Chronic toxicity and oncogenicity study on acrylamide incorporated in the drinking water of Fischer 344 rats

Johnson, Keith A.; Gorzinski, S.J.; Bodner, Kenneth M.; Campbell, R. A.; Wolf, Claude H.; Friedman, Marvin A.; Mast, Richard

doi:10.1016/0041-008x(86)90109-2

Cited by 397 publications

(325 citation statements)

References 24 publications

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“…17 Adding to the complexity, the mode of exposure between animals and humans differs, and we currently do not know about the bioavailability of acrylamide in foods. While evidence from animal 11,19 and risk assessment models 6,28 suggests a small increase in risk in humans, risk assessment models have generally assumed a linear dose-response relation at low levels of exposure, 29 but this is not known for certain. The level of uncertainty in these models is indeed substantial, being an 8-to 9-fold difference in potential risk due to a range from a relative risk of Incidence rate per 100,000 person-years.-2 Data adjusted for age at screening.-3 Data adjusted for age at screening, body mass index, education, alcohol intake, energy intake, saturated fat intake and fiber intake.- 4 Reference category.…”

Section: Discussionmentioning

confidence: 99%

“…Animals exposed to very high levels of acrylamide have shown an increased incidence of cancer in the lung, mammary gland, oral cavity and intestinal and reproductive tract. 11 Only 4 epidemiologic studies to date have explored whether exposure to acrylamide through diet could increase the risk of human cancer. [12][13][14][15][16] The evidence from these studies was converging, showing that intake of dietary acrylamide was not associated with an increased risk of several cancers.…”

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confidence: 99%

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Prospective study of dietary acrylamide and risk of colorectal cancer among women

Mucci

Adami

Wolk

2005

Intl Journal of Cancer

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There has been considerable discourse about whether exposure to acrylamide in foods could increase the risk of human cancer. Acrylamide is classified as a probable human carcinogen, and animal studies have demonstrated an increased incidence of tumors in rats exposed to very high levels. Still, epidemiologic data of the effect of dietary acrylamide remain scant. We have undertaken the first prospective study of acrylamide in food and risk of colon and rectal cancers using prospective data from the Swedish Mammography Cohort. The cohort comprised 61,467 women at baseline between 1987 and 1990. Through 2003, the cohort contributed 823,072 person-years, and 504 cases of colon and 237 of rectal cancer occurred. Mean intake of acrylamide through diet was 24.6 lg/day (Q25-70 5 18.7-29.9). Coffee (44%), fried potato products (16%), crisp bread (15%) and other breads (12%) were the greatest contributors. After adjusting for potential confounders, there was no association between estimated acrylamide intake and colorectal cancer. Comparing extreme quintiles, the adjusted relative risks (95% CI; p for trend) were for colorectal cancer 0.9 (0.7-1.3; p 5 0.80), colon cancer 0.9 (0.6-1.4; p 5 0.83) and rectal cancer 1.0 (0.6-1.8; p 5 0.77). Furthermore, intake of specific food items with elevated acrylamide (e.g., coffee, crisp bread and fried potato products) was not associated with cancer risk. In this large prospective study, we found no evidence that dietary intake of acrylamide is associated with cancers of the colon or rectum. Epidemiologic studies play an important role in assessing the possible health effects of acrylamide intake through food. ' 2005 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Prospective study of dietary acrylamide and risk of colorectal cancer among women

Mucci

Adami

Wolk

2005

Intl Journal of Cancer

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“…The predominant DNA adduct of N7-(2-carbamoyl-2-hydroxyethyl)-guanine (N7-GA-Gua) is formed in all tested organs at 100-fold higher levels than is N3-(2-carbamoyl-2-hydroxyethyl)-adenine (N3-GA-Ade) (Gamboa da Costa et al, 2003). Increased incidences in a number of benign and malignant tumors in a variety of organs have been observed in rodents exposed to AA (Bull et al, 1984;Friedman et al, 1995;Johnson et al, 1986;Rice, 2005).…”

