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Some Studies on BHT, BHA & TBHQ

Research Menu Page ||| Last update 07/29/2012

  • BHA:
    According to the National Toxicology Program's Twelfth Annual Report on Carcinogens (2011) BHA   "is reasonably anticipated to be a human carcinogen..."

  • BHT:
    According to the Toxicology Data Network, BHT is absorbed and stored in fat tissue. In animal studies, there is limited evidence of carcinogenicity, but its suitability for use as a food additive is questioned because of "increased liver weights & abnormal cellular behavior."

  • BHT:
    Chemical Database: BHT - includes a list of 151 synonyms.

  • BHT (For cosmetics)
    Final report on the safety assessment of BHT (2002).
    Quotes:
    § "In addition to liver and kidney effects, BHT applied to the skin was associated with toxic effects in lung tissue."
    § "BHT itself was not generally considered genotoxic, although it did modify the genotoxicity of other agents."

  • TBHQ:
    According to the Toxicology Data Network, TBHQ human health effects include chronic neurotoxic effects and vision disturbances, as well as proliferation of certain lymphocytes. In animal studies, TBHQ induced convulsions, liver enlargement, and increase in cytochrome P450.


Listed in reverse date order, linked to extracts below and abstracts in MedLine:

Gultekin 2012 Allergic and Immunologic Reactions to Food Additives.
Dwyer-Nield 2010 Epistatic interactions govern chemically-induced lung tumor susceptibility and Kras mutation site in murine C57BL/6J-ChrA/J chromosome substitution strains.
Naveena 2008 Comparative Efficacy of Pomegranate Juice, Pomegranate Rind Powder Extract and BHT as Antioxidants in Cooked Chicken Patties.
Meier 2007 Mechanistic Basis for Inflammation and Tumor Promotion in Lungs of BHT-Treated Mice: Electrophilic Metabolites Alkylate and Inactivate Antioxidant Enzymes.
Meyer 2006 Attenuation of the pulmonary inflammation response following butylated hydroxytoluene (BHT) treatment of cytosolic phospholipase A2 null mice.
Soubra 2006     Dietary exposure of children and teenagers to benzoates, sulphites, butylhydroxyanisol (BHA) and butylhydroxytoluen (BHT) in Beirut (Lebanon).
Bauer 2005     Toll-Like Receptor 4 in Butylated Hydroxytoluene (BHT)–Induced Mouse Pulmonary Inflammation and Tumorigenesis.
Klein 2003     Effects of dietary butylated hydroxytoluene on aflatoxin B(1)-relevant metabolic enzymes in turkeys.
Umemura 2002 The mouse rasH2/BHT model as an in vivo rapid assay for lung carcinogens.
Sarafian 2002      Synergistic cytotoxicity of Delta(9)-tetrahydrocannabinol (THC in marijuana smoke) and butylated hydroxyanisole. (BHA)
LeClercq 2000 Estimates of the theoretical maximum daily intake of erythorbic acid, gallates, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) in Italy: a stepwise approach.
Yu 2000 Molecular mechanisms of butylated hydroxylanisole-induced toxicity: induction of apoptosis through direct release of cytochrome c.
Patrick 1999 Depigmentation with tert-butyl hydroquinone using black guinea pigs.
Malkinson 1999 Lung tumor promotion by BHT.
Chung 1999 Effects of butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) on the acetylation of 2-aminofluorene and DNA-2-aminofluorene adducts in the rat.
Tryphonas 1999 The effect of butylated hydroxytoluene on selected immune surveillance parameters in rats bearing enzyme-altered hepatic preneoplastic lesions.
Takami 1999 Antioxidants reversibly inhibit the spontaneous resumption of meiosis.
Stolze 1999 Free radical formation and erythrocyte membrane alterations during MetHb formation induced by the BHA metabolite, tert-butylhydroquinone (TBHQ) .
Safer 1999 Hepatotoxicity induced by the anti-oxidant food additive, butylated hydroxytoluene (BHT), in rats: an electron microscopical study.
McFarlane 1997 Hepatic and associated response of rats to pregnancy, lactation and simultaneous treatment with butylated hydroxytoluene.
Gudz 1997 Effect of butylhydroxytoluene and related compounds on permeability of the inner mitochondrial membrane.
Peters 1996 Glutathione conjugates of tert-butyl-hydroquinone, a metabolite of the urinary tract tumor promoter 3-tert-butyl-hydroxyanisole, are toxic to kidney and bladder.
Siman 1996 Effect of butylated hydroxytoluene on alpha-tocopherol content in liver and adipose tissue of rats.
Jobling 1995 A variety of environmentally persistent chemicals, including some phthalate plasticizers, are weakly estrogenic.
Kahl 1993 Toxicology of the synthetic antioxidants BHA and BHT in comparison with the natural antioxidant vitamin E.
Tanaka 1993 Three generation toxicity study of butylated hydroxytoluene administered to mice.
Parke 1992 Safety aspects of food preservatives.
Park 1990 Induction of Hepatic Tumors with Butylated Hydroxyanisole [BHA] in the Self-fertilizing Hermaphroditic Fish Rivulus ocellatus marmoratus.
Briggs 1989 Short-term effects of butylated hydroxytoluene on the Wistar rat liver, urinary bladder and thyroid gland.
Moch 1988 Forestomach Lesions Induced by Butylated Hydroxyanisole and Ethylene Dibromide: A Scientific and Regulatory Perspective
Thompson 1988 Cytotoxicity of butylated hydroxyanisole and butylated hydroxytoluene in isolated rat hepatocytes.
Zoccarato 1987 Inhibition by some phenolic antioxidants of Ca2+ uptake and neurotransmitter release from brain synaptosomes.
Ito 1986 Modifying Effects of Antioxidants on Chemical Carcinogenesis
Romano 1986 Studies on the Mechanisms by Which Tumor Promoters Stimulate the Growth of Primary Neonatal Rat Hepatocytes.
Kahl 1984 Synthetic antioxidants: biochemical actions and interference with radiation, toxic compounds, chemical mutagens and chemical carcinogens.
Ohno 1984 Differentiation induction of murine erythroleukemia cells by butylated hydroxytoluene.
Kovaleva 1983 Effect of antioxidants on the release of 3H-serotonin by rat brain synaptosomes.
Gould 1982 Inhibition of norepinephrine uptake into synaptic vesicles by butylated hydroxytoluene.
Juhlin 1981 Recurrent urticaria: clinical investigation of 330 patients.
Vorhees 1981 Developmental neurobehavioral toxicity of butylated hydroxyanisole (BHA) in rats.
Osmundsen 1980      Contact urticaria from nickel and plastic additives (butylhydroxytoluene, oleylamide).
Kawano 1980 Species and strain differences in the butylated hydroxytoluene (BHT)-producing induction of hepatic drug oxidation enzymes.
Meyer 1980 Behavioural and developmental effects of butylated hydroxytoluene dosed to rats in utero and in the lactation period.
Stokes 1974 The effect of butylated hydroxyanisole and butylated hydroxytoluene on behavioral development of mice.


