Lucy M. Carpenter

Effects of low doses and low dose rates of external ionizing radiation: Cancer mortality among nuclear industry workers in three countries

Studies of the mortality among nuclear industry workforces have been carried out, and nationally combined analyses performed, in the U.S., the UK and Canada. This paper presents the results of internationally combined analyses of mortality data on 95,673 workers (85.4% men) monitored for external exposure to ionizing radiation and employed for 6 months or longer in the nuclear industry of one of the three countries. These analyses were undertaken to obtain a more precise direct assessment of the carcinogenic effects of protracted low-level exposure to external, predominantly gamma, radiation. The combination of the data from the various studies increases the power to study associations between radiation and specific cancers. The combined analyses covered a total of 2,124,526 person-years (PY) at risk and 15,825 deaths, 3,976 of which were due to cancer. There was no evidence of an association between radiation dose and mortality from all causes or from all cancers. Mortality from leukemia, excluding chronic lymphocytic leukemia (CLL)--the cause of death most strongly and consistently related to radiation dose in studies of atomic bomb survivors and other populations exposed at high dose rates--was significantly associated with cumulative external radiation dose (one-sided P value = 0.046; 119 deaths). Among the 31 other specific types of cancer studied, a significant association was observed only for multiple myeloma (one-sided P value = 0.037; 44 deaths), and this was attributable primarily to the associations reported previously between this disease and radiation dose in the Hanford (U.S.) and Sellafield (UK) cohorts. The excess relative risk (ERR) estimates for all cancers excluding leukemia, and leukemia excluding CLL, the two main groupings of causes of death for which risk estimates have been derived from studies of atomic bomb survivors, were -0.07 per Sv [90% confidence interval (CI): -0.4, 0.3] and 2.18 per Sv (90% CI: 0.1, 5.7), respectively. These values correspond to a relative risk of 0.99 for all cancers excluding leukemia and 1.22 for leukemia excluding CLL for a cumulative protracted dose of 100 mSv compared to 0 mSv. These estimates, which did not differ significantly across cohorts or between men and women, are the most comprehensive and precise direct estimates of cancer risk associated with low-dose protracted exposures obtained to date. Although they are lower than the linear estimates obtained from studies of atomic bomb survivors, they are compatible with a range of possibilities, from a reduction of risk at low doses, to risks twice those on which current radiation protection recommendations are based.(ABSTRACT TRUNCATED AT 400 WORDS)

23-valent pneumococcal polysaccharide vaccine in HIV-1-infected Ugandan adults: double-blind, randomised and placebo controlled trial.

BACKGROUND Infection with Streptococcus pneumoniae is a frequent and serious problem for HIV-immunosuppressed adults. Vaccination is recommended in the USA and Europe, but there are no prospective data that show vaccine efficacy. METHODS 1392 (937 female) HIV-1-infected adults in Entebbe, Uganda, were enrolled. 697 received 23-valent pneumococcal polysaccharide vaccine and 695 received placebo. The primary endpoint was first event invasive pneumococcal disease. Secondary endpoints included vaccine serogroup-specific invasive disease, all (probable and definite) pneumococcal events, all-cause pneumonia, and death. FINDINGS First invasive events occurred in 25 individuals (24 bacteraemias, one pyomyositis), 15 in the vaccine arm and ten in the placebo arm (hazard ratio [HR] 1.47; 95% CI 0.7-3.3). 22 isolates (88%) were of vaccine-specific serogroups with 15 events in the vaccine arm compared with seven in the placebo arm (HR 2.10; 0.9-5.2). All pneumococcal events had a similar distribution (20 vs 14; HR 1.41; 0.7-2.8) though all-cause pneumonia was significantly more frequent in the vaccine arm (40 vs 21; HR 1.89; 1.1-3.2). Mortality was unaffected by vaccination. INTERPRETATION 23-valent pneumococcal polysaccharide vaccination is ineffective in HIV-1-infected Ugandan adults and probably has little, or no, public health value elsewhere in sub-Saharan Africa. Increased rates of pneumococcal disease in vaccine recipients may necessitate a reappraisal of this intervention in other settings.

