The importance of tar and nicotine in determining cigarette smoking habits.

Cigarette consumption and inhaling, assessed using carboxyhaemoglobin levels, were studied in 1786 men to investigate the importance of tar and nicotine as determinants of smoking habits. No prior warning was given that smoking habits would be studied. Neither nicotine nor tar yields materially influenced the number of cigarettes smoked a day. Both nicotine and tar yields were negatively associated with inhaling (p less than 0.001) but after allowing for either of the two yields the effect of the other on inhaling was no longer statistically significant. There was, therefore, no indication as to whether nicotine or tar was the more important determinant of smoking habit.

Urinary riboflavin excretion after a load test in rural China as a measure of possible riboflavin deficiency.

Urinary excretion of riboflavin was measured in 3318 adults 4 h after an oral dose of riboflavin. Male and female subjects aged 35-64 years were selected from 65 mostly rural counties located in 24 provinces of China. Counties were selected to represent a range of seven of the most prevalent cancer mortality rates in China and within counties households were selected at random. Urinary riboflavin excretion levels after a load test, erythrocyte glutathione reductase activity coefficients (EGR-AC), dietary riboflavin intakes, and a large number of other biochemical, dietary, and environmental parameters were measured. Mean dietary intake of riboflavin was 75 per cent of the Chinese recommended dietary allowances (CRDA). Mean meat intake per reference man was very low (26.4 +/- 23.7 g/d) in comparison to Western standards and milk was not consumed at all in most counties. Mean EGR activity coefficients measured on 'blood pools' for both males (1.47 +/- 0.14) and females (1.48 +/- 0.16) indicated that more than two-thirds of the population surveyed was in the medium or high risk category of riboflavin deficiency. Using current reference standards of less than 1.4 mg for 4-h urinary excretion of riboflavin after a 5 mg load, more than 70 per cent of the individuals examined exhibited low levels usually associated with high risk of riboflavin deficiency. In view of the lack of specificity for clinical indications of riboflavin deficiency and the tentative validity of the present CRDA, the interpretation of the data is problematic. We suggest that the present CRDA for this vitamin is set too high and requires critical review and possibly some revision.

Alpha-fetoprotein screening for open spina bifida: effect of routine biparietal diameter measurement to estimate gestational age.

The estimation of gestational age by "dates" (time since the first day of the last menstrual period) and by means of an ultrasound scan examination (measurement of fetal biparietal diameter) lead to different results when screening for open spina bifida by maternal serum alphafetoprotein (A.F.P.) measurement. This paper provides estimates of the detection rate for open spina bifida, the false positive rate, and the odds of being affected given a positive A.F.P. result when gestational age is estimated according to the two methods. Estimates are also given on the odds of being affected for individuals with a particular serum A.F.P. result. The estimates may be useful to those concerned with the development and design of screening programmes for open spina bifida as well as to clinicians concerned with providing risk estimates for individual patients.

Smoking and dementia in male British doctors: prospective study.

OBJECTIVE: To assess the possible association between smoking and dementia. DESIGN: Prospective study. SETTING: Cohort of British male doctors followed up since 1951. SUBJECTS: 34 439 male British doctors, with 24 133 deaths recorded. RESULTS: For all types of dementia combined the relative risk was 0.96 (95% confidence interval 0.78 to 1.18), based on 473 deaths at a mean age of 81 years. For probable or definite Alzheimer's disease, the relative risk in continuing smokers was 0.99 (0.78 to 1.25), based on 370 deaths at a mean age of 82 years. In aggregate, however, the other prospective studies indicate a direct, although not clearly significant, association between smoking and the onset of dementia in general and of Alzheimer's disease in particular. CONCLUSIONS: Contrary to previous suggestions persistent smoking does not substantially reduce the age specific onset rate of Alzheimer's disease or of dementia in general. If anything, it might increase rather than decrease the rate, but any net effect on severe dementia cannot be large in either direction.

Emerging tobacco hazards in China: 1. Retrospective proportional mortality study of one million deaths.

