Distinct mutational spectrum of the p53 gene in lung cancers from Chinese women in Hong Kong.

Accumulating evidence suggests that the p53 gene is a good target for molecular epidemiological studies to search for risk factors in carcinogenic events. The lung cancer incidence for females in Hong Kong is unusually high, ranking among the highest in the world despite a low percentage with a history of smoking. To gain insights into possible etiological risk factors responsible for this high incidence, we examined p53 mutations in 35 lung cancer specimens from Chinese females living in Hong Kong and compared them with 35 matched cases from Japanese women as well as previously reported p53 mutations in the world literature. p53 mutations in exons 5-8 were present in 20 and 31% of the Hong Kong and Japanese cases, respectively. Notably, single-base deletions within runs of identical bases were observed in 3 (43%) of the 7 mutations in the Hong Kong cases, in contrast to the absence of such mutations in the controls and the extreme scarcity in the literature, suggesting that distinct environmental and/or genetic factor(s) might be involved. Although the frequent occurrence of characteristic single-base deletions could be a reflection of mutator mutations leading to inefficient mismatch repair of slipped strand mispairings, none of the lung cancer specimens exhibited such microsatellite instabilities.

Birthplace and yield of nipple aspirate fluid in Chinese women.

The different rates of breast cancer found between Chinese women in Asia compared with Chinese-born women in the United States suggest that dietary and environmental factors may be of etiological significance. We evaluated the proportion of 480 premenopausal Chinese women who yielded nipple aspirate fluid (NAF) by birthplace in Asia versus the United States and by reproductive and other risk factors. Birthplace was used as a surrogate for presumed differences in exposures during gestation, childhood, and adolescence that might influence yield of NAF in premenopausal women. In United States-born Chinese women compared with Asia-born Chinese women, the proportion yielding NAF was 44 of 95 (46.3%) versus 120 of 385 (31.2%), respectively. The relative risk of yield of NAF in United States-born women compared with Asia-born women was odds ratio = 2.37 (95% confidence interval, 1.26-4.47). Independent positive associations of NAF yield were also found with history of parity and breast feeding, cerumen phenotype, and a negative association with ever use of oral contraceptives. These findings support the hypothesis that early environmental exposures may have long-lasting physiological effects discernible in the breast glands of adult women.

Improved nutrition after the detection and treatment of occult gastroparesis in nondiabetic dialysis patients.

Malnutrition in dialysis patients is of multifactorial etiology and is associated with greatly increased morbidity and mortality. A low serum albumin level is one of the most powerful predictors of death and may persist despite optimization of the dialysis prescription. We retrospectively reviewed our experience in improving nutrition in nondiabetic patients with unexplained hypoalbuminemia. Using radionuclide solid-phase gastric emptying scans, we identified 6 patients who had occult gastroparesis. These patients (one on hemodialysis and five on peritoneal dialysis) were then treated with prokinetic medications (erythromycin elixir or metoclopramide) selected on the basis of their effectiveness in improving the scanning results after being given intravenously. Gastric emptying half-times improved from a median of 122 minutes (range, 95 to >300 minutes; normal, < or = 90 minutes) to 12 +/- 2 minutes (mean +/- SEM). The serum albumin increased from 3.3 +/- 0.04 g/dL to 3.7 +/- 0.08 g/dL at 3 months, with every patient's value higher than 3.5 g/dL. This improvement was statistically significant (P = 0.008) over the 5-month period of observation, which encompassed the 2 months before and 3 months after treatment. There was a linear improvement (P = 0.008) that showed a quadratic trend (P = 0.078) for a plateau at the final sampling point. The serum blood urea nitrogen, creatinine, and hematocrit levels remained unchanged (P > 0.1). We conclude that gastric emptying scans are valuable in identifying occult gastroparesis in high-risk patients and can guide the selection of prokinetic therapy, which may significantly increase serum albumin levels.

Diet as a confounder of the association between air pollution and female lung cancer: Hong Kong studies on exposures to environmental tobacco smoke, incense, and cooking fumes as examples.

