Concise International Chemical Assessment Document 33

Concise International Chemical Assessment Document 33

24

11.1.2

Criteria for setting tolerable intakes/

concentrations or guidance values for

barium and barium compounds

No single study is appropriate as the basis for a

lifetime tolerable intake for barium. The US EPA (1998)

developed a reference dose (RfD) of 0.07 mg/kg body

weight per day with a uncertainty factor of 3 applied to a

NOAEL of 0.21 mg/kg body weight per day for barium

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 & Levy

(1984) epidemiological study, and the medium- and long-

term exposure rat studies that employed adequate diets

and investigated both cardiovascular and renal end-

points (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. In

addition, the approach includes a consideration of

supporting information from single-exposure and

mechanistic studies as well as from medium-term and

long-term exposure studies of animals on low-mineral

diets.

The identification of hypertension as a health end-

point of concern is supported by findings of hyperten-

sive 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 on both blood pressure and

kidney function in animals. Although the experimental

study by Wones et al. (1990), together with the epide-

miological study by Brenniman & Levy (1984), did not

report any significant effects on blood pressure, they

establish a NOAEL in humans of 0.21 mg barium/kg

body weight per day. The animal data suggest that the

kidney may also be a sensitive target for ingested barium

from low-level exposure (Schroeder & Mitchener, 1975a;

NTP, 1984; McCauley et al., 1985); although the human

studies investigated hypertensive effects, the clinical

surveillance data did not uncover any renal dysfunction

or any other health abnormalities. Therefore, 0.21 mg

barium/kg body weight per day is used as the basis to

derive the tolerable intake for barium. The use of a

NOAEL from human studies increases the confidence in

the derivation of the tolerable intake value, which is

defined as an estimate (with uncertainty spanning

perhaps an order of magnitude) of a daily exposure of

the human population (including sensitive subgroups)

that is likely to be without an appreciable risk of

deleterious effects during a lifetime.

Therefore, the tolerable intake can be calculated as

the NOAEL of 0.21 mg/kg body weight per day divided

by an uncertainty factor of 10 to account for some data-

base deficiencies and potential differences between

adults and children, giving a tolerable intake of

0.02 mg/kg body weight per day.

Regarding inhalation exposure, the human

(Pendergrass & Greening, 1953; Doig, 1976; Seaton et al.,

1986) and animal inhalation (Muller, 1973; Tarasenko et

al., 1977) and intratracheal (Tarasenko et al., 1977;

Uchiyama et al., 1995) studies suggest that the

respiratory system is a target of barium toxicity. The data

also suggest that systemic effects, such as hyper-

tension, may occur following inhalation exposure

(Tarasenko et al., 1977; NIOSH, 1982; Zschiesche et al.,

1992). The human studies cannot be used to derive a

reference concentration (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 of the only animal

medium-term/long-term inhalation exposure studies

(Muller, 1973; Tarasenko et al., 1977) precludes deriving

an RfC for barium from the animal data.

Under EPA’s Guidelines for Carcinogen Risk

Assessment (US EPA, 1986), barium would be classified

as Group D, not classifiable as to human carcinogenicity.

Although adequate long-term oral exposure studies in

rats and mice have not demonstrated carcinogenic

effects, the lack of adequate inhalation studies precludes

an assessment of the carcinogenic potential of inhaled

barium. Under the Proposed Guidelines for Carcinogen

Risk Assessment (US EPA, 1996, 1999), barium is consid-

ered not likely to be carcinogenic to humans following

oral exposure, and its carcinogenic potential cannot be

determined following inhalation exposure. Thus,

derivation of slope factors and unit risk values is

precluded.

Barium compounds exhibit close relationships with

calcium and strontium, which are also alkaline earth

metals. Owing to its similarity to calcium in its chemical

properties and because it lies below calcium in the

periodic table, barium is thought to interact with calcium

through biochemical pathways involving calcium

binding protein and compete for binding sites (IPCS,

1990). Hypertensive effects of barium in rats (Perry et al.,

1989) may have been due to inadequate calcium levels in

the diet.

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