Cannabidiol safety considerations: Development of a potential acceptable daily intake value and recommended upper intake limits for dietary supplement use.

Consumer use of hemp-derived products continues to rise, underscoring the need to establish evidence-based safety guidance. The present study sought to develop recommendations for oral upper intake limits of cannabidiol (CBD) isolate. Sufficiently robust and reliable data for this purpose were identified from published human clinical trials and guideline-compliant toxicity studies in animal models. Based on the metrics used in this assessment, a potential Acceptable Daily Intake (ADI) value of 0.43 mg/kg-bw/d (e.g., 30 mg/d for 70-kg adult) was determined for the general population based on liver effects in human studies. This value applies to the most sensitive subpopulations, including children, over a lifetime of exposure and from all sources, including food. For dietary supplements with adequate product labeling intended for use by healthy adults only, a potential Upper Intake Limit (UL) of 70 mg/d was determined based on reproductive effects in animals. For healthy adults, except those trying to conceive, or currently pregnant or lactating, a conservative dietary supplement UL of 100 mg/d was identified based on liver effects; however, as the target population excludes individuals at risk for liver injury, an alternative dietary supplement UL of 160 mg/d for this population can also be considered.

Use of acceptable daily intake (ADI) as a health-based benchmark in nutrition research studies that consider the safety of low-calorie sweeteners (LCS): a systematic map.

BACKGROUND: It is well-recognized that consumers face many challenges in understanding and applying nutritional guidance for low-calorie sweeteners (LCS). Thus, this research aims to (1) assess how benchmarks for safe levels of consumption of LCS are utilized by researchers, and (2) understand how varying use of such benchmarks may contribute to challenges in understanding and applying nutritional guidance for LCS consumption. METHODS: A systematic mapping exercise was employed to characterize when and how acceptable daily intake (ADI) values are used as health-based benchmarks in nutrition research studies that consider the safety of LCS. RESULTS: Based on results from charting 121 studies, our findings demonstrate that comparisons of LCS intake to an ADI derived by an authoritative body have been made in a diverse set of published literature, varying widely in their objectives, approaches, and populations of interest. The majority of studies compared the ADI to intake in a population under study; these represent the type of comparison that is most consistent with the intent of the ADI. Other applications of the ADI included use as a benchmark in experimental studies, risk-benefit analyses, and metabolism studies. CONCLUSION: Although most instances of ADI use were reasonable within the context of the individual studies' objectives, the diversity in use by original-study authors amplifies the continued need for development of "best practices" regarding the use and interpretation of the ADIs in current research. Using comparisons to the ADI can be a helpful way to provide context to research findings. However, in doing so, it is important that researchers utilize the value in a manner specific with its intent, as the ADI is a metric that represents an estimate of the amount of a substance that can be consumed daily over a lifetime without presenting an appreciable risk to health.

Assessment of the in vivo genotoxic potential of three smoke flavoring primary product mixtures.

Smoke flavorings are mixtures generated from wood pyrolysis that are filtered to remove tar and are often considered healthier alternatives to conventional smoking processes. While the latter is mostly unregulated, smoke-flavoring primary products (SFPPs) are undergoing the 10-year required re-evaluation in the European Union (EU). To comply with recent smoke flavor guidance, in vivo micronucleus studies in rats and transgenic rodent (TGR) mutation assays in Muta™Mice were conducted on three SFPPs. For most studies, typical limit doses were exceeded to comply with regulatory requests. Exposure to SFPPs by oral gavage did not result in significant increases in bone marrow micronucleus formation. Except for one group, exposure to SFPPs via feed for 28 days did not result in significant increases in mutant frequency (MF) in the glandular stomach or liver. One group exposed to a maximal feasible dietary dose of 50,000 ppm (>10,000 mg/kg bodyweight per day) exhibited a statistically significant increase in liver MF; however, the MF in all mice in this group were within the historical vehicle control 95% quantile confidence intervals and therefore not considered biologically relevant. Based on estimates of human dietary exposure to each SFPP, the margin of exposure (MOE) values in the TGR assays exceed 10,000. The MOE for one unintentionally present constituent, 2,5(H)-furanone, also exceeds 10,000. Collectively, these data indicate that these SFPPs pose no genotoxic risk and are safe alternatives to conventional smoking.

