Mortality in British military participants in human experimental research into chemical warfare agents at Porton Down: cohort study.

OBJECTIVE: To investigate any long term effects on mortality in participants in experimental research related to chemical warfare agents from 1941 to 1989. DESIGN: Historical cohort study. Data sources Archive of UK government research facility at Porton Down, UK military personnel records, and national death and cancer records. Participants 18,276 male members of the UK armed forces who had spent one or more short periods (median 4 days between first and last test) at Porton Down and a comparison group of 17,600 non-Porton Down veterans followed to 31 December 2004. MAIN OUTCOME MEASURES: Mortality rate ratio of Porton Down compared with non-Porton Down veterans and standardised mortality ratio of each veteran group compared with the general population. Both ratios adjusted for age group and calendar period. RESULTS: Porton Down veterans were similar to non-Porton Down veterans in year of enlistment (median 1951) but had longer military service (median 6.2 v 5.0 years). After a median follow-up of 43 years, 40% (7306) of Porton Down and 39% (6900) of non-Porton Down veterans had died. All cause mortality was slightly greater in Porton Down veterans (rate ratio 1.06, 95% confidence interval 1.03 to 1.10, P<0.001), more so for deaths outside the UK (1.26, 1.09 to 1.46). Of 12 cause specific groups examined, rate ratios in Porton Down veterans were increased for deaths attributed to infectious and parasitic (1.57, 1.07 to 2.29), genitourinary (1.46, 1.04 to 2.04), circulatory (1.07, 1.01 to 1.12), and external (non-medical) (1.17, 1.00 to 1.37) causes and decreased for deaths attributed to in situ, benign, and unspecified neoplasms (0.60, 0.37 to 0.99). There was no clear relation between type of chemical exposure and cause specific mortality. The mortality in both groups of veterans was lower than that in the general population (standardised mortality ratio 0.88, 0.85 to 0.90; 0.82, 0.80 to 0.84). CONCLUSIONS: Mortality was slightly higher in Porton Down than non-Porton Down veterans. With lack of information on other important factors, such as smoking or service overseas, it is not possible to attribute the small excess mortality to chemical exposures at Porton Down.

Cancer morbidity in British military veterans included in chemical warfare agent experiments at Porton Down: cohort study.

OBJECTIVE: To determine cancer morbidity in members of the armed forces who took part in tests of chemical warfare agents from 1941 to 1989. DESIGN: Historical cohort study, with cohort members followed up to December 2004. DATA SOURCE: Archive of UK government research facility at Porton Down, UK military personnel records, and national death and cancer records. PARTICIPANTS: All veterans included in the cohort study of mortality, excluding those known to have died or been lost to follow-up before 1 January 1971 when the UK cancer registration system commenced: 17,013 male members of the UK armed forces who took part in tests (Porton Down veterans) and a similar group of 16,520 men who did not (non-Porton Down veterans). MAIN OUTCOME MEASURES: Cancer morbidity in each group of veterans; rate ratios, with 95% confidence intervals, adjusted for age group and calendar period. RESULTS: 3457 cancers were reported in the Porton Down veterans compared with 3380 cancers in the non-Porton Down veterans. While overall cancer morbidity was the same in both groups (rate ratio 1.00, 95% confidence interval 0.95 to 1.05), Porton Down veterans had higher rates of ill defined malignant neoplasms (1.12, 1.02 to 1.22), in situ neoplasms (1.45, 1.06 to 2.00), and those of uncertain or unknown behaviour (1.32, 1.01 to 1.73). CONCLUSION: Overall cancer morbidity in Porton Down veterans was no different from that in non-Porton Down veterans.

Exposures recorded for participants in the UK Chemical Warfare Agent Human Research Programme, 1941-1989.

