Toxicological Review of Barium and Compounds

A second reviewer indicated that a choice of 5% extra risk over a 10% extra risk as the 

BMR was only briefly presented in the Toxicological Review.  This reviewer suggested that if 

the effect is moderately adverse as stated, meaning that it is neither very severe and it occurs at 

only the highest exposure dose, then a higher level of extra risk would be tolerated.  The 

reviewer did not see a scientific justification for using a 5% extra risk, instead of a 10% extra 

risk which is the standard approach. 

A third reviewer indicated the selection of a 5% BMR may not be scientifically justified. 

This reviewer stated that the lack of an adequate database could require the use of a lower 

percentage extra risk as the BMR (i.e., 0%).  For these reasons, this reviewer recommended 

using the standard default benchmark of 10% extra risk.  

A fourth reviewer indicated the choice of 5% BMR was arbitrary in view of the 

limitations of the data base.  This reviewer stated additional explanation should be represented in 

the text.  A fifth reviewer indicated that, because of the limited dose-response data, BMD 

modeling at any BMR was not warranted.  This reviewer indicated the only feasible approach 

was a NOAEL/LOAEL approach for determining the point of departure for deriving the RfD. 

Response: The selection of a BMR depends, in part, on the relative severity of the critical effect 

and whether there are sufficient data to predict the shape of the dose-response curve at low 

doses.  The reviewers commented on both of these issues.  

Nephropathy was observed in approximately half of the animals in the high dose group, 

and these lesions were associated with a significant decrease in survival.  Lesions observed at 

intermediate dose were deemed to be on a continuum leading to severe nephropathy.  For this 

reason, the effects at this dose were considered irreversible and of a substantial nature to warrant 

the use of a lower benchmark response.  The BMR at 10% extra risk is provided for comparison 

purposes. 

The other issue of concern is the suitability of the data for low-dose extrapolation. The 

dose-response information for chemical-related nephropathy in male mice contains two data 

points: the high dose group with lesions in 32% of the animals and the middle dose group with 

lesions in 3% of the animals.  The incidence of nephropathy in the middle dose group was not 

statistically significant, but the histomorphology and severity of the lesions indicates that they 

were not spontaneous in origin.  Moreover, these data provide an increased level of confidence 

in the BMD model predictions for effects in the low dose range. 

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For this assessment, a BMR of 5% extra risk was used to derive the RfD because it was 

determined that nephropathy was a substantially severe adverse effect and because the data 

supported modeling to this effect level (i.e., a response was measured near this effect level). 

Additional text discussing the selection of BMR was added to Section 5.1.2 and to Appendix B. 

D1) Are the choices of uncertainty factors transparently and objectively described? 

Comment: The reviewers generally agreed with the choice of uncertainty factors (UFs) and 

largely indicated that the description of their selection was transparent.  One reviewer thought 

that it should be emphasized that the application of a 10-fold UF is a default EPA policy. 

Another reviewer felt that the rationale for the choice of UFs should contain more detail.  For 

example, the evidence of interspecies differences could be summarized.  A third reviewer noted 

that describing the application of the data base deficiency UF is especially difficult because, 

unlike the other UFs, the rationale is often chemical-specific. 

Response: EPA’s practice is to examine all of the relevant health effect data and apply default 

assumptions when the data are insufficient or there are data gaps.  The application of 10-fold 

UFs in situations where data are lacking is a standard EPA practice based on empirically derived 

data (U.S. EPA, 2002).  An explanation for each uncertainty factor is provided below (in 

response to Question D2) and in Section 5.1.3 of the Toxicological Review.  Additional 

information about the application of UFs can be found in A Review of the Reference Dose and 

Reference Concentration Processes (U.S. EPA, 2002) available at: 

http://www.epa.gov/iris/RFD_FINAL[1].pdf. 

D2) Do the data support use of different values than those proposed? 

Comment: The reviewers generally agreed with the proposed UF values.  One reviewer 

expressed concern about the 10-fold UF for interspecies variability and the threefold UF data 

base deficiency.  This reviewer stated that the available information about factors that contribute 

to intraspecies susceptibility is limited and inconsistent but ultimately concluded that it was 

reasonable to retain the 10-fold UF.  Regarding the threefold UF for data base deficiencies, this 

reviewer thought that it was inappropriate to consider limitations in the data base for areas 

unrelated to the critical effect of nephropathy (i.e., neurotoxicity).  A second reviewer agreed 

that  neurotoxicity data, if they were available, would not be likely to affect the RfD and 

therefore should not be used as a justification for this UF.  This reviewer thought that other 

factors, such as the lack of a two-generation reproductive toxicity study, might justify the use of 

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