Section: Introductionmentioning

confidence: 99%

Genotoxic effects of acrylamide and glycidamide in mouse lymphoma cells

Mei

Churchwell

et al. 2008

Food and Chemical Toxicology

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In addition to occupational exposures to acrylamide (AA), concerns about AA health risks for the general population have been recently raised due to the finding of AA in food. In this study, we evaluated the genotoxicity of AA and its metabolite glycidamide (GA) in L5178Y/ Tk +/− mouse lymphoma cells. The cells were treated with 2-18 mM of AA or 0.125-4 mM of GA for 4 h without metabolic activation. The DNA adducts, mutant frequencies and the types of mutations for the treated cells were examined. Within the dose range tested, GA induced DNA adducts of adenine and guanine [N3-(2-carbamoyl-2-hydroxyethyl)-adenine and N7-(2-carbamoyl-2-hydroxyethyl)-guanine] in a linear dose-dependent manner. The levels of guanine adducts were consistently about 60-fold higher across the dose range than those of adenine. In contrast, no GAderived DNA adducts were found in the cells treated with any concentrations of AA, consistent with a lack of metabolic conversion of AA to GA. However, the mutant frequency was significantly increased by AA at concentrations of 12 mM and higher. GA was mutagenic starting with the 2 mM dose, suggesting that GA is much more mutagenic than AA. The mutant frequencies were increased with increasing concentrations of AA and GA, mainly due to an increase of proportion of small colony mutants. To elucidate the underlying mutagenic mechanism, we examined the loss of heterozygosity (LOH) at four microsatellite loci spanning the entire chromosome 11 for mutants induced by AA or GA. Compared to GA induced mutations, AA induced more mutants whose LOH extended to D11Mit22 and D11Mit74, an alteration of DNA larger than half of the chromosome. Statistical analysis of the mutational spectra revealed a significant difference between the types of mutations induced by AA and GA treatments (P = 0.018). These results suggest that although both AA and GA generate mutations through a clastogenic mode of action in mouse lymphoma cells, GA induces mutations via a DNA adduct mechanism whereas AA induces mutations by a mechanism not involving the formation of GA adducts.

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“…It was reported recently that fried carbohydrate-rich food (e.g., French fries and potato chips) are a major source of human dietary AA intake (Tareke et al, 2000(Tareke et al, , 2002. These findings arose worldwide concern, since it was previously well established that AA is toxic to the human nervous system (Bachmann et al, 1992;Tilson, 1981), and likewise it was determined that neurotoxicity, reproductive toxicity, and tumorigenicity in laboratory animals manifested after AA exposure (Dearfield et al, 1988;Johnson et al, 1986). Further, it has been reported that AA can cause pathological alterations in the brain and spinal cord in rats leading to neurobehavioral modifications (LoPachin and Gavin, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…The fact that carcinogenicity was previously observed as a result of 2.0 mg/kg/day AA exposure in the 2-year Fischer 344 rat bioassay has strongly suggested the public health importance of further studying exposure to AA. In particular, AA exposure resulted in increased tumor incidence in the mammary gland, central nervous system, thyroid gland-follicular epithelium, oral tissues, uterus, and clitoral gland in female rats, as well as tumors of thyroid gland-follicular epithelium and scrotal mesothelium in male rats compared to control animals (Johnson et al, 1986). More recent carcinogenicity studies have demonstrated Harderian gland adenoma, alveolar/bronchiolar adenoma of the lung, squamous cell neoplasms of the forestomach in both male and female B6C3F 1 mice exposed to 0.175 mM or higher AA concentrations (Beland et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of <i>cII</i> gene mutation in the brains of Big Blue mice exposed to acrylamide and glycidamide in drinking water

Shelton

Townsend

et al. 2016

J. Toxicol. Sci.

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-Potential health risks for humans from dietary exposure to acrylamide (AA) and its reactive epoxide metabolite, glycidamide (GA), exist because substantial amounts of AA are found in a variety of fried and baked starchy foods. AA is tumorigenic in rodents, and a large number of studies indicate that AA is genotoxic in multiple organs of mice and rats. Although AA is neurotoxic, there are no reports on AA-induced gene mutations in the mouse brain. Therefore, to investigate if gene mutation can be induced by AA or its metabolite GA, we screened brains for cII mutant frequency (MF) and scored for mutation types in previously treated male and female Big Blue mice with 0, 1.4 mM, and 7.0 mM AA or GA in drinking water for up to 4 weeks. High doses of AA and GA induced similar cII MFs in males and females but only the induced cII MF in males was significantly higher than the corresponding male control MF (p < 0.05). Molecular analysis of the cII mutants from males showed that AA and GA each induced at least a 2.5-fold increase in the incidence of G:C → T:A, A:T → T:A, and A:T → C:G transversions compared to the vehicle controls, with similar mutational spectra observed when comparing AA with GA treatment. These results suggest that the MFs and types of mutations induced by AA and GA in the brain are consistent with AA exerting its genotoxicity via metabolism to GA.

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Chronic toxicity and oncogenicity study on acrylamide incorporated in the drinking water of Fischer 344 rats

Cited by 397 publications

References 24 publications

Prospective study of dietary acrylamide and risk of colorectal cancer among women

Prospective study of dietary acrylamide and risk of colorectal cancer among women

Genotoxic effects of acrylamide and glycidamide in mouse lymphoma cells

Evaluation of <i>cII</i> gene mutation in the brains of Big Blue mice exposed to acrylamide and glycidamide in drinking water

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