Benefit-risk of coffee consumption and all-cause mortality: A systematic review and disability adjusted life year analysis.

BACKGROUND: Recommendations and guidance from scientific bodies do not provide clear messages about potential health risks or benefits of coffee consumption. Numerous studies have demonstrated inverse (beneficial) effects of coffee consumption for many adverse outcomes such as cancer and cardiovascular disease; fewer studies demonstrate risks. However, the risk-benefit relationship has not yet been fully assessed using quantitative metrics preferred by policy makers (disability-adjusted life years [DALYs]). OBJECTIVE: Conduct a quantitative analysis of the risk-benefit for coffee consumption and all-cause mortality using the Benefit-Risk Analysis for Foods (BRAFO) framework and the DALY as a quantitative metric. METHOD: A systematic search and appraisal of meta-analyses investigating coffee consumption and all-cause mortality was conducted. Using the BRAFO framework, evidence was assessed in context of potential risks or benefits associated with the reference scenario - coffee consumption (assessed by varying the consumption level in three analyses) in adults aged 15+ versus the alternative scenario of no coffee consumption. DALYs were used to quantify risks and benefits based on risk ratios from meta-analyses with populations from the United States. RESULTS: Meta-analyses consistently report an inverse (beneficial) relationship between coffee consumption and all-cause mortality; subsequently, even while varying consumption amounts and prevalence of coffee consumption, DALYs calculated consistently demonstrated findings in the direction of prevention of healthy years of life lost with variable magnitude. More than 3.5 million DALYs, or ∼3.35% of estimated years of healthy life lost could be prevented by consuming one cup of coffee per day, up to 4.7% of estimated years of healthy life lost could be prevented at current consumption rates ranging from 1 to 8 cups/day, and even more benefit could be seen (prevention of an estimated 6% of years of healthy life lost) if consumers all drank 3 cups of coffee per day. IMPACT: Policy that directs consumers to avoid drinking coffee may be a detriment to the overall health of the population given the substantial potential benefits of coffee consumption on all-cause mortality for adults.

Assessing the food safety risk of ochratoxin A in coffee: A toxicology-based approach to food safety planning.

Under the Food Safety Modernization Act (FSMA) and preventive controls (PCs) regulations, food manufacturers must consider whether PCs are needed for potential hazards present in food. The mycotoxin ochratoxin A (OTA) is considered a chemical hazard under FSMA. It is produced by several fungal species and can be present in various agricultural commodities, including coffee. OTA presents a unique scenario in food safety, because it is known to be a potential risk; because heating may destroy it, but not completely; and because the hazard profile suggests it is not acutely toxic at the occurrence levels in coffee, although at high exposure levels, it is potentially nephrotoxic and carcinogenic in animal models. In the absence of US compliance levels, it is important for the risk assessor and risk manager to determine whether PCs are warranted. To address this complex situation in the coffee industry, we combined food safety and toxicology risk assessment principles to examine the available information on OTA hazard and risk in coffee. Exposure and health-based benchmarks for OTA in coffee, established by reviewing peer-reviewed literature, food recall databases, and authoritative reviews, resulted in large margins-of-exposure for both single and repeated exposure scenarios. Furthermore, no evidence was identified from historical data to suggest OTA is acutely toxic in humans from coffee consumption or other exposure sources. Therefore, findings from this assessment indicate that no PC is warranted for US coffee manufactures, based on the low severity and likelihood of risk according to margin-of-exposure estimates and historical data.

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

Calcium nitrate has been reported to benefit reproductive outcomes in sows and their offspring when administered via the feed (15 to 19 mg/kg-body weight [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 d. 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 the European Food Safety Authority'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.

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

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-d 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.

Key Findings and Implications of a Recent Systematic Review of the Potential Adverse Effects of Caffeine Consumption in Healthy Adults, Pregnant Women, Adolescents, and Children.

