El consumo de café: su asociación con el riesgo de padecer cáncer / Coffee consumption: its association with the risk of cancer

RESUMEN El café y su impacto en la salud es un tema en el que resulta válido profundizar. Históricamente, el consumo de café se ha asociado con efectos adversos, como problemas cardiovasculares y varios tipos de cáncer. Pero en gran cantidad de fuentes bibliográficas contemporáneas se enfatiza en los efectos beneficiosos de su consumo, sin mencionar los daños que puede ocasionar a la salud. Se hace esta revisión bibliográfica con el objetivo de profundizar en lo más actualizado sobre los beneficios y perjuicios del consumo del café y su relación con la aparición del cáncer. En la revisión se consultaron artículos de las bases de datos PubMed, SciELO, ClinicalKey y LILACS. Se constató que el consumo de café no se asocia con la aparición de diferentes tipos de cánceres, y que el consumo moderado aporta propiedades protectoras para la salud. Teniendo en cuenta el carácter multifactorial del cáncer, los autores consideran que suponer que el consumo de esta bebida puede impedir carcinogénesis, es una tesis que debe ser interpretada con cautela (AU).

ABSTRACT Coffee and its impact on health is a topic on which it is valid to deepen. Historically, coffee consumption has been associated with side effects, such as cardiovascular problems and several types of cancer. But many contemporary bibliographic sources emphasize the beneficial effects of its consumption, without mentioning the damage it can cause to health. This bibliographic review is done with the aim of deepening into the most updated knowledge about the benefits and harms of coffee consumption and its relationship with the appearance of cancer. Articles from PubMed, SciELO, ClinicalKey and LILACS databases were reviewed. It was found that coffee consumption is not associated with the appearance of different types of cancers, and that moderate consumption provides protective properties for health. In view of the multifactorial character of cancer, the authors consider that assuming that the consumption of this drink can prevent carcinogenesis is a thesis that should be taken with caution (AU).

Chemical Analysis, Toxicity Study, and Free-Radical Scavenging and Iron-Binding Assays Involving Coffee (Coffea arabica) Extracts.

We aimed to analyze the chemical compositions in Arabica coffee bean extracts, assess the relevant antioxidant and iron-chelating activities in coffee extracts and instant coffee, and evaluate the toxicity in roasted coffee. Coffee beans were extracted using boiling, drip-filtered and espresso brewing methods. Certain phenolics were investigated including trigonelline, caffeic acid and their derivatives, gallic acid, epicatechin, chlorogenic acid (CGA) and their derivatives, p-coumaroylquinic acid, p-coumaroyl glucoside, the rutin and syringic acid that exist in green and roasted coffee extracts, along with dimethoxycinnamic acid, caffeoylarbutin and cymaroside that may be present in green coffee bean extracts. Different phytochemicals were also detected in all of the coffee extracts. Roasted coffee extracts and instant coffees exhibited free-radical scavenging properties in a dose-dependent manner, for which drip coffee was observed to be the most effective (p < 0.05). All coffee extracts, instant coffee varieties and CGA could effectively bind ferric ion in a concentration-dependent manner resulting in an iron-bound complex. Roasted coffee extracts were neither toxic to normal mononuclear cells nor breast cancer cells. The findings indicate that phenolics, particularly CGA, could effectively contribute to the iron-chelating and free-radical scavenging properties observed in coffee brews. Thus, coffee may possess high pharmacological value and could be utilized as a health beverage.

Risk assessment of coffees of different qualities and degrees of roasting.

During the coffee beans roasting process, occurs the formation of polycyclic aromatic hydrocarbons, which are associated with the incidence of cancer in humans. This study aimed to evaluate the influence of coffee bean quality and roasting degree regarding mutagenicity, cytotoxicity and genotoxicity. Six samples of coffee drink made with roasted and ground Coffea arabica beans from different qualities and roast degrees were used after freeze-drying. Both commercial and special quality grains suffered light, medium and dark roasting. According to the Salmonella/microsome assay, the highest concentration of commercial grain sample (dark roast) significantly increased the number of revertants of the TA98 strain in the absence of metabolization. All the samples induced cytotoxicity to HepG2 cells. These effects can be ranked in the following order from most to least toxic: medium roast - special grain > light roast - special grain > dark roast - commercial grain > dark roast - special grain > light roast - commercial grain > medium roast - commercial grain. None of the samples induced genotoxicity in HepG2 cells. Our findings show that the harmful effects of coffee depend not only on the degree of roasting but also on the grain quality.

