Toxicological Review of Barium and Compounds

Comment: The reviewers were not aware of any other studies that should have been considered 

for the derivation of the RfD. 

Response: No response necessary. 

B1) Are renal lesions (nephropathy) the most appropriate critical effect for deriving 

the RfD?  Points relevant to this determination include whether this effect demonstrated a 

suitable dose-response relationship and whether the effect is considered adverse.  Are these 

issues objectively and transparently described? 

Comment: Four reviewers concluded that nephropathy was the most appropriate critical effect 

for deriving the RfD.  One reviewer noted that human data were insufficient to select a critical 

effect and that he was not qualified to judge the human relevance of the renal lesions in mice. 

A reviewer who supported the selection of nephropathy as the critical effect stressed that 

renal lesions were simply the best available data, but he did not think their use was completely 

justified.  In particular, this reviewer remarked that, while a dose-response relationship is 

suggested, a statistically significant association at a lower dose was not found.  Two other 

reviewers commented on the apparent lack of a dose-response trend.  Another reviewer noted 

that barium may be like other nephrotoxic metals that tend to exhibit their renal effects when 

body burdens are high and multiple toxic effects are likely to be seen. 

Response: A dose-response relationship for chemical-related nephropathy was observed for both 

male and female mice.  Evidence of the dose-response relationship was derived from the 

biologically significant findings of mild to moderate nephropathy at the intermediate dose (75 

mg/kg-day and 90 mg/kg-day for males and females, respectively).  These data in conjunction 

with the statistically significant increased incidence of nephropathy at the highest dose provide 

information about the effects of low dose and high dose exposures to barium in drinking water. 

The severity of lesions at the intermediate dose was an important consideration in the 

determination of biological significance of these findings.  The lesions observed at this dose 

were qualified as mild to moderate as opposed to minimal nephropathy which was observed in a 

few animals that received the low dose or were untreated.  Minimal nephropathy is likely to be 

associated with a background incidence of renal effects.  As one of the reviewers noted the 

effects observed in the high dose treatment group, which had a statistically significant increase in 

nephropathy, were quite severe and fatal in many cases.  

A-8

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B2) Is the rationale for not using hypertension as the critical effect justified and 

objectively and transparently presented?  Is this rationale correct? 

Comment: All five reviewers agreed that the rationale for not using hypertension as the critical 

effect was justified.  Several reviewers commented that the presentation could be clearer and 

suggested including additional information on the limitations of the studies.  One reviewer noted 

that due to the methodological limitations of the human studies, the effect of chronic barium 

ingestion on hypertension is unknown. 

Response: Two human studies have investigated the effects of barium ingestion on blood 

pressure (Brenniman et al., 1981; Wones et al.,1990).  Both investigations found no hypertensive 

effect with their highest exposure concentrations.  Brenniman et al. (1981) found no effect on 

hypertension between two communities with a 70-fold difference in the barium concentrations of 

their drinking water.  Wones et al. (1990) found no hypertensive effect in a before-and-after 

comparison of 11 subjects that were exposed to two concentrations of barium in their drinking 

water over the course of 10 weeks.  Coincidently, the same NOAEL of 0.21 mg/kg-day was 

identified for both studies.  These NOAELs were estimated by EPA using standard estimates for 

drinking water intake (2 L/day) and average body weight (70 kg). 

Neither Brenniman et al. (1981) nor Wones et al. (1990) provided sufficient data to 

support, or refute, the hypothesis that chronic barium exposure causes hypertension. 

Hypertension is a complex multifactorial condition. It is very possible that the effect of chronic 

barium exposure on blood pressure is relatively small compared to other determinates such as 

diet and exercise.  Wones et al. (1990) attempted to control for the effect of diet by providing a 

standard diet to all of the study participants.  Unfortunately, the power of this study was limited 

by the very small number of participants (n=11).  This study was also of a short exposure 

duration (4 weeks for each exposure concentration) that may not have been sufficient to observe 

a chronic effect.  Brenniman et al. (1981) also examined a relatively small number of subjects 

(n=85) in a subpopulation that was controlled for key risk factors.  Other limitations of the 

Brenniman et al. (1981) study include collecting replicate blood pressure measurements from 

individuals during a single 20-minute period, using community-wide exposure estimates, and not 

controlling for a number of important risk factors for hypertension, including diet and exercise. 

In the absence of dose-response data for barium-induced hypertension, it was not considered 

scientifically sound to base the RfD on this effect.  Additional text describing the limitations of 

these studies has been added to Section 5.1.1 of the Toxicological Review.  In addition, text has 

been added to indicate the effect of barium hypertension in humans is unknown. 

A-9

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