In 2016⁻2017, we conducted and published a systematic review on caffeine safety that set out to determine whether conclusions that were presented in the heavily cited Health Canada assessment, remain supported by more recent data. To that end, we reviewed data from 380 studies published between June 2001 and June 2015, which were identified from an initial batch of over 5000 articles through a stringent search and evaluation process. In the current paper, we use plain language to summarize our process and findings, with the intent of sharing additional context for broader reach to the general public. We addressed whether caffeine doses previously determined not to be associated with adverse effects by Health Canada (400 mg/day for healthy adults, 300 mg/day for pregnant women, 2.5 mg/kg body weight/day for adolescents and children, and 10 g/day for acute effects) remain appropriate for five outcome areas (acute toxicity, cardiovascular toxicity, bone & calcium effects, behavior, and development and reproduction) in healthy adults, pregnant women, adolescents, and children. We used a weight-of-evidence approach to draw conclusions for each of the five outcomes, as well as more specific endpoints within those outcomes, which considered study quality, consistency, level of adversity, and magnitude of response. In general, updated evidence confirms the levels of intake that were put forth by Health Canada in 2003 as not being associated with any adverse health effects, and our results support a shift in caffeine research from healthy to sensitive populations.

Systematic review of the potential adverse effects of caffeine consumption in healthy adults, pregnant women, adolescents, and children.

To date, one of the most heavily cited assessments of caffeine safety in the peer-reviewed literature is that issued by Health Canada (Nawrot et al., 2003). Since then, >10,000 papers have been published related to caffeine, including hundreds of reviews on specific human health effects; however, to date, none have compared the wide range of topics evaluated by Nawrot et al. (2003). Thus, as an update to this foundational publication, we conducted a systematic review of data on potential adverse effects of caffeine published from 2001 to June 2015. Subject matter experts and research team participants developed five PECO (population, exposure, comparator, and outcome) questions to address five types of outcomes (acute toxicity, cardiovascular toxicity, bone and calcium effects, behavior, and development and reproduction) in four healthy populations (adults, pregnant women, adolescents, and children) relative to caffeine intake doses determined not to be associated with adverse effects by Health Canada (comparators: 400 mg/day for adults [10 g for lethality], 300 mg/day for pregnant women, and 2.5 mg/kg/day for children and adolescents). The a priori search strategy identified >5000 articles that were screened, with 381 meeting inclusion/exclusion criteria for the five outcomes (pharmacokinetics was addressed contextually, adding 46 more studies). Data were extracted by the research team and rated for risk of bias and indirectness (internal and external validity). Selected no- and low-effect intakes were assessed relative to the population-specific comparator. Conclusions were drawn for the body of evidence for each outcome, as well as endpoints within an outcome, using a weight of evidence approach. When the total body of evidence was evaluated and when study quality, consistency, level of adversity, and magnitude of response were considered, the evidence generally supports that consumption of up to 400 mg caffeine/day in healthy adults is not associated with overt, adverse cardiovascular effects, behavioral effects, reproductive and developmental effects, acute effects, or bone status. Evidence also supports consumption of up to 300 mg caffeine/day in healthy pregnant women as an intake that is generally not associated with adverse reproductive and developmental effects. Limited data were identified for child and adolescent populations; the available evidence suggests that 2.5 mg caffeine/kg body weight/day remains an appropriate recommendation. The results of this systematic review support a shift in caffeine research to focus on characterizing effects in sensitive populations and establishing better quantitative characterization of interindividual variability (e.g., epigenetic trends), subpopulations (e.g., unhealthy populations, individuals with preexisting conditions), conditions (e.g., coexposures), and outcomes (e.g., exacerbation of risk-taking behavior) that could render individuals to be at greater risk relative to healthy adults and healthy pregnant women. This review, being one of the first to apply systematic review methodologies to toxicological assessments, also highlights the need for refined guidance and frameworks unique to the conduct of systematic review in this field.

Caffeine: Friend or Foe?

The debate on the safety of and regulatory approaches for caffeine continues among various stakeholders and regulatory authorities. This decision-making process comes with significant challenges, particularly when considering the complexities of the available scientific data, making the formulation of clear science-based regulatory guidance more difficult. To allow for discussions of a number of key issues, the North American Branch of the International Life Sciences Institute (ILSI) convened a panel of subject matter experts for a caffeine-focused session entitled "Caffeine: Friend or Foe?," which was held during the 2015 ILSI Annual Meeting. The panelists' expertise covered topics ranging from the natural occurrence of caffeine in plants and interindividual metabolism of caffeine in humans to specific behavioral, reproductive, and cardiovascular effects related to caffeine consumption. Each presentation highlighted the potential risks, benefits, and challenges that inform whether caffeine exposure warrants concern. This paper aims to summarize the key topics discussed during the session.