Exploration of the cellular effects of the high-dose, long-term exposure to coffee roasting product furan and its by-product cis-2-butene-1,4-dial on human and rat hepatocytes.

Coffee is the most popular hot beverage and caffeine is the most used psychoactive drug in the world. Roasting of coffee beans leads to the generation of minute quantities of undesirable compounds, such as furan. It is now thought that the toxicity of furan derives from its processing by CYP450 family of detoxifying enzymes, leading to the formation of cis-2-butene-1,4-dial (BDA). BDA has known cytotoxicity capacities, binding to proteins, nucleic acids, and glutathione (GSH). BDA also appears to mediate furan's toxic effects, since the inhibition of CYP450 family impedes the aforementioned toxicological effects of furan. There are some studies performed on furan's toxicity, but very few on BDA. Furthermore, the doses used in these studies appear to be fairly high when compared with the expected dosage one could be exposed to in a standard day. As such, to understand if furan and BDA could have toxic effects using more realistic doses and longer time frames, human and rat hepatocytes were exposed to furan or BDA for up to 96 h, and several biochemical parameters were assessed. We report here that human hepatocytes were more sensitive than rat's, in particular to furan, for we show a decrease in MTT reduction, ATP levels and increase in carbonyl formation and 8-OHdG accumulation in the longer time points. BDA was mostly ineffective, which we attribute to a low import rate into the cells. In conclusion, we show that there is potential for harm from furan in high doses, which should be carefully addressed.

Effects of Coffee Extracts with Different Roasting Degrees on Antioxidant and Anti-Inflammatory Systems in Mice.

Coffee roasting affects the taste, color, and aroma of coffee. The Maillard reaction, a major reaction during the roasting process, produces melanoidin, which affects the overall antioxidant capacity and anti-inflammatory effects of coffee. In this experiment, coffee roasting was divided into four degrees: Light, Medium, City, and French. To examine the in vivo antioxidant and anti-inflammatory effects of coffee extracts with different roasting degrees, we used 10-week-old male C57BL/6 mice. Mice were pre-treated with coffee extracts for 10 days by oral gavage (300 mg/Kg.B.W). After the last pre-treatment, lipopolysaccharide (LPS, 15 mg/Kg.B.W) was injected intraperitoneally for immune stimulation. Histopathological analysis showed that hepatic portal vein invasion and liver necrosis were severe in the LPS-treated group. However, these phenomena were greatly ameliorated when mice were pre-treated with Light- or Medium-roasted coffee extracts. Hepatic glutathione level was increased in the French group but decreased in the LPS-stimulated group. When mice were treated with LPS, mRNA expression level of tumor necrosis factor-alpha (TNF-α) was increased, whereas TNF-α expression was significantly reduced in the Light and Medium groups. Treatment with coffee extracts decreased the mRNA expression levels of interleukin 6 (IL-6) in mice stimulated by LPS, regardless of coffee roasting degrees. These effects decreased with the increasing coffee roasting degree. Results of luciferase reporter assay revealed that these effects of coffee extracts were transcriptionally regulated by the NF-κB pathway. Taken together, these results suggest that the roasting degree affects the antioxidant and anti-inflammatory effects of coffee extracts.

Roasted and green coffee extracts show antioxidant and cytotoxic activity in myoblast and endothelial cell lines in a cell specific manner.

Coffee is one of the most highly consumed beverages with potential beneficial health implications, however its molecular mechanism of action has not been completely elucidated yet. To that cause, the polyphenolic composition of different coffee extracts (from Light, Medium and Dark roasts as well as green beans) was examined by UHPLC-HRMS analysis, indicating chlorogenic acids isomers as the main constituents. In the following step, the toxicity of the extracts was tested in myoblasts and endothelial cells and differential toxicity of green and roasted samples was displayed as the myoblasts were more sensitive to green coffee extracts, in contrast to the endothelial cells. Subsequently, biologically relevant, non-cytotoxic extract concentrations were administered to explore their potential effect on cell redox status using flow cytometry and spectrophotometric assays. The results indicated that all coffee extracts improved cell redox status, however differences were observed between the two different cell lines tested, implying that coffee compounds display cell- and tissue-specificity. Glutathione levels were increased in almost all cases up to 70%, while the roasting degree affected the free radical scavenging potential of the extracts and their ability to protect from macromolecular oxidation as exhibited by the differences in ROS, CARB and TBARS levels, especially in the myoblasts.

