Search

Background: Most people with haemophilia who were treated with blood products before the introduction of virus-inactivation procedures were infected with the hepatitis-C virus (HCV). However, there is little quantitative information about the long-term effects on mortality of such infection., Methods: We carried out a cohort study of mortality from liver cancer and liver disease in 4865 haemophilic men and boys in the UK. They were treated between 1969 and 1985 with blood products carrying a high risk of HCV infection, and were followed up from first recorded exposure to Jan 1, 1993., Findings: Based on death-certificate information, mortality was 16.7 times higher than in the general population for liver disease (95% CI 12.5-22.0; 51 deaths), and 5.6 times higher (1.8-13.0; five deaths) for liver cancer. For men and boys with severe haemophilia who were not infected with HIV-1, the cumulative risks of death from chronic or unspecified liver disease or from liver cancer in the 25 years since first recorded exposure to high HCV-risk products were 1.4% (0.7-3.0) at all ages, and 0.10% (0.01-0.7), 2.2% (0.8-6.1), and 14.3% (4.5-40.9) for those with first recorded exposure at ages under 25, 25-44, and 45 or older. For those with haemophilia and HIV-1 infection, the corresponding risks were 6.5% (4.5-9.5) at all ages, and 3.8% (2.1-6.8), 17.1% (10.0-28.5), and 18.7% (6.4-47.6) in the three age-groups. In those with severe haemophilia, age-standardised all-cause mortality was stable during 1969-84 but increased during 1985-92 in both HIV-1-infected and HIV-1-uninfected groups. Among those not infected with HIV-1, the increase in all-cause mortality resulted largely from deaths attributed to chronic or unspecified liver disease or liver cancer in men aged over 45., Interpretation: There is an emerging risk of mortality from liver disease and liver cancer in the UK haemophilia population in individuals both infected and uninfected with HIV-1, which probably results from infection with hepatitis C.

During 1977-91, 6,278 males diagnosed with haemophilia were living in the UK. During 1979-86, 1,227 were infected with the human immunodeficiency virus (HIV-1) as a result of transfusion therapy (median estimated seroconversion date, October 1982). Among 2,448 with severe haemophilia, the annual death rate was stable at 8 per 1,000 during 1977-84; during 1985-92 death rates remained at 8 per 1,000 among HIV-seronegative patients but rose steeply in seropositive patients, reaching 81 per 1,000 in 1991-92. Among 3,830 with mild or moderate haemophilia, the pattern was similar, with an initial death rate of 4 per 1,000 in 1977-84, rising to 85 per 1,000 in 1991-92 in seropositive patients. During 1985-92, there were 403 deaths in HIV seropositive patients, whereas 60 would have been predicted from rates in seronegatives, suggesting that 85% of the deaths in seropositive patients were due to HIV infection. Most of the excess deaths were certified as due to AIDS or to conditions recognized as being associated with AIDS.

Leukemia mortality has been studied in 14,767 adult ankylosing spondylitis patients diagnosed between 1935 and 1957 in the United Kingdom, of whom 13,914 patients received X-ray treatment. By 1 January 1992, there were 60 leukemia deaths among the irradiated patients, almost treble that expected from national rates. Leukemia mortality was not increased among unirradiated patients. Among those irradiated, the ratio of observed to expected deaths for leukemia other than chronic lymphocytic leukemia was greatest in the period 1-5 years after the first treatment (ratio = 11.01, 95% confidence interval 5.26-20.98) and decreased to 1.87 (95% confidence interval 0.94-3.36) in the 25+ year period. There was no significant variation in this ratio with sex or age at first treatment. The ratio for chronic lymphocytic leukemia was slightly but not significantly raised (ratio = 1.44, 95% confidence interval 0.62-2.79). Most irradiated patients received all their exposure within a year. Based on a 1 in 15 random sample, the mean total marrow dose was 4.38 Gy. Doses were nonuniform, with heaviest doses to the lower spine. The risk for nonchronic lymphocytic leukemia was adequately described by a linear-exponential model that allowed for cell sterilization in heavily exposed parts of the marrow and time since exposure. Ten years after first exposure, the linear component of excess relative risk was 12.37 per Gy (95% confidence interval 2.25-52.07), and it was estimated that cell sterilization reduced the excess relative risk by 47% at 1 Gy (95% confidence interval 17%-79%). The average predicted relative risk in the period 1-25 years after exposure to a uniform dose of 1 Gy was 7.00.

