Primary brain tumours and specific serum immunoglobulin E: a case-control study nested in the European Prospective Investigation into Cancer and Nutrition cohort.

BACKGROUND: Case-control studies suggest that patients with allergic diseases have a lower risk of developing glioma but not meningioma or schwannoma. However, those data can be differentially biased. Prospective studies with objective measurements of immunologic biomarkers, like immunoglobulin E (IgE), in blood obtained before cancer diagnosis could help to clarify whether an aetiological association exists. METHODS: The present case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) measured specific serum IgE as a biomarker for the most common inhalant allergens in 275 glioma, 175 meningioma and 49 schwannoma cases and 963 matched controls using the ImmunoCAP specific IgE test. Subjects with an IgE level ≥0.35 kUA/l (kilo antibody units per litre) were classified as sensitized by allergens. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by adjusted conditional logistic regression models for each tumour subtype. The effect of dose-response relationship was assessed in five increasing IgE level categories to estimate P-values for trend. RESULTS: The risk of glioma was inversely related to allergic sensitization (OR = 0.73; 95% CI 0.51-1.06), especially pronounced in women (OR = 0.53; 95% CI 0.30-0.95). In dose-response analyses, for high-grade glioma, the lowest OR was observed in sera with the highest IgE levels (P for trend = 0.04). No association was seen for meningioma and schwannoma. CONCLUSION: The results, based on serum samples prospectively collected in a cohort study, provide some support for the hypothesis that individuals with allergic sensitization are at reduced risk of glioma and confirm results from previous case-control studies.

Environmental risk factors for sporadic acoustic neuroma (Interphone Study Group, Germany).

The only known risk factor for sporadic acoustic neuroma is high-dose ionising radiation. Environmental exposures, such as radiofrequency electromagnetic fields and noise are under discussion, as well as an association with allergic diseases. We performed a population-based case-control study in Germany investigating these risk factors in 97 cases with acoustic neuroma, aged 30 to 69 years, and in 194 matched controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated in multiple logistic regression models. Increased risks were found for exposure to persistent noise (OR=2.31; 95% CI 1.15-4.66), and for hay fever (OR=2.20; 95% CI 1.09-4.45), but not for ionising radiation (OR=0.91; 95 % CI 0.51-1.61) or regular mobile phone use (OR=0.67; 95% CI 0.38-1.19). The study confirms results of recently published studies, although the pathogenetic mechanisms are still unknown.

Simultaneous analysis of different tumor types in a long-term carcinogenicity study with scheduled sacrifices.

A statistical analysis of a long-term carcinogenicity study with noninbred CF-1 mice exposed to DDT for different durations of time is presented. The experiment included a high proportion of animals with scheduled sacrifices and thus permitted the use of statistical models for tumor prevalence and lethality. Three types of tumors, lymphomas and lung and liver tumors, were considered. The analysis attempted to model the joint behavior of these tumors in relation to time and treatment group. An apparently negative association in the occurrence of lymphomas and liver tumors was confirmed through separate analyses by accounting effectively for intercurrent mortality.

Association between brain tumors and menopausal status.

BACKGROUND: Several lines of evidence have implicated female hormones in the etiology of human brain tumors, meningiomas in particular. PURPOSE: To investigate the relationship between brain tumor development and the hormonal changes manifested during pregnancy and menopause, we analyzed data from female participants in a population-based case-control study of adult brain tumors. This study was conducted in 1987-1988 in the Rhein-Neckar-Odenwald area of the Federal Republic of Germany. METHODS: The study population consisted of 127 women with meningiomas, gliomas, and acoustic neuromas (case patients) and 233 control women who were selected from the general population and frequency-matched by age to the case patients. Information on parity, menopausal status, and previous gynecologic surgeries was obtained through a standardized questionnaire. Case patients and control subjects were compared with the use of the unconditional maximum likelihood estimation of the parameters in a logistic regression model. RESULTS: Our results were not statistically significant; nevertheless, they revealed some interesting trends. No association was found between parity and the development of any of the three histological subtypes of brain tumor (relative risk [RR] = 1.31; 95% confidence interval [CI] = 0.51-2.07). Menopausal women had a greatly reduced risk of developing meningiomas (RR = 0.58; 95% CI = 0.18-1.90), and this effect was most pronounced when menopause had been surgically induced by bilateral oophorectomy (RR = 0.12; 95% CI = 0.01-1.30). Menopausal women had a greater risk of developing gliomas or acoustic neuromas (RR = 1.77; 95% CI = 0.67-4.68), except when menopause was surgically induced, in which case the risk was reduced (RR = 0.33; 95% CI = 0.04-3.09). Oophorectomy after menopause did not appear to influence risk. CONCLUSIONS: Since the onset of menopause is accompanied by cessation of estrogen production, our results support the notion that female hormones play a role in the development of brain tumors.

