The effect of caffeine in the in vivo SCE and micronucleus mutagenicity tests

Aeschbacher, H.U.; Meier, H.; Jaccaud, E.

doi:10.1016/0165-7992(86)90076-x

Cited by 20 publications

(6 citation statements)

References 25 publications

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“…To date, no study has thoroughly examined differences in the spontaneous frequencies among the many mouse stocks used with the assay. Several studies have attempted to compare the relative sensitivity of mouse stocks to clastogens [Aeschbacher et al, 1979;Aeschbacher 1986;Hayashi et al, 1982;Styles et al, 1983;Sat0 et al, 1987Sat0 et al, , 1990Sat0 et al, , 1993 The Collaborative Study Group (CSGMT), 19881. The problem with the approach used in these studies is that it is difficult to put together a study that incorporates enough different mouse stocks and participating test facilities, along with a sufficient number and variety of chemicals, to come to a definitive conclusion.…”

Section: Introductionmentioning

confidence: 99%

Bone marrow micronucleus assay: A review of the mouse stocks used and their published mean spontaneous micronucleus frequencies

Salamone

Mavournin

1994

Environ and Mol Mutagen

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We have examined published negative control data from 581 papers on micronucleated bone marrow polychromatic erythrocytes (mnPCE) for differences in mean frequency and the frequency distribution profile among the mouse stocks used with the bone marrow micronucleus assay. For the 55 mouse stocks with published micronucleus assay data, the overall mean frequency is 1.95 mnPCE/1,000 PCE (1.95 mnPCE/1,000); for the 13 stocks most commonly used in the assay, it is 1.88 mnPCE/1,000. During the last 5 years, the mnPCE rate for these 13 major stocks has been 1.74 mnPCE/1,000. This current mean frequency is a substantial decrease from the mean of 3.07 mnPCE/1,000 observed for these 13 stocks for data published prior to 1981. Of the major stocks, the highest mean mnPCE negative control frequencies were observed for MS/Ae > BALB/c > C57Bl/6, and the lowest for CD-1 < Swiss Webster. We note that hybrid mouse stocks appear to have lower and less variable negative control frequencies than either of their parent strains and that the negative control frequency for some progeny stocks have diverged significantly from that of the parent stocks. Overall mean negative control frequencies appear to be correlated with breadth of the frequency distribution profile of published mean negative control values. Furthermore, a possible correlation between negative control frequency in the micronucleus assay and sensitivity to clastogens of different mouse strains may be indicated. The databases generated here allow us to define a range of norms for both the historical mean frequency and individual experimental mean frequencies for most stocks, but in particular, for the more commonly used mouse stocks. Our analysis, for the most part, bears out the recommendation of the first Gene-Tox Report on the micronucleus assay that the historical negative control frequency for a mouse stock should fall between 1 and 3 mnPCE/1,000. Eighty-six percent of the most commonly used mouse stocks have historical mean frequencies within this range. Though individual experimental mean values would not necessarily be expected to fall within the 1-3.00 mnPCE/1,000 range, 65.3% of the 2,327 published negative control values do, and 83.5% are < 3 mnPCE/1,000. The frequency with which an individual experimental mean value lies outside the 1.00 to 3.00 mnPCE/1,000 range differs among stocks and appears related to the mouse mean frequency. We suggest that the recommended range for historical mean frequency be extended slightly, to approximately 3.4 mnPCE/1,000, to accommodate some commonly used strains with overall mean negative control frequencies just above 3.00 mnPCE/1,000.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: Introductionmentioning

confidence: 99%

Bone marrow micronucleus assay: A review of the mouse stocks used and their published mean spontaneous micronucleus frequencies

Salamone

Mavournin

1994

Environ and Mol Mutagen

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“…Although earlier studies of caffeine effects in animals and man have failed to demonstrate significant genotoxic effects in vivo at doses near those that would result from the consumption of caffeinated beverages (30-33), the recent report by Chen et al (34) that chromosomal fragility in human lymphocytes cultured under low-folate conditions is linearly related to the level of coffee consumption of the donor supports the possibility that caffeine could exert significant effects in man under low-folate conditions. Previous studies of caffeine have shown little or no effect on micronucleus frequencies in mouse bone marrow at doses up to 200 mg/kg (31)(32)(33). However, these studies were carried out in mice maintained on commercial laboratory feeds, which contained adequate folate.…”

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confidence: 97%

Cytogenetic damage induced by folate deficiency in mice is enhanced by caffeine.