Syndromic management of sexually-transmitted infections and behaviour change interventions on transmission of HIV-1 in rural Uganda: a community randomised trial

BACKGROUND Treatment of sexually-transmitted infections (STIs) and behavioural interventions are the main methods to prevent HIV in developing countries. We aimed to assess the effect of these interventions on incidence of HIV-1 and other sexually-transmitted infections. METHODS We randomly allocated all adults living in 18 communities in rural Uganda to receive behavioural interventions alone (group A), behavioural and STI interventions (group B), or routine government health services and community development activities (group C). The primary outcome was HIV-1 incidence. Secondary outcomes were incidence of herpes simplex virus type 2 (HSV2) and active syphilis and prevalence of gonorrhoea, chlamydia, reported genital ulcers, reported genital discharge, and markers of behavioural change. Analysis was per protocol. FINDINGS Compared with group C, the incidence rate ratio of HIV-1 was 0.94 (0.60-1.45, p=0.72) in group A and 1.00 (0.63-1.58, p=0.98) in group B, and the prevalence ratio of use of condoms with last casual partner was 1.12 (95% CI 0.99-1.25) in group A and 1.27 (1.02-1.56) in group B. Incidence of HSV2 was lower in group A than in group C (incidence rate ratio 0.65, 0.53-0.80) and incidence of active syphilis for high rapid plasma reagent test titre and prevalence of gonorrhoea were both lower in group B than in group C (active syphilis incidence rate ratio, 0.52, 0.27-0.98; gonorrhoea prevalence ratio, 0.25, 0.10-0.64). INTERPRETATION The interventions we used were insufficient to reduce HIV-1 incidence in rural Uganda, where secular changes are occurring. More effective STI and behavioural interventions need to be developed for HIV control in mature epidemics.

Rates of HIV-1 transmission within marriage in rural Uganda in relation to the HIV sero-status of the partners.

OBJECTIVE To assess the efficacy of transmission of HIV-1 within married couples in rural Uganda according to the sero-status of the partners. DESIGN Estimation of HIV incidence rates for 2200 adults in a population cohort followed for 7 years comparing male-to-female with female-to-male transmission and sero-discordant with concordant sero-negative couples. METHODS Each year, adults (over 12 years of age) resident in the study area were linked to their spouses if also censused as resident. The HIV sero-status was determined annually. RESULTS At baseline 7% of married adults were in sero-discordant marriages and in half of these the man was HIV-positive. Among those with HIV-positive spouses, the age-adjusted HIV incidence in women was twice that of men (rate ratio (RR) = 2.2 95% confidence interval (CI) 0.9-5.4) whereas, among those with HIV-negative spouses, the incidence in women was less than half that of men (RR = 0.4, 95% CI 0.2-0.8). The age-adjusted incidence among women with HIV-positive spouses was 105.8 times (95% CI 33.6-332.7) that of women with HIV-negative spouses, the equivalent ratio for men being 11.6 (95% CI 5.8-23.4). CONCLUSION Men are twice as likely as women to bring HIV infection into a marriage, presumably through extra-marital sexual behaviour. Within sero-discordant marriages women become infected twice as fast as men, probably because of increased biological susceptibility. Married adults, particularly women, with HIV-positive spouses are at very high risk of HIV infection. Married couples in this population should be encouraged to attend for HIV counselling together so that sero-discordant couples can be identified and advised accordingly.

Seven-year trends in HIV-1 infection rates, and changes in sexual behaviour, among adults in rural Uganda