Effect of riboflavin, retinol, and zinc on micronuclei of buccal mucosa and of esophagus: a randomized double-blind intervention study in China.

A randomized double-blind intervention trial was done in Huixian, People's Republic of China, a population with a high incidence of esophageal cancer. The aim of the trial was to determine whether a once-a-week treatment with retinol (15 mg or 50,000 IU), riboflavin (200 mg), and zinc (50 mg) could result, after 1 year, in a lower prevalence of precancerous lesions of the esophagus in the group receiving the active treatment as compared with the prevalence in the group receiving a placebo. The results of the trial, published elsewhere, indicated that the treatment had no effect on the prevalence of precancerous lesions of the esophagus. In determining whether an effect could be detected when earlier end points are used, the prevalence of micronuclei was evaluated in exfoliated cells from the esophagus and from the buccal mucosa in the present study. In a subsample of 200 out of the original 610 study subjects, smears were taken from the buccal mucosa before and after treatment, and in 170 subjects esophageal smears were obtained during endoscopy only after treatment. The smears were fixed and kept at room temperature over 1 year before being evaluated for the presence of micronuclei by means of 4'-6-diamidino-2-phenylindole fluorescent staining. Smears from approximately half of the subjects were considered suitable for evaluation. No statistically significant difference in the prevalence of micronuclei in the buccal mucosa cells was observed before and after treatment (the mean percentage of micronucleated cells in the vitamin group upon first examination, before treatment started, 0.35%; 1 year after treatment, 0.31%) or between the treatment and the placebo group at the final examination. (The mean percentage of micronucleated cells in the vitamin-treated group was 0.31 and 0.39% in the placebo group.) However, a statistically significant reduction (P = .04) was observed in the prevalence of micronuclei in esophageal cells in the treatment group as compared to the placebo. (The mean percentage of micronucleated cells in the vitamin-treated group was 0.19%; it was 0.31% in the placebo group.

Dose-response study of N-nitrosoproline formation in rats and a deduced kinetic model for predicting carcinogenic effects caused by endogenous nitrosation.

A dose-response study on the endogenous formation of N-nitrosoproline in rats was carried out by feeding various doses of L-proline in the diet and sodium nitrite in the drinking water. N-Nitrosoproline excreted in the urine and feces of individual rats was monitored as an index for endogenous nitrosation of proline. The logarithm of the amount of N-nitrosoproline formed was found to be proportional to the logarithm of the product of the proline dose and the square of the nitrite dose, in agreement with in vitro studies. On the basis of these results, a kinetic model was formulated. Calculations were carried out with this model using published data on nitrosation and carcinogenic potency of selected N-nitrosamines. This allowed the estimation of the daily precursor dose quantity, [amine][nitrite]2, required to give 50% tumor incidence in rats after 2 years of feeding.

Dose and frequency effect in mouse skin tumor promotion.

In order to study the influence of both dose and application frequency of tumor-promoting agents on tumor development, we conducted a large-scale mouse skin two-stage carcinogenesis experiment. The back skins of 1110 CD-1 mice were painted once with 50 micrograms benzo(a)pyrene. These mice were divided into 24 groups according to subsequent schedules of 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment. Mice were treated with TPA at five different frequencies, i.e., daily, or every second, 4th, 8th, or 16th day, and six different TPA doses per application were used (0.1, 0.2, 0.4, 0.8, 1.6, or 3.2 micrograms), which allowed groups to be established with the same total dose of TPA applied per time unit. Six of the 30 frequency/dose combinations at extreme low or high frequency and dose were excluded. At each fixed frequency of TPA application, there was a good dose-response of TPA in mouse skin papilloma incidence. There was also a good application frequency-response relationship at fixed doses of TPA application. Within the set of groups in which animals received the same total dose of TPA per time unit, some variation was observed with respect to frequency of application. In general, TPA applications every 4th and 8th day tended to yield a small number of tumors.

