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Regulatory Toxicology and Pharmacology... Apr 2021Tumor data from rodent bioassays are used for cancer hazard classification with wide-ranging consequences. This paper presents a case study of the synthetic antioxidant... (Review)
Review
Tumor data from rodent bioassays are used for cancer hazard classification with wide-ranging consequences. This paper presents a case study of the synthetic antioxidant butylated hydroxyanisole (BHA), which IARC classified as Group 2B ("possibly carcinogenic to humans") on the basis of forestomach tumors in rodents following chronic dietary exposure to high levels. IARC later determined that the mechanism by which BHA induces forestomach tumors is not relevant to humans; however, the classification has not been revoked. BHA was listed on California Proposition 65 as a direct consequence of the IARC classification, and there is widespread concern among consumers regarding the safety of BHA driven by the perception that it is a carcinogen. While many regulatory agencies have established safe exposure limits for BHA, the IARC classification and Proposition 65 listing resulted in the addition of BHA to lists of substances banned from children's products and products seeking credentials such as EPA's Safer Choice program, as well as mandatory product labeling. Classifications have consequences that many times pre-empt the ability to conduct an exposure-based risk-based assessment., It is imperative to consider human relevance of both the endpoint and exposure conditions as fundamental to hazard identification.
Topics: Animals; Antioxidants; Butylated Hydroxyanisole; Carcinogens; Food Additives; Food Supply; Humans; Risk Assessment
PubMed: 33556417
DOI: 10.1016/j.yrtph.2021.104887 -
Report on Carcinogens : Carcinogen... 2011
Topics: Animals; Antioxidants; Butylated Hydroxyanisole; Carcinogens; Humans; Neoplasms
PubMed: 21850118
DOI: No ID Found -
Chemico-biological Interactions 1991Butylated hydroxyanisole (BHA) is a synthetic food antioxidant used to prevent oils, fats and shortenings from oxidative deterioration and rancidity. This review depicts... (Review)
Review
Butylated hydroxyanisole (BHA) is a synthetic food antioxidant used to prevent oils, fats and shortenings from oxidative deterioration and rancidity. This review depicts the current knowledge on BHA. The physical and chemical characteristics of BHA are summarized and its function as a food antioxidant is made clear. The toxicological characteristics of BHA and its metabolic fate in man and animal are briefly reviewed. Special emphasis is laid on the carcinogenicity of BHA in the forestomach of rodents and to related events in the forestomach and other tissues in experimental animals. At present there is sufficient evidence for carcinogenicity of BHA, but there is hardly any indication that BHA is genotoxic. Therefore risk assessment for this epigenetic carcinogen is based on non-stochastic principles. However, the mechanism underlying the tumorigenicity of BHA is not known. In the last part of this review an attempt is made to unravel the unknown mechanism of carcinogenicity. It is hypothesized that BHA gives rise to tumor formation in rodent forestomach by inducing heritable changes in DNA. Evidence is being provided that reactive oxygen species, in particular hydroxylradicals, may play a crucial role. The key question with respect to risk assessment for BHA is whether or not the underlying mechanism is thresholded, which is important for the choice of the appropriate model to assess the risk, if any, for man and to manage any potential risk.
Topics: Animals; Antioxidants; Butylated Hydroxyanisole; Carcinogens; Humans
PubMed: 1934145
DOI: 10.1016/0009-2797(91)90019-4 -
Journal of Hazardous Materials Nov 2019Butylated hydroxyanisole (BHA) isomers, as the widely used anthropogenic antioxidants in food, have been revealed to induce endocrine disrupting effects, while the...