Background: Exposure to the radioactive gas radon and its progeny (222Rn and its radioactive decay products) has recently been linked to a variety of cancers other than lung cancer in geographic correlation studies of domestic radon exposure and in individual cohorts of occupationally exposed miners., Purpose: This study was designed to characterize further the risks for cancers other than lung cancer (i.e., non-lung cancers) from atmospheric radon., Methods: Mortality from non-lung cancer was examined in a collaborative analysis of data from 11 cohorts of underground miners in which radon-related excesses of lung cancer had been established. The study included 64,209 men who were employed in the mines for 6.4 years on average, received average cumulative exposures of 155 working-level months (WLM), and were followed for 16.9 years on average., Results: For all non-lung cancers combined, mortality was close to that expected from mortality rates in the areas surrounding the mines (ratio of observed to expected deaths [O/E] = 1.01; 95% confidence interval [CI] = 0.95-1.07, based on 1179 deaths), and mortality did not increase with increasing cumulative exposure. Among 28 individual cancer categories, statistically significant increases in mortality for cancers of the stomach (O/E = 1.33; 95% CI = 1.16-1.52) and liver (O/E = 1.73; 95% CI = 1.29-2.28) and statistically significant decreases for cancers of the tongue and mouth (O/E = 0.52; 95% CI = 0.26-0.93), pharynx (O/E = 0.35; 95% CI = 0.16-0.66), and colon (O/E = 0.77; 95% CI = 0.63-0.95) were observed. For leukemia, mortality was increased in the period less than 10 years since starting work (O/E = 1.93; 95% CI = 1.19-2.95) but not subsequently. For none of these diseases was mortality significantly related to cumulative exposure. Among the remaining individual categories of non-lung cancer, mortality was related to cumulative exposure only for cancer of the pancreas (excess relative risk per WLM = 0.07%; 95% CI = 0.01-0.12) and, in the period less than 10 years since the start of employment, for other and unspecified cancers (excess relative risk per WLM = 0.22%; 95% CI = 0.08-0.37)., Conclusions: The increases in mortality from stomach and liver cancers and leukemia are unlikely to have been caused by radon, since they are unrelated to cumulative exposure. The association between cumulative exposure and pancreatic cancer seems likely to be a chance finding, while the association between cumulative exposure and other and unspecified cancers was caused by deaths certified as due to carcinomatosis (widespread disseminated cancer throughout the body) that were likely to have been due to lung cancers. This study, therefore, provides considerable evidence that high concentrations of radon in air do not cause a material risk of mortality from cancers other than lung cancer., Implications: Protection standards for radon should continue to be based on consideration of the lung cancer risk alone.

Mortality has been studied in 15,577 ankylosing spondylitis (AS) patients diagnosed between 1935 and 1957 in the UK, of whom 14,556 received X-ray treatment. By January 1, 1992 over half of the cohort had died. Among the irradiated patients, cancer mortality was significantly greater than expected from the national rates for England and Wales, with a ratio of observed deaths to expected (relative risk, RR) of 1.30, and significant increases individually for leukaemia, non-Hodgkin's lymphoma, multiple myeloma and cancers of the oesophagus, colon, pancreas, lung, bones, connective and soft tissue, prostate, bladder and kidney. Among the unirradiated patients, cancer mortality was lower than expected from national rates (RR = 0.79). Among irradiated patients, the RRs for leukaemia, lung cancer, and all other neoplasms all decreased significantly with increasing time since first treatment following an initial increase. By 35 years after first treatment, the radiation-related excess for lung cancer had completely disappeared, while for other neoplasms the RR remained significantly raised, although at a lower level than in earlier periods. Most irradiated patients received several courses of treatment within a 5-year period. Based on a 1 in 15 random sample, the mean total body dose received in this period was 2.64 Gy, with the heaviest dose to the vertebrae. A linear dose-response model for all neoplasms except leukaemia gave an excess RR of 0.18 Gy-1 in the period 5-24.9 years after first treatment, which decreased significantly to 0.11 Gy-1 in the period more than 25 years after first treatment. There was no evidence that a linear-quadratic model fitted the data better than a linear model. There were significant dose-response relationships individually for cancers of the lung, oesophagus, colon, pancreas, prostate, bladder and kidney.