OBJECTIVES: This study describes exposures to military veterans who participated between 1941 and 1989 in British research at Porton Down on the effects of exposure to chemical warfare agents and to defences against those agents. The study is part of a programme of epidemiological research initiated in response to service veterans' concerns about possible long-term health effects of their participation. METHODS: All entries in 97 books held in the Porton Down historical experimental archive covering the years 1939-1989 were reviewed. For tests between April 1941 and December 1989, data were abstracted on chemicals used, with additional detail abstracted for tests involving vesicants and nerve agents. For tests recorded during 1939-1941, similar data were abstracted for a representative sample of tests. RESULTS: Historical data were abstracted for 17 303 veterans included in the cohort study of 18,276 servicemen who took part in tests at Porton Down between 1941 and 1989. The median number of days per veteran on which tests were carried out was 2 days. The median difference between the last and first day of testing was 4 days. A large number of chemicals were tested over this period (n = 492). The type of chemical tested varied over time. Exposures were often modified by respirator use or use of protective clothing or protective equipment. It was possible to assign a quantitative measure of cumulative exposure to 73% of veterans exposed to the vesicant sulphur mustard--3491 (34%) of exposed veterans had cumulative exposures > or =10.63 mg and for 70% of veterans exposed to the nerve agent sarin--658 (29%) of exposed veterans had cumulative exposures > or =15.0 mg min m(-3). Ninety-three per cent of veterans exposed to sulphur mustard were classified to a semi-quantitative scale of dermal effect--3771 (37%) had a vesicle or necrosed area, and 69% of veterans exposed to sarin could be categorized by change in blood cholinesterase activity--1033 (31%) had a depression in cholinesterase activity of > or =30%. CONCLUSIONS: The experimental archive at Porton Down has proved to be a rich source of data on tests conducted between 1941 and 1989. It has been possible to categorize most veterans according to date of test, chemical group, chemical, type of protection and, for certain chemicals, level of exposure and/or degree of acute toxicity. These categorizations have been used to assign veterans to exposure groups for epidemiological analysis.

Risk factors for testicular cancer: a case-control study in twins.

Early life and anthropometric risk factors for testicular cancer were examined in a case-control study in England and Wales in which affected male twins were compared with their unaffected male co-twins. Questionnaire data was obtained for 60 twin pairs. Significantly raised risk of testicular cancer occurred in twins who had longer arms and legs than their co-twin. There was a significant excess of testicular cancer reported in non-twin brothers, as well as in twin brothers, of cases. Risk was also significantly raised in relation to cryptorchidism. The results on limb length suggest that factors, perhaps nutritional, affecting growth before puberty, may be causes of testicular cancer. The results on risk in brothers add to evidence of a large genetic component in aetiology of the tumour. The risk associated with cryptorchidism in the twins accords with the hypothesis that cryptorchidism is causally associated with testicular cancer because it is a cause of the malignancy, rather than because the same maternal factors experienced in utero cause both conditions.

Cancer mortality in relation to monitoring for radionuclide exposure in three UK nuclear industry workforces.

Cancer mortality in 40,761 employees of three UK nuclear industry facilities who had been monitored for external radiation exposure was examined according to whether they had also been monitored for possible internal exposure to tritium, plutonium or other radionuclides (uranium, polonium, actinium or other unspecified). Death rates from cancer were compared both with national rates and with rates in radiation workers not monitored for exposure to any radionuclides. Among workers monitored for tritium exposure, overall cancer mortality was significantly below national rates [standardized mortality ratio (SMR) = 83, 165 deaths; 2P = 0.02] and none of the cancer-specific death rates was significantly above either the national average or rates in non-monitored workers. Although the overall death rate from cancer in workers monitored for plutonium exposure was also significantly low relative to national rates (SMR = 89, 581 deaths; 2P = 0.005), mortality from pleural cancer was significantly raised (SMR = 357, nine deaths; 2P = 0.002); none of the rates differed significantly from those of non-monitored workers. Workers monitored for radionuclides other than tritium or plutonium also had a death rate from all cancers combined that was below the national average (SMR = 86, 418 deaths; 2P = 0.002) but prostatic cancer mortality was raised both in relation to death rates in the general population (SMR = 153, 37 deaths; 2P = 0.02) and to death rates in radiation workers who had not been monitored for exposure to any radionuclide [rate ratio (RR) = 1.65; 2P = 0.03]. Mortality from cancer of the lung was also significantly increased in workers monitored for other radionuclides compared with those of radiation workers not monitored for exposure to radionuclides (RR = 1.31, 164 deaths; 2P = 0.01). For cancers of the lung, prostate and all cancers combined, death rates in monitored workers were examined according to the timing and duration of monitoring for radionuclide exposure, with rates of radiation workers not monitored for any radionuclide forming the comparison group. In tritium-monitored workers, RRs for prostatic cancer varied significantly according to the number of years in which they were monitored (2P = 0.03). In workers monitored for plutonium exposure, RRs for all cancers combined increased with the number of years in which they were monitored (2P = 0.04) and with the number of years since first monitoring (2P = 0.0003). There was little suggestion of systematic variation in RRs for workers monitored for other radionuclides in relation to the timing or duration of monitoring, nor did it appear that their raised rates of cancer of the lung and prostate were explained by external radiation dose. These analyses of cancer mortality in relation to monitoring for radionuclide exposure reported in a large cohort of nuclear industry workers suggest that certain patterns of monitoring for some radionuclides may be associated with higher death rates from cancers of the lung, pleura, prostate and all cancers combined. Some of these findings may be due to chance. Moreover, because of the paucity of related data and lack of information about other possible exposures, such as whether plutonium workers are more likely to be exposed to asbestos, firm conclusions cannot be drawn at this stage. Further investigations of the relationship between radionuclide exposure and cancer in nuclear industry workers are needed.