ObjectiveTo assess trends in HIV-1 infection rates and changes in sexual behaviour over 7 years in rural Uganda. MethodsAn adult cohort followed through eight medical–serological annual surveys since 1989–1990. All consenting participants gave a blood sample and were interviewed on sexual behaviour. ResultsOn average, 65% of residents gave a blood sample at each round. Overall HIV-1 prevalence declined from 8.2% at round 1 to 6.9% at round 8 (P = 0.008). Decline was most evident among men aged 20–24 years (11.7 to 3.6%;P < 0.001) and women aged 13–19 (4.4% to 1.4%;P = 0.003) and 20–24 (20.9% to 13.8%;P = 0.003). However, prevalence increased significantly among women aged 25–34 (13.1% to 16.6%;P = 0.04). Although overall incidence declined from 7.7/1000 person-years (PY) in 1990 to 4.6/1000 PY in 1996, neither this nor the age-sex specific rates changed significantly (P > 0.2). Age-standardized death rates for HIV-negative individuals were 6.5/1000 PY in 1990 and 8.2/1000 PY in 1996; corresponding rates for HIV-positive individuals were 129.7 and 102.7/1000 PY, respectively. There were no significant trends in age-adjusted death rates during follow-up for either group. There was evidence of behaviour change towards increase in condom use in males and females, marriage at later age for girls, later sexual debut for boys and a fall in fertility especially among unmarried teenagers. ConclusionsThis is the first general population cohort study showing overall long-term significant reduction in HIV prevalence and parallel evidence of sexual behaviour change. There are however no significant reductions in either HIV incidence or mortality.

Mortality of doctors in different specialties: findings from a cohort of 20000 NHS hospital consultants.

OBJECTIVES: To examine patterns of cause specific mortality in NHS hospital consultants according to their specialty and to assess these in the context of potential occupational exposures. METHODS: A historical cohort assembled from Department of Health records with follow up through the NHS Central Register involving 18,358 male and 2168 female NHS hospital consultants employed in England and Wales between 1962 and 1979. Main outcome measures examined were cause specific mortality during 1962-92 in all consultants combined, and separately for 17 specialty groups, with age, sex, and calendar year adjusted standardised mortality ratios (SMRs) for comparison with national rates, and rate ratios (RRs) for comparison with rates in all consultants combined. RESULTS: The 2798 deaths at ages 25 to 74 reported during the 30 year study period were less than half the number expected on the basis of national rates (SMR 48, 95% confidence interval (95% CI) 46 to 49). Low mortality was evident for cardiovascular disease, lung cancer, other diseases related to smoking, and particularly for diabetes (SMR 14, 95% CI 6 to 29). Death rates from accidental poisoning were significantly raised among male consultants (SMR 227, 95% CI 135 to 359), the excess being most apparent in obstetricians and gynaecologists (SMR 934); almost all deaths from accidental poisoning involved prescription drugs. A significantly raised death rate from injury and poisoning among female consultants was due largely to a twofold excess of suicide (SMR 215, 95% CI 93 to 423), the rate for this cause being significantly raised in anaesthetists (SMR 405). Compared with all consultants, significantly raised mortality was found in psychiatrists for all causes combined (RR 1.12), ischaemic heart disease (RR 1.18), and injury and poisoning (RR 1.46); in anaesthetists for cirrhosis (RR 2.22); and in radiologists and radiotherapists for respiratory disease (RR 1.68). There were significant excesses of colon cancer in psychiatrists (RR 1.67, compared with all consultants) and ear, nose, and throat surgeons (RR 2.25); melanoma in anaesthetists (RR 3.33); bladder cancer in general surgeons (RR 2.40); and laryngeal cancer in ophthalmologists (RR 7.63). CONCLUSIONS: Lower rates of smoking will have contributed substantially to the low overall death rates found in consultants, but other beneficial health related behaviours, and better access to health care, may have also played a part. The increased risks of accidental poisoning in male consultants, and of suicide in female consultants are of concern, and better preventive measures are needed. The few significant excesses of specific cancers found in certain specialties have no obvious explanation other than chance. A significant excess mortality from cirrhosis in anaesthetists might reflect an occupational hazard and may warrant further investigation.

A case-control study of human immunodeficiency virus infection and cancer in adults and children residing in Kampala, Uganda.

