Modeling the impact of changes in tobacco use on individual disease risks.

Reduced Risk Products (RRPs) do not burn tobacco and produce lower levels of toxicants than in cigarette smoke. The long-term effects of using RRPs on health are difficult to assess in a pre-market setting and a modeling approach is required to quantify harm reduction. The Population Health Impact Model (Weitkunat et al., 2015) follows a hypothetical population of individuals over time, creating their tobacco use histories and, based on these, estimating relative and absolute risks of lung cancer, ischemic heart disease, stroke and chronic obstructive pulmonary disease. Linking the tobacco use to the risk profile allow us to assess how the relative and absolute risks of these diseases vary between individuals aged 20, 30, 40 or 50 at baseline who have never smoked or who initiated smoking at 19 years old and either continued to smoke, quit smoking, or switched to RRPs with varying degrees of harm reduction. The simulations suggest that, for smokers in their 20s-30s quitting, or switching to RRP primarily prevents the accrual of risk, while in their 40s-50s it reduces risk. Though tobacco prevention has been the primary approach to limit smoking-related diseases, RRPs can also substantially reduce risks in individuals who do not quit.

Daytime sleepiness and sleep quality among Malaysian medical students.

Poor sleep quality and daytime somnolence is reported to be associated with cardiovascular events, road traffic accident, poor academic performance and psychological distress. Some studies documented that it is prevalent in most populations but its frequency among medical students has not been documented in Malaysia. This is a self-administered questionnaire survey of medical students from International Medical University, Malaysia. Daytime sleepiness of medical students was assessed using Epworth Sleepiness Scale (ESS). Student scoring ESS > 11 was regarded as having excessive daytime sleepiness. Psychological distress was measured using 12-item General Health Questionnaire (GHQ-12). A total of 799 medical students participated in this survey (response rate 69.5%). Daytime sleepiness occurred in 35.5%, psychological distress was present in 41.8% and 16.1% reported bad sleep quality. Daytime sleepiness was significantly more common among the clinical students, those with self-reported bad sleep quality and psychological distress; but unrelated to the number of hours sleep at night. We have documented high prevalence of daytime sleepiness, poor sleep quality and psychological distress. Higher frequency among clinical students and the significant relationship with psychological distress suggest possible link to the stressful clinical training.

Pax6 in the sepiolid squid Euprymna scolopes: evidence for a role in eye, sensory organ and brain development.

The cloning of a Pax6 orthologue from the sepiolid squid Euprymna scolopes and its developmental expression pattern are described. The data are consistent with the presence of a single gene encoding a protein with highly conserved DNA-binding paired and homeodomains. A detailed expression analysis by in situ hybridization and immunodetection revealed Pax6 mRNA and protein with predominantly nuclear localization in the developing eye, olfactory organ, brain lobes (optic lobe, olfactory lobe, peduncle lobe, superior frontal lobe and dorsal basal lobe), arms and mantle, suggestive of a role in eye, brain, and sensory organ development.

Accuracy of admission and clinical diagnosis of tumours as revealed by 2000 autopsies.

Admission, clinical and autopsy diagnoses of tumour were computed in 2000 consecutive cases, aged 30-80 years, using data collected in two university pathology departments in Budapest, Hungary. Based on diagnosis of tumour, regardless of site, as the underlying cause of death false-negative rates were 37.4% at admission and 8.8% clinically. Corresponding false-positive rates were 8.4 and 9.1%. General practitioners who correctly diagnosed a tumour as the cause of the terminal illness identified the primary site wrongly in 20.6% (90/436) of cases. Hospital clinicians did so in 20.4% (130/636) of cases. Overall, of site-specific tumours considered as the underlying cause of death at autopsy, 27.4% were incorrectly diagnosed clinically and 50.4% at admission. Diagnostic errors were particularly common for tumours of the lung, liver, ovary and gall bladder. Graduate and postgraduate education, planning of the health care system and quality of cancer care may benefit from statistical data derived from autopsy diagnoses.

Atherogenesis in the White Carneau pigeon. Further studies of the role of carbon monoxide and dietary cholesterol.

