Approaches to risk-benefit assessment of seafood consumption: lessons learned from an evidence scan.

Qualitative and quantitative risk-benefit assessments (RBA) can be used to support public health decisions in food safety. We conducted an evidence scan to understand the state of the science regarding RBA in seafood to help inform seafood dietary advice in the United States. We collected published RBA studies assessing seafood consumption, designed inclusion and exclusion criteria to screen these studies, and conducted systematic data extraction for the relevant studies published since 2019. Our findings indicate the selection of health risks and benefits does not generally follow a systematic approach. Uncertainty and variability in RBAs is often not addressed, and quantitative RBAs making use of a single health metric generally have not been leveraged to directly support published regulatory decisions or dietary guidance. To elevate the role of RBA in supporting regulatory decision-making, risk assessors and risk managers must work together to set expectations and goals. We identified the need for a prioritization phase (e.g., multicriteria decision analysis model) to determine the risks and benefits of greatest public health impact to inform the RBA design. This prioritization would consider not only the degree of public health impact of each risk and benefit, but also the potential for risks and benefits to converge on common health outcomes and their importance to subpopulations. Including a prioritization could improve the utility of the RBAs to better inform risk management decisions and advance public health. Our work serves to guide the United States Food and Drug Administration's approaches to RBA in foods.

Safety assessment of Urolithin A, a metabolite produced by the human gut microbiota upon dietary intake of plant derived ellagitannins and ellagic acid.

Urolithins are metabolites produced in the gut following consumption of ellagitannins and ellagic acid rich foods such as pomegranates, nuts and certain berries. Urolithin A (UA) is one of the predominant isoforms of urolithins in humans and has demonstrated compelling biological activities, suggesting potential benefits of direct consumption of UA. However, an evaluation of the safety of direct administration of UA has not yet been published. The aim of this study was to investigate for the first time the genotoxicity, toxicokinetics, and repeated dose safety of orally administered synthetic UA in rats. The battery of genotoxicity assays demonstrated that UA is not genotoxic. The ADME study showed that glucuronidated and sulfonated forms of UA are the predominant metabolites following both oral and i.v. administration. The 28-day (0, 0.175, 1.75, and 5.0% UA mixed in diet) and 90-day studies (0, 1.25, 2.5, and 5.0% UA mixed in diet) showed no alterations in clinical parameters, blood chemistry, or hematology, and did not indicate any target organs, or any specific toxic mechanisms. The NOAEL was the highest dose tested, 5% UA by weight in the diet, or 3451 mg/kg bw/day in males and 3826 mg/kg bw/day in females in the 90-day oral study.

Reassessment of MTBE cancer potency considering modes of action for MTBE and its metabolites.

A 1999 California state agency cancer potency (CP) evaluation of methyl tert-butyl ether (MTBE) assumed linear risk extrapolations from tumor data were plausible because of limited evidence that MTBE or its metabolites could damage DNA, and based such extrapolations on data from rat gavage and rat and mouse inhalation studies indicating elevated tumor rates in male rat kidney, male rat Leydig interstitial cells, and female rat leukemia/lymphomas. More recent data bearing on MTBE cancer potency include a rodent cancer bioassay of MTBE in drinking water; several new studies of MTBE genotoxicity; several similar evaluations of MTBE metabolites, formaldehyde, and tert-butyl alcohol or TBA; and updated evaluations of carcinogenic mode(s) of action (MOAs) of MTBE and MTBE metabolite's. The lymphoma/leukemia data used in the California assessment were recently declared unreliable by the U.S. Environmental Protection Agency (EPA). Updated characterizations of MTBE CP, and its uncertainty, are currently needed to address a variety of decision goals concerning historical and current MTBE contamination. To this end, an extensive review of data sets bearing on MTBE and metabolite genotoxicity, cytotoxicity, and tumorigenicity was applied to reassess MTBE CP and related uncertainty in view of MOA considerations. Adopting the traditional approach that cytotoxicity-driven cancer MOAs are inoperative at very low, non-cytotoxic dose levels, it was determined that MTBE most likely does not increase cancer risk unless chronic exposures induce target-tissue toxicity, including in sensitive individuals. However, the corresponding expected (or plausible upper bound) CP for MTBE conditional on a hypothetical linear (e.g., genotoxic) MOA was estimated to be ∼2 × 10(-5) (or 0.003) per mg MTBE per kg body weight per day for adults exposed chronically over a lifetime. Based on this conservative estimate of CP, if MTBE is carcinogenic to humans, it is among the weakest 10% of chemical carcinogens evaluated by EPA.

Toxicological evaluation of an olive extract, H35: Subchronic toxicity in the rat.

The safety of olive extract H35 containing 35% hydroxytyrosol (HT) was tested in a 90-day oral gavage study in Wistar rats. H35 was administered at 0, 345, 691 and 1381 mg/kg bw/day, equivalent to 0, 125, 250 and 500 mg HT/kg bw/day. Reductions in terminal body weight (9%), and a statistically significant reduction in body weight gain (17%, P < 0.05) at week 13 were observed in high dose males, as well as a statistically significant increase in relative weights of the liver, heart, and kidneys of high dose males and females. These changes were not accompanied by pathological or clinical observations and a trend towards reversal was observed in the recovery phase. H35 was well-tolerated and no toxicologically significant treatment-related changes were observed in condition and appearance of rats, neurobehavioral outcomes, motor activity assessments, functional observational battery (FOB), food intake, ophthalmoscopic examinations, hematology, clinical chemistry, urinalysis, necropsy findings, sperm parameters or estrus cycle. The lowest observed adverse effect level (LOAEL) was the 500 mg HT/kg bw/day based on statistically significant reductions in body weight gain and decreased body weight in males. The no observed adverse effect level (NOAEL) was 250 mg HT/kg bw/day, equivalent to 691 mg/kg bw/day of H35 extract.

