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Despite its popularity along with many proposed therapeutic applications, the safety profile of Aloe vera gel beverages remains unsettled. The putative toxicology concern has focused on the hydroxyanthraquinone derivatives (HADs) found in the latex portion of the Aloe leaf. Despite harvesting and processing designed to eliminate or significantly reduce these compounds, certain HADs, such as aloin, may be present and have been associated with carcinogenicity in non-decolorized whole leaf extract containing approximately 6400 ppm aloin A and 71 ppm aloin-emodin. Sprague Dawley rats had free access to drinking water or a commercially and widely available Aloe vera gel beverage (Forever Living Products) prepared from the inner leaves of Aloe barbadensis Miller containing 3.43 ppm total aloin for 90 days. Under the conditions of the study and based on the toxicological endpoints evaluated, there were no adverse test substance-related findings, including altered thyroid hormones. No histologic differences or histopathological changes were detected in the multiple tissues and organs examined. The Ki-67 proliferation assay demonstrated no increased cell proliferation in the liver, lungs, kidneys, or urinary bladder, which might have been attributed to the dietary administration of the Aloe vera gel beverage via drinking water for 90 days. These data lend increasing confidence regarding the safety of appropriately processed Aloe vera gel beverages, such as the beverage tested in this study., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The Aloe Vera Company, Scottsdale, AZ, funded the study, which was conducted at Product Safety Laboratories, Dayton, NJ. Allen W. Singer, and Mark R. Bauter are employees of Stage Bio, Mount Jackson, VA Product Safety Labs, Dayton, NJ 08810, respectively. A. Wallace Hayes, Peter Pressman, and Roger Clemens are members of the Scientific Advisory Board, The Aloe Vera Company and are paid consultants. Although the manuscript has been reviewed by the company, the conclusions and writing of the manuscript are entirely those of the authors., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The present paper provides the first integrative assessment of the capacity of dietary, endogenous and other agents to induce hormetic dose responses in oocytes, their supportive cells such as granulosa cells, blastocyst formation and early stage embryo development with the goal of improving fertility and reproductive success. The analysis showed that numerous agents enhance oocyte maturation and blastocyst/embryonic development in an hormetic fashion. These findings indicate that numerous agents improve oocyte-related biological functioning under normal conditions as well as enhancing its capacity to prevent damage from numerous chemical toxins and related stressor agents, including heat and age-related processes in pre-post conditioning and concurrent exposures. The present assessment suggests that hormetic-based lifestyles and dietary interventions may offer the potential to enhance healthy reproductive performance with applications to animal husbandry and human biology. The present findings also significantly extend the generality of the hormesis dose response concept to multiple fundamental biological processes (i.e., oocyte maturation, fertilization and blastocyst/embryo development)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Rutin is a flavonoid present in numerous fruits and vegetables and therefore widely consumed by humans. It is also a popular dietary supplement of 250-500 mg/day. There is considerable consumer interest in rutin due to numerous reports in the biomedical literature of its multi-system chemo-preventive properties. The present paper provides the first assessment of rutin-induced hormetic concentration/dose responses, their quantitative features and mechanistic basis, along with their biological, biomedical, clinical, and public health implications. The findings indicate that rutin-induced hormetic dose responses are widespread, being reported in numerous biological models and cell types for a wide range of endpoints. Of critical importance is that the optimal hormetic findings shown in in vitro systems are currently not achievable for human populations due to low gastrointestinal tract bioavailability. These findings have the potential to strengthen future experimental studies with rutin, particularly concerning study design parameters., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Quercetin is a polyphenol present in numerous fruits and vegetables and therefore widely consumed by humans with average daily dietary intakes of 10-20 mg/day. It is also a popular dietary supplement of 250-1000 mg/day. However, despite the widespread consumer interest in quercetin, due to its possible chemopreventive properties, the extensively studied quercetin presents a highly diverse and complex array of biological effects. Consequently, the present paper provides the first assessment of quercetin-induced hormetic concentration/dose responses, their quantitative features and mechanistic foundations, and their biological, biomedical, clinical, and public health implications. The findings indicate that quercetin-induced hormetic dose responses are widespread, being independent of biological model, cell type, and endpoint. These findings have the potential to enlighten future experimental studies with quercetin especially with respect to study design parameters and may also affect the appraisal of possible public health benefits and risks associated with highly diverse consumer consumption practices., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Aloe has a long history of topical and systemic use with testimonials of countless health benefits and is one of the most popular