Journal of the American College of Nutrition, Vol. 22, No. 3, 208-216 (2003)
Published by the American College of Nutrition
Effect of Five-Year Supplementation of Vitamin C on Serum Vitamin C Concentration and Consumption of Vegetables and Fruits in Middle-Aged Japanese: A Randomized Controlled Trial
Mi Kyung Kim, PhD,
Shizuka Sasazuki, MD,
Satoshi Sasaki, MD,
Shunji Okubo, MD,
Masato Hayashi, MD and
Shoichiro Tsugane, MD
Epidemiology & Biostatistics Division, National Cancer Center Research Institute East, Chiba (M.K.K., S.S., S.S., S.T.), JAPAN
Hiraka General Hospital, Yokote (S.O., M.H.), JAPAN
Address reprint requests to: Shoichiro Tsugane, M.D., Epidemiology and Biostatistics Division, National Cancer Center Research Institute, 6-5-1 Kashiwanoha, Kashiwa City, Chiba 277-8577, JAPAN. E-mail: stsugane{at}east.ncc.go.jp
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ABSTRACT
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Objective: This study was aimed at evaluating the effect of long-term vitamin C supplementation on serum and dietary vitamin C and identifying the factors associated with change in serum concentration.
Methods: A total of 439 subjects with atrophic gastritis initially participated in a randomized clinical trial using vitamin C and ß-carotene to prevent gastric cancer. We originally randomized the participants into four treatment groups using a 2x2 factorial design, whereby 0 or 15 mg/day ß-carotene and 50 or 500 mg/day vitamin C were administered in a double-blind manner. The ß-carotene component was terminated early after a mean treatment duration of four months. Before and upon early termination of ß-carotene supplementation, 134 subjects dropped out this trial, while 120 and 124 subjects took the vitamin C supplement at either 50 mg or 500 mg daily for five years.
Results: Changes in serum vitamin C were significantly higher in the high-dose group (38.5% increase, 95% CI = 27.0–49.9) than in the low-dose group (13.0% increase, 5.1–20.9) or in the dropout group (3.3% increase, -2.1–8.6) after five-year supplementation. The serum vitamin C at baseline was negatively associated with changes in serum vitamin C (p < 0.0001), while high-dose (p < 0.0001) and low-dose (p < 0.05) supplementation and female gender (p < 0.001) were positively associated. Dietary intake of vitamin C in the supplementation group was almost identical before and after five-year supplementation of vitamin C (2.31 mg/day decrease, 95% CI = -15.3–10.7), while a 17.7 mg/day decrease (95% CI = -44.2–8.86) was observed in the drop-out group.
Conclusion: Five-year vitamin C supplementation induces a remarkable increase in serum vitamin C concentration, and our intervention program appears to have no effect on dietary vitamin C intake.
Key words: vitamin C supplementation, serum vitamin C, fruit and vegetable intake, randomized controlled trial, Japanese
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INTRODUCTION
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For the last several decades a number of epidemiologic studies have shown that diets high in vegetables and fruits and/or high blood concentration of antioxidant vitamins may protect against cancers of the mouth, thorax, esophagus, lung, stomach, colon and rectum [1–4]. Several large-scale chemoprevention trials have also been conducted in China, Finland and the United States to test the efficacy of retinal ß-carotene, 
-tocopherol and other nutrients [5–7]. There is considerable controversy as to harmful effect of ß-carotene and cancer risk [7], whereas epidemiologic evidence, although not completely consistent, has shown that vitamin C, vitamin E and selenium are associated with a decreased cancer risk.
The plasma level of vitamin C and carotenoids may serve as biomarkers of consumption of vegetables and fruits that are the primary dietary sources of these vitamins [8–10]. In our previous study [11], an increase of serum vitamin C after three-month supplementation of 1000 mg/day vitamin C caused an increase of 88% to 95%, and the serum vitamin C reached nearly a steady-state after one month. Although the effects of several short-term feeding trials of a high fruit and vegetable diet on serum carotenoids and vitamin C have been reported [10–13], there is little research on the effects of long-term vitamin C supplementation on serum vitamin C.