Chinese females in Hong Kong, where only about a third of the lung cancer cases can be attributed to a history of active smoking, have a world age-standardized lung cancer incidence rate of 32.6 per 100 000, which is among the highest in the world. Trends in Hong Kong's female lung cancer mortality also indicate a tripling in mortality rates from 1961 to 1990. The characteristically high Chinese female lung cancer incidence among nonsmokers is also found among overseas Chinese communities in Singapore and Hawaii. To help elucidate the role of ingested and inhaled substances in the etiology of lung cancer, four epidemiological studies have been conducted in Hong Kong over the last 15 years: (1) a retrospective study of 200 cases and 200 neighbourhood controls, (2) a cross-sectional study measuring personal exposures to nitrogen dioxide among 362 children and their mothers, (3) a site monitoring study of 33 homes measuring airborne carcinogens, and (4) a telephone survey of 500 women on their dietary habits and exposure to air pollutants. Selected data from each study were drawn to evaluate exposures to three major air pollutants (environmental tobacco smoke, incense, and cooking fumes), their relationship with lung cancer risk, and their association with dietary habits. Generally in this population, nutritionally poorer diets were characterized by higher consumption of alcohol and preserved/cured foods, whereas better diets were characterized by higher intakes of fresh fruits, vegetables, and fish. For environmental tobacco smoke, exposure was only moderately high in Hong Kong (36% have current smokers at home), lung cancer risk was equivocal with exposure, and it was associated with poorer diets among wives with smoking husbands. Incense was identified as a major source of exposure to nitrogen dioxide and airborne carcinogens, but it had no effect on lung cancer risk among nonsmokers and significantly reduced risk (trend, P-value = 0.01) among smokers, even after adjusting for smoking. The last finding may be explained by the relatively better diets among smoking women who burned incense versus those who did not. Although about 94% of the Chinese women cook on a regular basis, and the cooking fires were associated with increased airborne carcinogens, nonsmoking women who cooked for more than 25 years had a 60% reduction in lung cancer risk and the trend was highly significant (P < 0.001). Again, this unexpected finding may be due to the confounding effects of diet. Female controls who cooked for more than 25 years had a poorer diet than those who cooked for shorter durations. These three examples were chosen to illustrate the complexities of assessing air pollution exposure, and understanding the behavioral and dietary dynamics underlying lung cancer risk assessments. Our conclusion is that diet can be an important confounding factor affecting lung cancer risk estimates from air pollution exposures among Chinese women living in an affluent urban environment.

Risk factors associated with lung cancer in Hong Kong.

The purpose of this study was to investigate the risk factors associated with lung cancer in Hong Kong. Three hundred and thirty-one histologically or cytologically proven consecutive cases of lung cancer and the same number of in- and out-patients without cancer matched for age and sex were recruited for this study using a detailed questionnaire completed by a trained interviewer. Smoking was the most important risk factor associated with lung cancer but the attributable risk (AR) was estimated to be 45.8% in men and 6.2% in women, considerably lower compared with those estimated in early 1980s. In addition, among women, exposure to environmental tobacco smoke (ETS) at work+/-at home and lack of education, were independent risk factors for lung cancer with adjusted odds ratio (OR) 3.60, (95% confidence interval (CI) 1.52-8.51) and OR 2.41 (95% CI 1.27-4.55), respectively. Among men, exposure to insecticide/pesticide/herbicide, ETS exposure at work or at home, and a family history of lung cancer and were independent risk factors with adjusted OR 3.29 (95% CI 1.22-8.9, OR 2.43, 95% CI 1.24-4.76 and OR 2.37, 95% CI 1.43-3.94, respectively). Exposure to incense burning and frying pan fumes were not significant risk factors in both sexes. A moderate or high consumption of fat in the diet was associated with increased risk in men but decreased risk in women. The results of this study suggested that as the prevalence of smoking declined, the influence of smoking as a risk factor for lung cancer decreased even further. Moreover, the contribution of other environmental, occupational and socioeconomic factors may be more apparent as etiological factors for lung cancer in a population with relatively high lung cancer incidence but low AR from active smoking.

Worldwide epidemiological patterns of lung cancer in nonsmokers.