Risks of breast and testicular cancers in young adult twins in England and Wales: evidence on prenatal and genetic aetiology.

BACKGROUND: Aetiology of breast and testicular cancers may have prenatal factors, possibly exposure of the fetus to high concentrations of maternal oestrogen. Dizygotic twinning probably involves high hormone concentrations, and therefore, dizygotic twins might be at raised risk of these cancers. The aetiologies of breast and testicular cancers have genetic components, for breast cancer, especially at younger ages. Twins of these probands may, therefore, be at high risk. We investigated risk in twins of patients with breast cancer at young ages or with testicular cancer. METHODS: We identified twins with breast cancer incident at ages younger than 45 years and with incident testicular cancer in England and Wales during 1971-89 by cross-matching national cancer-registration and births records. We determined zygosity by questionnaires to the patients. The twins of probands were followed up for cancer incidence and death. We analysed risks of breast and testicular cancer in dizygotic twins compared with monozygotic twins, and in monozygotic and dizygotic twins of probands. FINDINGS: We identified 500 twins with breast cancer and 194 with testicular cancer. We found a non-significantly raised risk of breast cancer in dizygotic compared with monozygotic twins younger than 30 years (odds ratio 2.3 [95% CI 0.9-5.9]) but not older. The overall risk of testicular cancer was significantly higher in dizygotic twins than in monozygotic twins (1.5 [1.1-2.2]) consequent on a risk for seminomas was high (3.2 [1.6-6.5]; p = 0.001). Risk of breast cancer was significantly raised in female twins of probands (standardised incidence ratio 7.7 [4.9-12.2], p < 0.001). The relative risk of breast cancer was 34.7 (9.5-126.5) in monozygotic twins of women in whom breast cancer had occurred before age 35 years. The cumulative risk of breast cancer for these twins by age 40 years was 29% (13-56). The relative risk of testicular cancer was 37.5 (12.3-115.6) in twins of men with testicular cancer. The cumulative risk by age 40 years in monozygotic twins of men with testicular cancer was 14% (4-46). INTERPRETATION: The higher risks of these cancers in dizygotic than in monozygotic twins support a prenatal aetiology, and are compatible with aetiology related to raised maternal concentrations of free, unbound oestrogens. The results for twins of probands have implications for genetic aetiology; appropriate clinical action for monozygotic twins needs consideration.

Data linkage methods used in maternally-linked birth and infant death surveillance data sets from the United States (Georgia, Missouri, Utah and Washington State), Israel, Norway, Scotland and Western Australia.

In this paper we describe the methods used to link birth and infant mortality and morbidity surveillance data sets into sibships using deterministic or multistage probabilistic linkage methods. We describe nine linked data sets: four in the United States (Georgia, Missouri, Utah and Washington State), and four elsewhere (Scotland, Norway, Israel and Western Australia). Norway and Israel use deterministic methods to link births and deaths into sibships. The deterministic linkage is usually dependent on the availability of national identification numbers. In both countries they assign these numbers at birth. Deterministic linkage is usually highly successful, and the major problem is the validation of linkages. In the United States, Western Australia and UK linkage is multistage and probabilistic. This approach is usually dependent on the calculation linkage weights from sociodemographic variables. The success rates of probabilistic methods are above 80%. Maternally-linked perinatal data open new vistas for epidemiological research. Recurrence of poor perinatal outcomes is more appropriately studied using longitudinally-linked data sets. In addition, the emergence of risk factors and the recurrence of risk factors can be studied.