Toxicological Review of Barium and Compounds

B2) 

Is the rationale for not using hypertension as the critical effect justified and 

objectively and transparently presented?  Is this rationale correct? 

B3) 

Is the rationale for not using increased kidney weight justified and objectively 

and transparently presented?  Is this rationale correct? 

C. Method of Analysis

Benchmark dose modeling has been used to derive the point of departure for determining 

the proposed RfD. 

C1) 

Is there a suitable chemical-related dose-response relationship to justify 

benchmark dose modeling of nephropathy?  Is discussion of this effect 

objectively and transparently presented? 

C2)

Is the explanation for the choice of 5% extra risk as the benchmark response for 

increased nephropathy transparently presented?  Is the choice of 5% extra risk 

scientifically justifiable? 

D. Uncertainty Factors

A total uncertainty factor of 300 was applied to the point of departure: 10 for interspecies 

differences, 10 for intraspecies variation, and 3 for deficiencies in the data base. 

D1) 

Are the choices of uncertainty factors transparently and objectively described? 

D2) 

Do the data support the use of different values than those proposed? 

Scientific Comments from External Peer Review 

A1)  Is the NTP (1994) chronic animal study the most appropriate and scientifically 

justifiable principal study for deriving the RfD?  If not, what other study (or studies) 

should be chosen and why? 

A-5

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Comment: All five reviewers agreed that the NTP (1994) animal study was the most appropriate 

and scientifically justifiable principal study for deriving the RfD.  Several reviewers commented 

that, although the NTP study was the best available study, its ability to predict the effects of 

chronic barium ingestion in humans was limited.  A reviewer commented that there is some 

uncertainty about whether the mouse is the most appropriate species for predicting the human 

response to barium ingestion.  Another reviewer noted that, absent any mechanistic data that 

would indicate that the rat is a more appropriate model, the most sensitive species should be 

used.  This reviewer also remarked on the numerous strengths of the study, including the 

excellent study design and methods, a chronic exposure duration, and quality dose-response data. 

Another reviewer expressed concern that the NTP (1994) study did not report the dietary intake 

of barium or account for it in the exposure estimates. 

Response: EPA chose the NTP (1994) chronic animal study as the critical study for deriving the 

barium RfD because the observed incidence of nephropathy in mice provided the best available 

dose-response data.  Recognizing there may be potential differences in the toxicodynamics and 

toxicokinetics of barium between mice and humans, EPA has utilized a 10-fold interspecies 

uncertainty factor in the derivation of the RfD.  As one of the reviewers noted, mice were more 

sensitive than rats to the nephrotoxic effects of barium.  Treatment-related nephropathy was 

observed in rats exposed for 13-weeks, but in the 2-year study the high incidence rate of 

spontaneous lesions masked any treatment-related effect. 

Barium was not listed as a contaminant of the NIH-07 rat and mouse ration in Appendix 

L of the NTP Technical Report (1994), but it is not clear if NTP analyzed the feed for this 

element.  Barium serum levels in both rats and mice provided a biological measure of their 

relative exposures.  The dose-dependent increases in barium serum concentrations of treated 

animals, and the significant difference between the treated and control groups, supports the 

assumption that drinking water was the primary source of barium exposure.  

A2)  Is the explanation for why the human studies were not used as coprincipal 

studies transparent and scientifically objective? 

In the development of the existing RfD, hypertension was selected as a co-critical 

effect.  Evidence of hypertension was not observed in any of the principal studies.  The 

existing NOAEL is based on the highest exposure level in the human studies where no 

hypertension was observed.  In this case, was the selection of hypertension as the critical 

effect and the derivation of the NOAEL scientifically objective and appropriate? 

A-6

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Comment: The reviewers unanimously agreed that the human studies (Brenniman and Levy, 

1984; Wones et al., 1990) should not be used as coprincipal studies in the derivation of the RfD. 

Two reviewers thought the rationale for not using the human studies was logical, transparent, 

and objective.  Two other reviewers suggested that EPA should elaborate on the limitations of 

the human studies.  It was not clear to one reviewer that the NOAEL from the human studies was 

no longer a key data point used in the derivation of the RfD. 

Two reviewers noted that it would be inappropriate to interpret the negative findings of 

the human studies as evidence that barium has no effect on the cardiovascular system.  One of 

these reviewers recommended explicitly stating that the studies were inappropriate for evaluating 

the effect of barium on blood pressure because of methodological limitations. 

Only one reviewer addressed the second part of the question, which asked whether the 

selection of hypertension as the co-critical effect for the existing (1998) RfD was scientifically 

objective and appropriate.  This reviewer stated that the authors and reviewers of the 1998 

assessment were cognizant that an effect level for cardiovascular effects had not been defined. 

Moreover, the decision at the time to base the RfD on a NOAEL was supported by a logical 

rationale.  However, he also stated that it was appropriate and scientifically justifiable for EPA to 

refine the oral assessment and he endorsed the selection of nephropathy in mice as the critical 

effect. 

Response: There are methodological and design limitations associated with both the Brenniman 

et al. (1981) and Wones et al. (1990) studies that limit the utility of their data.  More importantly, 

neither study provided sufficient data to support, nor refute, the hypothesis that chronic barium 

exposure causes hypertension.  It was not considered scientifically justifiable to base the RfD on 

hypertension  in the absence of dose-response data that support an association between chronic 

barium exposure and this effect.  As several of the reviewers noted, this does not mean that an 

association between chronic barium exposure and hypertension has been ruled out, only that 

there are insufficient data to draw a conclusion at this point in time.  Additional text concerning 

the limitations of the human studies and the rationale for selecting the animal data were added to 

Sections 4.1 and 5.1 of this Toxicological Review. 

A3) Are you aware of any other studies that may be relevant to the derivation of the 

RfD? 

A-7

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