A review of published reports on lung cancer was done to describe its worldwide epidemiological pattern and to elucidate the contribution of smoking and nonsmoking risk factors in its aetiology. Among lung cancer patients, roughly 98% of males worldwide, and 70-90% of European and American females, reported a history of smoking. Asian women had much lower (6-57%) rates of smoking. Mortality rates among female nonsmokers showed about a four-fold difference, being lowest in India and Japan, intermediate in the USA, and highest among the Chinese. There was some indication that incidence rates among nonsmokers may have increased in some societies in this century. The usefulness of histological comparisons among nonsmokers seemed limited since its distribution did not vary by place or ethnicity; about 70% were adenocarcinomas. In Western populations, younger lung cancer patients were more likely to have been smokers, whereas the opposite was true in Asian populations. Thus the epidemiological patterns of lung cancer in Western and non-Western societies are likely to be different, with nonsmoking risk factors being more important among women in general, and Asian women in particular.

Concepts of disease causation, treatment and prevention among Hong Kong Chinese: diversity and eclecticism.

The health beliefs, knowledge, and choices of therapeutic intervention for 25 common ailments were described and analyzed for the Chinese in Hong Kong. Acceptance of the co-existence of the ideas and treatment regimens from both Western and Chinese medical traditions were prevalent. For health problems in which Western medicine has already isolated a specific causative agent or developed effective treatment or preventive methods, many informants were familiar with these biomedical concepts, and even more expressed willingness to use these methods to alleviate their symptoms. In addition, however, there was a group of views on causation, treatment, and prevention that arose from folk observations or Chinese classical medicine that supplemented the views imported from the West. This occurred when the etiological factors for specific health problems were not well understood or identified in biomedicine, or when other environmental factors, usually attributed to 'lifestyle', were identified by informants as mediating factors affecting risk for disease from the individual's point of view. These latter views helped explain why some become ill and others do not, although all may have been exposed to the same etiological agent identified in biomedicine.

The use of food to treat and prevent disease in Chinese culture.

Interviews of 50 Chinese families in Hong Kong in 1981 indicated that the proper selection, timing and preparation of food was the most salient lay method of dealing with the prevention and treatment of some 59 common symptoms and illnesses. The food prescriptions and proscriptions were based on the traditional concept of maintaining body homeostasis through avoidance of: (1) excess 'hot'/'cold' or 'wet'/'dry' qualities of body energy; (2) disturbance of energy flow; or (3) inadequate energy levels. Various health problems were classified as being due to imbalances of these energy states. Excess 'hot'/'cold' or 'wet'/'dry' ailments were dealt with by increased consumption of foods of the opposite character; those due to disturbance of the normal flow of energy was avoided by the reduced intake of 'irritating' or 'poisonous' foods; and various tonics were believed to raise the amount of energy flow in the body. A rich knowledge of complex dietary rules was found to be prevalent among the lay public because the traditional rules filled explanatory and behavioural niches left open in Western medicine. Dietary manipulation was used to complement Western medicine in the multiple stages of the disease process by playing a predominant role at the beginning and end of the period of pathogenesis.

Life-history correlates of environmental tobacco smoke: a study on nonsmoking Hong Kong Chinese wives with smoking versus nonsmoking husbands.

Studies to evaluate the effects of environmental tobacco smoke (ETS, passive smoking) often use nonsmoking wives with smoking discordant husbands. To see whether there were differences in exposures and behavior patterns among never-smoked wives with never-smoked vs ever-smoked husbands, the life-history profiles of 136 ever-married women with mean age of 59 were analyzed on 97 quantifiable variables. Overall, the results demonstrated that wives with never-smoked husbands had 'healthier' lifestyles than wives with smoking husbands. The former were better off in terms of socio-economic status, more conscientious housewives, ate better diets, and had better indices of family cohesiveness. They also fared better in variables that reflected health status with lower frequencies of the following: miscarriages/abortions, inhaling through the mouth, chronic cough, and chest X-rays. The differences were usually largest when comparing wives of never-smoked vs heavily smoking (greater than 20 cigarettes/day) husbands. The results indicate some correlates of passive smoking that can act as important confounders when evaluating health risks among families with smoking husbands.

Dietary and lifestyle correlates of passive smoking in Hong Kong, Japan, Sweden, and the U.S.A.