Lung cancer mortality in a cohort of 4320 miners first employed during 1948-1959 at the Jáchymov and Horní Slavkov uranium mines in West Bohemia and followed until 1 January 1991 has been studied to gain a greater understanding of the consequences of exposure to radon and its progeny. Among men whose exposure rates never exceeded 10 working levels, excess relative risks per unit exposure were greater in younger men, and exposures received in the periods 15-24, 25-34 and 35+ years previously were found to have 47, 24 and 0% of the effect of exposures 5-14 years previously. Within this low-exposure-rate group excess relative risk increased linearly with time-weighted cumulative exposure and did not depend on exposure rate or duration of exposure. For men who spent less than 20% of their employment at the Jáchymov mine the excess relative risk per working level month was 1.36% (95% confidence interval 0.52-3.54) in the baseline category (age group 55+ and exposure received 5-14 years previously). For men who spent more than 20% of their employment at Jáchymov, the corresponding excess relative risk per working level month was higher by a factor of 1.80 (95% confidence interval 1.27-2.97). The difference may be due to the fact that men who spent more than 20% of their employment at Jáchymov were exposed to the much higher levels of arsenic in the dust at the Jáchymov mine than at other mines. When men with exposure rates above 10 working levels were included in the analysis, patterns of risk were complex and depended on both exposure rate and duration of exposure in addition to the factors mentioned above. If these findings are confirmed elsewhere, calculation of risk estimates for extrapolation to modern occupational or environmental exposures should be based on miners with exposure rates below about 10 working levels. Further investigation is desirable of the influence of dusts containing arsenic on lung cancer risk in miners exposed to radon.

Objectives: To study the long term effects of participation in the United Kingdom's atmospheric nuclear weapon tests and experimental programmes and to test hypotheses generated by an earlier report, including the possibility that participation in tests caused small hazards of leukaemia and multiple myeloma., Design: Follow up study of mortality and cancer incidence., Subjects: 21,358 servicemen and civilians from the United Kingdom who participated in the tests and a control group of 22,333 non-participants., Main Outcome Measures: Numbers of deaths; standardised mortality ratios; relative risks of mortality from all causes and 27 types of cancer., Results: During seven further years of follow up the numbers of deaths observed in participants were fewer than expected from national rates for all causes, all neoplasms, leukaemia, and multiple myeloma (standardised mortality ratios 0.86, 0.85, 0.57, and 0.46); death rates were lower than in controls (relative risks 0.99, 0.96, 0.57, and 0.57; 90% confidence intervals all included 1.00). In the period more than 10 years after the initial participation in tests the relative risk of death in participants compared with controls was near unity for all causes (relative risk 0.99 (0.95 to 1.04) and all neoplasms (0.95 (0.87 to 1.04)); it was raised for bladder cancer (2.69 (1.42 to 5.20)) and reduced for cancers of the mouth, tongue, and pharynx (0.45 (0.22 to 0.93)) and for lung cancer (0.85 (0.73 to 0.99)). For leukaemia mortality was equal to that expected from national rates but greater than in controls for both the whole follow up period (1.75 (1.01 to 3.06)) and the period 2-25 years after the tests (3.38 (1.45 to 8.25))., Conclusion: Participation in nuclear weapon tests had no detectable effect on expectation of life or on subsequent risk of developing cancer or other fatal diseases. The excess of leukaemia in participants compared with controls seems to be principally due to a chance deficit in the controls, but the possibility that participation in the tests may have caused a small risk of leukaemia in the early years afterwards cannot be ruled out.