Butylated hydroxyanisole (BHA) isomers, as the widely used anthropogenic antioxidants in food, have been revealed to induce endocrine disrupting effects, while the mechanism how BHA isomers regulate the lipogenic differentiation remains to be elucidated. Using 3T3-L1 differentiation model, the effects of BHA isomers, including 2-tert-butyl-4-hydroxyanisole (2-BHA), 3-tert-butyl-4-hydroxyanisole (3-BHA) and their mixture (BHA), on adipogenesis were tested. The results showed that 3-BHA and BHA promoted adipocyte differentiation and enhanced the cellular lipid accumulation through the regulation of the transcriptional and protein levels of the adipogenetic biomarkers, while 2-BHA had no effect. The effective window for 3-BHA induced lipogenesis was the first four days during 3T3-L1 differentiation. BHA isomers showed no binding affinities for peroxisome proliferator activated receptor γ (PPARγ). Instead, the upstream of PPARγ signaling pathway, i.e. the phosphorylation of cAMP-response element binding protein (CREB), upregulation of CAAT/enhancer-binding proteins β (C/EBPβ) and elevated cell proliferation during postconfluent mitosis stage were induced by 3-BHA exposure. Altogether, this study revealed the adipogenic effect of 3-BHA through interference with the upstream events of the PPARγ signaling pathway. The authorized usage of BHA as food additives and its occurrence in human sera can potentially contribute to the incidence of obesity, which is of high concern.
Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Animals; Antioxidants; Binding, Competitive; Butylated Hydroxyanisole; Cell Differentiation; Food Additives; Isomerism; Mice; PPAR gamma; Protein Binding
PubMed: 31238218
DOI: 10.1016/j.jhazmat.2019.120794 -
Journal of the Science of Food and... Oct 2023Butylated hydroxyanisole (BHA) is mainly used as a food additive due to its antioxidant properties, which prevent or delay oxidation reactions and extend the storage... (Review)
Review
Butylated hydroxyanisole (BHA) is mainly used as a food additive due to its antioxidant properties, which prevent or delay oxidation reactions and extend the storage life of products. The widespread use of BHA has led to its extensive presence in various environmental matrices and human tissues. Food intake is the main route of human exposure to BHA. Under different conditions, BHA can produce different metabolites, with tert-butyl hydroquinone (TBHQ) being one of the major products. Several studies have shown that BHA could cause thyroid system damage, metabolic and growth disorders, neurotoxicity, and carcinogenesis. Mechanisms such as endocrine disruption, genotoxicity, disturbances of energy metabolism, reactive oxygen species (ROS) production, signaling pathways, and imbalances in calcium homeostasis appear to be associated with the toxic effects of BHA. Avoiding the toxic effects of BHA to the maximum extent possible is a top priority. Finding safe, non-toxic and environmentally friendly alternatives to BHA should be the focus of subsequent research. In all, this review summarized the current situation related to BHA and might make recommendations for future research directions. © 2023 Society of Chemical Industry.
Topics: Humans; Butylated Hydroxyanisole; Antioxidants; Oxidation-Reduction; Food Additives; Reactive Oxygen Species
PubMed: 37127924
DOI: 10.1002/jsfa.12676 -
Neuroscience Letters Jul 2017Butylated hydroxyanisole is a synthetic antioxidant. It may affect the function of the nerve system. The objective of the present study is to investigate the direct...
Butylated hydroxyanisole is a synthetic antioxidant. It may affect the function of the nerve system. The objective of the present study is to investigate the direct effects of butylated hydroxyanisole on rat brain neurosteroidogenic 5α-reductase 1 (SRD5A1), 3α-hydroxysteroid dehydrogenase (AKR1C14), and retinol dehydrogenase 2 (RDH2). Rat SRD5A1, AKR1C14, and RDH2 were cloned and expressed in COS1 cells, and the effects of butylated hydroxyanisole on these enzyme activities were measured. Butylated hydroxyanisole inhibited SRD5A1, AKR1C14, and RDH2 with IC values of 4.731±0.079μM, 5.753±0.073μM, and over 100μM, respectively. Butylated hydroxyanisole is a competitive inhibitor for both SRD5A1 and AKR1C14. Docking analysis shows that butylated hydroxyanisole binds to the dihydrotestosterone-binding site of AKR1C14. In conclusion, butylated hydroxyanisole is a potent inhibitor of SRD5A1 and AKR1C14, thus reducing the formation of active neurosteroids.
