Benefit-risk analysis for foods (BRAFO): Evaluation of exposure to dietary nitrates

Wikoff, Daniele; Thompson, Chad M.; Rager, Julia E.; Chappell, Grace A.; Fitch, Seneca; Doepker, Candace

doi:10.1016/j.fct.2018.08.031

Cited by 18 publications

(12 citation statements)

References 71 publications

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“…In fact, research surrounding dietary nitrate historically focused on intakes from processed meat and their association with poor health outcomes, primarily cancer [44]. In addition, it is reasonable to expect that not all sources of nitrate are equal with regards to their potential health effects [45]. This is especially relevant given the complex bioactivity of nitrate, nitrite and NO metabolism, in which pro-inflammatory constituents including sodium and saturated fat intakes (common to processed meat and discretionary choices) can interfere with NO production, while anti-inflammatory constituents including vitamin C, polyphenols and antioxidants (common to vegetables) can favor NO production from nitrate [46,47,48].…”

Section: Discussionmentioning

confidence: 99%

Vegetable Nitrate Intakes Are Associated with Reduced Self-Reported Cardiovascular-Related Complications within a Representative Sample of Middle-Aged Australian Women, Prospectively Followed up for 15 Years

et al. 2019

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Nitric oxide (NO) facilitates anti-atherosclerotic effects. Vegetables are a major source of dietary nitrate. Experimental data indicates that dietary nitrate can significantly reduce major risk factors for atherosclerosis and subsequent cardiovascular disease (CVD), as nitrate can be metabolized to produce NO via the nitrate-nitrite-NO pathway. The purpose of this study was to prospectively investigate the association between habitual dietary nitrate intakes and the incidence of self-reported CVD-related complications within a representative sample of middle-aged Australian women (1946–1951 cohort of the Australian Longitudinal Study on Women’s Health). Women free from disease at baseline who had completed the food frequency questionnaire data were included. Generalized estimating equations were used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) across quartiles for nitrate intakes. Of the 5324 women included for analysis, there were 1951 new cases of CVD-related complications over 15-years of follow-up. Women reporting higher total dietary nitrate intakes (Q4 > 78.2 mg/day) and vegetable nitrate intakes (Q4 > 64.4 mg/day) were 25% and 27% reduced risk of developing CVD-related complications respectively, compared with women reporting low total (Q1 < 45.5 mg/day) and vegetable nitrate intakes (Q1 < 34.8 mg/day). Our findings were consistent with other observational data indicating that dietary nitrate may explain some of the cardiovascular benefits of vegetable consumption.

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Section: Discussionmentioning

confidence: 99%

Vegetable Nitrate Intakes Are Associated with Reduced Self-Reported Cardiovascular-Related Complications within a Representative Sample of Middle-Aged Australian Women, Prospectively Followed up for 15 Years

et al. 2019

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“…A rapidly growing body of scientific evidence has evaluated nitrate in the context of human health benefits ( Bryan and Loscalzo, 2017 ). The production of nitric oxide following the oral consumption of nitrate is believed to be the mechanism for the most well-established benefit to human health of improved cardiovascular health (reviewed by Wikoff et al, 2018 ). Nitric oxide is typically formed by oral bacteria, which reduce nitrate to nitrite and nitrite to nitric oxide.…”

Section: Introductionmentioning

confidence: 99%

“…MetHb manifests when tissues are significantly deprived of oxygen ( Mensinga et al, 2003 ; EFSA, 2020 ). In an evaluation of nitrate toxicity in humans, Wikoff et al (2018) reported that concerns regarding MetHb have been recently recognized to be confounded by high levels of bacterial contamination in drinking water ( USEPA, 1991 ; ATSDR, 2017 ; OEHHA, 2018 ; Wikoff et al, 2018 ). For example, nitrate levels in drinking water were thought to cause MetHb in infants; however, exposure to high bacterial loads in drinking water was later determined to be a more likely cause of MetHb ( Wikoff et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Review of potential risks associated with supplemental dietary exposure to nitrate-containing compounds in swine—a paradox in light of emerging benefits