After confirming the feasibility of a population-based chemoprevention study through a pilot investigation [11], we started a population-based randomized double-blinded controlled trial that was originally undertaken to evaluate the vitamin C and/or ß-carotene supplementation on the ten-year cumulative incidence rate of gastric cancer. After modification of the study protocol, the study purpose was changed to evaluate the five-year change in serum pepsinogens, which we regarded as a measure of the progression of chronic atrophic gastritis. The first objective of this report was to evaluate the effect of five-year vitamin C supplementation on the serum vitamin C concentration and to identify the factors associated with change in the serum concentration. The second objective was to evaluate the effects of an intervention trial of vitamin C supplementation on dietary consumption of vegetables and fruits.
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SUBJECTS AND METHODS
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Subjects
Target subjects were men and women 40 to 69 years of age living in a village within the Yokote Public Health Center District in Akita Prefecture, one of the regions with the highest mortality from gastric cancer in Japan, who participated in annual screening programs for circulatory diseases conducted by each municipality under the National Health and Welfare Services Law for the Aged. We measured their serum concentration of pepsinogen (PG) I, II and calculated PG I/II ratio and asked persons diagnosed with chronic atrophic gastritis (defined as PG I <70 ng/mL and PG I/II <3.0) to take diet supplements containing vitamin C and/or ß-carotene. The recruitment of study participants was conducted from June through September, 1995, in the first year. It was originally scheduled to be continued up to 1998, when at least 1,812 subjects were expected to participate. This sample size would have permitted the detection of a 40% reduction of the ten-year cumulative incidence of gastric cancer in the intervention group (from 7% to 4%) with 5% alpha-error (two-sided) and 80% power. However, in response to a NCI report [14] indicating that two ß-carotene trials had shown no benefit and potential harm from the supplement on Jan. 18, 1996, we decided to modify the initial study protocol by removing the ß-carotene supplementation and by stopping further recruitment of study participants. The ß-carotene supplementation lasted only for three to six months. Fig. 1 shows the trial profile. Out of 439 persons initially participating in the study, 134 dropped out before and upon the study protocol modification, and these subjects were included in this study as a referent group without vitamin C supplementation. Of the 305 remaining participants, 244 completed the study. Since the purpose of this study was to examine the effect of five-year supplementation, 61 subjects (24 on low-dose and 37 on high-dose) who dropped out after the protocol modification were excluded from the analysis.
Design
The rationale, design and methods of the study, the characteristics of the participants, and the measures of compliance have been described in detail elsewhere [15]. At the outset, we prescribed capsules containing full doses of ß-carotene (15 mg/day) and vitamin C (500 mg/day) to all participants for four weeks. We conducted this "run-in" procedure in order to identify and exclude at an early stage the subjects who either did not comply or showed side effects. We then randomized the remaining participants into four treatment groups using a 2x2 factorial design, whereby 0 or 15 mg/day ß-carotene and 50 or 500 mg/day vitamin C were supplemented in a double-blind manner. After the study protocol was modified, ß-carotene supplementation was halted, but the prescription of vitamin C was continued for five years. We obtained informed consent again from individuals willing to take part in the modified trial, and provided them with new capsules containing vitamin C only (50 mg/day or 500 mg/day). Compliance with treatment was constantly encouraged and monitored by nurses who interviewed the participants and recorded pill counts every three months. We also monitored adverse effects using a questionnaire at every visit. The study protocol was approved by our institutional ethics committee.
Demographic, Lifestyle and Medical Information
At recruitment, all participants were given a self-administered questionnaire on weight, height and demographic details, such as marital and occupational status, education attainment, smoking status, alcohol consumption, disease history, family history of disease and general health status. Body mass index (BMI, kg/m2) was calculated as body weight divided by the square of body height.
Dietary Intake
The dietary section was a 108-item semiquantitative food frequency questionnaire, concentrating on habitual consumption of food and beverage during one year at study entry and after supplementation (fifth year). The frequency of usual consumption of the various foods was recorded by the following categories: ≥7 times/day, 4–6 times/day, 2–3 times/day, 1 times/day, 5–6 times/week, 3–4 times/week, 1–2 times/week, 1–3 times/month and never or less than 1 time/month. The midpoint of the interval (5 times/day, 2.5 times/day, etc) was used to calculate the frequency of intake. The usual portion size was also included in the questionnaire, and subjects were asked to describe their usual portion size as small, medium or large [16]. For carrots, spinach, pumpkins, cabbage and radishes, an actual-size photograph of the vegetables was shown. Nutrient intakes were computed from the questionnaire using the Standard Food Composition Tables published by the Science and Technology Agency of Japan [17]. Data on carotenoid composition in fruit and vegetables provided by the carotenoid food-composition database were used to estimate daily intake of individual carotenoids from food intake assessed by the food-frequency questionnaire [18]. Validity of the food frequency questionnaire was assessed in a validation study. The median correlation coefficients between the intakes obtained from FFQ and those obtained from 28-day semi-weighed dietary records were 0.52 and 0.41 for 15 nutrients and 0.38 and 0.32 for 19 food groups in 102 men and 113 women, respectively. The correlation coefficients for vitamin C, vegetables and fruit intake were 0.42, 0.33 and 0.61 in men and 0.32, 0.35 and 0.50 in women (unpublished data).