The following excerpts are in alphabetical order by first author.



  1. Toll-Like Receptor 4 in Butylated Hydroxytoluene (BHT)–Induced Mouse Pulmonary Inflammation and Tumorigenesis Bauer AK, Dixon D, DeGraff LM, Cho HY, Walker CR, Malkinson AM, Kleeberger SR. Journal of the National Cancer Institute. 2005 Dec 7;97(23):1778-81.
    " ...We also measured primary tumor formation in these mice after single-carcinogen injection ... followed by BHT treatment ... Mice with functional Tlr4 had reduced lung permeability, leukocyte inflammation, and primary tumor formation ... compared with mice with mutated Tlr4.... To our knowledge, this is the first model to demonstrate a modulatory role for Tlr4 in chronic lung inflammation and tumorigenesis. "

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  2. Short-term effects of butylated hydroxytoluene on the Wistar rat liver, urinary bladder and thyroid gland. Briggs D, Lok E, Nera EA, Karpinski K, Clayson DB. Cancer Lett 1989 Jul 1;46(1):31-6
    " ... treatment of rats with 0.5% dietary BHT leads to a time-limited increase in liver cell [3H]thymidine labeling that subsided to control values within 8 days. This increase in [3H]thymidine labeling in the liver is accompanied by an unexpectedly large increase in the mitotic index. ... "

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  3. Effects of butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) on the acetylation of 2-aminofluorene and DNA-2-aminofluorene adducts in the rat. Chung JG, Toxicol Sci 1999 Oct;51(2):202-10
    "...This is the first demonstration that synthetic phenolic antioxidants decrease the N-acetylation of carcinogens and formation of DNA-carcinogen adducts in vivo. "