Blood, retinol and zinc riboflavin status in relation to precancerous lesions of the esophagus: findings from a vitamin intervention trial in the People's Republic of China.

Data from a double-blind intervention trial in China are reanalyzed to explore auxiliary information. The trial had shown that in a high-risk area for esophageal cancer the dietary supplementation of apparently healthy individuals with a combination of retinol, riboflavin, and zinc did not lead to a different prevalence of precancerous lesions of the esophagus among those receiving the active treatment compared to a placebo group. However, improvement of blood retinol and zinc levels were also observed in the placebo group. The logistic regression analysis presented in this paper illustrates that those individuals who showed large increases in retinol, riboflavin, and zinc blood levels were more likely to have a histologically normal esophagus at the end of the trial. This effect is clearer for retinol than for riboflavin and zinc and it is independent of whether the change was caused by the active treatment or occurred otherwise.

An epidemiological study of precursor lesions of esophageal cancer among young persons in a high-risk population in Huixian, China.

The occurrence of chronic esophagitis, considered a precursor condition for esophageal cancer, among persons 15 to 26 yr of age and risk factors for the disease were investigated in Huixian, Henan Province, a high-risk area for esophageal cancer in the People's Republic of China. The 538 study subjects underwent an esophagoscopy with guided biopsies and cytology, a physical examination, an interview with a questionnaire including known and suspected risk factors for esophageal lesions, and collection of a 10-ml blood sample and overnight urine. One-third of the subjects was selected from households with a case of esophageal cancer in the past 6 yr and two-thirds came from control households. Histologically confirmed very mild, mild, and moderate esophagitis was observed in 31.6%, 10.7%, and 1.1% of 354 male and 30.4%, 4.3%, and 1.1% of 184 female subjects, respectively. In the multivariate case-control analysis of mile and moderate esophagitis compared with very mild esophagitis and normal subjects, the prevalence of mild and moderate disease was found to be positively associated with the consumption of burning hot beverages [odds ratio (OR) = 4.7], the prevalence of esophagitis among siblings (OR = 4.4), and family history of esophageal cancer (OR = 1.8) and negatively associated with the frequent consumption of fresh fruits (OR = 0.3) and wheat flour products (OR = 0.4). Weaker associations were seen for cigarette smoking and the use of cottonseed oil as the main cooking oil. Univariate associations seen with a clinical diagnosis of oral leukoplakia (OR = 2.7) and seborrheic dermatitis (OR = 3.7) are probably due to common risk factors such as smoking and nutritional deficiency. The present findings suggest that exposures early in life to environmental risk factors and nutritional deficiency may be responsible for inflammation and a weakened esophageal epithelium, resulting in a condition possibly more favorable for the development of esophageal cancer.

Urinary excretion of N-nitrosamino acids and nitrate by inhabitants of high- and low-risk areas for esophageal cancer in Northern China: endogenous formation of nitrosoproline and its inhibition by vitamin C.

A total of 238 samples of 24-h urine were collected from inhabitants of high-risk (Lin-xian) and low-risk (Fan-xian) areas for esophageal cancer in northern China, according to three protocols: (a) from undosed subjects; (b) from subjects who had ingested 100 mg L-proline three times a day 1 h after each meal; and (c) from subjects in Lin-xian who had ingested 100 mg ascorbic acid together with 100 mg L-proline three times a day 1 h after each meal. As an index of individual exposure to N-nitroso compounds or their precursors, ingested in food and/or formed endogenously, the levels of four urinary N-nitrosamino acids and nitrate were determined. The amounts of N-nitrosoproline, N-nitrosothiazolidine 4-carboxylic acid, N-nitrososarcosine, and nitrate excreted in the 24-h urine of undosed subjects in Lin-xian were significantly higher than those in Fan-xian, indicating a higher exposure of the inhabitants in the high-risk area to N-nitroso compounds and their precursors. Ingestion of L-proline resulted in a marked increase in urinary N-nitrosoproline levels in inhabitants from both areas, suggesting that endogenous nitrosation may occur to a larger extent when appropriate amine precursors are ingested in foods. Intake of moderate doses of ascorbic acid by high-risk subjects effectively reduced the urinary levels of N-nitrosamino acids to those found in undosed subjects in the low-risk area. If N-nitroso compounds formed in vivo are among the causative factors for esophageal cancer in this area of northern China, ascorbic acid appears to be effective in lowering the body burden of these carcinogenic compounds, thus offering a rational basis for long-term intervention studies in this area.