Biochemical Analysis
Fasting blood samples collected upon entry in the study and at five years were analyzed for serum vitamin C and lipids. The subjects were asked not to eat or drink anything except water after nine o’clock on the day before blood sampling. The serum was sampled between nine and eleven o’clock in the morning. All samples were stored at -70°C to -85°C and were analyzed simultaneously after the completion of the five-year supplementation. Sera for ascorbic acid measurement were stabilized by addition of meta-phosphoric acid (Wako Pure Chemical, Osaka, Japan). Serum ascorbic acid was measured by the following method [19]. Briefly, 450 µL of the samples was sequentially mixed with 0.15 mL of 0.15% dithiothreitol (Nacalai Tesque Inc., Kyoto, Japan), 0.15 mL of 0.5% N-ethylmaleimide (Nacalai Tesque Inc., Kyoto, Japan), and 0.75 mL of trichloroacetic acid (Wako Pure Chemical, Osaka, Japan). After centrifugation, the supernatant was mixed with 0.75 mL of a chromogen (phosphate: water: 1.8% FeCl3: 4% dipyridyl = 1:1:1:2), incubated at 37°C for 30 minutes, and the optical density at 525 nm was then measured with a UV/Vis spectrophotometer (V-550, Nihon Bunko, Tokyo, Japan). The interassay coefficient of variation for vitamin C is 2.2%. All assays were conducted by persons blinded to the intervention assignment and the questionnaire data.
Statistical Analysis
Baseline characteristics, nutrient intake and food consumption were summarized in terms of the mean and standard deviation for continuous variables, frequencies and percentages for categorical variables. Comparisons of continuous variable between two supplementation groups and the dropout group were examined by one-way ANOVA followed by the Duncan test. ANCOVA was also used to adjust for possible differences due to the possible confounding variables. Comparisons of categorical variable between two supplementation groups and the dropout group were performed with the chi-square test. A p value <0.05 was considered to indicate statistical significance. The serum vitamin C variable was log-transformed to improve normality. The effect of possible confounding factors was examined by multiple regression analysis. The change in log-transformed serum vitamin C concentration between baseline and five years after vitamin C supplementation was used as the dependent variable for the model. Gender, age, smoking status, ethanol intake, change in vitamin C intake, and log-transformed serum vitamin C concentration at baseline and two dummy variables for vitamin C supplementation group were included simultaneously in the model as independent variables. The interaction between vitamin C supplementation group and alcohol drinking and smoking status (as dummy variables) was tested by adding a cross-product variable in the regression models for log-transformed serum vitamin C concentration. The Statistical Analysis System, Version 6.12 (SAS Institute Inc., Cary, NC) software package was used for data analysis.
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RESULTS
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General Characteristics of Study Subjects
The general characteristics of the study subjects together with their mean baseline intake of energy, dietary fiber and vitamins of the study subjects are presented in Table 1. There were no differences in any baseline characteristics between the two supplementation groups (low-dose and high-dose group) and the dropout group. Compliance in taking the vitamin capsules was 92.9% in men and 95.4% in women.
Effect of Long-Term Oral Vitamin C Supplementation on Serum Vitamin C Concentrations
Serum vitamin C concentrations at baseline and after one-year and five-year vitamin C supplementation, during which the subjects had received either low-dose (50 mg/day) or high-dose vitamin C (500 mg/day) or dropped out before and upon the modification of the study protocol are shown in Table 2. At baseline, the mean concentration of serum vitamin C (log-transformed and untransformed) did not differ between the low-dose group, the high-dose group and the dropout group. Serum vitamin C concentrations were markedly and significantly increased at one year and slightly decreased after five years of vitamin C supplementation. At one- and five-year follow-up, the serum concentrations significantly differed among the three groups. Changes in serum vitamin C concentrations were significantly higher in the high-dose group (21.3 µmol/L increase) than in the low-dose group (5.72 µmol/L increase), or the dropout group (0.50 µmol/L decrease) after five years of vitamin C supplementation. After adjustment for gender, age, body mass index, ethanol intake, smoking status, consumption of vegetables and fruits, a significant difference was still maintained. In the high-dose group receiving 500 mg/day, the serum vitamin C concentration increased by 38.5% after five years, which is a significantly higher increase than in the other two groups.