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  4. Epistatic interactions govern chemically-induced lung tumor susceptibility and Kras mutation site in murine C57BL/6J-ChrA/J chromosome substitution strains. Dwyer-Nield LD, McQuillan J, Hill-Baskin A, Radcliffe RA, You M, Nadeau JH, Malkinson AM. International Journal of Cancer 2010 Jan 1;126(1):125-32.
    " Cancer susceptibility results from interactions between sensitivity and resistance alleles. We employed murine chromosome substitution strains to study how resistance alleles affected sensitive alleles during chemically-induced lung carcinogenesis. ... CSS6 mice were resistant to lung carcinogenesis induced by 3-methylcholanthrene (MCA). Tumor multiplicity increased if BHT administration followed urethane exposure, showing that a Chr 6 gene(s) regulates sensitivity to chemically-induced tumor promotion. ... "

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  5. Inhibition of norepinephrine uptake into synaptic vesicles by butylated hydroxytoluene. Gould JM, Saxer J, Biochem Biophys Res Commun 1982 Jun 30;106(4):1106-11
    "Butylated hydroxytoluene (BHT), a widely used antioxidant food preservative, has been found to be a potent inhibitor of norepinephrine uptake into synaptic vesicles isolated from rat brain. BHT levels as low as one per 400 phospholipid molecules were sufficient to cause 75% inhibition of norepinephrine accumulation at 30°C. The same levels of BHT which inhibited neurotransmitter transport also caused a significant increase in the fluorescence polarization of the membrane probe 1,6-diphenyl-1,3,5-hexatriene embedded in synaptic vesicle membranes, suggesting that BHT may block transport indirectly by decreasing the transmembrane mobility of a norepinephrine carrier protein."

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  6. Effect of butylhydroxytoluene and related compounds on permeability of the inner mitochondrial membrane. Gudz T, Eriksson O, Kushnareva Y, Saris NE, Novgorodov S., Arch Biochem Biophys 1997 Jun 1;342(1):143-56
    " Mitochondrial inner membrane contains a latent pore (PTP) that when opened uncouples mitochondrial energy transduction and allows rapid equilibration of low-molecular-weight solutes between the matrix and exterior. Based on sensitivity of the PTP to well-known free radical scavenger butylhydroxytoluene (BHT), it has been proposed that increased steady-state level of oxygen radicals, and subsequent radical attack of proteins and lipids, is a central event in activation of this pore . . . BHT operates independently of its free radical scavenging activity. . . ."

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  7. Allergic and Immunologic Reactions to Food Additives. Gultekin F, Doguc DK. CClinical Reviews in Allergy & Immunology. 2012 Jan 27. [Epub ahead of print]
    " For centuries, food additives have been used for flavouring, colouring and extension of the useful shelf life of food, as well as the promotion of food safety. During the last 20 years, the studies implicating the additives contained in foods and medicine as a causative factor of allergic reactions have been proliferated considerably. In this review, we aimed to overview all of the food additives which were approved to consume in EU and find out how common and serious allergic reactions come into existence following the consuming of food additives. "

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  8. Modifying effects of antioxidants on chemical carcinogenesis. Ito N, Hirose M, Fukushima S, Tsuda H, Tatematsu M, Asamoto M, Toxicologic Pathology. 1986;14(3):315-23.
    " ...BHA clearly induced squamous cell carcinomas in both the rat and hamster forestomach. The tumorigenic action of crude BHA on the forestomach is largely due to 3-tert-BHA. ...BHT demonstrated promotion potential for urinary bladder and MNU-initiated thyroid carcinogenesis and inhibited DMBA-initiated ear duct carcinogenesis. ... No effects of any of the antioxidants on glandular stomach carcinogenesis were found. The results clearly demonstrated that antioxidants have different effects (promoting or inhibitory influences) depending on the organ studied and suggest the importance of a whole body approach to their investigation. "

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  9. A variety of environmentally persistent chemicals, including some phthalate plasticizers, are weakly estrogenic. Jobling S, Reynolds T, White R, Parker MG, Sumpter JP. Environ Health Perspect. 1995 Jun;103(6):582-7.
    "Sewage, a complex mixture of organic and inorganic chemicals, is considered to be a major source of environmental pollution. . . . Recently, it has been suggested that environmental estrogens may be etiological agents in several human diseases, including disorders of the male reproductive tract and breast and testicular cancers. The current finding that some phthalate compounds and some food additives are weakly estrogenic in vitro, needs to be supported by further studies . . ."

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  10. Recurrent urticaria: clinical investigation of 330 patients. Juhlin L, Br J Dermatol 1981 Apr;104(4):369-81
    Of 330 consecutive patients with recurrent urticaria, "A personal history of rhinitis, asthma or atopic dermatitis was recorded in more than one-third. Nasal polyps, migraine and arthralgia were found in 6-7% of the patients. Severe psychiatric problems were mentioned by 16%. Abdominal problems, mainly gastritis, were described by 44%.... Provocation tests with various food additives such as azo dyes, benzoates, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA) sorbic acid, quinoline yellow, carotene, canthaxanthine, annatto and nitrite revealed one or more positive reactions in one-third of the patients..."

