Systematic review of adverse human health effects following oral exposure to inorganic nitrate and nitrite

Inorganic nitrate and nitrite are naturally occurring anions that play an essential role in Earth's nitrogen cycle. The general population is exposed to nitrate and nitrite from both food and drinking water sources. However, there is evidence that under certain exposure conditions, nitrate and nitrite may be associated with adverse health effects across multiple organ systems. Therefore, a systematic review was undertaken to identify, evaluate, and synthesize the available human evidence for adverse health effects following oral exposure to inorganic nitrate and nitrite. This review includes a literature search that builds upon health assessments by federal, state, and international health agencies, supplemented by a comprehensive search for recently published literature (January 2016-August 2024). Studies underwent screening in two stages (title and abstract, full-text) using a Populations, Exposures, Comparators, Outcomes (PECO) criteria. PECO-relevant studies were evaluated for risk of bias and sensitivity, then synthesized by health effect type. Overall, 267 PECO-relevant human studies were identified examining cancer and non-cancer health outcomes. Database characteristics varied widely across health effects, as did the characterization of nitrate and nitrite exposure. Overall, there were more consistent patterns of increased risk for certain cancer sites (urinary tract, bladder, and kidney; prostate; thyroid), type 2 diabetes, and birth defects. For other endpoints, there was less consistency across studies, and in some cases, evidence was too sparse to identify patterns of association. This review serves not only to identify potential hazards of nitrate and nitrite exposure but also data gaps that would benefit from further research.