MacGregor

Schlegel

Wehr

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

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Folate deficiency in Swiss mice increased the incidence of micronuclei in peripheral blood erythrocytes, indicating increased chromosomal damage in nucleated erythrocyte precursors. Caffeine enhanced the incidence of micronuclei in blood and bone marrow by up to 5-fold in folatedeficient mice at doses that did not significantly alter the micronucleus frequency in the presence of adequate dietary folate. The lower dose of caffeine used in this study (75 mg/kg) approaches doses received by humans who consume large amounts of caffeinated beverages. Since folate deficiency and caffeine consumption are highly prevalent in the human population, the potential for a similar interaction in man should be evaluated.The occurrence of micronuclei in peripheral blood and bone marrow erythrocytes has been used as an indicator of cytogenetic damage in laboratory animals and man (1-3). Two recent studies indicate that folate deficiency and caffeinatedbeverage consumption may elevate the frequency of micronucleated erythrocytes in man. Caffeinated-coffee consumption was associated with an elevated frequency of micronucleated erythrocytes in a cross-sectional study of genotoxic risk factors (4), and folate supplementation lowered micronucleus frequency to normal in an individual with a marginal folate deficiency and an abnormally high micronucleus frequency (5). These studies suggest that folate status and caffeinated-beverage consumption may be risk factors for cytogenetic damage in man.Mild-to-moderate folate deficiency (6-9) and caffeinatedbeverage consumption (10) are both highly prevalent in the general population. Folate deficiency affects up to 60% of low-income and elderly persons (8,11) and is also common in subpopulations, such as alcoholics (12) Folate deficiency in pregnant women has been reported to range from 2% to 50%, depending on the population studied (25). Folate deficiency during pregnancy is associated with an elevated incidence of birth defects (26).Severe folate deficiency induced by antifolate drugs has been shown to increase the frequency of micronuclei in mouse bone marrow erythrocytes (27, 28), but we are not aware of previous reports of increased micronucleus frequencies induced by dietary folate deficiency in laboratory animals.Fragile-site expression induced in vitro by conditions of limiting folate is known to be strongly enhanced by caffeine, leading to micronucleus formation and increased frequencies of chromosome breaks (18,29). Under these conditions, caffeine increases folate-related breakage events, often by more than an order of magnitude. There appear to be no data indicating whether a similar interaction occurs in mammals in vivo. Although earlier studies of caffeine effects in animals and man have failed to demonstrate significant genotoxic effects in vivo at doses near those that would result from the consumption of caffeinated beverages (30-33), the recent report by Chen et al. (34) that chromosomal fragility in human lymphocytes cultured under low-folate conditions is linearly ...

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“…In a large number of in vivo genotoxicity tests (micronuclei, SCE's, chromosome aberrations aneuploidy, dominant lethal), both at somatic and germ cell levels, caffeine gave negative results, although few positive results were observed in some studies (see also references in D'Ambrosio (), IARC (), OECD () and by FDA ()). Significant induction of SCE's, chromosome aberrations and micronuclei were observed following in vivo treatment of Chinese hamsters and mice (Basler et al., ; Aeschbacher et al., ; Haynes et al., ; Choudhury and Palo, ). However, these increases were observed only at the highest dose levels and were generally small in quantitative terms.…”

Section: Assessmentmentioning

confidence: 99%

Scientific Opinion on Flavouring Group Evaluation 49, Revision 1 (FGE.49Rev1): xanthine alkaloids from the priority list

Silano

Bolognesi²,

Castle³

et al. 2017

EFS2

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Following a request from the European Commission, the EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF) was requested to deliver a scientific opinion on the safety assessment of the flavouring substances caffeine .016] and theobromine .032] in the Flavouring Group Evaluation 49, Revision 1. Consequent to the 2015 scientific opinion from the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) on the safety of caffeine from all dietary sources, the CEF Panel considered it inappropriate to evaluate the two substances through the Procedure. For caffeine, the Panel based its assessment on the safety threshold of 5.7 mg/kg body weight (bw) per day for adults, except pregnant/lactating women, and 3 mg/kg bw per day for children, adolescents, pregnant and lactating women, as established by the NDA Panel. The safety evaluation of theobromine takes into account that approximately 11% of an oral dose of caffeine is metabolised to theobromine and that both substances have a similar pharmacological profile. For the exposure assessment, a brand loyalty model was chosen. In this model, it was assumed that a consumer is exposed on a long-term basis to a specific category of food (i.e. non-alcoholic beverages), containing caffeine or theobromine at their respective maximum use levels. For the rest of the categories, normal use levels applied. Daily dietary exposure to caffeine and theobromine (excluding systemic exposure) added as a chemically defined flavouring substance ranged 0-2.3 and 0-0.4 mg/kg bw, respectively, across all population groups. The Panel concluded that caffeine .016] and theobromine .032] would not be expected to present safety concern based on their estimated levels of intake from their use as flavouring substances.

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The effect of caffeine in the in vivo SCE and micronucleus mutagenicity tests

Cited by 20 publications

References 25 publications

Bone marrow micronucleus assay: A review of the mouse stocks used and their published mean spontaneous micronucleus frequencies

Bone marrow micronucleus assay: A review of the mouse stocks used and their published mean spontaneous micronucleus frequencies

Cytogenetic damage induced by folate deficiency in mice is enhanced by caffeine.

Scientific Opinion on Flavouring Group Evaluation 49, Revision 1 (FGE.49Rev1): xanthine alkaloids from the priority list

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