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  11. Toxicology of the synthetic antioxidants BHA and BHT in comparison with the natural antioxidant vitamin E Kahl R, Kappus H, Z Lebensm Unters Forsch 1993 Apr;196(4):329-38
    "...Specific toxic effects to the lung have only been observed with BHT. The other described toxic effects of BHA and BHT are less characteristic and often occur only after high dosage and long-term treatment. However, BHA induces in animals tumours of the forestomach, which are dose dependent, whereas BHT induces liver tumours in long-term experiments. ... all published findings agree with the fact that BHA and BHT are tumour promoters. In contrast to BHA and BHT, vitamin E is not carcinogenic."

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  12. Synthetic antioxidants: biochemical actions and interference with radiation, toxic compounds, chemical mutagens and chemical carcinogens. Kahl R, Toxicology 1984 Dec;33(3-4):185-228
    "...The beneficial interactions of antioxidants with physical and chemical noxae are contrasted to those leading to unfavorable effects. ... At present, the latter one can most adequately be characterized as tumor promotion at least in the case of butylated hydroxytoluene..."

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  13. Species and strain differences in the butylated hydroxytoluene (BHT)-producing induction of hepatic drug oxidation enzymes. Kawano S, Nakao T, Hiraga K, Jpn J Pharmacol 1980 Dec;30(6):861-70
    " [rats and mice given] (BHT)-containing diet for 6 days produced a marked increase in hepatic weight and microsomal protein content. However, the augmentations of cytochrome P-450 content and drug oxidation activities were much more significant, i.e. 2.5-fold and more than three-fold increases were observed on a body weight basis, respectively. BHT-induced cytochrome P-450 cannot be distinguished from phenobarbital (PB)-induced cytochrome in many respects..."

    Another strain of mice was identified that did not have either hepatic enlargement nor cytochrome P-450 increase, and "did not produce an extremely high mortality." How that mortality compares with the mortality of the other mice and rats was not specified in the abstract.

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  14. Effects of dietary butylated hydroxytoluene on aflatoxin B(1)-relevant metabolic enzymes in turkeys. Klein PJ, Van Vleet TR, Hall JO, Coulombe RA Jr, Food Chem Toxicol 2003 May;41(5):671-8
    " ... To test whether BHT protects against aflatoxicosis in turkeys, we supplemented the feed of 10-day-old male white turkeys with low (1000 ppm) and high (4000 ppm) BHT for 20 days. ... Hepatocellular hydropic degeneration was observed in the BHT-only group, but not in the AFB(1) + BHT groups. ... this antioxidant may prove to be a viable feed additive for the reduction of aflatoxicosis in turkeys. "

    Note: Aflatoxin is introduced to turkeys through feeding them contaminated food. We do not know at this time what percentage of turkeys in the market have been affected by aflatoxins, what percentage already contain BHT, or how much of it would be retained in the meat.

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  15. Effect of antioxidants on the release of 3H-serotonin by rat brain synaptosomes Kovaleva ES, Prilipko LL, Muranov KO, Kagan VE, Biull Eksp Biol Med 1983 Oct;96(10):55-7
    "..All free radical scavengers used inhibited 3T-hydroxytryptamine uptake and stimulated 3H-hydroxytryptamine release, with the efficacy being reduced in the following order: 7-hydroxyaminazine greater than butylated hydroxytoluene greater than paginol-2-methyl-6-ethyl-3-hydroxypyridine greater than alpha-tocopherol..."

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  16. Estimates of the theoretical maximum daily intake of erythorbic acid, gallates, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) in Italy: a stepwise approach. Leclercq C, Arcella D, Turrini A. Food & Chemical Toxicology. 2000 Dec;38(12):1075-84.
    " The three recent EU directives which fixed maximum permitted levels (MPL) for food additives for all member states also include the general obligation to establish national systems for monitoring the intake of these substances in order to evaluate their use safety. In this work, we considered additives with primary antioxidant technological function for which an acceptable daily intake (ADI) was established by the Scientific Committee for Food (SCF): gallates, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) and erythorbic acid. ... the theoretical maximum daily intake (TMDI) of BHT was above the current ADI. The three food categories found to be main potential sources of BHT were "pastry, cake and biscuits", "chewing gums" and "vegetables oils and margarine"; they overall contributed 74% of the TMDI. Actual use of BHT in these food categories is discussed, together with other aspects such as losses of this substance in the technological process and percentage of ingestion in the case of chewing gums."