botanical medicines in the world for the management of a wide variety both of benign and serious ailments including irritable bowel syndromes, osteoarthritis, Type II diabetes mellitus, and viral respiratory illness. The human consumption of Aloe vera extract in beverage form has substantially grown over the last several decades, in no small part, due to the increased consumer interest in alternative approaches to health benefits. The principal aim of the present paper is to characterize the research to date that has explored the genotoxic potential of Aloe vera inner leaf gel extract and decolorized whole leaf extract used in commercially available food-grade drinkable products which contain no more than 10 ppm aloin. Despite prevailing public health opinion, especially in Europe, the consensus of the reviewed studies retrieved from the peer-reviewed literature together with a mutagenic evaluation of an Aloe vera whole leaf decolorized spray-dried powder is that these products are not genotoxic., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Cardiovascular diseases (CVDs) are the leading cause of death worldwide. The majority of cardiovascular complications are secondary to atherosclerosis. Extensive evidence has showed that environmental pollutants such as cigarette smoke and automobile exhaust increase the risk of developing atherosclerosis. Acrolein, a highly reactive unsaturated aldehyde, is found as a contaminant in air, food and water. Investigations during the last decades have shown that acrolein via various mechanisms such as oxidative stress, enhancement of inflammatory processes and the activation of matrix metalloproteases can initiate and accelerate atherosclerotic lesions formation. Furthermore, exposure to acrolein has been suggested to induce or exacerbate systemic dyslipidemia, an important risk factor for the development of atherosclerosis. Finally, there are reports which indicate acrolein can increase platelet activation and stimulation of the coagulation cascade which subsequently leads to thrombosis. Even a modest reduction of pollutants such as acrolein can have substantial effects on population health. Public health efforts to reduce acrolein exposures from known sources may lower the prevalence of vascular disease. This review focuses on the potential pathways and mechanisms behind the acrolein-induced atherothrombotic effects., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Breast cancer is the most common cause of cancer mortality among women worldwide; therefore, a strategy to defeat breast cancer is an extremely important medical issue. One of the major challenges in this regard is multidrug resistance (MDR). Resveratrol, a well-known phytoestrogen, may be helpful as part of an overall strategy to defeat breast cancer. The mixed agonist and antagonist role of resveratrol for the estrogen receptor makes it a controversial but interesting molecule in cancer therapy, especially in hormone dependent cancers. Several in vitro investigations have suggested that resveratrol can reverse multidrug resistance. However, poor bioavailability of resveratrol is a potential limitation for resveratrol treatment and cancer outcome in vivo. Fortunately, combination therapy with other selected compounds improves resveratrol's bioavailability and/or a delay in its metabolism. This review summaries the available published literature dealing with the effects of resveratrol on multidrug resistance in cancer and more specifically, breast cancer., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Lycopene, a carotenoid, is known for its antioxidant properties. Little is known, though, about the relationship of dietary tomato-juice intake and risks factors, like inflammation, insulin resistance and hyperlipidemia, implicated in metabolic syndrome. In the present study, we examined whether supplementation with tomato-juice has any implication on the risk status of patients with metabolic syndrome. A comparative study was conducted in 27 individuals diagnosed with metabolic syndrome. Fifteen of them were instructed to use commercially available tomato-juice as refreshment 4 times a week over a period of two months and twelve individuals served as the control group. Several parameters reflective of the metabolic syndrome were monitored both in the group supplemented with tomato juice and in the control group (ADMA for entdothelial function, TNF-α and IL-6 for inflammation, FIRI for insulin resistance). There was a significant improvement in the inflammation status and the endothelial dysfunction of the tomato-juice supplemented patients. At the same time, insulin resistance improved and a pronounced decrease in LDL was recorded, along with a slight increase in HDL. The results of the present study suggest an alleviating effect of tomato-juice with regard to risk factors associated with metabolic syndrome., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

α-Linolenic acid (ALA), a carboxylic acid with 18 carbons and three cis double bonds, is an essential fatty acid needed for human health and can be acquired via regular dietary intake of foods that contain ALA or dietary supplementation of foods high in ALA, for example flaxseed. ALA has been reported to have cardiovascular-protective, anti-cancer, neuro-protective, anti-osteoporotic, anti-inflammatory, and antioxidative effects. ALA is the precursor of longer chain omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), but its beneficial effects on risk factors for cardiovascular diseases are still inconclusive. The recommended intake of ALA for cardiovascular health is reported to be 1.1-2.2g/day. Although there are limited toxicological data for ALA, no serious adverse effects have been reported. The evidence on an increased prostate cancer risk in association with dietary ALA is not conclusive. Based