Cells Deficient in the Fanconi Anemia Protein FANCD2 are Hypersensitive to the Cytotoxicity and DNA Damage Induced by Coffee and Caffeic Acid.

Epidemiological studies have found a positive association between coffee consumption and a lower risk of cardiovascular disorders, some cancers, diabetes, Parkinson and Alzheimer disease. Coffee consumption, however, has also been linked to an increased risk of developing some types of cancer, including bladder cancer in adults and leukemia in children of mothers who drink coffee during pregnancy. Since cancer is driven by the accumulation of DNA alterations, the ability of the coffee constituent caffeic acid to induce DNA damage in cells may play a role in the carcinogenic potential of this beverage. This carcinogenic potential may be exacerbated in cells with DNA repair defects. People with the genetic disease Fanconi Anemia have DNA repair deficiencies and are predisposed to several cancers, particularly acute myeloid leukemia. Defects in the DNA repair protein Fanconi Anemia D2 (FANCD2) also play an important role in the development of a variety of cancers (e.g., bladder cancer) in people without this genetic disease. This communication shows that cells deficient in FANCD2 are hypersensitive to the cytotoxicity (clonogenic assay) and DNA damage (γ-H2AX and 53BP1 focus assay) induced by caffeic acid and by a commercial lyophilized coffee extract. These data suggest that people with Fanconi Anemia, or healthy people who develop sporadic mutations in FANCD2, may be hypersensitive to the carcinogenic activity of coffee.

Coffee drinking and colorectal cancer risk: an evaluation based on a systematic review and meta-analysis among the Japanese population.

OBJECTIVE: It remains unclear whether coffee drinking is associated with colorectal cancer risk. We performed a systematic review and meta-analysis of epidemiologic studies on this issue among the Japanese population. METHODS: Original data were obtained from MEDLINE searches using PubMed or from searches of the 'Ichushi' database, complemented with manual searches. Meta-analysis was performed by using the random effects model to estimate the summary relative risk with 95% confidence interval according to the study design. The final judgment was made based on a consensus of the research group members with consideration for both epidemiological evidence and biological plausibility. RESULTS: We identified five cohort studies and nine case-control studies. Of these, one cohort study reported a strong inverse association (in women only), whereas three case-control studies reported a strong inverse association with colon or rectal cancer. In meta-analysis, high consumption of coffee was not appreciably associated with colorectal cancer risk among cohort studies, whereas it was associated with significantly lower risk of colorectal or colon cancer among case-control studies. The summary relative risk/odds ratio (95% confidence interval) for the highest versus lowest categories of coffee consumption was 0.95 (0.77-1.17) and 0.78 (0.65-0.95) for cohort and case-control studies, respectively. CONCLUSIONS: The evidence is insufficient to support that coffee drinking increases or decreases the risk of colorectal cancer among the Japanese population.

Furan in heat-treated foods: formation, exposure, toxicity, and aspects of risk assessment.

Furan is formed in a variety of heat-treated foods through thermal degradation of natural food constituents. Relatively high levels of furan contamination are found in ground roasted coffee, instant coffee, and processed baby foods. European exposure estimates suggest that mean dietary exposure to furan may be as high as 1.23 and 1.01 µg/kg bw/day for adults and 3- to 12-month-old infants, respectively. Furan is a potent hepatotoxin and hepatocarcinogen in rodents, causing hepatocellular adenomas and carcinomas in rats and mice, and high incidences of cholangiocarcinomas in rats at doses ≥ 2 mg/kg bw. There is therefore a relatively low margin of exposure between estimated human exposure and doses that cause a high tumor incidence in rodents. Since a genotoxic mode of action cannot be excluded for furan-induced tumor formation, the present exposures may indicate a risk to human health and need for mitigation. This review summarizes the current knowledge on mechanisms of furan formation in food, human dietary exposure to furan, and furan toxicity, and highlights the need to establish the risk resulting from the genotoxic and carcinogenic properties of furan at doses lower than 2 mg/kg bw.

Coffee consumption, genetic susceptibility and bladder cancer risk.

