Module 3 - Strategic case studies in practice

ICH Q3D(R1) Guideline

BARIUM

Summary of PDE for Barium

Barium (Ba)

Oral 1460

Parenteral

Inhalation

PDE (µg/day)

730

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Introduction

Barium (Ba) is a dense, silver-white, soft alkaline earth metal that oxidizes readily in moist air and reacts with water. The Ba(2+) ion and the water soluble compounds of barium (chloride, nitrate, hydroxide) are toxic. The insoluble compounds of barium, such as barium sulfate, do not generate free Ba(2+) ions in the gastrointestinal tract and therefore are generally nontoxic to humans. Barium is nutritionally not essential and no metabolic function is known. Barium sulfate has multiple uses e.g., as a radiocontrast medium, a colorant in paint and in the manufacture of glass and other products (ATSDR, 2007). In animals and humans, the kidney appears to be the most sensitive target of toxicity resulting from repeated ingestion of soluble barium salts. Chronic rodent studies support the evidence for an association between barium exposure and renal toxicity (NTP, 1994). The lesions were characterized by tubule dilatation, renal tubule atrophy, tubule cell regeneration, hyaline cast formation, multifocal interstitial fibrosis, and the presence of crystals, primarily in the lumen of the renal tubules. These changes were characterized as morphologically distinct from the spontaneous degenerative renal lesions commonly observed in aging mice. Effects on blood pressure may be the most sensitive endpoint observed in humans after environmental exposure (WHO, 2004). Repeated exposure to barium oxide via inhalation may cause bronchitis, including cough, phlegm, and/or shortness of breath (CICAD, 2001). Safety Limiting Toxicity

PDE – Oral Exposure

In an evaluation conducted in two towns in Illinois, no significant differences in blood pressure or in the prevalence of cardiovascular or kidney disease was found between populations drinking water containing a mean barium concentration of 7.3 mg/L or 0.1 mg/L (WHO, 2004). Using the NOAEL of 7.3 mg/L obtained from this study, and using 2 L/day as an estimation of water intake, the oral PDE can be calculated as:

PDE = 14.6 mg/d / 1 x 10 x 1 x 1 x 1 = 1.46 mg/d =1460 µg/day

PDE – Parenteral Exposure

No relevant data on parenteral exposure to barium compounds were found. The bioavailability of barium is estimated to be 20-60% in adults and infants, respectively (ATSDR, 2007). Thus, the parenteral PDE was calculated by dividing the oral PDE by a modifying factor of 2 (as described in Section 3.1).

PDE = 1460 µg/d / 2 = 730 µg/day

PDE – Inhalation Exposure

No relevant data on inhalation exposure to barium compounds were found. United States Department of Labor (US DoL, 2013) has a reported Time Weighted Average (TWA) of 0.5 mg/m 3 based on soluble barium salts.

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