Based on the distribution of serum vitamin C concentrations at baseline, serum vitamin C concentrations were divided into quartiles. Mean serum vitamin C concentrations of each quartile were 54.7, 70.5, 82.2 and 101.7 µmol/L, respectively (Table 3). Fig. 2 also shows the serum vitamin C concentrations at each point by supplementation group. Table 3 indicates that the range between the mean values of serum vitamin C in the highest quartile and the lowest quartile clearly shrank after one and five years, compared with those at baseline. Thus, the mean vitamin C concentration of the subjects in the highest quartile initially declined from 101.7 µmol/L at baseline to 94.5 µmol/L after five years. Similarly, the mean vitamin C concentration of subjects in the lowest quartile initially increased from 54.7 µmol/L at baseline to 84.7 µmol/L after five years. As a result, the mean difference in serum vitamin C concentration between the highest (Q4) and lowest quartile (Q1) declined from 47.0 µmol/L at baseline to 9.8 µmol/L after five years. Consequently, the mean serum vitamin C concentrations became similar at one and five years after vitamin C supplementation, except in the highest quartile.
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Fig. 2. Changes in serum vitamin C concentration by quartiles of serum vitamin C at baseline. The quartiles are based on the distribution of serum vitamin C concentrations at baseline by supplementation group.
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Results from the final multivariate regression models for predicting the change between baseline and five years in the serum vitamin C concentrations are shown in Table 4. In the overall subjects, the serum vitamin C concentration at baseline was significantly (p < 0.0001) and negatively related with changes in serum vitamin C concentrations during the supplementation period (R2 for this model = 0.60). In addition, the high-dose (p < 0.0001) and low-dose (p < 0.05) supplementation and female gender (p < 0.01) were significantly and positively associated with changes in serum vitamin C concentrations. The most important variable in predicting an increase in the serum vitamin C concentration was the baseline serum vitamin C concentration (partial R2 in this model = 0.46). Even in the two supplementation groups (high-dose and low-dose), the baseline serum vitamin C concentration (log-transformed) was found to be inversely related to change in the serum vitamin C concentration. Also, the female gender was positively related to change in concentration in the low-dose group. Overall R2 for predicting changes in the serum vitamin C concentration was 0.66 in the low-dose group and 0.55 in the high-dose group. In the dropout group, the serum vitamin C concentration at baseline was significantly and negatively related with the change in serum vitamin C concentration during the five-year period (R2 for this model = 0.52).
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Table 4. Multiple Regression Analysis for the Changes in Log Transformed Serum Vitamin C Concentration during the Study Period
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Effect of Long-Term Vitamin C Supplementation on Consumption of Vegetables and Fruits
Dietary intake of fiber, vitamin A & C and vegetables and fruits of the study subjects before and after supplementation is illustrated in Table 5. Dietary intake of vitamin C in the supplementation group was almost identical before and after its five-year supplementation (2.31 mg/day decrease, 95% CI = -15.3–10.7), while a 17.7 mg/day decrease (95% CI = -44.2–8.86) was observed in the dropout group, although it did not reach statistical significance. After vitamin C supplementation, the dietary vitamin C intake of the supplementation group (144 mg/day) was significantly higher than that of the dropout group (116 mg/day). For consumption of vegetables, three subgroups were added (green/yellow vegetables, pickled vegetables and other vegetables) on the basis of the amount of vitamin content. The total vegetable intake and especially the other vegetable (Chinese cabbage, radish etc) intake of the supplementation group was significantly higher than in the dropout group five years after supplementation. Change in total vegetable intake showed a 72.7 g/day increase in the supplementation group and a 18.1 g/day increase in the dropout group.
There were no substantial adverse effects of vitamin C supplementation (high and low dose) such as pain and flatulence of abdomen, nausea and vomiting which were monitored by questionnaire at three-month intervals.