From epidemiologic studies in several countries, passive smoking has been associated with increased risk for lung cancer, respiratory diseases, and coronary heart disease. Since the relative risks derived from those studies are weak, i.e. relative risk less than two, we investigated whether poorer diets and less healthy lifestyles might act as confounders and be correlated with having a smoking husband on a cross-cultural basis. Characteristics of never-smoked wives with or without smoking husbands were compared between 530 women from Hong Kong, 13,047 from Japan, 87 from Sweden, and 144 from the U.S. In all four sites, wives with smoking husbands generally ate less healthy diets. They had a tendency to eat more fried food but less fruit than wives with nonsmoking husbands. Other healthy traits, e.g. avoiding obesity, dietary cholesterol and alcohol, or taking vitamins and participating in preventive screening were also less prevalent among wives with smoking husbands. These patterns suggest that never-smoked wives with smoking husbands tend to share the same less healthy dietary traits characteristic of smokers, and to have dietary habits associated with increased risk for lung cancer and heart disease in their societies. These results emphasize the need to take into account the potential confounding effects of diet and lifestyle in studies evaluating the health effects of passive smoking, especially since it is known that the current prevalence rates of smoking among men is indirectly associated with social class and education in affluent urban societies.

Strategy for the treatment of noncompliant hypertensive hemodialysis patients.

Hypertensive hemodialysis patients noncompliant for their medications do not benefit from pharmacologic advances in the treatment of high blood pressure, and increase their already high risk of cardiovascular complications. The medical staff often becomes frustrated by severe hypertension in those who refuse to take medicines at home, drink excessive fluids, miss multiple dialysis sessions and sign-off dialysis early. In addition to addressing the psychosocial, financial, educational and substance abuse problems which contribute to noncompliance, we have developed a medication strategy to serve as an at least interim means of lowering blood pressure. Antihypertensive agents which have long half-lives in renal failure (lisinopril) and/or are intrinsically long acting (transdermal clonidine and amlodipine) were administered on dialysis days by the unit personnel to those patients who did not or would not take that or any dose on their own. The lisinopril and amlodipine were assured to have been taken on at least the dialysis days (thrice weekly), and the clonidine patch replaced weekly. Sixteen patients were thus treated when they failed to reliably self-administer medications. They had a significant decline in the predialysis systolic pressure of 15 mm Hg (175 +/- 6 to 160 +/- 5 mm Hg), diastolic of 12 mm Hg (103 +/- 3 to 91 +/- 3 mm Hg), and mean pressure of 13 mm Hg (127 +/- 4 to 114 +/- 4 mm Hg). There was an improvement in post-dialysis bood pressures, with the mean pressure declining 13 mm Hg from 110 +/- 4 to 97 +/- 4 mm Hg. Many individuals had erratic blood pressure control, having intermittently missed dialysis and hence unit-administered medicine, as well as continued fluid or drug abuse. The patients had uniformly excellent acceptance of this regimen, even spontaneously requesting it, and had no appreciable adverse effects. In summary while noncompliance is being addressed by the entire medical team, dialysis unit administration of long-acting medicines helps many hypertensive dialysis patients who would otherwise be at increased risk for severe cardiovascular complications.

Diet and lung cancer 20+ years later: more questions than answers?

A critical review of epidemiological studies on diet and lung cancer over the last 20+ years has not provided overwhelming evidence that higher consumption of vegetables, fruit, low-fat/low-cholesterol foods or such micronutrients as carotenoids, selenium and vitamins A, C or E is associated with reduced lung cancer risk. Results from case-control studies have been more positive, with about one half showing fruit and vegetables or their associated micronutrients to be associated with reduced risk. However, most results from cohort and serum micronutrient studies, which avoid the problems of inaccurate accounting of diet and recall bias, were statistically insignificant. Moreover, although most studies were conducted on white male smokers in North America and Europe, the few studies which found significant contrary trends were among subjects of different backgrounds, i.e., black American males and Chinese women in China. Since male smokers vs. nonsmokers in Europe, North America and Japan have been shown in other studies to be lower consumers of fruit/vegetables, and less likely to pursue "perceived healthier lifestyles," the possibility that some of the epidemiological findings on diet and lung cancer are artifactually due to inadequate adjustment for behavioral correlates of smoking and health seekers in a particular society must be considered. This is especially true with recent chemoprevention trials showing higher lung cancer incidence and deaths among consumers of beta-carotene supplements vs. placebo.

Dietary habits and lung cancer risk among Chinese females in Hong Kong who never smoked.