Radiation-induced cancer mortality rates among atomic bomb survivors with doses of at least 100 rad and patients with ankylosing spondylitis given X-ray therapy have been compared for the first time. The estimated average mean bone marrow dose for the spondylitics is more than twice that for atomic bomb survivors, and yet spondylitics experienced only half the risk of radiation-induced leukemia of atomic bomb survivors. For sites that were heavily irradiated in the spondylitics, provisional estimates indicate comparable doses in the two studies, and similar levels of cancer risk were observed. For these sites, when information from the studies was combined, there were statistically significant excesses for cancers of the esophagus, stomach, lung, and ovaries, multiple myeloma, other lymphomas, and tumors of the spinal cord and nerves. Very high relative risks (RR's) for tumors of the spinal cord and nerves were observed in both studies. For sites that were lightly irradiated in the spondylitics, in addition to previously documented sites, there was a statistically significant excess of cancers of the liver and gallbladder among atomic bomb survivors. A previous subdivision of cancer sites into radiosensitive and other tissues was not supported by the atomic bomb survivor data. Changes in the rates of radiation-induced cancers with age at exposure and time since exposure were studied and compared with the use of generalized linear modeling of the RR's and also by examination of the excess mortality rates. The level of agreement between the two studies was high; provided it is accepted that the reduced level of leukemia risk in the spondylitics is due to cell sterilization, no inconsistencies were found. For a group of solid tumors selected from heavily irradiated sites in the spondylitics, excess risk increased with both age at exposure and time since exposure and RR decreased with age at exposure, but it did not vary with time since exposure between about 5 and at least 30 years following exposure. The finding of a constant RR with time since exposure did not extend to all remaining neoplasms other than leukemia, because the RR for these neoplasms increased with time since exposure in atomic bomb survivors.

An adolescent haemophiliac group (all less than 1 per cent Factor VIII) and a normal, similarly aged, 'control group' of boys were examined to measure joint laxity in an effort to identify a causative factor for bleeding. Definitive laxity was found in the thumb joints and in finger extension of haemophiliacs compared with normal boys. The haemophiliacs who were more lax-jointed showed no tendency towards an increased number of bleeds when they were followed for 100 days. Possible explanations for these phenomena are discussed.

Adult male mice had the lower halves of their bodies exposed in a waveguide system to 2.45 GHz microwave radiation for 30 min. The half body dose-rate of 43 W kg-1 had been shown in a previous study [7] to deplete severely the heat-sensitive stages of sperm production. The males were mated at intervals to adult hybrid females over the following 8-10 weeks. There was no significant reduction in post-implantation survival, suggesting that the microwave exposure did not have a mutagenic effect on the male germ cells. However, pregnancy rate was significantly reduced in weeks 3, 4, 5 and 6; reaching a minimum of about 10% of the control value in weeks 4 and 5. The occurrence of low values in weeks 4 and 5 correlated well with the expected reductions in sperm count due to the pattern of depletion of the spermatogenic epithelium of the testes. Thus it was concluded that the reduced pregnancy rate resulted from reduced male fertility. Pre-implantation survival can also be affected by reduced sperm count [8] and was significantly reduced in this study but it correlated less well with the anticipated heat response. A further study is in progress looking at the contribution of sperm count and sperm abnormality to the results.