Two experiments are described. In the first, 3 pairs of groups of 20 female White Carneau pigeons were fed on diets containing 0.5%, 1% or 2% cholesterol. Birds in one group from each pair were exposed to 150 ppm carbon monoxide (CO) for 6 h on 5 days of each week for 52 weeks, sufficient to raise their carboxyhaemoglobin (COHb) levels to approximately 10%, while those in the other group were sham-exposed under similar conditions. In the second experiment, 3 groups of 40 female pigeons were each fed on a diet containing 1% cholesterol, one group being exposed to CO to give COHb levels of 20%, one to give COHb levels of 10% and one being sham exposed. In addition, 20 birds in the second experiment were fed on the 1% cholesterol diet but were neither exposed to CO nor sham-exposed. Cholesterol enriched diets caused mean plasma cholesterol values in each group to rise sharply within 4 weeks of starting them, but the levels reached were as high with diets containing 0.5% cholesterol as for diets containing 1% or 2% added cholesterol. Exposure to CO increased plasma and aortic cholesterol levels, though this increase was only statistically significant for aortic levels in the second experiment. In both experiments combined exposure to the 1% cholesterol diet and CO resulted in a significant decrease in aortic triglyceride content. The incidence and severity of coronary artery atherosclerosis was associated with increasing dietary cholesterol. It was also associated with exposure to CO in birds given 0.5% or 1%, but not 2%, dietary cholesterol; the increase in birds given 1% was related to the dose of CO. Possible mechanisms are discussed for this effect of CO, which is not found in normally fed birds.

Intervention studies on cancer.

This paper (and an extensive supplementary report) considers how far cancer/risk factor associations based on epidemiology have been confirmed by evidence from 226 studies involving interventions other than smoking. Many are small, uncontrolled, of unrepresentative populations, concern cancer markers not cancer, and may involve combinations of agents. Many agents suspected of causing cancer are untested by intervention trials. For seven of 16 agents tested (fibre, folic acid, low-fat diet, riboflavin, zinc, vitamin Bs, and vitamin D), the evidence is clearly inadequate to confirm or deny the epidemiology, while the evidence relating to calcium only concerns biomarkers. For other agents, the evidence relating to cancer itself is weak. In studies where cancer is the endpoint, only three effects have been replicated: (a) selenium supplementation and decreased liver cancer incidence, (b) treatment by the retinoid etretinate and reduced bladder tumours in susceptible individuals, and (c) beta-carotene supplementation and increased lung cancer incidence. Studies involving pre-cancerous conditions as the endpoint, which have a number of practical advantages, more frequently report benefits of intervention. Thus, oral pre-cancerous lesions can certainly be reduced by beta-carotene, vitamin A, and other retinoids, and possibly by vitamin E. It also seems that retinoids can reduce pre-cancerous cervix, skin and lung lesions, that vitamin C and the NSAID sulindac can reduce colonic polyps, and that sunscreens can reduce solar keratoses. Our findings clearly show that the great majority of causal relationships suggested by epidemiology have not been validated by intervention trials. This may be partly due to lack of suitable studies of adequate size or duration, or to using single dietary compounds as agents that are by themselves not responsible for the epidemiologically-observed associations between diet and cancer. However, this lack of validation must cause concern in view of the markedly conflicting evidence on beta-carotene and lung cancer between epidemiological and intervention studies. More intervention studies are needed, but in their absence, caution in interpreting epidemiological findings is warranted.

Trends in cigarette consumption cannot fully explain trends in British lung cancer rates.

STUDY OBJECTIVES: To determine whether British lung cancer (LC) trends are adequately explained by cigarette smoking trends, and whether modelling using aggregated smoking prevalence estimates can validly replace modelling using individual smoking histories. METHODS: Observed LC trends for 1955-1985 for both sexes and three age groups were compared with multistage model predictions using smoking history data from two surveys (HALS, AHIP). The modelling used the individual smoking data directly or aggregated prevalence estimates. It allowed for variation in age of starting and stopping smoking, amount smoked, tar levels, and environmental tobacco smoke (ETS) exposure. RESULTS: Observed male LC rates fell faster than predicted by a model (with the first and penultimate stages assumed affected by smoking) that allowed for variation in amount smoked and in tar level (with some provision for "compensation"), and was based on aggregated smoking data from HALS. The discrepancy equated to an annual change unexplained by smoking of -2.4%, -2.8%, and -1.9% for ages 35-44, 45-54, and 55-64. The annual unexplained changes were less in women, and reversed at age 55-64; -1.7%, -0.8%, and +0.8% for the three ages. They were similar using individual smoking histories (-2.6%, -1.8%, and -1.6%; women, -0.9%, -0.5%, and +0.2%). The discrepancies were unexplained by plausible alternative multistage parameters, full allowance for tar reduction, alternative estimates of amount smoked, or ETS. CONCLUSIONS: British LC trends cannot be fully explained by cigarette consumption trends, implying factors other than cigarette smoking contribute importantly to overall risk. Predictions using aggregated prevalence estimates provide useful information.

