Induction of early lesions in the forestomach of rats by 3-tert-butyl-4-hydroxyanisole (BHA)

Altmann, Hans; Wester, P.W.; Matthiaschk, G.; Grunow, W.; Heijden, C.A. van der

doi:10.1016/0278-6915(85)90265-0

Cited by 53 publications

(19 citation statements)

References 12 publications

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“…Consonant with these results, Ito's group (1984) noted promoting effects with 5,000 ppm BHA. These results are supported by finding increased proliferative lesions with 20,000 ppm BHA, fewer with-5,000 ppm, and none with 2,500 ppm; but even with 20,000 ppm BHA feeding, reversibility was noted 1-2 weeks after stopping the intake of BHA (Iverson et al, 1985;Altmann et al, 1985). Thus, current information suggests 1) the existence of a threshold, and 2) reversibility.…”

Section: Quantitative Carcinogenesissupporting

confidence: 75%

Types and amounts of carcinogens as potential human cancer hazards

Weisburger

Williams

1989

Cell Biol Toxicol

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Current knowledge on the mechanisms of chemical carcinogenesis forms the basis for application of select short-term in vitro and in vivo tests to detect potential human carcinogens, for ultimate application to hazard assessment. Chemical carcinogenesis involves a series of distinct steps, proceeding from the initiation of a neoplastic cell, through its promotion, development, and progression to cancer. Some chemicals act in each of these stages as initiators, cocarcinogens, promoters, or inhibitors of carcinogenesis. Chemicals can be classified as operating by genotoxic or epigenetic mechanisms, and appropriate tests can be used to detect such properties. These abbreviated tests provide enhanced qualitative decision-making potential since they are based on mechanisms of action. Advances in molecular biology may provide additional tests to detect cancer risk. The quantitative data available from in vitro dose-response studies indicate that carcinogenic effects are dose dependent and, therefore, a threshold or no-effect level probably exists, which is low for potent carcinogens (especially genotoxins) and high for weaker ones (particularly epigenetic agents).

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Section: Quantitative Carcinogenesissupporting

confidence: 75%

Types and amounts of carcinogens as potential human cancer hazards

Weisburger

Williams

1989

Cell Biol Toxicol

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“…Mutagenicity tests on these three agents were negative (83, 84). Short-term toxicity studies on BHA revealed that at dietary levels capable of inducing marked epithelial hyperplasia stomach tumors developed (84), but at known subcarcinogenic levels no hyperplasia was observed (85). Studies on a series of fatty acids showed that propionic, butyric, and valeric acids all induced hyperplasia and papillomatous growths in the rat forestomach but longer-chain fatty acids produced neither lesion (Table 9; 86).…”

Section: Forestomach Changes and Tumors In Rodentsmentioning

confidence: 96%

Role of Persistent, Non-Genotoxic Tissue Damage in Rodent Cancer and Relevance to Humans

Grasso¹,

Sharratt²,

Cohen³

1991

Annu. Rev. Pharmacol. Toxicol.

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This review has focused on the importance of cellular proliferation in neoplasia induced by nongenotoxic carcinogens and has not attempted to address the mechanisms involved in the progression from the hyperplastic to the neoplastic state. Major advances in this area are likely in the next decade and should explain how cells in an abnormally high proliferative state are rendered more vulnerable either to the action of endogenous or environmental mutagens or to defects in cell reproduction, thus providing the stimulus for progression to neoplasia (165). In this review evidence has been presented to support the hypothesis that sustained tissue damage induced by nongenotoxic compounds in rodents predisposes to tumor development. The evidence has been obtained by drawing from the published findings of experimental rodent studies conducted over the past 50 years. The experience gained at various sites in the rodent including the connective tissue, liver, bladder, and forestomach shows the existence of a threshold dose for various test materials/agents, below which neither sustained tissue damage nor tumor induction occurs but above which level both effects are manifest. Taken collectively, an overall picture emerges that sustained cell proliferation renders various sites in the rodent vulnerable to tumor development. The validity of this hypothesis is of importance to the evaluation of carcinogenic risk of chemicals to humans. For those nongenotoxic carcinogens known to cause characteristically defined and sustainable tissue damage as a precursor of tumor development in rodents, it should be possible to establish a threshold dose below which both effects disappear and upon which a safety margin in humans can be based. Some limited evidence supports an association between chronic tissue injury and neoplastic development in humans. Note, however, that certain types of induced tissue damage may be rodent-specific and therefore have no relevance for humans. We conclude that the appearance of persistent tissue damage predisposes to tumor development in rodents exposed to nongenotoxic carcinogens and that systematic studies in rodents should provide a rational basis for arriving at a safety margin in humans exposed to such agents.