This describes a retrospective study in which 88 lung cancer patients and 137 district-matched controls were interviewed concerning the effects of diet on lung cancer risk among Hong Kong Chinese women who never smoked tobacco. Those in the lowest tertile of consuming fresh fruit or fresh fish had statistically significant adjusted relative risks (RRs) of 2.4 and 2.8, respectively. The protective effects of diet, i.e., higher consumption of leafy green vegetables, carrots, tofu, fresh fruit, and fresh fish, were confined mostly to those with adenocarcinoma or large cell tumors. Only fresh fruit was found to positively, and smoked meats to negatively, affect the risk of squamous or small cell tumors. Foods high in vitamin C, retinol, and calcium seemed to exert larger effects. Subjects from larger households were shown to be more frequent consumers of fresh vegetables, fruit, and fish. Because the lifetime weighted household size could be used as a surrogate index of past dietary quality, when it was combined with current dietary intakes of fresh fruit, the RR increased as either factor decreased in a dose-response manner. The adjusted RR was 5.8 at the lowest level. Further testing of the validity of the lifetime weighted household size as an index of past dietary quality is needed.

Do cooking fuels pose a risk for lung cancer? A case-control study of women in Hong Kong.

Two hundred female lung cancer patients and 200 female district controls in Hong Kong were interviewed about their previous use of various types of cooking fuels to assess whether any association could be found with lung cancer risk. Mixed results were found when the data were analyzed in terms of ever-exposed vs never-exposed duration, and relationship with smoking. Cases were found to have slightly more exposure to kerosene, whereas controls were likely to have used the cleaner, but more expensive, liquid petroleum gas (LPG) type of fuel. Because the evidence was conflicting if evaluated in terms of consistency, strength, specificity, and coherence of the associations, it was concluded that the small differences in exposure levels between the cases and controls probably reflected their socio-economic circumstances rather than risk for lung cancer. No interaction effect was found between kerosene exposure and smoking.

An analysis of some risk factors for lung cancer in Hong Kong.

Lung cancer has been the major cause of cancer death in Hong Kong for more than a decade. Although it is known that some 95% of male cases can be attributed to smoking, the etiological factors in women remain elusive. Among "never-smoked" female cases, increases in attributable risk from passive smoking were limited to only some of the histological types of lung carcinomas, and an overall analysis of all types did not reveal any significant increase in relative risk from this source. Other environmental factors which encourage bronchial irritation are suspected. Methodological differences may explain the differences in proportional distributions of histological lung tumor types noted between previous reports, and the risk values attributed therein to active and passive smoking.

Factors affecting breast-feeding among Hong Kong Chinese.

PIP: 413 mothers attending maternal and child health (MCH) clinics located throughout Kowloon and Hong Kong Island were surveyed in the summer of 1983 to evaluate the impact of programs to promote breastfeeding and to facilitate understanding of other social, cultural, economic, attitudinal, or hospital factors which may influence the choice of infant feeding patterns among postnatal mothers. The interviews were limited to mothers who had given birth within the last 2 years. The mothers ranged in age from 17-42 years. Of the total sample of 413 babies, 116 (28.1%) had been breastfed at least once, and these infants were counted as incidence cases. Among these 116 breastfed infants, the duration of breastfeeding was estimated among 88 of the infants whose breastfeeding had ceased. The remaining 28 were excluded from the analysis because they were still young and breastfeeding was continuing at the time of the interview. The mean duration of breastfeeding was 10 weeks but about 1/3 of these babies had been breastfed for less than 1 week. 61% of the breastfed babies stopped breastfeeding after 1 month of age; only 11 babies had been breastfed for over 6 months. There was no difference in the incidence or duration of breastfeeding among male and female infants. The incidence of breastfeeding was found to be directly related to increasing levels of education in either parent. The middle income group had both the lowest incidence and shortest duration of breastfeeding in comparison with other groups. Although the incidence of breastfeeding was highest among the highest income group, only 11.1% had the infant breastfeeding for 7 or more weeks. Breastfed infants in the families with the lowest income level had some 51.7% of their breastfed infants feeding on the breast for more than 7 weeks. Approximately 30% of the mothers believed that breast milk was superior to infant formulas, and 2/3 of these mothers actually breastfed their babies. The lowest rates for breastfeeding (14.1%) occurred in hospitals where mothers and newborns were separated and the latter were fed on a scheduled basis. The most conducive environment was where infants were fed on demand and mothers and infants stayed in the same room.^ieng

Altered state of consciousness in a compulsive water drinker.