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  17. Lung tumor promotion by BHT, Malkinson, AM, Crisp Data Base National Institutes Of Health 1999
    "...The food additive, butylated hydroxytoluene (BHT), encourages the development of tumors from previously initiated cells. ...Chronic administration of BHT to inbred mice down-regulates the pulmonary concentrations of the alpha isozyme of protein kinase C (PKCa) and calpain in promotion-sensitive strains ... " The researchers are searching for the gene responsible.

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  18. Hepatic and associated response of rats to pregnancy, lactation and simultaneous treatment with butylated hydroxytoluene. McFarlane M, et al., Food Chem Toxicol 1997 Aug;35(8):753-67
    "...Dams [mother rats] receiving BHT at a nominal dose of 500 mg/kg body weight/day showed liver enlargement accompained by induction of pentoxyresorufin O-depentylase and glutathione S-transferase, and proliferation of the endoplasmic reticulum. Pups from these dams were of the same weight at birth as controls but lost weight during the lactation period. This deficit was not recovered by the time the experiment was terminated. ..."

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  19. Mechanistic basis for inflammation and tumor promotion in lungs of 2,6-di-tert-butyl-4-methylphenol-treated mice: electrophilic metabolites alkylate and inactivate antioxidant enzymes. Meier BW, Gomez JD, Kirichenko OV, Thompson JA. Chemical Research in Toxicology 2007 Feb;20(2):199-207.
    " ... This study provides evidence that indicates Prx6, SOD1, and possibly other antioxidant enzymes in mouse lung are inhibited by BHT-derived QMs leading to enhanced levels of reactive oxygen species and inflammation and providing a mechanistic basis for the effects of BHT on lung tumorigenesis. "

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  20. Behavioural and developmental effects of butylated hydroxytoluene dosed to rats in utero and in the lactation period. Meyer O, Hansen E, Toxicology 1980;16(3):247-58
    "...The applied dose of BHT [500 mg/kg to rats] exerted a significant adverse effect on body weight in both F0 and F1-animals and on several developmental parameters in F1-animals. The effects arose during the lactation period."

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  21. Attenuation of the pulmonary inflammatory response following butylated hydroxytoluene treatment of cytosolic phospholipase A2 null mice. Meyer AM, Dwyer-Nield LD, Hurteau G, Keith RL, Ouyang Y, Freed BM, Kisley LR, Geraci MW, Bonventre JV, Nemenoff RA, Malkinson AM. Am J Physiol Lung Cell Mol Physiol. 2006 Jun;290(6):L1260-6.
    " Administration of butylated hydroxytoluene (BHT) to mice causes lung damage characterized by the death of alveolar type I pneumocytes and the proliferation and subsequent differentiation of type II cells to replace them. Herein, we demonstrate this injury elicits an inflammatory response marked by chemokine secretion, alveolar macrophage recruitment, and elevated expression of enzymes in the eicosanoid pathway. ... "

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  22. Forestomach Lesions Induced by Butylated Hydroxyanisole and Ethylene Dibromide: A Scientific and Regulatory Perspective Moch RW, Toxicologic Pathology 1988;16(2):172-83.
    "Selected pathology lesions from 9 studies, 5 with butylated hydroxyanisole (BHA) and 4 with ethylene dibromide (EDB) are reviewed and their relative importance in regulatory evaluation is discussed." In several studies, rats, mice, and hamsters, were fed BHA and developed a variety of tumors. Beagle dogs fed BHA for half a year did not seem to develop tumors. These studies "facilitated regulatory decision-making regarding the potential toxicity/carcinogenicity of these compounds to man."

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  23. Comparative efficacy of pomegranate juice, pomegranate rind powder extract and BHT as antioxidants in cooked chicken patties. Naveena BM, Sen AR, Vaithiyanathan S, Babji Y, Kondaiah N. Meat Science 2008 Dec;80(4):1304-8.
    " A study was carried out to evaluate the antioxidant potential of pomegranate juice (PJ), rind powder extract (RP) and butylated hydroxyl toluene (BHT) in cooked chicken patties during refrigerated storage. ... The PJ or RP at a level of 10mg equivalent phenolics/100g meat would be sufficient to protect chicken patties against oxidative rancidity for periods longer than the most commonly used synthetic antioxidant like BHT. "

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  24. Differentiation induction of murine erythroleukemia cells by butylated hydroxytoluene. Ohno Y, Takuma T, Asahi K, Isono K, FEBS Lett 1984 Jan 9;165(2):277-9
    "Butylated hydroxytoluene (BHT) ... has been found to induce the differentiation of murine erythroleukemia cells. BHT also amplifies the differentiation inducing activity of DMSO."

