Risk assessment of trace hydrazine in a 2020 bottled water-associated nonviral hepatitis outbreak

Between August 1 and December 3, 2020, a 124-day outbreak of nonviral hepatitis occurred in geographically limited regions of Nevada and California, resulting in 21 hospitalized cases (18 in Nevada, 3 in California), including 18 intensive care unit admissions and one fatality in an adult female with preexisting conditions. In March 2021, a multi-agency investigation led by the Southern Nevada Health District (SNHD), Centers for Disease Control and Prevention (CDC), U.S. Food and Drug Administration (FDA), and others identified consumption of Real Water, an alkalinized bottled water product, as the likely cause. On March 24, 2021, a recall was issued and the company ceased production of Real Water. Despite extensive investigation, no definitive causative agent was identified. However, trace concentrations of hydrazine, a known hepatotoxin, were detected in select product batches, prompting concerns regarding its potential role in the outbreak. This study presents a quantitative risk assessment of hydrazine exposure from daily consumption of retail bottled Real Water products during the outbreak period. Estimated intake was calculated based on age-, sex-, and body weight-specific water consumption patterns and measured hydrazine concentrations (mean: 0.0505 mg/L; maximum: 0.3 mg/L). Sub-chronic acceptable daily intakes (ADIs) of 0.09 mg/kg-day for adults and 0.04 mg/kg-day for children were developed based on toxicological data from isoniazid (INH) studies. Hydrazine and INH share similar profiles regarding hepatotoxicity, with hydrazine acting as a major mediator of INH-induced liver injury. Calculated hazard quotients for all demographic groups were <1.0, with the highest estimated intake (0.005 mg/kg-day) resulting in an HQ of 0.12. These findings indicate that hydrazine exposure <i>via</i> retail Real Water consumption could not have caused the observed hepatic injuries, supporting the conclusion of the Centers for Disease Control (CDC) that the etiologic agent remains unidentified.