on the limited data currently available, it may be concluded that ALA may be beneficial as a nutraceutical/pharmaceutical candidate and is safe for use as a food ingredient., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Mycotoxins are toxic metabolites produced by fungal species that commonly contaminate staple foods and feeds. They represent an unavoidable problem due to their presence in globally consumed cereals such as rice, maize and wheat. Most mycotoxins are immunosuppressive agents and some are carcinogens, hepatotoxins, nephrotoxins, and neurotoxins. Worldwide trends envision a stricter control of mycotoxins, however, the changing global environment may not be the ideal setting to control and reduce the exposure to these toxins. Although new technologies allow us to inspect the multi-mycotoxin presence in foods, new sources of exposure, gaps in knowledge of mycotoxins interactions, appearance of "emergent" mycotoxins and elucidation of consequent health effects can complicate their control even more. While humans are adapting to cope with environmental changes, such as food scarcity, decreased food quality, mycotoxin regulations, crop production and seasonality, and other climate related modifications, fungal species are also adapting and increased cases of mycotoxin adverse health effects are likely to occur in the future. To guarantee access to quality food for all, we need a way to balance global mycotoxin standards with the realistic feasibility of reaching them, considering limitations of producers and designing strategies to reduce mycotoxin exposure based on sound research., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Findings about involvement of reactive oxygen species (ROS) not only in defense processes, but also in a number of pathologies, stimulated discussion about their role in etiopathogenesis of various diseases. Yet questions regarding the role of ROS in tissue injury, whether ROS may serve as a common cause of different disorders or whether their uncontrolled production is just a manifestation of the processes involved, remain unexplained. Dogmatically, increased ROS formation is considered to be responsible for development of the so-called free-radical diseases. The present review discusses importance of ROS in various biological processes, including origin of life, evolution, genome plasticity, maintaining homeostasis and organism protection. This may be a reason why no significant benefit was found when exogenous antioxidants were used to treat free-radical diseases, even though their causality was primarily attributed to ROS. Here, we postulate that ROS unlikely play a causal role in tissue damage, but may readily be involved in signaling processes and as such in mediating tissue healing rather than injuring. This concept is thus in a contradiction to traditional understanding of ROS as deleterious agents. Nonetheless, under conditions of failing autoregulation, ROS may attack integral cellular components, cause cell death and deteriorate the evolving injury., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Sucralose is a non-nutritive sweetener that is approximately 600 times sweeter than table sugar. It is currently approved for use in over 80 countries. Evidence from chronic studies demonstrates that this compound is not carcinogenic. This report summarizes the results of genotoxicity studies that were part of the original safety assessment of sucralose-conducted early in the safety investigation and shared with regulatory agencies around the world. Studies included the Ames (Salmonella typhimurium) reverse mutation test, the Escherichia coli pol A+/A- test, an in vitro chromosome damage assay in human lymphocytes, mutation in TK +/- mouse lymphoma cells, an in vivo chromosome aberration test in rats and two separate micronucleus tests in mice. All results were evaluated as negative. These results support the overall conclusion by regulatory and heath agencies that sucralose is safe for its intended use., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Measuring the mutagenicity of urine is widely viewed as a means of evaluating human exposure to potentially genotoxic materials. Diet and cigarette smoking have both been reported to affect the mutagenicity of human urine, but the relationship between smoking status and the expression of diet-related urinary mutagenicity is unknown. It has been reported that some promutagens are more active in in vitro assays when tested in the presence of urine from smokers than when tested in the presence of urine from non-smokers. We aimed to determine whether the differences in urinary mutagenicity between smokers and non-smokers result from increased urinary mutagenicity from dietary heterocyclic amine mutagens in smokers compared with non-smokers. Groups of smokers and non-smokers (6-12) were given identical diets, previously shown to be low in heterocyclic amines and very low in mutagenicity. The diet consisted exclusively of raw food and of food cooked in boiling water. After a 2-day dietary stabilization period, 24-hour urine samples were collected for three consecutive days. The regimen was repeated in the following week. For comparison, both groups were also placed on a "western" diet, consisting of a variety of foods prepared by several cooking methods, designed to reflect what a typical United States family might consume. Urine was concentrated using XAD-2 resin and then assayed for mutagenic activity in the Ames test. The urine of smokers was significantly more mutagenic than that of non-smokers when on both the raw/boiled and the "western" diets. These results indicate that the increased urinary mutagenicity observed in smokers compared with non-smokers is not due to enhanced mutagenicity of diet-related heterocyclic amine mutagens in the urine of smokers.