OBJECTIVE: We evaluated the bladder cancer risk associated with coffee consumption in a case-control study in Spain and examined the gene-environment interactions for genetic variants of caffeine-metabolizing enzymes. METHODS: The analyses included 1,136 incident cases with urothelial carcinoma of the urinary bladder and 1,138 controls. Odds ratios (OR) and 95% confidence intervals (CI) were adjusted for area, age, gender, amount of cigarette smoking, and years since quitting among former smokers. RESULTS: The OR (95% CI) for ever consumed coffee was 1.25 (0.95-1.64). For consumers of 1, 2, 3, and 4 or more cups/day relative to never drinkers, OR were, respectively, 1.24 (0.92-1.66), 1.11 (95% CI 0.82-1.51), 1.57 (1.13-2.19), and 1.27 (0.88-1.81). Coffee consumption was higher in smokers compared to never smokers. The OR for drinking at least 4 cups/day was 1.13 (0.61-2.09) in current smokers, 1.57 (0.86-2.90) in former smokers, and 1.23 (0.55-2.76) in never smokers. Gene-coffee interactions evaluated in NAT2, CYP1A2, and CYP2E1-02 and CYP1A1 were not identified after adjusting for multiple testing. CONCLUSION: We observed a modest increased bladder cancer risk among coffee drinkers that may, in part, be explained by residual confounding by smoking. The findings from the gene-coffee interactions need replication in further studies.

Coffee consumption and risk of type 2 diabetes, cardiovascular diseases, and cancer.

Numerous epidemiological studies have evaluated the association between coffee consumption and risk of type 2 diabetes, coronary heart disease, and various cancers. This paper briefly reviews the evidence for a relation between coffee consumption and these conditions, with particular attention to methodological issues. Several early studies suggested that coffee consumption could result in a marked increase in risk of coronary heart disease and several types of cancer. However, more recent prospective cohort studies that are less prone to selection and information bias have not confirmed these findings. High consumption of unfiltered types of coffee, such as French press and boiled coffee, has been shown to increase low-density-lipoprotein-cholesterol concentrations. In addition, limiting caffeinated coffee intake during pregnancy seems a prudent choice. However, evidence has been accumulating that frequent consumption of coffee may reduce risk of type 2 diabetes and liver cancer. Further experimental studies are warranted to elucidate the underlying mechanisms and possibly identify the components in coffee that are responsible for these putative effects. In sum, the currently available evidence on coffee and risk of cardiovascular diseases and cancer is largely reassuring, and suggests that, for the general population, addressing other health-related behaviors has priority for the prevention of chronic diseases.

Categorizing mistaken false positives in regulation of human and environmental health.

One of the concerns often voiced by critics of the precautionary principle is that a widespread regulatory application of the principle will lead to a large number of false positives (i.e., over-regulation of minor risks and regulation of nonexisting risks). The present article proposes a general definition of a regulatory false positive, and seeks to identify case studies that can be considered authentic regulatory false positives. Through a comprehensive review of the science policy literature for proclaimed false positives and interviews with authorities on regulation and the precautionary principle we identified 88 cases. Following a detailed analysis of these cases, we found that few of the cases mentioned in the literature can be considered to be authentic false positives. As a result, we have developed a number of different categories for these cases of "mistaken false positives," including: real risks, "The jury is still out," nonregulated proclaimed risks, "Too narrow a definition of risk," and risk-risk tradeoffs. These categories are defined and examples are presented in order to illustrate their key characteristics. On the basis of our analysis, we were able to identify only four cases that could be defined as regulatory false positives in the light of today's knowledge and recognized uncertainty: the Southern Corn Leaf Blight, the Swine Flu, Saccharin, and Food Irradiation in relation to consumer health. We conclude that concerns about false positives do not represent a reasonable argument against future application of the precautionary principle.

Coffee consumption and stomach cancer risk in a cohort of Swedish women.

Few prospective studies have examined the relationship between coffee consumption and risk of stomach cancer, and the findings have been inconsistent. We prospectively investigated the association of long-term coffee consumption with risk of stomach cancer in a population-based cohort study of 61,433 Swedish women. Information on coffee consumption was collected with a food-frequency questionnaire at baseline (1987-1990) and updated in 1997. During a mean follow-up of 15.7 years from 1987 through June 2005, 160 incident cases of stomach cancer were diagnosed. Coffee consumption was positively associated with the risk of stomach cancer. Compared to women who consumed 1 or fewer cups of coffee per day, the multivariate hazard ratios were 1.49 (95% = 0.97-2.27) for women who drank 2-3 cups per day and 1.86 (95% CI = 1.07-3.25) for those who drank 4 or more cups per day (p for trend = 0.01). An increase of 1 cup of coffee per day was associated with a statistically significant 22% increased risk of stomach cancer (hazard ratio = 1.22; 95% CI = 1.05-1.42). These prospective data suggest that coffee consumption may increase the risk of stomach cancer in a dose-response manner. This finding needs to be confirmed in other prospective studies.

