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(Bauer et al. 1957; Losee et al. 1974; Miller et al. 1985; Sowden 1958; Sowden and Stitch 1957; Sowden 

and Pirie 1958).  Significant increases in the levels of barium in bone were found in rats administered 

barium chloride in the diet or barium as a component of Brazil nuts for 29 days (Stoewsand et al. 1988); 

this study did not examine other tissues.  A study by McCauley and Washington (1983) in which rats 

were exposed to barium chloride and barium carbonate in drinking water found the following non-skeletal 

distribution (skeletal tissue was not examined in the study) 24 hours after ingestion:  heart > eye > 

skeletal muscle > kidney > blood > liver. 

3.4.2.3  Dermal Exposure  

No studies were located regarding distribution of barium in humans or animals after dermal exposure. 

3.4.2.4  Other Routes of Exposure 

Human injection studies support the findings of the inhalation and oral exposure studies.  Barium is 

rapidly cleared from the blood and distributed to bone (Bauer et al. 1957; Harrison et al. 1966, 1967; 

Newton et al. 1991).  A long-term study of barium retention in humans injected with 

133

Ba found that 

after the first couple of years, bone turnover was the most significant contributor to barium losses from 

the skeleton (Newton et al. 2001). 

3.4.3 

Metabolism 

Barium is not metabolized in the body, but it may be transported or incorporated into complexes or 

tissues. 

3.4.4 

Elimination and Excretion 

3.4.4.1  Inhalation Exposure 

No studies have been located regarding excretion of barium following inhalation exposure in humans.  

Studies in animals demonstrate that the fecal excretion of barium exceeds urinary excretion (Cember et al. 

1961; Cuddihy and Griffith 1972; Cuddihy et al. 1974).  In dogs, 30% of the total barium excretion was 

accounted for by urine (Morrow et al. 1964).   

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3.4.4.2  Oral Exposure  

A study of two humans ingesting a normal diet found that fecal excretion of barium was 2–3 times higher 

than urinary excretion over a 30-day period (Tipton et al. 1966).  A 29-day rat study also demonstrated 

that the feces was the primary route of excretion following exposure to barium chloride in the diet or 

barium from brazil nuts (Stoewsand et al. 1988).  

3.4.4.3  Dermal Exposure  

No studies were located regarding excretion of barium in humans or animals after dermal exposure. 

3.4.4.4  Other Routes of Exposure 

Several human studies have examined the excretion of barium following parenteral administration.  These 

studies confirm the findings of the inhalation or oral exposure studies that barium is primarily excreted in 

the feces.  In a study, one subject receiving an intravenous injection of 

133

Ba, 84% of the radiolabelled 

barium was excreted within the first 6 days, primarily in the feces (75% of total dose) (Harrison et al. 

1967; Newton et al. 1977).  The ratio of fecal to urinary barium excretion in six subjects injected with 

133

Ba ranged from 6 to 15 for the first 2 weeks (Newton et al. 1991). 

A study in rats (Edel et al. 1991) found that biliary excretion did not significantly contribute to the total 

amount of barium excreted in the feces, suggesting that other physiological routes were responsible for 

fecal barium.  A study of rabbits administered an intravenous injection of radiolabelled barium also found 

that barium was primarily excreted in the feces.  After the first day, fecal excretion was approximately 

twice as high as urinary excretion.  The barium was primarily excreted in the first 5 days after exposure; 

after 9 days, approximately 50% of the dose was excreted (Liniecki 1971).   

3.4.5 

Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models  

Physiologically based pharmacokinetic (PBPK) models use mathematical descriptions of the uptake and 

disposition of chemical substances to quantitatively describe the relationships among critical biological 

processes (Krishnan et al. 1994).  PBPK models are also called biologically based tissue dosimetry 

models.  PBPK models are increasingly used in risk assessments, primarily to predict the concentration of 

potentially toxic moieties of a chemical that will be delivered to any given target tissue following various 

combinations of route, dose level, and test species (Clewell and Andersen 1985).  Physiologically based 

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pharmacodynamic (PBPD) models use mathematical descriptions of the dose-response function to 

quantitatively describe the relationship between target tissue dose and toxic end points.   

PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to 

delineate and characterize the relationships between:  (1) the external/exposure concentration and target 

tissue dose of the toxic moiety, and (2) the target tissue dose and observed responses (Andersen and 

Krishnan 1994; Andersen et al. 1987).  These models are biologically and mechanistically based and can 

be used to extrapolate the pharmacokinetic behavior of chemical substances from high to low dose, from 

route to route, between species, and between subpopulations within a species.  The biological basis of 

PBPK models results in more meaningful extrapolations than those generated with the more conventional 

use of uncertainty factors. 

The PBPK model for a chemical substance is developed in four interconnected steps:  (1) model 

representation, (2) model parameterization, (3) model simulation, and (4) model validation (Krishnan and 

Andersen 1994).  In the early 1990s, validated PBPK models were developed for a number of 

toxicologically important chemical substances, both volatile and nonvolatile (Krishnan and Andersen 

1994; Leung 1993).  PBPK models for a particular substance require estimates of the chemical substance-

specific physicochemical parameters, and species-specific physiological and biological parameters.  The 

numerical estimates of these model parameters are incorporated within a set of differential and algebraic 

equations that describe the pharmacokinetic processes.  Solving these differential and algebraic equations 

provides the predictions of tissue dose.  Computers then provide process simulations based on these 

solutions. 

The structure and mathematical expressions used in PBPK models significantly simplify the true 

complexities of biological systems.  If the uptake and disposition of the chemical substance(s) are 

adequately described, however, this simplification is desirable because data are often unavailable for 

many biological processes.  A simplified scheme reduces the magnitude of cumulative uncertainty.  The 

adequacy of the model is, therefore, of great importance, and model validation is essential to the use of 

PBPK models in risk assessment. 

PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the 

maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994).  

PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in 

humans who are exposed to environmental levels (for example, levels that might occur at hazardous waste 

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