The metabolism of penicillic acid (PA), a carcinogenic mycotoxin, was studied in vitro using subcellular fractions of mouse-liver homogenates. PA reacted with glutathione (GSH) both enzymatically and non-enzymatically. Each reaction was of equal importance. The in vitro metabolism of PA using different hepatic subcellular fractions was essentially non-enzymatic when GSH was absent, but metabolism was strikingly increased when GSH was available. In the microsomal preparation in the presence of GSH 75% of the added PA was biotransformed within 30 min to metabolite(s) that were not extractable with organic solvents. HPLC analysis indicated that the metabolite(s) were more polar than the parent compound.

The LD50 for rubratoxin B dissolved in dimethylsulphoxide and administered to Syrian golden hamsters by ip injection was 0.4 (0.2-0.8) mg/kg body weight. The greatest number of deaths occurred 6-24 hr after administration. Gross alterations consisted of congestion of the liver, spleen and kidneys and histopathological alterations involved congestion of the spleen and congestion and mild degenerative changes in hepatocytes. In a second study, rubratoxin B was administered ip daily for 1 wk at doses of 25, 50 and 75% of the ip LD50. Mortality was greatest in the 50 and 75% dose groups. Toxicity was cumulative with multiple doses. Gross alterations were similar to those found in the LD50 study. Histopathological alterations included renal tubular degeneration and necrosis and focal necrosis of hepatocytes. The morphopathogenesis of lesions following a single ip LD50 dose was evaluated in a third study. Histopathological alterations were limited to the kidney and were characterized by renal tubular degeneration and necrosis. Renal lesions were first seen at 2 hr after administration and increased in severity to a maximum at 20 hr. Tubular regeneration was first seen at 24 hr and was found to the end of the test period (72 hr). Serum activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and serum concentrations of total and indirect bilirubin were increased by 8 hr after dosing and returned to control values by the end of the test period. In a fourth study, rubratoxin B was administered ip daily for 1 wk at a dose of 25% of the ip LD50. Gross alterations were similar to those in the other studies. Histopathological alterations included progressive renal tubular degeneration and necrosis. Serum activities of AST and ALT and concentration of blood urea nitrogen (BUN) were progressively increased with increasing numbers of doses. Urinalysis indicated progressive renal tubular damage.

The LD50 for rubratoxin B dissolved in dimethylsulphoxide and administered to ICR mice by ip injection was 0.31 (0.22-0.43) mg/kg body weight. Gross alterations consisted of congestion of the liver and spleen and pallor and mottling of the kidneys. The histopathological alterations seen were hepatic and splenic congestion and renal tubular degeneration. The morphopathogenesis of lesions following a single ip LD50 dose was evaluated in a second study. Hepatic lesions were observed in mice killed between 8 and 40 hr after dosing and included diffuse sinusoidal congestion with mild sinusoidal ectasia, leucostasis, multifocal cytoplasmic vacuolation and necrosis of individual hepatocytes. Renal lesions were mild, not time-dependent, and consisted of mild degenerative changes in tubular epithelial cells of the outer stripe of the outer zone of the medulla. The activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum were increased 2 hr after dosing, peaked at 4 hr and returned to control values by the end of the test period. In a third study, rubratoxin B was administered ip daily for 1 wk at doses of 25, 50 and 75% of the ip LD50. Toxicity was dose related and cumulative with multiple doses at the highest dose. In a fourth study, rubratoxin B was administered ip at a dose of 75% of the ip LD50 daily for 1 wk. Histopathological alterations included hepatic congestion and mild sinusoidal ectasia, multifocal necrosis of hepatocytes, splenic congestion and mild renal tubular degeneration. Serum activities of AST and ALT were increased after multiple doses of rubratoxin B.