Case-control study of lifetime occupational and recreational physical activity and risks of colon and rectal cancer.

Important aspects of the inverse relation between physical activity and colon cancer risk are still under discussion. In 2000-2003, 239 incident cases of colorectal cancer confirmed by histopathology and 239 hospital-based controls, matched by age and gender, were enrolled. In standardized interviews, data on occupational and recreational physical activity for ages 20, 30, 40, 50 and 60 years were collected from 98 colon cancer cases, 141 rectal cancer cases, and from 193 controls. Besides lifestyle and sociodemographic characteristics, a detailed food frequency questionnaire was assessed. In multivariate logistic regression for colon cancer, significant risk reductions for the highest quartile of total physical activity were found for almost all ages. For lifetime mean physical activity, the multivariate odds ratio for the highest quartile was 0.37 [95% confidence interval (CI) 0.17, 0.83]. For lifelong constantly high-exercisers compared with lifelong non-exercisers an odds ratio of 0.26 (95% CI 0.08, 0.84) was estimated. For rectal cancer, no consistent association with physical activity was found. No confounding effects were observed but the authors found effect modification with total energy intake. These data support an inverse association of colon cancer risk and physical activity which is most expressed if activity is kept up throughout life.

Micronuclei in esophageal cells of Chinese youths in a high-incidence area for esophageal cancer in China.

An epidemiologic survey among 538 young persons between 15 and 26 years of age in a high-risk area for esophageal cancer in the People's Republic of China revealed a high prevalence of esophagitis. Histologically confirmed very mild, mild, and moderate esophagitis was observed in 31.6%, 10.7%, and 1.1% of 354 male and 30.4%, 4.3%, and 1.1% of 184 female subjects. The prevalence of micronuclei in esophageal smears was assayed in a subsample to investigate its possible association with esophagitis and with risk factors for esophageal lesions. Of the 186 subjects, 2.7% had mild or moderate esophagitis, 19.9% had very mild esophagitis, and 77.4% were normal. The frequency distribution of micronucleated cells in the esophageal mucosa was similar for the three diagnostic groups. Mean percentages of micronucleated cells did not differ by diagnosis of esophagitis, household status, current smoking status, presence of oral leukoplakia, or consumption of burning hot beverages or fresh fruit. Higher mean percentages were observed in the older age group of both sexes, but the difference was not statistically significant. The results suggest that if esophagitis is considered an important precursor state in the development of esophageal cancer, the scoring of micronuclei does not appear to be an efficient test for mild forms of esophagitis.

CYP1A1 messenger RNA levels in placental tissue as a biomarker of environmental exposure.

The human CYP1A1 gene codes for an inducible enzyme system involved in biotransformation of certain xenobiotics, including polycyclic aromatic hydrocarbons; some of the metabolites are carcinogenic and mutagenic. Effects of environmental exposures (smoking, air pollution, and diet) on CYP1A1 gene induction in placental tissue and the modulation of induction by the CYP1A1 MspI RFLP were evaluated in two groups from Poland: 70 mother-child pairs from Krakow, a city with elevated air pollution; and 90 pairs from Limanowa, a less polluted area. Compared to placentas from nonsmoking women, CYP1A1 mRNA levels were significantly increased in placentas from current smokers (P < 0.001). Ex-smokers also had significantly higher placental mRNA levels, including women who quit smoking prior to pregnancy (P < 0.01). A marginal increase in CYP1A1 mRNA with environmental tobacco smoke exposure was evident. Within Krakow, there was an increase in CYP1A1 mRNA with ambient pollution at the place of residence for each woman, which was significant among women who were not employed away from the home (P < 0.05 controlling for smoking status, diet, and use of coal for heating). Significant increases in mRNA were associated with dietary consumption of smoked meat, cheese, and fish (P < 0.01). The CYP1A1 MspI RFLP was not a significant determinant of CYP1A1 mRNA levels after controlling for smoking and other variables. Human placenta provides a readily available and responsive system that can serve as a model for evaluating environmental and genetic determinants of CYP1A1 induction.