Uganda offers a unique setting in which to study the effect of human immunodeficiency virus‐1 (HIV‐1) on cancer. HIV‐1 is prevalent there, and cancers which are known to be HIV‐associated, such as Kaposis sarcoma and Burkitts lymphoma, are endemic. Adults residing in Kampala, Uganda, presenting with cancer in city hospitals were interviewed and had an HIV test. Of the 302 adults recruited, 190 had cancers with a potentially infectious aetiology (cases). The remaining 112 adults with tumours not known to have an infectious aetiology formed the control group. In addition, 318 children who were also Kampala residents were recruited and tested for HIV: 128 with cancer (cases) and 190 with non‐malignant conditions (controls). HIV seroprevalence was 24% in adult controls and 6% in childhood controls. The odds of HIV seropositivity among cases with specific cancers (other than Kaposis sarcoma in adults) were compared with that among controls, using odds ratios (ORs), estimated with unconditional logistic regression. All ORs were adjusted for age (<5, 5–14, 15–19, 30–44, 45+) and sex and, in adults, also for the number of lifetime sexual partners (1 or 2, 3–9, 10+). In adults, HIV infection was associated with a significantly (p < 0.05) increased risk of non‐Hodgkins lymphoma [OR = 6.2, 95% confidence interval (CI) 1.9–19.9, based on 21 cases] and conjunctival squamous‐cell carcinoma (OR = 10.9, 95% CI 3.1–37.7, based on 22 cases) but not with cancer at other common sites, including liver and uterine cervix. In children, HIV infection was associated with a significantly increased risk of Kaposis sarcoma (OR = 94.9, 95% CI 28.5–315.3, based on 36 cases) and Burkitts lymphoma (OR = 7.5, 95% CI 2.8–20.1, based on 33 cases) but not with other cancers. The pattern of HIV‐associated cancers in Uganda is broadly similar to that described elsewhere, but the relative frequency of specific cancers, such as conjunctival carcinoma, in HIV‐infected people differs.

Mortality From Cerebrovascular Disease in a Cohort of 23 000 Patients With Insulin-Treated Diabetes

Background and Purpose— Disease of the cardiovascular system is the main cause of long-term complications and mortality in patients with type I (insulin-dependent) and type II (non-insulin-dependent) diabetes. Cerebrovascular mortality rates have been shown to be raised in patients with type II diabetes but have not previously been reported by age and sex in patients with type I diabetes. Methods— A cohort of 23 751 patients with insulin-treated diabetes, diagnosed under the age of 30 years from throughout the United Kingdom, was identified during 1972 to 1993 and followed up for mortality until the end of December 2000. Age- and sex-specific mortality rates and standardized mortality ratios (SMRs) were calculated. Results— There were 1437 deaths during the follow-up, 80 due to cerebrovascular disease. Overall, the cerebrovascular mortality rates in the cohort were higher than the corresponding rates in the general population, and the SMRs were 3.1 (95% CI, 2.2 to 4.3) for men and 4.4 (95% CI, 3.1 to 6.0) for women. When stratified by age, the SMRs were highest in the 20- to 39-year age group. After subdivision of cause of death into hemorrhagic and nonhemorrhagic origins, there remained a significant increase in mortality from stroke of nonhemorrhagic origin. Conclusions— Analyses of mortality from this cohort, essentially one of patients with type I diabetes, has shown for the first time that cerebrovascular mortality is raised at all ages in these patients. Type I diabetes is at least as great a risk factor for cerebrovascular mortality as type II diabetes.