Kathon biocide (KB), a 75:25 mixture of 5-chloro-2-methyl-4-isothiazolin-3-one (KI) and 2-methyl-4-isothiazolin-3-one (KII), is a broad-spectrum antimicrobial agent. The absorption and disposition of 14C label were studied in male Sprague-Dawley rats following iv or dermal administration of KB 14C labelled in the carbonyl carbon of either KI or KII. KI-labelled Kathon was distributed rapidly following an iv dose (0.8 mg/kg). Total 14C label in the plasma was rapidly eliminated, with the data best described by a three-compartment model. Total 14C label concentration in the blood, however, remained constant at 3 ppm from 6 to 96 hr after administration and represented 29% of the dose, indicating that KI-labelled Kathon and/or metabolites was sequestered by the cellular fraction of blood. Elimination of 14C label from the tissues examined was biphasic, with a terminal half-life of more than 4 days; by 96 hr, faeces, urine and CO2 accounted for 35, 31 and 4% of the dose, respectively. Following a single 24-hr dermal application of 0.2 ml of an aqueous solution containing 2000 ppm [14C]KB (400 micrograms), rats absorbed 94% of KI-labelled KB and 82% of KII-labelled KB. However, the systemic bioavailability of KB was substantially less than this, since approximately half of the absorbed KB was associated with the skin at the application site 24 hr after the application. Percutaneous absorption was not affected by concentration over the range 500-4000 ppm. As the concentration of KI-labelled KB in the applied solution increased from 500 to 4000 ppm, the relative amount of 14C label associated with the skin decreased, while that in the excreta increased, indicating greater systemic penetration at higher concentrations. Low amounts of 14C label were found in the testes (less than 2 ppb) and blood (24 ppb) 28 days after a single dermal application of KI-labelled KB. Four consecutive daily applications of KI-labelled KB did not influence the proportion of the dose absorbed from the skin. However, the proportion of the dose excreted was higher than after a single application of an equivalent amount of KB.

The LD50 for rubratoxin B dissolved in dimethylsulphoxide and administered to Mongolian gerbils by ip injection was 2.0 (2.26-1.77) mg/kg body weight. The gross alterations observed at autopsy were pallor and mottling of the kidneys and liver and congestion of the spleen. The histopathological alterations seen were renal tubular degeneration and necrosis, degenerative changes in hepatocytes, and congestion of the spleen. The morphopathogenesis of lesions after a single ip LD50 dose was evaluated in a second study. The histopathological alterations that were observed were focal degeneration and necrosis of hepatocytes and renal tubular degeneration and necrosis. Hepatic lesions were observed in gerbils killed between 2 and 12 hr after dosing and included multifocal cytoplasmic vacuolation and coagulative necrosis of hepatocytes. The renal lesions were first observed 2 hr after dosing and increased to maximum severity at 40 hr after dosing. Tubular regeneration accompanied ongoing tubular necrosis at the end of the test period. The activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum were increased 4 hr after dosing, peaked at 24 hr and remained elevated to the end of the test period. Serum K+ concentration was increased 16 hr after dosing and remained elevated to the end of the test period. In a third study, rubratoxin B was administered ip once daily for 7 days at doses of 25, 50 or 75% of the ip LD50. Toxicity was dose related and cumulative with multiple doses. Histopathological alterations included renal tubular degeneration and necrosis, mild tubular dilation and focal necrosis of hepatocytes. In a fourth study, rubratoxin B was administered ip at a dose of 25% of the ip LD50 once daily for 7 days. Histopathological alterations included renal tubular degeneration, mild renal tubular dilation and focal necrosis of hepatocytes. Activities of AST and ALT in serum were slightly increased after multiple doses of rubratoxin B. Results of urinalysis indicated hepatic and renal tubular damage.

The effects of cooking methods on the in vitro mutagenicity of individual foods, the in vitro mutagenicity of meals containing those foods, and the mutagenic exposure of human volunteers following consumption of the meals were examined using Ames bacterial strain TA98 with S-9 metabolic activation. Three methods of food preparation--boiling, baking and frying/flame-broiling--were compared. With meats, frying or broiling resulted in higher in vitro mutagenicity (10- to 50-fold) than did baking or boiling, whereas for carbohydrates, eggs or vegetables mutagenicity did not vary markedly with cooking method. The observed (experimental) mutagenic activity of the meals was quite similar to their calculated (predicted) mutagenicity, obtained by summing the mutagenicity of the individual foods in the meal. The close agreement between experimental and predicted mutagenicity indicated that components of the meal did not interact in either a synergistic or inhibitory manner. The mutagenicity of fried flame-broiled meals was approximately 10-fold greater than the mutagenicity of baked or broiled meals, which were similar in mutagenicity. The mutagenicity of human urine following consumption of the meals was related to the in vitro mutagenicity of the meals themselves. The in vitro mutagenicity of meals is markedly affected by the cooking method used to prepare them and the mutagenicity of the diet may be reflected in the mutagenicity of body fluids.