Toxicological Review of Barium and Compounds

B3) Is the rationale for not using increased kidney weight justified and objectively 

and transparently presented?  Is this rationale correct? 

Comment: Three of the reviewers stated that the rationale for not using kidney weight was 

correct.  Two of these reviewers noted that altered organ weight is a nonspecific effect that is 

difficult to interpret.  One reviewer stated that he was not qualified to judge the relevance of the 

animal data.  Another reviewer thought the kidney weight data should be examined further to 

ascertain whether it would add to the weight of evidence for defining nephropathy as the critical 

effect.  Three reviewers indicated that information related to kidney weight could be more 

clearly presented. 

Response: A NOAEL for increased kidney weight in rats was used as 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 (see Table 5–1).  Increased kidney weight was 

predominantly observed in the subchronic studies.  In addition, female rats were the only 

chronically exposed animals with significantly increased kidney weights.  There are no known 

studies that definitively link changes in kidney weight to overt renal toxicity.  Nevertheless, 

changes in kidney weight have often been utilized as a precursor effect to kidney toxicity in the 

absence of information indicating otherwise.  In the case of barium, NTP (1994) concluded that 

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).  Additional text has been added to 

Section 5.1.2 of this Toxicological Review to clarify the rationale for not choosing kidney weight 

changes as the critical effect following barium exposure. 

C1) Is there a suitable chemical-related dose-response relationship to allow for 

benchmark dose modeling of nephropathy?  Is discussion of this effect objectively and 

transparently presented? 

Comment:  Four of the reviewers generally agreed with the proposed application of benchmark 

dose (BMD) modeling.  One reviewer stated that it was inappropriate to use BMD modeling 

because the available data do not provide sufficient dose-response information and suggested 

that EPA use the NOAEL/LOAEL approach to derive the RfD.  One of the four reviewers who 

supported the use of BMD modeling indicated that, because of limitations in the barium data 

base, he had concerns about the method for choosing a benchmark dose.  This reviewer stated 

that it would be helpful to provide more information about BMD modeling, particularly the 

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limitations associated with it.  Another reviewer noted that, while the frequency of nephropathy 

was a scientifically valid response to use for modeling, the degree of nephropathy is a subjective 

measure recorded by pathologists.  This reviewer thought that it would be helpful if more 

information was provided about the various types of endpoints EPA uses in their health 

assessments and their relative value.  Two of the reviewers indicated that the presentation of the 

BMD modeling was reasonable and justified.  

Response: The draft Benchmark Dose Technical Support Document (p. 17; U.S. EPA, 2000c), 

discusses the minimum data set for calculating a BMD and states “there must be at least a 

statistically or biologically significant [underline added for emphasis] dose-related trend in the 

selected endpoint.”  The trend of increasing incidences of nephropathy was not found to be 

statistically significant in mice with chronic exposure to barium in drinking water.  Statistical 

significance was noted only at the highest dose.  However, the trend is considered to be 

biologically significant because of the increased severity of the lesions (see Section 5.1.2 of the 

Toxicological Review).  Additional text discussing the application of BMD modeling for this 

endpoint was added to Section 5.1.2 and Appendix B of the Toxicological Review.  Additional 

information about BMD can be found in the Benchmark Dose Technical Guidance Document 

(U.S. EPA, 2000c).  Additional information about the types of endpoints that EPA uses in its 

health assessments can be found in the guidance documents on the IRIS web site 

(http://www.epa.gov/iris/backgr-d.htm). 

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? 

Comment: The reviewers provided divergent responses to this charge question.  One reviewer 

strongly supported the choice of 5% extra risk for the benchmark response (BMR), rather than 

the default 10% value normally used by EPA but thought that a better explanation for this choice 

was needed.  This reviewer indicated that the scientific rationale for using a lower added risk as 

the point of departure could include two points.  First, that the histopathological lesions detected 

were severe lesions in terms of the magnitude of injury and that these were not subtle effects 

observed early in the dose-response relationship pathway.  Secondly, post-repair tubular function 

is likely to be subpar (i.e., any reversibility is likely to be partial).  The reviewer stated that these 

irreversible effects are likely to be more grave than reversible effects.  This reviewer also added 

that kidney disease from all etiologies is more common in older individuals, further indicating 

that one should minimize the risk of high intake of a nephrotoxic substance. 

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