A relatively normal 16-year-old Chinese woman with a six-month history of compulsive water drinking resulting in a comatose state is reported. The drinking was perpetuated by an enjoyable altered state of consciousness after ingestion of an average of 20 litres of water per day. Treatment by fluid restriction and, later, simple education was successful. The subjective dimension of an altered state of consciousness may provide an important explanation for the obscure aetiology.

An ecological study of trends in cancer incidence and dietary changes in Hong Kong.

Cancer incidence rates from the Hong Kong Cancer Registry show significant increases in lung and colon cancers and decreases in nasopharyngeal cancer in both sexes from 1973 to 1992. Moreover, cervical cancer and male esophageal cancer have declined significantly, and changes in the trends of cancer of the following sites were of borderline significance: decreasing male laryngeal and female esophageal cancers and increasing prostate and female breast cancers. These changes have occurred along with dietary shifts in the population, from a diet predominantly of rice and small portions of meat, vegetables, and fish to one with larger portions of all foods but rice and eggs. The latter data were gathered from six government household surveys from 1963-64 to 1994-95. By combining the two data sets, correlation coefficients were calculated for per capita consumption patterns of eight foods (rice, pork, beef, poultry, saltwater fish, freshwater fish, fresh vegetables, and eggs) and cancer incidence data of the same year or 10 years later. Higher meat intakes were significantly and positively correlated with cancers of the colon, rectum, prostate, and female breast. The correlations also suggested that current diets were more influential than diets a decade before for cancers of the lung, esophagus, rectum, and prostate. Cancers of the nasopharynx and colon were significantly correlated with current and past diets. These results support the hypothesis that intakes of meat and its associated fat are risk factors for colon, rectal, prostate, and female breast cancers.

Low whole blood and erythrocyte levels of glutathione in hemodialysis and peritoneal dialysis patients.

Dialysis patients are reported to have impaired antioxidant mechanisms, including those involving glutathione-dependent enzymes. This study used high-performance liquid chromatography assays that directly measure total (oxidized + reduced) glutathione and its precursor cysteine (CYS) to compare the whole blood of hemodialysis (prehemodialysis and posthemodialysis) and peritoneal dialysis patients to that of blood donors with no known kidney disease (n=20 in each group). The levels in erythrocytes were calculated from that data (as nmol/g hemoglobin) because these cells are the major compartment of blood glutathione and their survival may be shortened by oxidant damage. Both dialysis groups had significantly (P=0.0001) higher CYS levels in the plasma compartment than the controls (251 nmol/mL), with prehemodialysis levels (432 nmol/mL) being greater than peritoneal dialysis levels (334 nmol/mL). Hemodialysis acutely lowered CYS levels (215 nmol/mL) below those of controls. Expressed per milliliter whole blood, both dialysis groups had significantly (P=0.0001) lower glutathione levels than controls (1,276 nmol/mL), with prehemodialysis and peritoneal dialysis levels being similar (778 and 912 nmol/mL). Values increased prehemodialysis to posthemodialysis, consistent with hemoconcentration. Expressed per gram hemoglobin, the dialysis groups had significantly (P < 0.015) lower glutathione levels than the controls (8,938 nmol/g hemoglobin), with similar prehemodialysis, posthemodialysis, and peritoneal dialysis values (7,207, 7,315, and 7,915 nmol/g hemoglobin, respectively). In summary, hemodialysis and peritoneal dialysis patients are at increased risk from oxidative stress due to glutathione deficiency in whole blood and erythrocytes.

Lung cancer risk and mutagenicity of tea.

To study the possible association between drinking tea and lung cancer, epidemiological and experimental materials were collected from the Chinese population in Hong Kong. In a retrospective study of 200 female lung cancer patients and 200 matched controls, all subjects were interviewed concerning their eating habits, smoking histories, and lifetime exposures to environmental pollutants. Analysis of the data demonstrated an adjusted and statistically significant increased lung cancer risk of 2.7 among those who drank green tea. Several brands of tea commonly drank in Hong Kong were assayed for mutagenicity using Ames' assay. Significantly elevated levels of mutagenic activity were found to be present after metabolic activation using cell-free extracts of cecal bacteria from rats. These data suggest that further research is needed to understand the possible consequences to human health of ingestants taken at low doses but long duration over the normal lifespan, and the possible interactive effect between mutagens in tea and other ingestants and inhalants in human cancer etiology.