OBJECTIVE: To assess the hazards at an early phase of the growing epidemic of deaths from tobacco in China. DESIGN: Smoking habits before 1980 (obtained from family or other informants) of 0.7 million adults who had died of neoplastic, respiratory, or vascular causes were compared with those of a reference group of 0.2 million who had died of other causes. SETTING: 24 urban and 74 rural areas of China. SUBJECTS: One million people who had died during 1986-8 and whose families could be interviewed. MAIN OUTCOME MEASURES: Tobacco attributable mortality in middle or old age from neoplastic, respiratory, or vascular disease. RESULTS: Among male smokers aged 35-69 there was a 51% (SE 2) excess of neoplastic deaths, a 31% (2) excess of respiratory deaths, and a 15% (2) excess of vascular deaths. All three excesses were significant (P<0.0001). Among male smokers aged >/70 there was a 39% (3) excess of neoplastic deaths, a 54% (2) excess of respiratory deaths, and a 6% (2) excess of vascular deaths. Fewer women smoked, but those who did had tobacco attributable risks of lung cancer and respiratory disease about the same as men. For both sexes, the lung cancer rates at ages 35-69 were about three times as great in smokers as in non-smokers, but because the rates among non-smokers in different parts of China varied widely the absolute excesses of lung cancer in smokers also varied. Of all deaths attributed to tobacco, 45% were due to chronic obstructive pulmonary disease and 15% to lung cancer; oesophageal cancer, stomach cancer, liver cancer, tuberculosis, stroke, and ischaemic heart disease each caused 5-8%. Tobacco caused about 0.6 million Chinese deaths in 1990 (0.5 million men). This will rise to 0.8 million in 2000 (0.4 million at ages 35-69) or to more if the tobacco attributed fractions increase. CONCLUSIONS: At current age specific death rates in smokers and non-smokers one in four smokers would be killed by tobacco, but as the epidemic grows this proportion will roughly double. If current smoking uptake rates persist in China (where about two thirds of men but few women become smokers) tobacco will kill about 100 million of the 0.3 billion males now aged 0-29, with half these deaths in middle age and half in old age.

Emerging tobacco hazards in China: 2. Early mortality results from a prospective study.

OBJECTIVE: To monitor the evolving epidemic of mortality from tobacco in China following the large increase in male cigarette use in recent decades. DESIGN: Prospective study of smoking and mortality starting with 224 500 interviewees who should eventually be followed for some decades. SETTING: 45 nationally representative small urban or rural areas distributed across China. SUBJECTS: Male population aged 40 or over in 1991, of whom about 80% were interviewed about smoking, drinking, and medical history. MAIN OUTCOME MEASURE: Cause specific mortality, initially to 1995 but later to continue, with smoker versus non-smoker risk ratios standardised for area, age, and use of alcohol. RESULTS: 74% were smokers (73% current, only 1% former), but few of this generation would have smoked substantial numbers of cigarettes since early adult life. Overall mortality is increased among smokers (risk ratio 1.19; 95% confidence interval 1.13 to 1.25, P<0.0001). Almost all the increased mortality involved neoplastic, respiratory, or vascular disease. The overall risk ratios currently associated with smoking are less extreme in rural areas (1.26, 1.12, or 1.02 respectively for smokers who started before age 20, at 20-24, or at older ages) than in urban areas (1.73, 1.40, or 1.16 respectively). CONCLUSION: This prospective study and the accompanying retrospective study show that by 1990 smoking was already causing about 12% of Chinese male mortality in middle age. This proportion is predicted to rise to about 33% by 2030. Long term continuation of the prospective study (with periodic resurveys) can monitor the evolution of this epidemic.

Recent trends in cancer mortality in the UK.

Comparisons of survival rates of given diseases with different treatments or in different places often gave misleading results until the introduction of controlled trials. Recent reports of relatively low survival rates following the treatment of cancer in the UK compared to the rates in other countries, not based on controlled trials, may consequently be misleading. Their validity has, therefore, been tested by comparing the levels and trends in mortality--the ultimate criterion by which the success or failure of any system of care can be judged. For this purpose, rates and trends in rates over 20-50 years have been compared in five European countries of similar economic status (France, Italy, the Netherlands, Sweden, and the UK). The UK rates are not generally worse than those in the other countries and are sometimes better. Exceptions were cancer of the lung, large bowel, and breast, the first of which is explained by differences in the prevalence of smoking.

Mortality from cancer in relation to smoking: 50 years observations on British doctors.

A total of 34,439 male British doctors, who reported their smoking habits in November 1951, were followed, with periodic up date of changes in their habits, until death, emigration, censoring. or November 2001. Information was obtained about their mortality from 28 of the 30 types of cancer in men reviewed by the International Agency for Research on Cancer (no death was recorded from the other two). In all, 11 of the 13 types in men that the Agency classed as liable to be caused by smoking were significantly related to smoking and the findings for the other two, which caused only few deaths, suggested they might be. Of the 13 types in men for which the Agency found only sparse or inconsistent data and for which we had data, only two appeared to be possibly related (one positively, one negatively), and the 638 deaths for the summed group were clearly unrelated to smoking. Of the two types for which the Agency thought that the relationship with smoking might be due to bias or confounding, the findings for one (prostate cancer) tended to support the belief that smoking was unrelated, and those for the other (colorectal cancer) showed a weak relationship with smoking, which (in a small subset) could not be attributed to confounding with the consumption of alcohol.