OBJECTIVE--To estimate the cumulative incidence of AIDS by time since seroconversion in haemophiliacs positive for HIV and to examine the evidence for excess mortality associated with HIV in those who had not yet been diagnosed as having AIDS. DESIGN--Analysis of data from ongoing national surveys. SETTING--Haemophilia centres in the United Kingdom. PATIENTS--A total of 1201 men with haemophilia who had lived in the United Kingdom during 1980-7 and were positive for HIV. INTERVENTION--None. END POINTS--Diagnosis of AIDS; death in those not diagnosed as having AIDS. MEASUREMENTS AND MAIN RESULTS--Estimation of cumulative incidence of AIDS and number of excess deaths in seropositive patients not diagnosed with AIDS. Median follow up after seroconversion was 5 years 2 months. Eight five patients developed AIDS. Cumulative incidence of AIDS five years after seroconversion was 4% among patients aged less than 25 at first test positive for HIV, 6% among those aged 25-44, and 19% among those aged greater than or equal to 45. There was little evidence that type or severity of haemophilia or type of factor VIII or IX that had caused HIV infection affected the rate of progression to AIDS. Mortality was increased among those who had not been diagnosed as having AIDS, especially among those with "AIDS related complex." Thirteen deaths were observed among 36 patients diagnosed as having AIDS related complex against 0.65 expected, and 34 deaths in 1080 other patients against 22.77 expected; both calculations were based on mortality rates observed in haemophiliacs in the United Kingdom in the late 1970s. CONCLUSIONS--Rate of progression to AIDS depended strongly on age. There is a substantial burden of fatal disease among patients positive for HIV who have not been formally diagnosed as having AIDS.

Epidemiological studies of active smokers have shown that the duration of smoking has a much greater effect on lung cancer risk than the amount smoked. This observation suggests that passive smoking might be much more harmful than would be predicted from measures of the level of exposure alone, as it is often of very long duration frequently beginning in early childhood. In this paper we have investigated this using a multistage model with five stages. The model is shown to provide an excellent fit to data on the incidence of lung cancer among smokers, ex-smokers and non-smokers in a cohort of male British doctors. Contrary to our expectation the model predicted only a slight increase in relative risk with increasing duration of passive exposure. Allowing for exposures early in life does not therefore explain the discrepancy between the relative risk of about 1.5 calculated from epidemiological studies of lung cancer and the low levels of exposure indicated by cotinine measurements in those passively exposed.

Two long-term studies of cancer mortality in population exposed to high doses of ionizing radiation are described briefly. Statistical analysis plays a key role in establishing to what extent it is appropriate to generalize from the experience of these populations to that of other populations who have been exposed, usually at lower doses. Two examples of recent analyses are given. First, a detailed comparison of the cancer mortality experience in the two studies has been carried out; this has shown a high level of agreement between them. In the second example the relation between the radiogenic risk and the baseline age-specific cancer risk in the two populations has been studied. Results are again in good agreement and show that for a group of epithelial tumours of non-sex-specific sites exposure to radiation multiplies the baseline risk.

Reasons are discussed for basing cancer risk estimates of low-dose radiation effects on extrapolations from populations exposed to high doses, rather than directly on studies of low-dose effects. Some of the major studies used for this purpose are described, together with difficulties encountered in extrapolating from them. Some recent statistical work to aid the evaluation of radiation risk from these studies is reviewed.

Altogether 22,347 men who participated in the United Kingdom's atmospheric nuclear weapon tests and experimental programmes in Australia and the Pacific Ocean between 1952 and 1967 were identified from the archives of the Ministry of Defence and followed up. Their mortality and incidence of cancer were compared with those in 22,326 matched controls selected from the same archives. The risk of mortality in the participants relative to that in the controls was 1.01 for all causes and 0.96 for all neoplasms. Thirty eight causes of death were examined separately. Significant differences in mortality were found for leukaemia, multiple myeloma, and other injury and poisoning, with higher rates in the participants, and for cancers of the prostate and kidney and chronic bronchitis, with higher rates in the controls. The mortality from leukaemia and multiple myeloma in the participants was slightly greater than would have been expected from national values (standardised mortality ratios of 113 and 111, respectively), but in the controls it was substantially lower (standardised mortality ratios of 32 and 0, respectively). Examination of the rates of leukaemia and multiple myeloma in groups of participants showed very little difference between groups characterised by recorded doses of external radiation or type of test participation and failed to indicate any specific hazard. Evidence obtained from participants who reported themselves voluntarily (or were reported by relatives or friends) suggested that 17% of participants may have been omitted from the main study group but that any resulting bias was small. Most of the differences observed between the participants and controls were interpreted as due to chance, but some may be due to differences in smoking habits. Participation in the test programme did not seem, in itself, to have caused any detectable effect on the participants' expectation of life, apart from possibly causing small risks of developing leukaemia and multiple myeloma.