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  25. Contact urticaria from nickel and plastic additives (butylhydroxytoluene, oleylamide). Osmundsen PE, Contact Dermatitis 1980 Dec;6(7):452-4
    "...In one of the patients contact with plastic articles also provoked urticaria. A 20-min patch test with several articles of plastic (polyethylene and PVC) and with butylhydroxytoluene (BHT) 1% in ethanol elicited urticarial reactions. BHT is used as an antioxidant in plastic..."

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  26. Induction of hepatic tumors with butylated hydroxyanisole in the self-fertilizing hermaphroditic fish Rivulus ocellatus marmoratus, Park EH, Chang HH, Cha YN., Jpn J Cancer Res. 1990 Aug;81(8):738-41.
    "The three-day-old larvae of self-fertilizing hermaphroditic fish Rivulus ocellatus marmoratus were fed a diet containing the antioxidant butylated hydroxyanisole (BHA) at levels of 0.01-0.8% for 12 days. Six months after BHA administration, hepatic tumors were found in all groups of BHA-treated fish. The BHA-induced tumor incidences were clearly dose-dependent. These results show that dietary BHA is hepatocarcinogenic in Rivulus even at 0.01% dose."

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  27. Safety aspects of food preservatives. Parke DV, Lewis DF, Food Addit Contam 1992 Sep-Oct;9(5):561-77
    "...although most preservatives are now considered to be without potential adverse effects and are classified as GRAS, [Generally Regarded As Safe] there have been problems concerning the safety of some of these chemicals, including the possibility of allergies from benzoic acid and sulphites, the formation of carcinogenic nitrosamines from nitrites, and the possible rodent carcinogenicity of BHA and BHT..."

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  28. Depigmentation with tert-butyl hydroquinone using black guinea pigs., Patrick E, Juberg DR, O'Donoghue J, Maibach HI. Food Chem Toxicol 1999 Feb-Mar;37(2-3):169-75
    " tert-Butyl hydroquinone (TBHQ) has important and functional uses in consumer and commercial applications, some of which involve human exposure primarily through dermal (skin) contact. . . . . Repetitive exposure to concentrations of 1.0% and 5.0% TBHQ and HQ were slightly to moderately irritating, while 0.1% of each of these test materials produced only weak irritant responses. . . . this study showed that TBHQ causes depigmentation in black guinea pigs at concentrations of 1% or greater. . . "

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  29. Glutathione conjugates of tert-butyl-hydroquinone, a metabolite of the urinary tract tumor promoter 3-tert-butyl-hydroxyanisole, are toxic to kidney and bladder. Peters MM, Rivera MI, Jones TW, Monks TJ, Lau SS. Cancer Research, Vol. 56, p. 1006-1011, March 1996
    Also see this article & other articles citing it in Cancer Research
    " 3-tert-Butyl-4-hydroxyanisole and tert-butyl-hydroquinone (TBHQ) are antioxidants known to promote renal and bladder carcinogenesis [cancer] in the rat, although the mechanisms of these effects are unclear....Because some chemicals may induce carcinogenesis by a mechanism involving cytotoxicity followed by sustained regenerative hyperplasia, our results suggest that the toxicity of GSH conjugates of TBHQ to kidney and bladder may contribute to the promoting effect of 3-tert-butyl-4-hydroxyanisole and TBHQ in these tissues. "

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  30. Inhibitors of ADP-ribosyl transferase suppress the mitogenic actions exerted by tumour promoters, but not those evoked by peptide mitogens, in primary neonatal rat hepatocytes. Romano F, Menapace L, Armato U. Carcinogenesis. 1988 Dec;9(12):2147-54.
    " A significant stimulation of ... new DNA synthetic activity was elicited in primary neonatal rat hepatocytes [liver cells] ... by the addition of a single dose (10(-10) mol/l) of each of several tumour promoters [i.e. 12-O-tetradecanoylphorbol-13-acetate (TPA), phenobarbital, nafenopin, saccharin, teleocidin, benzoyl peroxide butylhydroxytoluene (BHT), dichlorodiphenyltrichloroethane (DDT), lindane, clofibrate and melittin]. ... "

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  31. Hepatotoxicity induced by the anti-oxidant food additive, butylated hydroxytoluene (BHT), in rats: an electron microscopical study. Safer AM, al-Nughamish AJ, Histol Histopathol 1999 Apr;14(2):391-406
    BHT resulted in a significant increase in liver weight. The liver cells presented gradual vacuolization, cytoplasmic disintegration, "moth-eaten" appearance, ballooning degeneration, hepatocellular necrosis, aggregation of chromatin material around the periphery of the nuclear envelope, SER proliferation, RER clumping with broken cisternae, withered and autolyzed mitochondria, augmentation of lipid droplets and glycogen depletion.