Serum retinol and subsequent risk of cancer.

In a prospective study of about 22,000 men attending a well person screening centre, serum samples were collected and stored. The concentration of retinol was measured in the stored serum samples from 227 men subsequently notified as having cancer and from 454 unaffected controls, matched for age, smoking history and duration of storage of the serum samples. The mean serum retinol concentration of the cancer subjects who developed cancer before the elapse of one year since the time blood was collected was significantly lower than the mean concentration of their matched controls (641 and 722 micrograms l-1 respectively, P less than 0.001). For subjects whose cancer developed one to two years after blood had been collected, the difference was less (650 and 701 micrograms l-1 respectively, P less than 0.01). For subjects whose cancer developed three or more years after blood was collected, the mean retinol level was higher than in their controls, although not statistically significantly so (694 and 663 micrograms l-1 respectively). These findings suggest that the inverse association between serum retinol and risk of cancer that was previously observed was due to low serum retinol being a metabolic consequence of cancer rather than a precursor of cancer.

Low serum-vitamin-A and subsequent risk of cancer. Preliminary results of a prospective study.

In a prospective study of about 16 000 men, serum samples were collected and stored. Vitamin-A (retinol) levels were later measured in the stored samples from the 86 men who were subsequently notified as having developed cancer and in the stored samples from 172 controls who did not develop cancer. Low retinol levels were associated with an increased risk of cancer. The association was independent of age, smoking habits, and serum-cholesterol level aand was greatest for men who developed lung cancer (mean retinol level 187 i.u./dl compared with 229 i.u./dl for the controls, p < 0.005). The risk of cancer at any site for men with retinol levels in the lowest quintile was 2.2 times greater than the risk for men with levels in the highest quintile (p < 0.025). These results suggest that measures taken to increase serum-retinol levels in man may lead to a reduction in cancer risk.

Relative intakes of tar, nicotine, and carbon monoxide from cigarettes of different yields.

The relative intakes of tar, nicotine, and carbon monoxide were estimated in 2455 cigarette smokers, who freely smoked their usual brands of cigarette. The estimates were derived by using an objective index of inhaling based on the measurement of carboxyhaemoglobin divided by the carbon monoxide yield of the cigarettes smoked, after background and carry over carboxyhaemoglobin effects had been allowed for. Separate analyses were performed according to the yield and type (plain, filter, etc) of cigarette smoked. The analyses based on yield indicated that the extent of inhaling was adjusted sufficiently to achieve similar intakes of nicotine/carbon monoxide regardless of the nicotine/carbon monoxide yield. It was not, however, sufficiently increased to achieve a similar intake of tar as the tar yield of the cigarette decreased. The analyses based on type of cigarette indicated that the extent of inhaling was adjusted to achieve similar intakes of tar and nicotine regardless of the type of cigarette smoked, but that this led to a greater intake of carbon monoxide among filter cigarette smokers than that among smokers of plain cigarettes--more so than would have been expected from their relative carbon monoxide yields. Two conclusions arise from these results. Firstly, any harmful effects of nicotine/carbon monoxide are unlikely to be materially reduced by smoking cigarettes with lower yields of nicotine/carbon monoxide, but the harmful effects of tar are likely to be reduced by smoking cigarettes with lower tar yields. These predictions appear to be borne out by epidemiological observations. Secondly, any harmful effects of carbon monoxide on the cardiovascular system will be greater in smokers of modern filter cigarettes than in smokers of modern plain cigarettes, provided that these two groups of smokers are otherwise similar with respect to risk of cardiovascular disease.

Inhaling and lung cancer: an anomaly explained.

An objective index of inhaling cigarette smoke based on carboxyhaemoglobin concentrations and the carbon monoxide yields of cigarettes was used to investigate possible systematic differences in the extent of inhaling among light and heavy smokers when classified according to their self described inhaling habits. A total of 2108 men who smoked cigarettes were studied. Heavy smokers (20 or more cigarettes a day) had a higher average inhaling index than light smokers (fewer than 20 cigarettes a day) both among those who said that they inhaled and among those who said that they did not. This observation, together with indirect evidence that heavy smokers who inhale deeply may to some extent avoid depositing smoke condensate on their main bronchial epithelium, explains a hitherto unresolved anomaly--namely, that the risk of lung cancer is less among heavy cigarette smokers who say that they inhale than it is among those who say that they do not inhale.

Effect of estimating gestational age by ultrasound cephalometry on the specificity of alpha-fetoprotein screening for open neural-tube defects.