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DISCUSSION
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The results of the present study indicated that the serum vitamin C concentration only in the high-dose group (500 mg daily) was markedly increased at one year (31.4 µmol/L increase) and after five years (21.3 µmol/L increase) of vitamin C supplementation. The previous study [20] reported that the change in serum vitamin C was 20.1 µmol/L after two-month supplementation of vitamin C (500 mg daily). Our previous pilot study [11] with 1000 mg daily of vitamin C for three months revealed a highly significant increase in serum vitamin C (64.2 µmol/L) due to the vitamin C supplementation. The results of these two earlier studies [11,20] corroborate the similar increase observed in the present study, even though the duration of supplementation in these studies was much shorter than in our study. The EPIC-Norfolk prospective study [21] suggests that the 20 µmol/L rise in plasma ascorbic acid concentration, equivalent to about a 50 g per day increase in fruit and vegetable intake, was associated with about a 20% reduction in risk of all-cause mortality (p < 0.0001). A prospective cohort study [1] in China, in which the highest tertile of serum concentration of ascorbic acid at baseline was associated with a reduced risk of progression to dysplasia or gastric cancer (OR = 0.2, 0.1–0.7, p for trend = 0.006) compared with subject with the lowest tertile level. In the present study, the mean serum vitamin C concentration at five years in the high-dose group (21.3 µmol/L increase) was over 85 percentile of baseline serum vitamin C. Based on previous study [1,21], our finding suggests that the increase in serum vitamin C afforded by 500 mg vitamin C supplementation for five years might have clinical and public health implications.
Unlike ß-carotene [11], the concentration of ascorbic acid in the plasma and other body fluids does not increase proportionally as the daily oral dose of vitamin C is increased. Blanchard et al. [22] suggest that both saturable gastrointestinal absorption and nonlinear renal clearance of ascorbate act additively to produce the ceiling effect in plasma concentrations. As a consequence of this ceiling effect, the serum vitamin C concentration tends to approach an upper limit. An NIH study [23] of vitamin C depletion-repletion pharmacokinetics, in which vitamin C doses ranging from 30 to 2500 mg daily, showed a sigmoid relationship between the ascorbate dose and the steady-state plasma concentration. The plasma concentration produced by the present RDA (60 mg/day) was on the bottom third of the steep portion of the curve; the 200-mg dose was beyond the steep portion, and plateau plasma vitamin C was close to maximum at 500 mg daily. Plasma vitamin C completely saturated at the 1000 mg daily dose. In most randomized clinical trials of vitamin C, there was no apparent adverse effect of a higher dose of vitamin C (less than 1000 mg daily). The recommended daily allowance of vitamin C was 50 mg according to the Ministry of Health and Welfare of Japan at the time of designing this study [24]. As a prophylactic antioxidant we chose to administer ten times the daily dose recommended in Japan and gave 500 mg ascorbic acid in capsule form. This amount of vitamin C is half of that we tested in a pilot study [11], in which no adverse effect was observed from taking 1000 mg of vitamin C. Data from other large intervention trials, with higher doses of vitamin C, suggest that there was no information about the potential hazards of less than 1000 mg daily [11,23].
According to several cross-sectional studies, circulating concentration of vitamin C is known to be influenced by multiple dietary factors and lifestyle factors, including gender, age, smoking status, alcohol consumption and dietary intake of vitamins and fruits and vegetables [9,25,26]. Moreover, in a three-month vitamin C supplementation study [11], it was reported that vitamin C supplementation and serum vitamin C concentration at baseline were associated with a change in serum vitamin C concentration. In our multivariate regression analysis, after the adjustment for suspected confounding factors, we found that the serum vitamin C concentration at baseline, female gender, and vitamin C supplementation significantly correlated with the change in serum vitamin C concentrations. Contrary to the observational cross-sectional studies, cigarette smoking, alcohol drinking and age were not associated with the change in serum vitamin C concentrations after vitamin C supplementation.
The present result clearly showed a reduced range between the mean values of the highest and the lowest quartiles of the baseline concentration of serum vitamin C after the one- and five-year interval, respectively. These findings suggest that the observed five-year change in serum vitamin C may largely reflect the regression to the mean effect in addition to supplementation of vitamin C and the real yearly biological change. The measurement error and the physiological fluctuation may be major causes for the regression to the mean within the intra-individual changes in biomarkers during a particular time interval. Moreover, the regression to the mean effect resulting from these unintentional factors may inevitably introduce the regression dilution bias for risk assessment in a cohort study setting the biomarkers as risk factors at baseline [27]. This phenomenon has been reported in other studies regarding the serum cholesterol concentration [28] as well as in our previous pilot study [11]. Owing to the regression to the mean effect, single measurement of serum vitamin C is not a good biomarker for dietary intake of vitamin C in either a supplemented or even an unsupplemented group.