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  32. Synergistic cytotoxicity of Delta(9)-tetrahydrocannabinol (THC in marijuana smoke) and butylated hydroxyanisole. (BHA)    Sarafian TA, Kouyoumjian S, Tashkin D, Roth MD, Toxicol Lett 2002 Jul 21;133(2-3):171-9
    " ... BHA alone, at concentrations of 10-200 microM, produced limited cell toxicity but significantly enhanced the necrotic death resulting from concurrent exposure to THC. ... The combination was synergistic in this respect, reducing ATP levels to <15% of control. Exposure to marijuana smoke in conjunction with BHA, a common food additive, may promote deleterious health effects in the lung. "

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  33. Effect of butylated hydroxytoluene on alpha-tocopherol content in liver and adipose tissue of rats. Siman CM, Eriksson UJ, Toxicol Lett 1996 Oct;87(2-3):103-8
    The results show that BHT has adverse effects in the liver. BHT is metabolized by the cytochrome P450 system in the liver and may be converted to prooxidative compounds during this process.

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  34. Dietary exposure of children and teenagers to benzoates, sulphites, butylhydroxyanisol (BHA) and butylhydroxytoluen (BHT) in Beirut (Lebanon) Soubra L, Sarkis D, Hilan C, Verger P., Regulatory Toxicology & Pharmacology. 2007 Feb;47(1):68-77.
    ". . .The aim of this paper is to assess the actual intake of the food additives listed above for a group of the Lebanese population (students aged between 9 and 18 years old) likely to be highly exposed to food additives through the consumption of processed foods. . .Overall 420 samples of foods and beverages were analysed. . . The acceptable daily intake (ADI) could be exceeded for sulphites and BHT by a fraction of the population, in particular within children of 9-13 years old. Among all food additive-containing foods, the highest contributors were: soft drinks to benzoates intake, nuts and canned juices to sulphites intake, bread and biscuits to BHA intake and chewing gum to BHT intake."

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  35. The effect of butylated hydroxyanisole and butylated hydroxytoluene on behavioral development of mice. Stokes JD, Scudder CL, Dev Psychobiol 1974 Jul;7(4):343-50
    "The chronic ingestion of .5% butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT) by pregnant mice and their offspring resulted in a variety of behavioral changes. Compared to controls, BHA-treated offspring showed increased exploration, decreased sleeping, decreased self-grooming, slower learning, and a decreased orientation reflex. BHT-treated offspring showed decreased sleeping, increased social and isolation-induced aggression, and a severe deficit in learning."

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  36. Free radical formation and erythrocyte membrane alterations during MetHb formation induced by the BHA metabolite, tert-butylhydroquinone (TBHQ). Stolze K, Nohl H., Free Radical Research 1999 Apr;30(4):295-303
    " . . . tBHQ significantly increased the amount of high molecular weight degradation products of erythrocyte membrane constituents. These changes were only observed when incubations were performed in the presence of oxygen. . . These observations can be interpreted in terms of metabolic activation of the antioxidant BHA via tBHQ . . . thereby leading to harmful effects on erythrocyte (red blood cell) membrane structures. Moreover, deleterious effects on other biological membranes are also likely to occur. "

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  37. Antioxidants reversibly inhibit the spontaneous resumption of meiosis. Takami M, Preston SL, Toyloy VA, Behrman HR., The American Journal of Physiology 1999 Apr;276(4 Pt 1):E684-8

    Reproductive Biology Section. . . Yale University School of Medicine

    " We previously showed that the cell-permeant antioxidant 2(3)-tert-butyl-4-hydroxyanisole (BHA) inhibited germinal vesicle breakdown (GVBD) in oocyte (egg)-cumulus complexes (OCC) of the rat. . . . Spontaneous GVBD in OCC incubated for 2 h was significantly inhibited . . .by . . . NDGA . . . BHA . . . octyl gallate . . . ethoxyquin . . . . . . BHT . . . Antioxidants that had no effect on oocyte maturation at the same concentration . . . included ascorbic acid, vitamin E, and Trolox. . . . Oocyte maturation was induced by incubation of follicles for 3 h with human chorionic gonadotropin (hCG), and this response was inhibited by BHA or NDGA. These findings support the conclusion that cell-permeant antioxidants inhibit spontaneous resumption of meiosis (special cell division for eggs or sperms), which may implicate a role of oxygen radicals in oocyte maturation"