A carcinogenicity study of styrene-7,8-oxide in rats.

Styrene-7,8-oxide (200 mg/kg body wt) was given orally to female BDIV rats on 17th day of pregnancy. Their offspring received 96 weekly doses of styrene oxide (100-150 mg/kg body wt). Following the continuous administration of styrene oxide, an increased incidence, statistically significant, of forestomach tumours was observed in rats of both sexes. The incidence of tumours occurring at other sites was similar in treated and control animals. The present results show that styrene oxide is a direct-acting carcinogen producing benign and malignant tumours of the forestomach.

Use of quantitative epidemiologic data in regulatory approaches to air pollution.

Ambient air is a complex mixture containing a variety of substances, some of which are known to be carcinogenic. To develop a homogeneous approach for regulating the emission of these compounds, their individual carcinogenic potential needs to be placed on a comparable scale. The unit risk may be considered as an appropriate measure that condensates dose-response analyses of epidemiologic data into a single, easily interpretable estimate. Given the information on the carcinogenic potency of single compounds, more information on the occurrence of the components and the relation of emissions to specific emittents needs to be considered. In Germany, an approach has been developed that combines different assumptions on complex mixtures for the regulation of the overall risk. This paper outlines some of the principal aspects of the underlying concepts.

Tel Aviv-Heidelberg three-generation offspring study: genetic determinants of apolipoprotein A1 and apolipoprotein B.

The contribution of major gene and multifactorial effects on variation of plasma apolipoproteins A1 and B has been tested in a large sample of population-based Israeli pedigrees. Our most parsimonious and best fitting model for both apolipoproteins is consistent with Mendelian transmissibility, with significant contribution of major genes (with 2 alleles recessive and dominant within each locus) and polygenes, but neglects effects of common sib environment as well as related intergeneration differences in polygenic effects. Total genetic effects explain 71 and 58% of phenotypic variance of APO-A1 and APO-B levels. The major genes account for about 44 and 32% of the variance in APO-A1 and APO-B, respectively, and the frequency of the recessive alleles determining the high level of apolipoproteins under the study in the Israeli population is in the vicinity of 40% at each locus.

Tel Aviv-Heidelberg three-generation offspring study: genetic determinants of plasma fibrinogen level.

Elevated plasma fibrinogen concentrations (fibrinogen) are an important independent risk factor of atherosclerotic disease. Using the kinetic method, we measured fibrinogen in 808 individuals, of which 757 were members of 204 pedigrees. Correlation analysis and two-way analysis of variance (ANOVA) showed a significant association of fibrinogen with age, body mass index (BMI), sex, smoking habits, sport activity, and other lifestyle factors. However, multivariate regression analysis of fibrinogen established an independent significant contribution of only the first three factors. Fibrinogen levels adjusted respectively were subjected to complex segregation analysis. Our aim was to identify the contribution of major gene effects and residual (within the genotype) family correlations on fibrinogen variation. Results of this study suggest codominant alleles at a major locus accounting for 39% of variation. There was also evidence of a significant residual parent/offspring correlation.

Reproducibility and relative validity of food group intake in a food frequency questionnaire developed for the German part of the EPIC project. European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: For the German part of the European Prospective Investigation into Cancer and Nutrition (EPIC), a self-administered, optically-readable food frequency questionnaire (FFQ), including 158 food items and 87 coloured portion size photographs, was developed to assess the usual food and nutrient intake of individuals during the past year. In 1991/1992, the reproducibility and validity of the questionnaire measurements were studied according to the EPIC protocol. This article reports the results on reproducibility and relative validity of measurement of food group intake. METHODS: A total of 104 men and women aged 35-64 years, who are members of the local health insurance institution, AOK Heidelberg, participated in this study. Reproducibility of the questionnaire measurements was obtained by a repeated administration of the FFQ to the same study subjects at a 6-month interval. The mean of 12 24-hour dietary recalls applied at monthly intervals served as reference method for the estimation of the relative validity of questionnaire measurements. A second version of the FFQ that integrated questions on general food consumption patterns was also investigated. RESULTS: Spearman test-retest correlations of food group intake ranged from 0.49 for bread to 0.89 for alcoholic beverages (median = 0.70). Spearman correlations between food group intake values derived from the 24-hour diet recalls and the FFQ completed in the summer of 1992 varied from 0.14 for legumes to 0.90 for alcoholic beverages (median = 0.45). Correction for attenuation due to within-person error in the reference method as well as the correction for general consumption patterns improved the correlations. CONCLUSION: The results indicate that our newly developed FFQ gives reproducible estimates of food group intake. Large day-to-day variation in food group intake complicated the evaluation of FFQ validity. Overall, moderate levels of relative validity were observed for estimates of food group intake.