The epidemiology of conjunctival squamous cell carcinoma in Uganda

As part of a larger investigation of cancer in Uganda, we conducted a case–control study of conjunctival squamous cell carcinoma in adults presenting at hospitals in Kampala. Participants were interviewed about social and lifestyle factors and had blood tested for antibodies to HIV, KSHV and HPV-16, -18 and -45. The odds of each factor among 60 people with conjunctival cancer was compared to that among 1214 controls with other cancer sites or types, using odds ratios, estimated with unconditional logistic regression. Conjunctival cancer was associated with HIV infection (OR 10.1, 95% confidence intervals [CI] 5.2–19.4; P<0.001), and was less common in those with a higher personal income (OR 0.4, 95% CI 0.3–1.2; P<0.001). The risk of conjunctival cancer increased with increasing time spent in cultivation and therefore in direct sunlight (χ2 trend=3.9, P=0.05), but decreased with decreasing age at leaving home (χ2 trend=3.9, P=0.05), perhaps reflecting less exposure to sunlight consequent to working in towns, although both results were of borderline statistical significance. To reduce confounding, sexual and reproductive variables were examined among HIV seropositive individuals only. Cases were more likely than controls to report that they had given or received gifts for sex (OR 3.5, 95% CI 1.2–10.4; P=0.03), but this may have been a chance finding as no other sexual or reproductive variable was associated with conjunctival cancer, including the number of self-reported lifetime sexual partners (P=0.4). The seroprevalence of antibodies against HPV-18 and -45 was too low to make reliable conclusions. The presence of anti-HPV-16 antibodies was not significantly associated with squamous cell carcinoma of the conjunctiva (OR 1.5, 95% CI 0.5–4.3; P=0.5) and nor were anti-KSHV antibodies (OR 0.9, 95% CI 0.4–2.1; P=0.8). The 10-fold increased risk of conjunctival cancer in HIV infected individuals is similar to results from other studies. The role of other oncogenic viral infections is unclear.

Mortality of employees of the Atomic Weapons Establishment, 1951-82.

A total of 22,552 workers employed by the Atomic Weapons Establishment between 1951 and 1982 were followed up for an average of 18.6 years. Of the 3115 who died, 865 (28%) died of cancer. Mortality was 23% lower than the national average for all causes of death and 18% lower for cancer. These low rates were consistent with the findings in other workforces in the nuclear industry and reflect, at least in part, the selection of healthy people to work in the industry and the disproportionate recruitment of people from the higher social classes. At some time during their employment 9389 (42%) of the workers were monitored for exposure to radiation, the average cumulative whole body exposure to external radiation being 7.8 mSv. Their mortality was generally similar to that of other employees, even when exposures were lagged by 10 years. The rate ratio after a 10 year lag in workers with a radiation record compared with other workers was 1.01 (95% confidence interval 0.92 to 1.10) for all causes of death and 1.06 (0.89 to 1.27) for all malignant neoplasms. The only significant differences were for prostatic cancer (rate ratio 2.23; 95% confidence interval 1.13 to 4.40) and for cancers of ill defined and secondary sites (rate ratio 2.37; 1.23 to 4.56). Cancers of lymphatic and haemopoietic tissues were notable for their low occurrence in the study population, with only four deaths from leukaemia and two from multiple myeloma in workers with a radiation record, 9.16 and 3.55 deaths respectively being expected on the basis of national rates. Among workers who had a radiation record 3742 (40%) were also monitored for possible internal exposure to plutonium, 3044 (32%) to uranium, 1562 (17%) to tritium, 638 (7%) to polonium, and 281 (3%) to actinium. In these workers mortality from malignant neoplasms as a whole was not increased, but after a 10 year lag death rates from prostatic and renal cancers were generally more than twice the national average, these excesses arising in a small group of workers monitored for exposure to multiple radionuclides. Though mortality from lung cancer in workers monitored for exposure to plutonium was below the national average, it was some two thirds higher than in other radiation workers, the excess being of borderline statistical significance. Mortality from malignant neoplasms as a whole showed a weak and non-significant increasing trend with increasing level of cumulative whole body exposure to external radiation. When the exposures were lagged by 10 years the trend became stronger and significant, the estimated increase in relative risk per 10 mSv being 7.6% (95% confidence interval 0.4% to 15.3%). This trend was confined almost entirely to workers who were also monitored for exposure to radionuclides (p<0.001), the main contributions coming from lung cancer and prostatic cancer. Exposures of the lung and prostate from internal sources of radiation were not quantified, except for the contribution from tritium. It was therefore not possible to assess the extent to which the associations were due to internally deposited radionuclides rather than external exposure. The finding for prostatic cancer taken in conjunction with the results of other studies suggest a specific occupational hazard in a small group of workers in the nuclear industry who had comparatively high exposures to external radiation and who were also monitored for internal exposure to multiple radionuclides. Research is needed to discover whether any of the radionuclides and other substances concerned are concentrated in the prostate. The occurrence of lung cancer in this workforce requires further investigation taking into account smoking habits and tissue doses from inhaled radionuclides.