A highly significant association is noted between the frequency of diagnostic radiological examinations and the relative level of funding in the English Regional Health Authorities as calculated by the Resource Allocation Working Party in 1977 (DHSS, 1976). It is argued that this supports the recommendations of the Resource Allocation Working Party, and their suggestion that Standardized Mortality Ratios can be used as a proxy measure for morbidity. The finding implies that the level of diagnostic radiology is likely to rise if more funds become available, and this conclusion is supported by consideration of the level of diagnostic radiology in other industrialized countries. The correlation with level of funding is also investigated for a number of other indicators of hospital use. Strong associations exist for some usage indicators for out-patients, but not for in-patients.

A paper in a previous volume of this journal (Ingram, DM, Nutr Cancer 3, 75-80, 1981) reported that at the beginning of World War II there was a marked decrease in breast cancer mortality in England and Wales that coincided with a marked reduction in the consumption of sugar, meat, and fat, and a marked increase in the consumption of cereals and vegetables. Reexamination of the mortality data described in that paper shows that the apparent sudden decrease in breast cancer mortality at the beginning of World War II is an artefact caused by a change in the method of selecting the cause of death from jointly stated causes, which was introduced in 1940. After adjusting for this change, trends in age-specific mortality rates are described. Breast cancer mortality rates were greater in 1980 than in 1911 in the age group of 35-84 years, but this overall increase was interrupted by a period of decreasing mortality between the 1930s and the 1950s in the age group of 50-69 years. It is possible that some of this decrease was due to dietary changes; however, the evidence is poor and other factors that affect incidence and survival must be considered.

Mortality up to 1 January 1983 has been studied in 14,106 patients with ankylosing spondylitis given a single course of X-ray treatment during 1935-54. For neoplasms other than leukaemia or colon cancer, mortality was 28% greater than that of members of the general population of England and Wales, and this increase is likely to have been a direct consequence of the treatment. The proportional increase reached a maximum of 71% between 10.0 and 12.4 years after irradiation and then declined. There was only a 7% increase in mortality from these tumours more than 25.0 years after irradiation and only for cancer of the oesophagus was the relative risk significantly raised in this period. Neither the magnitude of the relative risk, nor its temporal pattern following treatment, were greatly influenced by the age of the patient at first treatment. For leukaemia there was a threefold increase in mortality that is also likely to have been due to the radiotherapy. The relative risk was at its highest between 2.5 and 4.9 years after the treatment and then declined, but the increase did not disappear completely, and the risk was still nearly twice that of the general population more than 25.0 years after treatment. There was some evidence that the risks of acute myeloid, acute lymphatic, and chronic myeloid leukaemia were all increased, but no evidence of any increase in chronic lymphatic leukaemia. The relative risk appeared to be greatest for acute myeloid leukaemia. For colon cancer, which is associated with spondylitis through a common association with ulcerative colitis, mortality was increased by 30%. For non-neoplastic conditions there was a 51% increase in mortality that was likely to be associated with the disease itself rather than its treatment. The increase was apparent for a wide range of diseases and was not confined to diseases that have been associated clinically with ankylosing spondylitis.

Glomerular capillary basement membrane thickness (BMT) was measured in 23 rats which had had streptozocin-induced diabetes for 14 months and in 12 age-matched controls. Diabetic rats were randomly allocated to different groups, either receiving no treatment or treated with a low carbohydrate diet or insulin, or both. Control rats were randomly allocated to a normal or low carbohydrate diet. Among the diabetic rats mean plasma glucose concentrations for the groups ranged from 27-4 mmol/l (494 mg/100 ml) in the untreated rats to 9-8 mmol/l (177 mg/100 ml) in those receiving both a low carbohydrate diet and insulin. A highly significant positive relation was found between BMT and plasma glucose concentration for individual rats. When BMT was corrected for body weight a similar relation was observed.