Egg consumption and cardiovascular disease among diabetic individuals: a systematic review of the literature.

BACKGROUND: This study reviewed epidemiological and experimental evidence on the relationship between egg consumption and cardiovascular disease (CVD) risks among type II diabetes mellitus (T2DM) individuals, and T2DM risk in nondiabetic subjects. RESULTS: Four of the six studies that examined CVD and mortality and egg consumption among diabetics found a statistically significant association. Of the eight studies evaluating incident T2DM and egg consumption, four prospective studies found a statistically significant association. Lack of adjustment for dietary confounders was a common study limitation. A small number of experimental studies examined the relationship between egg intake and CVD risk biomarkers among diabetics or individuals with T2DM risk factors. Studies among healthy subjects found suggestive evidence that dietary interventions that include eggs may reduce the risk of T2DM and metabolic syndrome. CONCLUSION: Differences in study design, T2DM status, exposure measurement, subject age, control for confounders and follow-up time present significant challenges for conducting a meta-analysis. Conflicting results, coupled with small sample sizes, prevent broad interpretation. Given the study limitations, these findings need to be further investigated.

Transactivation of gene expression by NF-κB is dependent on thioredoxin reductase activity.

The redox-sensitive transcription factor NF-κB mediates the expression of genes involved in inflammation and cell survival. Thioredoxin reductase-1 (TR1) and its substrate thioredoxin-1 act together to reduce oxidized cysteine residues within the DNA-binding domain of NF-κB and promote maximal DNA-binding activity in vitro. It is not clear, however, if NF-κB is regulated via this mechanism within living cells. The purpose of this study was to determine the mechanism of NF-κB modulation by TR1 in cells stimulated with the inflammatory cytokine tumor necrosis factor-α (TNF). In both control cells and cells depleted of TR1 activity through chemical inhibition or siRNA knockdown, TNF stimulation resulted in degradation of the cytoplasmic NF-κB inhibitor IκB-α and translocation of NF-κB to the nucleus. Similarly, the DNA-binding activity and redox state of NF-κB were unaffected by TR1 depletion. In contrast, NF-κB-mediated gene expression was markedly inhibited in cells lacking TR1 activity, suggesting that the transactivation potential of NF-κB is sensitive to changes in TR1 activity. Consistent with this concept, phosphorylation of the transactivation domain of NF-κB was inhibited in the presence of curcumin. Surprisingly, another TR1 inhibitor, 1-chloro-2,4-dinitrobenzene, had no effect, and siRNA knockdown of TR1 actually increased phosphorylation at this site. These results demonstrate that TR1 activity controls the transactivation potential of NF-κB and that more than one mechanism may mediate this effect.

Thioredoxin reductase-1 knock down does not result in thioredoxin-1 oxidation.

The active site of thioredoxin-1 (Trx1) is oxidized in cells with increased reactive oxygen species (ROS) and is reduced by thioredoxin reductase-1 (TrxR1). The purpose of the present study was to determine the extent to which the redox state of Trx1 is sensitive to changes in these opposing reactions. Trx1 redox state and ROS generation were measured in cells exposed to the TrxR1 inhibitors aurothioglucose (ATG) and monomethylarsonous acid (MMA(III)) and in cells depleted of TrxR1 activity by siRNA knock down. The results showed that all three treatments inhibited TrxR1 activity to similar extents (90% inhibition), but that only MMA(III) exposure resulted in oxidation of Trx1. Similarly, ROS levels were elevated in response to MMA(III), but not in response to ATG or TrxR1 siRNA. Therefore, TrxR1 inhibition alone was not sufficient to oxidize Trx1, suggesting that Trx1-independent pathways should be considered when evaluating pharmacological and toxicological mechanisms involving TrxR1 inhibition.

The structure of DNA dictates purine atom site selectivity in alkylation by primary diazonium ions.

The 1-propanediazonium ion, generated from N'-nitro-N-nitroso-N-propylguanidine in aqueous solutions, was reacted with the purine nucleosides dGuo and dAdo or single-stranded or double-stranded DNA. After nucleobase liberation by acid hydrolysis, the percent yields of products were determined by LC/MS using either isotopically distinct internal standards in the case of the nucleoside reactions or an internal standard and the ratios of response factors of all other products that were separately determined in the case of the reactions with DNA. In the reactions of nucleosides, products of both n-propylation and iso-propylation at all of the heroatoms were observed. For these reactions, the yields of the three most abundant n-propyl adducts of Gua are in the order O6 > N7 > N2, in the ratio of 9.0/6.4/1, while for Ade, the order of the yields of N-propyl products is N1 > N7 > N3 > N6 in the ratio 2.5/1.8/1.1/1. The ratios of n-propylated to iso-propylated products at each site, P(n)/P(i), generally a measure of enhancement of S(N)2 displacement on the diazonium ion, vary with each heteroatom but by no more than a factor of 6 for Gua and a factor of 3 for Ade. In the reactions with duplex DNA, products of reactions at all sites could not be detected. In addition, much larger selectivities are observed, similar to what has been observed by others in the reactions with ethanediazonium ion. Thus, P(n)/P(i) = 30, 21, and 0.9 for N7, O6, and N2 of Gua. Similarly, the values of P(n)/P(i) are 11 and 8 for N3 and N7 of Ade. Reactions with single-stranded DNA give values of P(n)/P(i) that are intermediate between the nucleoside reactions and the reactions of duplex DNA in most cases. The factors responsible for the relatively small atom site selectivities intrinsic to the nucleosides are analyzed, and reasons for enhanced S(N)2 nucleophilicity in duplex DNA are discussed.