Mortality and type of cigarette smoked.

Twenty-five years ago, cigarette smokers in the United Kingdom smoked plain cigarettes with an average tar yield of probably about 35 mg. Now smokers predominantly smoke filter cigarettes and average tar yields have been reduced by half. Epidemiological evidence comparing mortality in smokers of differing types of cigarettes is reviewed. Compared with smokers of higher tar plain cigarettes, smokers of lower tar filters cigarettes have a reduced mortality for lung cancer, for cancer of the buccal cavity, pharynx, larynx, oesophagus, and bladder, for chronic bronchitis and emphysema, and for cirrhosis of the liver. They also have a slightly significant. Problems of interpretation and limitations of the available evidence are discussed. No worthwhile evidence is yet available on smokers of "low tar' (0-10 mg) cigarettes and data are sparse on lifetime smokers of filter cigarettes. Continuing research is important to understand the situation fully, but the trends of lower mortality to be associated with lower tar and nicotine levels are promising.

Risks of lung cancer, chronic bronchitis, ischaemic heart disease, and stroke in relation to type of cigarette smoked.

In a case control study of over 12 000 inpatients aged 35-74, risk of lung cancer, chronic bronchitis, and, particularly in those aged 35-54, ischaemic heart disease was positively associated with the number of manufactured cigarettes smoked daily and was negatively associated with long term giving up. Risk of stroke was not clearly related to smoking. Among manufactured cigarette smokers, lung cancer risk tended to be lowest in those who had always smoked filter cigarettes. This pattern was, however, evident only in men who additionally smoked pipes, cigars or handrolled cigarettes and in women, not being seen in men who smoked only manufactured cigarettes. Risk of lung cancer was not clearly related to time of switch to filter cigarettes. A markedly lower risk of chronic bronchitis was seen in men, but not women, who smoked filter rather than plain cigarettes. Heart disease risk did not vary by type of cigarette smoked 10 years before admission, but, compared with those who had never smoked filter cigarettes, those who had ever smoked filter cigarettes had a higher risk in men and a lower risk in younger women. Compared with the general population, markedly more controls were ex-smokers, suggesting incipient disease, whether or not smoking related, may alter smoking habits, thus affecting the interpretability of the findings. Control smokers were also relatively much more likely to report smoking plain cigarettes than expected. This comparison, not made in other studies relating risk to type of cigarette smoked, indicates that great care must be taken in verifying validity of reported smoking habits. While our findings are compatible with other evidence that risk of lung cancer and chronic bronchitis is probably reduced by switching from plain to filter cigarettes, they underline the difficulties in obtaining valid evidence from epidemiological studies.

Lung cancer and passive smoking: association of an artefact due to misclassification of smoking habits?

1775 subjects were asked about their current use of tobacco products or nicotine chewing gum. 1537 provided a sample of saliva for cotinine analysis. Of 808 who claimed not to be users of such products, 20 (2.5%) had cotinine values above 30 ng/ml, suggesting their self-reports were false. In another study, 540 subjects were interviewed on two occasions. 10% of subjects claiming on one occasion never to have smoked made inconsistent statements on the other occasion. A third study showed a strong tendency for smokers to marry smokers. Bias caused by misclassification of smoking habits coupled with between-spouse smoking habit concordance can completely explain reported apparent excesses in lung cancer risk in non-smokers married to smokers.

Difficulties in assessing the relationship between passive smoking and lung cancer.