The relative validity of vitamin intakes derived from a food frequency questionnaire compared to 24-hour recalls and biological measurements: results from the EPIC pilot study in Germany. European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: For the European Prospective Investigation into Cancer and Nutrition (EPIC) study Germany, a self-administered food frequency questionnaire (FFQ) was developed and tested for its relative validity and reproducibility in 1991/1992. Study participants were 92 potential cohort members. This paper reports results regarding retinol, carotenoids, tocopherols and ascorbic acid. METHODS: Study participants were invited to the study centre in Heidelberg once a month over one year. At each visit, a 24 hour recall was obtained. The FFQ was filled in twice with a 6-month interval (FFQ1, FFQ2). In addition, a questionnaire on general consumption frequencies of 14 broad food groups was completed. This information was combined with estimates derived from FFQ2 and frequency-corrected food and nutrient intakes were calculated (FFQcorr). Blood specimens were taken in winter and summer 1992. RESULTS: The intraclass correlation of the FFQ ranged from 0.65 to 0.67 for retinol, tocopherols, carotenoids, and ascorbic acid. Intake of carotenoids by FFQcorr showed de-attenuated Pearson correlation coefficients with blood values in the order of 0.37, and with recall data of 0.44. Respective correlations for retinol were 0.21 and 0.29, for tocopherols 0.18 and 0.52, and for ascorbic acid 0.36 and 0.69. Errors of FFQcorr and 24-hour diet recalls were not correlated. CONCLUSIONS: In general, it was demonstrated that the FFQ was able to rank participants into biologically meaningful categories of intake or blood concentrations for carotenoids and ascorbic acid, but misclassification was higher for tocopherol and retinol.

Reproducibility and relative validity of energy and macronutrient intake of a food frequency questionnaire developed for the German part of the EPIC project. European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: For use in the German part of the European Prospective Investigation into Cancer and Nutrition (EPIC) a self-administered, optically readable food frequency questionnaire (FFQ) was developed to assess individuals' usual food and nutrient intake over the past year. The food list comprised 158 food items for which the typical portion size, the consumption frequency (1-6 times) and the time period (day, week, month, or year) were requested. This paper reports the results of the reproducibility and relative validity of nutrient intakes obtained by this instrument. METHODS: The study was carried out from October 1991 to October 1992. During this period, 104 men and women, aged 35-64 years, completed a 24-hour recall once a month, and the FFQ in the middle and at the end of this study. A short questionnaire on global consumption patterns was used to adjust the food consumption frequency given in the FFQ. RESULTS: Reproducibility correlations varied from 0.59 for saturated fat to 0.88 for alcohol, with most values falling between 0.60 and 0.70. Energy-adjustment decreased the observed correlations for all nutrients. Correlations between nutrient intake values from the 12-day average of dietary recalls and the FFQ corrected for food consumption frequency ranged from 0.42 for polyunsaturated fat to 0.88 for alcohol, followed by 0.65 for dietary fibres. After de-attenuation and energy-adjustment the range of correlations was somewhat wider (0.43-0.75, without alcohol). With regard to classification, on average, 36% of subjects fell into the same quintile, and 75% into within-one quintile when classified by the frequency-corrected FFQ compared to the quintiles based on recalled data. CONCLUSIONS: In summary, the newly developed FFQ showed fairly good reproducibility and relative validity for most evaluated nutrients. The between-subject variation of nutrients in the German cohort (including the participants from East Germany) is likely to be greater than that among the subjects of the pilot phase. A revised version of the FFQ corrected for food consumption frequency is used in the EPIC study.