A total of 1268 women had a maternal serum alpha-fetoprotein (AFP) screening test for open neural-tube defects between 15 and 22 weeks gestation and a routine ultrasound examination at their first antenatal visit. All had a singleton infant without a neural-tube defect. AFP values were expressed as multiples of the normal median at the relevant gestational age (MoM). The percentage of women with raised maternal serum AFP levels was less when gestation was estimated by the fetal biparietal diameter (BPD) than when the time since the first day of the last menstrual period (LMP) was used; 1.8% compared with 2.3% at a serum AFP cut-off level of 2.5 MoM. Different ultrasound policies were compared for their effect on AFP screening and the best was found to be routine BPD measurement used together with a higher cut-off level than usual. For example, using a cut-off level of 3.0 MoM the detection rate for open spina bifida at 16-18 weeks gestation would be about 88% and the proportion of unaffected singleton pregnancies with raised levels only 0.9%. These results are materially better than those achieved by a policy of scanning only those women with a raised AFP level (79% and 1.4% respectively with a more conventional cut-off level of 2.5 MoM) or, in addition, scanning those with doubtful gestational ages (82% and 1.7% respectively with a cut-off level of 2.5 MoM).

Carbon monoxide in breath in relation to smoking and carboxyhaemoglobin levels.

Carboxyhaemoglobin (COHb) levels were studied in 11 249 men. The distribution among the 2613 men who smoked cigarettes was well separated from that in 6641 non-smokers (including ex-smokers). The distribution for 2005 cigar and pipe smokers was intermediate, though some of the highest COHb levels occurred in cigar smokers. Using a COHb cut-off level of 2%, 81% of cigarette smokers, 35% of cigar and pipe smokers, and 1.0% of non-smokers had raised COHb levels. In a subsidiary experiment alveolar air samples were collected from 162 smokers and 25 non-smokers using a simple breath sampling technique. Carbon monoxide concentrations in alveolar breath were highly correlated with COHb levels (r = 0.97) indicating that COHb levels can be estimated reliably by measuring the concentration of carbon monoxide in breath. Alveolar carbon monoxide measurement is thus a simple method of estimating whether a person is likely to be a smoker.

Serum cotinine levels in pipe smokers: evidence against nicotine as cause of coronary heart disease.

Serum levels of cotinine (a principal metabolite of nicotine) were studied in men who did not smoke (28), and in men who smoked cigarettes only (150), cigars only (70), and pipes only (56). The mean cotinine level for pipe smokers was 389 ng/ml, significantly higher than the mean level for cigarette and cigar smokers (306 and 121 ng/ml, respectively); no cotinine was detected in the serum from any of the non-smokers. Large prospective studies have shown that pipe smokers have no material excess risk of coronary heart disease but cigarette smokers do, so that our observations indicate that nicotine is unlikely to be the major cause of the excess coronary heart disease mortality in cigarette smokers.

Inhaling habits among smokers of different types of cigarette.

Inhaling habits were studied in 1316 men who freely smoked their usual brands of cigarette. An index of inhaling was calculated for each person by dividing the estimated increase in carboxyhaemoglobin level from a standard number of cigarettes by the carbon monoxide yield of the cigarette smoked. Smokers of ventilated filter cigarettes inhaled 82% more than smokers of plain cigarettes (p less than 0.001) and those who smoked unventilated filter cigarettes inhaled 36% more (p less than 0.001). Cigarette consumption was similar among smokers of each type of cigarette. Assuming that the intake of tar and nicotine is proportional to the inhaling index, the intake in either group of filter cigarette smokers would have been less than that in plain cigarette smokers. Among smokers of unventilated cigarettes, however, the intake would not have been much less.

Small biparietal diameter of fetuses with spina bifida: implications for antenatal screening.

The biparietal diameter of 20 fetuses with spina bifida was measured during pregnancy by ultrasound scanning, mainly in the second trimester. The mean result was 0.83 cm smaller than the value based on 186 unaffected pregnancies at the same gestational ages (P less than 0.001), suggesting that spina bifida fetuses are growth retarded. The practical consequence of this finding is that the routine use of ultrasound in pregnancy will increase the sensitivity of AFP screening for open spina bifida at 16 to 18 weeks gestation from 79 per cent as estimated by the UK Collaborative AFP Study to about 90 per cent or more.

Occupational exposure to hydrazine and subsequent risk of cancer.

Four hundred and twenty seven men with varying degrees of occupational exposure to hydrazine, a weak animal carcinogen, were studied to see if they provided any evidence of carcinogenicity to man. The observed mortality was close to that expected for lung cancer, other cancers, and all other causes, irrespective of the level of exposure. There were 49 deaths (61.47 expected) from all causes including five deaths from lung cancer (6.65 expected). The results show that no obvious hazards associated with hydrazine exposure have yet appeared but because of the small number of men studied they can only exclude gross hazards.