed to development of barium-
related hypertension. There is some evidence that reduced dietary calcium is a risk factor for
hypertension in humans (McCarron et al., 1984). In light of the possible association between
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