Furthermore, we investigated the effect of the long-term vitamin C intervention program on consumption of vegetables and fruits. During the trial, the supplementation group, defined as receiving either low-dose or high-dose vitamin C for five years, demonstrated a substantial increase in vegetable intake, especially pickled and other vegetable (Chinese cabbage, radish etc.), compared to the dropout group. Also, the dietary intake of vitamin C of the supplementation group was almost identical before and after five years, and a 2.31 mg/day decrease was observed in the supplementation group, against a 17.7 mg/day decrease in the dropout group. After vitamin C supplementation, the dietary vitamin C intake of the supplementation group (144 mg/day) was significantly (p < 0.05) higher than that of the dropout group (116 mg/day). In general, subjects who participate in a dietary supplementation program reportedly do not increase or even decrease their dietary intake [29]. Our intervention study was conducted in a selective group of motivated individuals (participation rate 78%), just like most intervention trials. The subjects took part in an annual health screening program, in which all participants in this study were diagnosed with chronic atrophic gastritis and may have been aware that they had a higher risk of developing gastric cancer. Consequently, participants, especially in the supplementation group (not in the dropout group), may have been particularly receptive to making dietary changes compared to the general population. Such dietary change results in increases in vegetable intakes. Therefore, this result suggests that our long-term intervention program may have no negative effect on consumption of vegetables high in vitamins, as different from any other intervention study.
The possible limitation of the present study is that our study subjects were serologically diagnosed with atrophic gastritis. More than half (52%) of screening participants were matched with this criterion. The prevalence of atrophic gastritis increased with age: 37% in 40–49 years, 52% in 50–59 years and 63% in 60–69 years. Therefore chronic atrophic gastritis was not especially prevalent in this area and is considered an aging phenomenon. The prevalence of atrophic gastritis was 55.4% (866/1,564) among screening program participants 40 to 59 years of age in another area within the same Yokote Public Health Center district (unpublished data). Moreover, the prevalence ranged from 9% to 27% among randomly selected men 40 to 49 years of age in five areas across Japan [30]. The highest prevalence was observed in the Yokote Public Health Center district (26%) and even in Tokyo (27%). Although the prevalence of atrophic gastritis was relatively higher than that in other areas, our study subjects were not a specially selected group in Japan. Nevertheless, there is a possibility that the effect of vitamin C supplementation on the serum vitamin C level may be different from the normal population. However, even though gastric juice concentrations were considerably lower in patients with atrophic gastritis than in patients with normal histological assessment, the plasma and mucosal concentrations were unaffected by the presence of atrophic gastritis [31].
In conclusion, the results of this study show that a five-year oral vitamin C supplementation (500 mg daily) of a diet in subjects with atrophic gastritis induces a remarkable increase in serum vitamin C concentration and that our intervention program appears to have no effect on consumption of vegetables high in vitamins. Whether changes in the serum concentration of vitamin C have an effect on cancer risk remains to be established.
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ACKNOWLEDGMENTS
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This study was supported in part by Grants-in-Aid for Cancer Research and for the Second-Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labor and Welfare of Japan and by the Foundation for the Promotion of Cancer Research, Japan. We are grateful to the following persons for their painstaking efforts in initiating, maintaining, modifying and setting the two study protocols: Dr. Yoshitaka Tsubono of the Division of Epidemiology, Tohoku University Graduate School of Medicine, Ms. Kaori Masugi, Mr. Takashi Sato, Dr. Tadashi Ogiwara, and other staff members at the Hiraka General Hospital, Ms. Kumiko Sasaki, Ms. Mikiko Takahashi, Mr. Shigeru Fujita, Mr. Seiji Fujita, and Mr. Shozo Sasaki (Mayor) of Sannai Village; Ms. Shizuko Kasuga, Ms. Masako Takahashi, Mr. Hiroyasu Kikuchi, Dr. Noriyuki Suzuki (director) and Dr. Yoshimichi Miyajima (former director) and Dr. Shinsuke Nagasawa (former director) of the Yokote Public Health Center; Dr. Kiyoshi Higuchi, former president of the Hiraka Medical Association; Dr. Rokuya Ishida, former president of the Hiraka Medical Association.
Received June 17, 2002.
Accepted November 11, 2002.
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ABSTRACT
INTRODUCTION