Genotoxicity of instant coffee and of some phenolic compounds present in coffee upon nitrosation.

Instant coffee exhibits genotoxic activity upon nitrosation at acidic pH values in the Ames tester strain TA100. Using adsorption chromatography (Amberlit XAD-2) it was observed that the major fraction of molecules responsible for the genotoxic activity upon nitrosation was not retained on this resin, suggesting that the polar molecules present in instant coffee could be responsible for the genotoxicity observed upon nitrosation. Some phenolic molecules present in instant coffee (catechol, caffeic acid, and chlorogenic acid) were also genotoxic upon nitrosation under the same experimental conditions. The concentrations of nitrosatable phenolic compounds in the studied coffee were determined by HPLC and their contributions to the total genotoxicity observed were studied. The results obtained suggest that besides phenolic compounds other molecules were also involved in the genotoxicity of this beverage upon nitrosation. Teratogenesis Carcinog. Mutagen. 20:241-249, 2000.

Analysis of the potential carcinogenicity of coffee and its related compounds in a medium-term liver bioassay of rats.

The potential carcinogenicity of coffee and related compounds was examined using a medium-term liver bioassay based on the induction of glutathione S-transferase placental form (GST-P)-positive foci in F344 rats. A total of 230 males were initially injected with diethylnitrosamine (200 mg/kg body weight, ip) or saline as controls and 2 wk later were fed on diet or drinking water supplemented as follows for 6 wk: 5% regular instant coffee; 5% decaffeinated instant coffee; freshly brewed coffee, 8 g in 140 ml water; 0.1% caffeine, 0.2% methylglyoxal, 0.2% glyoxal; or 0.3% theophylline in the drinking water (w/v); and 0.4% theobromine in the diet (w/w). All rats were subjected to two-thirds partial hepatectomy at wk 3 and killed at wk 8. The resultant values for GST-P-positive hepatic focus induction were slightly increased with methylglyoxal and decreased with glyoxal and theobromine compared with the corresponding controls. Although the increase in number of foci for methylglyoxal was statistically significant at P < 0.05, the value was within the historical control levels. Regular and decaffeinated instant coffee as well as fresh-brewed coffee, caffeine and theophylline exerted no effects on focus development. Thus, the coffee-related compounds examined demonstrated no obvious enhancing potential, and it is therefore concluded that coffee and its main constituents are not carcinogenic for the rat liver.

Potential teratogenic and neurodevelopmental consequences of coffee and caffeine exposure: a review on human and animal data.

The teratogenic effect of caffeine has been clearly demonstrated in rodents. The sensitivity of different animals species is variable. Malformations have been demonstrated in mice at 50-75 mg/kg of caffeine, whereas the lowest dose usually needed to induce malformations is 80 mg/kg in rats. However, when caffeine is administered in fractioned amounts during the day, 330 mg/kg/day are necessary to reach teratogenicity in rats. In rodents, the most frequently observed malformations are those of the limbs and digits, ectrodactyly, craniofacial malformations (labial and palatal clefts) and delays in ossification of limbs, jaw and sternum. Nevertheless, even in rodents, caffeine can be considered as a weak teratogenic agent, given the quite large quantities of caffeine necessary to induce malformations and the small number of animals affected. In humans, caffeine does not present any teratogenic risk. The increased risk of the most common congenital malformations entailed by moderate consumption of caffeine is very slight. However, caffeine potentiates the teratogenic effect of other substances, such as tobacco, alcohol, and acts synergistically with ergotamine and propranolol to induce materno-fetal vasoconstrictions leading to malformations induced by ischemia. Therefore, even though caffeine does not seem to be harmful to the human fetus when intake is moderate and spread out over the day, some associations, especially with alcohol, tobacco, and vasoconstrictive or anti-migraine medications should be avoided. Maternal consumption of caffeine affects brain composition, especially in case of a low-protein diet and also seems to interfere with zinc fixation in brain. Maternal exposure to caffeine induces also long-term consequences on sleep, locomotion, learning abilities, emotivity, and anxiety in rat offspring, whereas in humans, more studies are needed to ascertain long-term behavioral effects of caffeine ingestion by pregnant mothers.

The inhibitory effects of coffee on radical-mediated oxidation and mutagenicity.