Since 1981, numerous epidemiological studies have investigated the relationship between passive smoking and lung cancer in nonsmokers. The overall evidence, predominantly relating to women, indicates a weak association with the husband's smoking and many reviewers have concluded that this demonstrates a causal effect of exposure to environmental tobacco smoke (ETS). Interpreting weak associations is notoriously difficult, however, and this paper reviews problems specific to the ETS-lung cancer relationship. After describing how to select relevant studies and appropriate data, the methods for combining evidence together ('meta-analysis') are discussed, and the need to investigate sources of heterogeneity is emphasized. Separate consideration is given to various forms of bias that may affect overall relative risk estimates, including misclassification of active smoking status, confounding, systematic case-control differences, recall bias, diagnostic bias and publication bias. Sections on dose-response, multiple ETS exposure sources and other issues follow. The problems are illustrated from the available literature. It is shown there is no significant association of lung cancer with workplace, childhood or social ETS exposure or with smoking by the wife. Though statistically significant, the association with husband's smoking is weak and heterogeneous and varies widely according to various study characteristics. The association is markedly weakened by the adjustment for smoking misclassification bias and is likely to be affected by confounding and other sources of bias. While the precise extent of all the biases remains unclear, it seems impossible to conclude with any certainty that ETS causes lung cancer.

Accuracy of clinical diagnosis of lung cancer in Budapest in an institute specializing in chest diseases.

Among 250 consecutive autopsies (170 males and 80 females) performed at the Institute of Pulmonology in Budapest in 1996/7, there were 132 deaths in which cancer of the lung/bronchus was deemed to be the underlying cause of death. At autopsy, six cases previously thought to be dying from lung cancer were found to have died from other diseases (false positive rate = 5%). Twelve lung cancer deaths were also found to have been missed, a false negative rate of 9%, which was similar for adenocarcinoma, squamous carcinoma, and small cell carcinoma cases. Our findings confirmed the expectation expressed earlier that death certification of lung cancer would be more accurate in an institute specializing in chest diseases, to which patients had to be fit enough to be transferred, than in two general hospitals in Budapest. Nevertheless, since most cases certified as dying from lung cancer die without the benefits available in the specialized institute, the estimated false negative and positive rates for lung cancer death certification in Hungary remain high, at an estimated 56% and 30%, respectively. The much lower autopsy rates in most other countries than in Hungary points to there being considerable inaccuracy in lung cancer mortality rates internationally.

Environmental tobacco smoke and cancer of sites other than the lung in adult non-smokers.

Evidence from epidemiological studies relating environmental tobacco smoke (ETS) exposure to risk of cancer of sites other than the lung in adult non-smokers is reviewed. Problems common to many studies include small sample size, inadequate control of potential confounding, failure to consider the possibility of misclassification of smoking status, reliance on death certificate diagnosis, use of proxy respondents and the possibility of recall bias. A number of the studies have other obvious weaknesses. Publication bias is known to be a problem, with two very large prospective studies having reported only very limited results. For cancers of the digestive system, bladder and brain, there is little evidence of an association with ETS exposure. Some studies have reported a relationship with cancer of the breast, cervix or nasopharynx, but the overall evidence for these sites is inconsistent and inconclusive, as is that for total cancer incidence. All three studies of nasosinus cancer have reported a statistically significant association with ETS exposure, but they are small, control poorly for potential confounding and have other weaknesses. Taken as a whole, the epidemiological evidence provides little support for the view that ETS causes cancer of any of the sites considered.

Passive smoking.

Before 1980 the argument that passive smoking was a serious health hazard was rather tenuous. It was claimed that it produced allergic reactions, impaired driving ability, reduced exercise tolerance in patients with cardiorespiratory disease and increased the risk of bronchitis and pneumonia in first-year children. However, none of these claims provided convincing evidence relevant to the normal healthy adult nonsmoker. Many studies indicate that nonsmokers are unlikely to inhale more than a very small amount of those components of tobacco smoke traditionally considered harmful. It was surprising, therefore, when a study carried out in the USA showed reduced airways function and studies from Japan and Greece showed an increased lung cancer incidence, in nonsmokers passively exposed to tobacco smoke in comparison with nonsmokers not so exposed. A review of the detail of these studies suggests that none provides conclusive evidence that passive smoking is seriously harmful, a view supported by a recent large study that was carried out in the USA and in which no significant relationship was found between passive smoking and lung cancer. More research is urgently needed, particularly to explore the influence of potentially confounding factors.