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“…In this regard, certain physical and chemical irritants are weak tumor promoters in two stage carcinogenesis studies (Argyris and Slaga, 1981;Clark and Murray, 1978;Raick and Bardzy, 1973;Slaga et al, 1975). Further, irritation resulting in hyperplasia has been implicated as a causative factor in the development of tumors in other organs including the urinary bladder (Clayson and Pringle, 1966;Weil et al, 1967) and the rat forestomach (Altmann et al, 1985;Ghanayem et al, 1986). Thus, cutaneous irritation may be an important factor in the development of skin tumors in animals treated with PMDs.…”

Section: Introductionmentioning

confidence: 94%

A 90-Day Toxicity Study of the Effects of Petroleum Middle Distillates on the Skin of C3H Mice

et al. 1990

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Petroleum middle distillates (PMDs) elicit skin tumors in mouse epidermal carcinogenesis studies. The response is characterized by a long latency with only a small percentage of animals developing tumors. Although the carcinogenic activity of certain other petroleum hydrocarbons largely depends upon the presence of polycyclic aromatic hydrocarbons (PAHs), many PMDs contain relatively low concentrations of PAHs. PMDs are also irritating to mouse skin, and chronic irritation may be involved in the development of skin tumors. This study was conducted to investigate the patterns of cutaneous irritation elicited by topical application of PMDs having compositional differences. The three PMDs selected for study were a steam cracked gas oil (SCGO), a lightly refined paraffinic oil (LRPO), and a jet fuel (JF). Male C3H/HeNCr1BR mice (25/group) were treated topically (37.5 microliters 2x/week for 13 weeks) with 10%, 50% or 100% (undiluted) concentrations of each PMD. Catalytically cracked clarified oil (CCCO, 10%), a potent carcinogen to mouse skin, was also tested. The vehicle was a noncarcinogenic mineral oil with a viscosity of 90 SUS. Cutaneous changes were evaluated by gross observations and light microscopy. Cutaneous irritation was the only significant toxic response in this study. Neither the vehicle nor any of the 10% PMD concentrations produced significant cutaneous irritation. The 10% CCCO and 50% PMD treatments all elicited slight to moderate proliferative and inflammatory changes in mouse skin. Ulcers were also observed microscopically in mice treated with 10% CCCO and 50% SCGO. The 100% SCGO treatment produced evidence of necrosis on Days 1-7 but not later in the study despite continued treatment. In contrast, the irritating effects of 100% LRPO were not evident until 2-3 weeks of study, and at study completion were characterized by moderately severe inflammatory and proliferative changes. The effects of 100% JF were qualitatively similar to 100% LRPO but less marked. Thus, the SCGO caused a different pattern of cutaneous responses than either LRPO or JF. The possible relationships of these cutaneous changes to epidermal carcinogenesis are being studied further.

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Induction of early lesions in the forestomach of rats by 3-tert-butyl-4-hydroxyanisole (BHA)

Cited by 53 publications

References 12 publications

Types and amounts of carcinogens as potential human cancer hazards

Types and amounts of carcinogens as potential human cancer hazards

Role of Persistent, Non-Genotoxic Tissue Damage in Rodent Cancer and Relevance to Humans

A 90-Day Toxicity Study of the Effects of Petroleum Middle Distillates on the Skin of C3H Mice

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