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  38. Three generation toxicity study of butylated hydroxytoluene administered to mice. Tanaka T, Oishi S, Takahashi O. Toxicology Letters 1993 Mar;66(3):295-304
    " Butylated hydroxytoluene (BHT) was administered to mice, . . . in the diet at levels of 0 (control), 0.015, 0.045, 0.135, and 0.405%, . . . .The body weight of the pups of the 0.015% BHT group was increased at birth and during the lactation period for each generation. . . In the neurobehavioural parameters, a few parameters were increased in treatment groups; i.e., surface righting . . . and negative geotaxis . . . "

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  39. Cytotoxicity of butylated hydroxyanisole and butylated hydroxytoluene in isolated rat hepatocytes. Thompson D, Moldeus P, Biochem Pharmacol 1988 Jun 1;37(11):2201-7
    "...Using isolated rat liver mitochondria we observed that both BHA and BHT inhibited respiratory control primarily by stimulating state 4 respiration and thus acting as membrane uncouplers. BHA and BHT also effectively dissipated membrane potential across the mitochondrial membrane and caused the release of calcium and mitochondrial swelling. These mitochondrial effects were reflected by a rapid decrease in ATP levels in intact hepatocytes which preceded cell death...."

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  40. The effect of butylated hydroxytoluene on selected immune surveillance parameters in rats bearing enzyme-altered hepatic preneoplastic lesions. Tryphonas H, Lacroix F, Lok E, Jee P, Clayson DB, Hayward S, Miller D, Mehta R, Food Chem Toxicol 1999 Jul;37(7):671-81
    "...The induction of EAF and/or 0.5% BHT treatment resulted in a significant reduction in the natural killer (NK) cell activity of splenocytes...."

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  41. The mouse rasH2/BHT model as an in vivo rapid assay for lung carcinogens. Umemura T, Kodama Y, Hioki K, Nomura T, Nishikawa A, Hirose M, Kurokawa Y. Jpn J Cancer Res. 2002 Aug;93(8):861-6.
    " We have demonstrated the utility of a 9-week in vivo two-stage assay for lung cancer initiating agents, using transgenic mice ...and butylhydroxytoluene (BHT) as a potent lung promoter .... Additionally, use of BHT was validated for promotion of urethane (UR) carcinogenesis in male and female rasH2 mice.... In a dose-response study, effects were dose-dependent, the dose of 400 mg/kg causing eight-fold elevation as compared to the control.... " Note: This is a high dose of course, much more than you get in your Corn Flakes ..... but they wanted results in 5 weeks. How the small amount you get in various foods, administered through the day every day for 5 years .... or 50 years .... is going to affect YOU is unknown. Cigarettes don't kill you in 5 weeks, either.

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  42. Developmental neurobehavioral toxicity of butylated hydroxyanisole (BHA) in rats. Vorhees CV, Butcher RE, Brunner RL, Wootten V, Sobotka TJ, Neurobehav Toxicol Teratol 1981 Fall;3(3):321-9
    [There is a similar study on BHT, but no abstract available]
    "Comparison of the present results to a similar study using BHT clearly indicates that BHA at equivalent dietary doses is considerably less toxic than BHT. The present results also suggest that BHA is not a potent behavioral toxin, although it is developmentally toxic using non-behavioral measures."

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  43. Molecular mechanisms of butylated hydroxylanisole-induced toxicity: induction of apoptosis through direct release of cytochrome c. , Yu R, Mandlekar S, Kong AT., Molecular Pharmacology 2000 Aug;58(2):431-7
    " . . . the use of BHA as a chemopreventive agent against cancer in human has been challenged by the observation that BHA may exert toxic effect in some tissues of animals. . . Here, we report that BHA induces apoptosis (cell death) in freshly isolated rat hepatocytes (liver cells). . . ."

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  44. Inhibition by some phenolic antioxidants of Ca2+ uptake and neurotransmitter release from brain synaptosomes. Zoccarato F, Pandolfo M, Deana R, Alexandre A, Biochem Biophys Res Commun 1987 Jul 31;146(2):603-10
    "...While the Ca2+ uptake observed under non depolarizing conditions is not affected by these agents, the depolarization induced Ca2+ uptake is strongly inhibited. ..."

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