Doepker

Heintz

Ligt

et al. 2021

Translational Animal Science

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Calcium nitrate has been reported to benefit reproductive outcomes in sows and their offspring when administered via the feed (15–19 mg/kg-bw/day) during the periparturient period. Traditionally, dietary nitrate had been considered a methemoglobinemia (MetHb) risk in swine. Similar hazard concerns have existed in humans, but a recent benefit/risk analysis established that nitrate levels associated with well-recognized health benefits outweigh potential risks. A similar benefit/risk perspective in swine was lacking and challenged by sparse published hazard data, often referenced within larger reviews related to all livestock. The objective of this review was to better characterize the potential for adverse health and performance effects reported in the literature for swine consuming nitrate, and to provide metrics for evaluating the reliability of the studies reviewed. Supplemental exposure via feed or drinking water was considered for any life stage, dose, and exposure duration. More than 30 relevant studies, including case reports and reviews, examined calcium, potassium, sodium, or unspecified nitrate salts at doses up to 1,800 mg nitrate/kg-bw/day for exposures ranging from 1 to 105 days. The studies primarily evaluated weight gain, blood methemoglobin levels, or vitamin A homeostasis in sows or growing swine. An extensive review of the literature showed reports of adverse effects at low nitrate doses to be of low reliability. Conversely, reliable studies corroborate nitrate intake from feed or drinking water at levels equal to or greater than EFSA’s no-observed-adverse-effect level (NOAEL) for swine of 410 mg nitrate/kg-bw/day, with no MetHb or other adverse effects on reproduction, growth, or vitamin A levels. Using a weight-of-evidence evaluation, we have moderate to high confidence that the NOAEL for nitrate supplementation in swine is likely between 600 and 800 mg/kg-bw/day. These levels are several-fold higher than dietary nitrate concentrations (19 mg/kg-bw/day) that are known to benefit birth outcomes in sows. This review elucidates the quality and reliability of the information sources historically used to characterize nitrate in swine feed as a contaminant of concern. Results from this evaluation can assist risk managers (e.g., regulatory officials and veterinarians) in consideration of proposed benefits, as well as reassuring swine producers that low-level nitrate supplementation is not anticipated to be a concern.

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“…Dietary nitrate has traditionally been considered a contaminant of concern in foods for humans as well as swine ( Wikoff et al, 2018 ; Doepker et al, 2021 ). Reference documents such as the National Research Council Nutrient Requirements of Swine discuss low-level nitrate (290 to 490 ppm) in well water as being associated with toxicity ( NRC, 2012 ).…”

Section: Resultsmentioning

confidence: 99%

“…However, nitrate has begun to be recognized for favorable physiological effects and has been considered beneficial in the diets of both humans and swine ( Hord et al, 2009 ; van den Bosch et al, 2019a , b ). The reviews of Wikoff et al (2018) in humans and Doepker et al (2021) in swine suggest that the old case reports were confounded (potential bacterial contamination in well water) and lacking in detail. In fact, more recent work suggests that levels well above the 490 ppm value are safe in swine, up to ~600 to 800 mg/kg-bw/d ( Doepker et al, 2021 ).…”

Section: Resultsmentioning

confidence: 99%

Impact of calcium nitrate supplementation on the oxygen-carrying capacity of lactating sows and their offspring

Ligt

Saddoris-Clemons²,

Norton³

et al. 2021

Translational Animal Science

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Calcium nitrate supplementation has recently been suggested to provide potential benefits to sows and, in particular, their offspring when administered at a level of 1,200 ppm in feed shortly before farrowing through lactation. More specifically, nitrate supplementation has been suggested as one opportunity for improved placental and/or fetal blood flow and has been hypothesized in previous work to be important to the swine industry in light of the global trend toward larger litter sizes. The benefit is likely manifested through exposure to the nitrate moiety, but interestingly, nitrate has historically been considered a compound of concern for swine. High levels of nitrate once metabolized to nitrite can interfere with the oxygen-carrying capacity of hemoglobin, resulting in increased methemoglobin and, subsequently, methemoglobinemia (MetHb) if the animal is deprived of significant amounts of oxygen; however, the level of nitrate exposure necessary to induce MetHb in sows is not clearly defined. This work was undertaken to examine methemoglobin levels in sows and piglets exposed to the potentially beneficial levels of 1,200 and 6,000 ppm nitrate added to their diets over the course of the periparturient period. Other oxygen capacity blood variables were evaluated (e.g., hemoglobin, hematocrit, and various measures of hemoglobin and red blood cell volumes and concentrations), as well as performance endpoints (weight changes and feed intake) and general observations over the 27-day period. No evidence of treatment-related toxicity manifestation was observed at these supplemental levels. Nearly all oxygen-related variables were affected by time (independent of treatment), indicating adaptive general effects of farrowing. These findings support the hypothesis that MetHb is not a concern up to at least 6,000 ppm supplemental nitrate exposure, even in combination with additional nitrate in the sow’s daily diet. This work is important to help swine producers understand that consideration of nitrate benefit should outweigh concern for risk of nitrate-induced toxicity.

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Benefit-risk analysis for foods (BRAFO): Evaluation of exposure to dietary nitrates

Cited by 18 publications

References 71 publications

Vegetable Nitrate Intakes Are Associated with Reduced Self-Reported Cardiovascular-Related Complications within a Representative Sample of Middle-Aged Australian Women, Prospectively Followed up for 15 Years

Vegetable Nitrate Intakes Are Associated with Reduced Self-Reported Cardiovascular-Related Complications within a Representative Sample of Middle-Aged Australian Women, Prospectively Followed up for 15 Years

Review of potential risks associated with supplemental dietary exposure to nitrate-containing compounds in swine—a paradox in light of emerging benefits

Impact of calcium nitrate supplementation on the oxygen-carrying capacity of lactating sows and their offspring

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