Relationship of body-weight gain to longevity and to risk of development of nephropathy and neoplasia in Sprague-Dawley rats.

The relationship of weight gain to survival, risk of development of chronic progressive nephropathy and risk of development of various neoplasms has been studied in the control groups from two routine chronic toxicity studies in Sprague-Dawley rats. The groups comprised 100 CFY strain rats of each sex observed up to the age of 109 wk and 120 CD strain rats of each sex observed up to 111 wk of age (females) or 121 wk (males). The eventual incidence of tumours was found to be related to body weight at several ages. There was also a statistically significant association between high body weight at various ages and increased mortality, particularly in the CD strain and particularly in females. The 'heavy' rats proved to have an increased risk of developing both progressive nephropathy and certain tumours. This relationship was particularly marked for pituitary tumours in both sexes and for benign and malignant mammary tumours in females, and was significant irrespective of whether tumours coexisting with marked or severe progressive nephropathy were classified as fatal or incidental. There was also some evidence that increased body weight was positively associated with risk of islet-cell tumours and lipomatous tumours in males and fibromatous tumours in females. The observations illustrate how non-specific factors, such as those that affect body weight, may profoundly influence mortality and tumour incidence in chronic toxicity studies. The findings also highlight the difficulty of classifying particular neoplasms as incidental or fatal where other potentially life-threatening pathology (e.g. progressive nephropathy) is present.

Influence of food intake and sexual segregation on longevity, organ weights and the incidence of non-neoplastic and neoplastic diseases in rats.

In a small-scale experiment the effects of four variables were investigated in male and female Wistar rats fed on a standard laboratory chow and not deliberately exposed to any carcinogen. The variables investigated were (i) diet restriction by limiting access to food to 6.5 hr/day instead of 24 hr/day; (ii) housing males in a single-sex room as distinct from a mixed-sex room; (iii) life-long segregation of males from females, as distinct from access to one virgin female for 5 days during each alternate week; and (iv) uniparity in females versus life-long virginity. The endpoints compared were body-weight gain, longevity, visible and palpable swellings, absolute and relative organ weights, microscopically confirmed malignant neoplasms that contributed to death before the end of the study at 2 yr, incidence of other neoplasms in decedents and rats killed at the end of the study, and the incidence of various non-neoplastic conditions including myocardial inflammation and fibrosis, chronic progressive nephropathy, liver glycogen storage and fatty degeneration, mammary gland hyperplasia and secretory activity, pancreatic polyarteritis, radiculoneuropathy and certain testicular changes. The results indicated major beneficial effects of dietary restriction on most of the endpoints. By comparison the other variables had only marginal effects. Leydig-cell hyperplasia and neoplasia occurred at significantly higher incidences in males housed intermittently with females than in permanently segregated males. No convincing differences were seen between females that littered once and those that remained virgins. The relevance of these findings to the prediction of cancer mortality risk in man and to the design of rodent carcinogenicity studies is discussed.

The Biosure Study: influence of composition of diet and food consumption on longevity, degenerative diseases and neoplasia in Wistar rats studied for up to 30 months post weaning.

The 1200-rat Biosure Study had six interrelated aims: (1) To see whether dietary restriction (80% ad lib.) reduces the age-standardized incidence of fatal or potentially fatal neoplasia before the age of 30 months. (2) To see whether the beneficial effects of diet restriction can be achieved by (a) limiting the daily period of access to food to 6 hr, or by (b) limiting the energy value of the diet. (3) To see whether reduced calorie intake between weaning and age 4 months influences survival and/or incidence of non-neoplastic and neoplastic diseases. (4) To compare effects of food consumption, energy intake and protein intake on survival and disease. (5) To study the relationships between body weight at different ages with eventual survival and disease incidence. (6) To provide a database for studying relationships between various in-life measurements and eventual survival and disease incidence in individual animals. Twelve groups of SKF Wistar rats consisting of 50 animals of each sex were fed according to different dietary regimens from when they were weaned at the age of 3 wk until they died, or had to be killed because they were sick, or until the experiment was terminated at 30 months. For five of the 12 dietary regimens, satellite groups consisting of 30 animals per sex were maintained in parallel and used to supply information on the effect of diet on circulating hormone levels during the course of the study. During the 13 wk post weaning a Standard Breeder diet (SB) was provided either ad lib. (four groups), 80% ad lib. (three groups), or with access to food limited to 6 hr per day (one group). During this same period two other groups were fed a Low Nutrient Breeder diet (LB) ad lib. A further group was fed a Low Nutrient Maintenance (high fibre) diet (LM) ad lib. Finally, one group was fed the high protein Porton Rat diet (PR) ad lib.(ABSTRACT TRUNCATED AT 400 WORDS)