Hydrogen peroxide (H2O2) has been implicated as a major contributor to coffee mutagenicity and genotoxicity in vitro. We have used three assays to show the gradual formation of H2O2 in freshly prepared roasted ground coffee and in instant coffees over time reaching levels of 400-450 microM after a 1-h incubation period. Formation of H2O2 occurs through an auto-oxidation process where polyphenolics, in the presence of transition metals, reduce atmospheric oxygen. However, because of these polyphenolics, coffee also possesses in vitro antioxidant activity as shown by its capacity to inhibit lipid peroxidation in Fenton-catalysed hydroxylation reactions. The pro- and antioxidative effects of coffee are also reflected in its mutagenic and antimutagenic activity in the Ames test. Coffee is directly mutagenic in strains TA100 and TA102 due to H2O2 formation. However, coffee is also an antioxidant and antimutagen. This beverage exerts a strong protective effect against the mutagenicity and cytotoxicity induced by the oxidant t-butylhydroperoxide (t-BOOH). Thus, coffee, like many antioxidants, exhibits dual effects in vitro which are highly dependent upon parameters such as dose, atmospheric oxygen, transition metals as well as the biological and chemical endpoints used for measurement. Consequently, the data obtained on the pro- and antioxidant properties of foods and beverages from in vitro bioassays must be interpreted with caution and the results are not easily extrapolated in vivo to assess the impact on human health.

Effect of coffee drinking on cell proliferation in rat urinary bladder epithelium.

A possible effect of freshly brewed drip coffee on urinary bladder carcinogenesis was investigated in male Wistar rats using cell proliferation in urinary bladder epithelium as the indicator of tumour promotion. Male rats were given either undiluted coffee brew (100% coffee), coffee diluted 10 times (10% coffee) or tap water (controls), as their only source of drinking fluid for 2 or 6 wk. Uracil, known to induce cell proliferation in urinary bladder epithelium, was included in the study as a positive control. In rats receiving 100% coffee, body weights, liquid intake and urinary volume were decreased. Neither histopathological examination of urinary bladder tissue nor the bromodeoxyuridine labelling index revealed biologically significant differences between rats receiving coffee and the tap water controls. Uracil increased the labelling index and induced hyperplasia of the urinary bladder epithelium, as expected. It was concluded that these results produced no evidence that drinking coffee predisposes to tumour development in the urinary bladder.

An update on research with coffee/caffeine (1989-1990).

The interest in research with coffee has been increasing in recent years, and this has resulted in a surge of publications dealing with a variety of pharmaco-physiological effects of coffee/caffeine. This review attempts to update the information on the research with coffee/caffeine, including epidemiological studies, laboratory investigations and tests with volunteers, published in 1989 and 1990. It groups published articles according to observed or investigated biological effects. The most significant findings and differences between studies are pointed out with brief commentaries on the results. The overall assessment for the safety of drinking coffee and the effect of coffee on human health, based on the literature published in 1989 and 1990, indicates that certain controversial issues are still unresolved.

A carcinogenicity study of instant coffee in Swiss mice.

Commercially available regular instant coffee was given in the diet to barrier-maintained, specified pathogen-free Swiss mice for 2 yr. Groups of 150 males and 150 females were fed diets containing 10, 25 or 50 g instant coffee powder/kg. The animals had already been exposed to coffee in utero. Coffee increased the energy expenditure of the animals as shown by increased daily calorific intake and depressed growth. The overall tumour incidence was inversely correlated to the coffee intake, and no unusual tumour or site of origin was found. The most frequent neoplasms were lymphosarcomas, bronchiolo-alveolar adenomas and adenocarcinomas, as well as hepatocellular adenomas. The incidence of total neoplasms (benign and malignant) decreased from 70.6 and 56.8% in control males and females, respectively, to 34.8 and 36.2%, respectively, in the high-dose group. This decrease, which was essentially due to a reduction in the number of lymphosarcomas and hepatocellular adenomas, was associated with a slower growth rate. The number of leiomyomas in the uterus was slightly increased due to coffee intake as shown by the analysis of positive trend (P less than or equal to 0.05). However, the incidence of this benign tumour was very low; 2.72% of mice affected in the high-dose group, 1.37% in the low-dose group and 0% in the control and medium-dose groups. From this study it is concluded that instant coffee did not increase the incidence of malignant neoplasms in mice when fed at dietary levels of up to 5% for 2 yr.