Topics: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; Alcohol Oxidoreductases; Animals; Binding Sites; Butylated Hydroxyanisole; COS Cells; Chlorocebus aethiops; Membrane Proteins; Molecular Docking Simulation; Oxidoreductases
PubMed: 28552457
DOI: 10.1016/j.neulet.2017.05.034 -
Food and Chemical Toxicology : An... 1986Studies on the potential genotoxicity and epigenetic effects of BHA are reviewed. BHA was not DNA-reactive, but studies showed that it did have an effect on membrane... (Review)
Review
Studies on the potential genotoxicity and epigenetic effects of BHA are reviewed. BHA was not DNA-reactive, but studies showed that it did have an effect on membrane systems, blocking exchange between hepatocytes and epithelial cells. The available data strongly suggest that BHA is an epigenetic carcinogen that produces forestomach neoplasms through a promoting effect. Standard food safety procedures are suggested as appropriate for setting safe levels of exposure.
Topics: Animals; Butylated Hydroxyanisole; Butylated Hydroxytoluene; Humans; Liver Neoplasms; Stomach Neoplasms
PubMed: 3542763
DOI: 10.1016/0278-6915(86)90303-0 -
Pharmacology & Therapeutics 1996Butylated hydroxyanisole (BHA), at high doses, has been found to induce forestomach squamous cell carcinomas in rodents, but not glandular cell or other types of... (Review)
Review
Butylated hydroxyanisole (BHA), at high doses, has been found to induce forestomach squamous cell carcinomas in rodents, but not glandular cell or other types of neoplasms. BHA is not DNA-reactive, and the epigenetic mechanism of tumor formation involves cytotoxicity and enhanced cell proliferation, which are mostly reversible. Humans lack a forestomach and, therefore, are predicted to be much less sensitive than rodents to the effects of BHA. Also, the exposures to humans are well below doses producing the epigenetic effects in rodents. It has been concluded that BHA is an agent whose rodent carcinogenicity is conditionally species-specific and not relevant to humans.
Topics: Animals; Butylated Hydroxyanisole; Carcinogenicity Tests; Carcinogens; Cell Division; Humans; Neoplasms; Rats; Risk Assessment; Species Specificity
PubMed: 8910953
DOI: 10.1016/0163-7258(96)00066-6 -
Food and Chemical Toxicology : An... 1999Butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) are widely used antioxidant food additives. They have been extensively studied for potential... (Comparative Study)
Comparative Study Review
Butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) are widely used antioxidant food additives. They have been extensively studied for potential toxicities. This review details experimental studies of genotoxicity and carcinogenicity which bear on cancer hazard assessment of exposure to humans. We conclude that BHA and BHT pose no cancer hazard and, to the contrary, may be anticarcinogenic at current levels of food additive use.
Topics: Administration, Oral; Animals; Anticarcinogenic Agents; Antioxidants; Butylated Hydroxyanisole; Butylated Hydroxytoluene; Carcinogenicity Tests; Carcinogens; Consumer Product Safety; Diet; Dose-Response Relationship, Drug; Food Additives; Methylnitronitrosoguanidine; Mutagenicity Tests
PubMed: 10541460
DOI: 10.1016/s0278-6915(99)00085-x -
The Science of the Total Environment Feb 2020Butylated hydroxyanisole (BHA), a synthetic phenolic antioxidant (SPA), has been used as a food additive. However, BHA acts as an environmental hormone, i.e., endocrine...
Butylated hydroxyanisole (BHA), a synthetic phenolic antioxidant (SPA), has been used as a food additive. However, BHA acts as an environmental hormone, i.e., endocrine disruptor. Here, we investigated BHA-induced male reproductive dysfunction in mouse Leydig and Sertoli cells. We found that BHA suppressed proliferation and induced cell cycle arrest in TM3 and TM4 cells. Furthermore, we investigated mitochondrial permeabilization, expression profiles of pro-apoptotic and anti-apoptotic proteins, calcium influx, and endoplasmic reticulum (ER) stress in testicular cells after BHA treatment. The results indicated that BHA-mediated calcium dysregulation and ER stress downregulated steroidogenesis- and spermatogenesis-related genes in mouse testis cell lines. Additionally, proliferation of both TM3 and TM4 cells in response to BHA treatment was regulated via the Mapk and Akt signaling pathways. Therefore, constant BHA exposure may lead to testicular toxicity via mitochondrial dysfunction, ER stress, and abnormal calcium levels in the testis.
Topics: Animals; Butylated Hydroxyanisole; Calcium; Endoplasmic Reticulum Stress; Homeostasis; Male; Mice; Spermatogenesis; Testis
PubMed: 31710847
DOI: 10.1016/j.scitotenv.2019.134775