Determination of trace elements in some natural drugs by atomic absorption spectrometry.

Fifteen kinds of common plants, animals, and minerals used as traditional medicines by the Chinese people have been subjected to analysis by atomic absorption spectrometry for its content of seven metals: lead, cadmium, arsenic, mercury, copper, cobalt, and manganese. The concentrations of these elements are significantly different according to their vegetal, animal, or mineral origin. The average values found for lead, cadmium, arsenic, cobalt, and manganese in drugs of mineral origin are higher than those derived from plants and animals, except for copper, which was higher in drugs of animal origin. Our results suggest that the user of traditional Chinese crude drugs should be warned of the potential danger of heavy-metal poisoning because their concentrations seem to be higher than the maximum values allowed by health agencies in several countries.

Intrapleural administration of fibres induces mesothelioma in rats in the same relative order of hazard as occurs in man after exposure.

1. The dose-response data for the induction of mesothelioma, in rats, by the intrapleural administration of the fibrous zeolite, erionite, has been compared to the published data for the crocidolite and chrysotile forms of asbestos. Erionite is more than two orders of magnitude more carcinogenic than either of the two forms of asbestos examined. 2. The relative sensitivity of the intrapleural and intraperitoneal routes of injection were also examined. The sensitivity of the intraperitoneal over the intrapleural route of administration was considerably greater for all the forms of asbestos examined but not for erionite. 3. The relationship for different fibres, between the number of fibres required to give animals mesothelioma, at the 50% or 10% observable tumour effect level (OTEL) was examined, and a ranking of relative carcinogenicity was made. 4. This showed that the data derived from the dose responses obtained by the intrapleural administration of fibres to rats ranked the relative carcinogenicity of erionite, crocidolite and chrysotile in accord with the known clinical mesothelioma induction in man after exposure to these fibres. Examination of the carcinogenicity ranking from data derived from intraperitoneal injections of fibres was not in accord with the known clinical mesothelioma induction in man for the various asbestos types examined.

Risks of premature death and cancer predicted by body weight in early adult life.

In a study of 30 months duration, involving 600 male and 600 female Wistar rats fed on 12 different diets/dietary regimes, none of which involved deliberate exposure to any known genotoxic carcinogen, highly significant between-group differences were observed in survival and incidence of various neoplastic and non-neoplastic diseases. A full report of the findings is being prepared. Here we report that, irrespective of diet or dietary regime, there were highly significant correlations of body weight at 29 weeks of age with premature death (P less than 0.0001 in both males and females), with development of benign or malignant neoplasm of any site (P less than 0.0001 in males and P less than 0.01 in females) and with development of malignant neoplasm at any site (P less than 0.0001 for sexes combined). Numerous kinds of neoplasm contributed to these overall correlations. The most significant were pituitary tumour (P less than 0.0001), mammary gland tumour (P less than 0.0001), squamous or anaplastic carcinoma of the jaw (P less than 0.001), and subcutaneous mesodermal tumours (P less than 0.05). The 20% of rats that were heaviest at 29 weeks were more than twice as likely to die prematurely than the lightest 20% (2.56 times--males, and 2.11 times--females), and almost twice as likely to develop a malignant tumour (1.87 times for the sexes combined). These findings have important implications for the design and interpretation of carcinogenicity tests in rodents and of laboratory and human studies of relationships between diet, ageing-related degenerative diseases, and cancer.