An examination, with a meta-analysis, of studies of childhood leukaemia in relation to population mixing.

BACKGROUND: Marked influxes of people into rural areas, termed rural population mixing (PM), have been associated with excesses of childhood leukaemia (CL), consistent with mini-epidemics of a mainly immunising, subclinical infection to which CL is a rare response. For such situations of rural PM would promote contacts between infected and susceptible individuals, the latter tending to have a higher than average prevalence in rural or isolated areas. Confusion has arisen from some workers applying the term PM to non-rural situations lacking known recent change. METHODS: Available PM studies using the original definition of influxes were examined, a meta-analysis carried out of studies of CL in relation to exposure to high levels of rural PM, and also a detailed analysis by age group. RESULTS: The meta-analysis of 17 studies shows a significant CL excess in association with rural PM: overall relative risk (RR) at ages 0-14: 1.57; 95% confidence interval 1.44-1.72; at 0-4 years 1.72 (1.54-1.91). This contrasts with the absence of an excess of CL in similarly exposed urban areas (RR 1.00; 0.93-1.07), pointing to a high level of immunity there. The mixed results of studies using other definitions of PM were summarised. The excess associated with rural PM below age 2 years (RR 1.51; 1.17, 1.92) was not appreciably different from that at later childhood ages. CONCLUSION: Much of the inconsistency among studies ostensibly about CL and PM reflects the use of definitions other than that originally proposed. The broad similarity of the CL excess below age 2 with that at older childhood ages is inconsistent with the Greaves' delayed infection hypothesis, since any infection underlying the former is difficult to consider as delayed.

Childhood leukaemia, nuclear sites, and population mixing.

The excess of childhood leukaemia (CL) in Seascale, near the Sellafield nuclear reprocessing site in rural NW England, suggested that an epidemic of an underlying infection, to which CL is a rare response, is promoted by marked population mixing (PM) in rural areas, in which the prevalence of susceptibles is higher than average. This hypothesis has been confirmed by 12 studies in non-radiation situations. Of the five established CL excesses near nuclear sites, four are associated with significant PM; in the fifth, the Krummel power station in Germany, the subject has not been thoroughly investigated.

Childhood leukaemia and ordnance factories in west Cumbria during the Second World War.

Much evidence has accumulated that childhood leukaemia (CL) is a rare response to a common, but unidentified, infection and in particular that situations involving the unusual mixing of urban and rural groups (approximating to, respectively, groups infected with, and susceptible to, the relevant microorganism) can produce localised epidemics with consequent increases of the infrequent leukaemic complication. During the Second World War, explosives production factories were built and operated at Drigg and Sellafield, and a shell filling factory at Bootle, in west Cumbria, England, requiring substantial numbers of construction workers to be brought into this remote and isolated area. Following the design of an earlier study of CL near large (post-war) rural construction sites, mortality from this disease was investigated with the help of the Office of National Statistics, in the area around these Cumbrian factories where local workers largely lived, during the construction period and with particular reference to the overlapping construction and operational phase when the mixing of local and migrant workers would have been greatest. An excess of leukaemia deaths at ages 1-14 was found during the construction period (observed 3; observed/expected (O/E) 2.2, 95% confidence interval (CI): 0.6, 6.0), which was more marked and statistically significant during the overlap with operations (O 3; O/E 4.5, 95% CI: 1.1, 12.2), especially at ages 1-4 (O 2; O/E 7.1, CI: 1.2, 23.6). A previous investigation did not detect this excess because it considered only a small part of west Cumbria that omitted the communities where most of the workforce lived, having incorrectly attributed the post-war expansion of the village of Seascale (situated between Drigg and Sellafield) to the wartime ordnance factories. The present findings are consistent with the results of the earlier study of rural construction projects and with the general evidence that marked rural-urban population mixing increases the risk of CL.

Cancer risks in a historical UK cohort of benzene exposed workers.

AIMS: To examine mortality from different causes and cancer incidence among a cohort of benzene workers in England and Wales. METHODS: A cohort of 5514 workers who had been occupationally exposed to benzene in 1966/67 or earlier was assembled by the former Factory Inspectorate and the Medical Research Council from details provided by 233 employers in England and Wales. The cohort was followed up for mortality (1968-2002) and cancer registrations (1971-2001). National mortality rates and cancer registration (incidence) rates were used to calculate standardised mortality ratios and standardised registration ratios. RESULTS: Mortality was close to expectation for all causes and significantly increased for cancer of the lip, cancer of the lung and bronchus, secondary and unspecified cancers, acute non-lymphocytic leukaemia (ANLL), and all neoplasms. Significant deficits were shown for three non-malignant categories (mental disorders, diseases of the digestive system, accidents). SMRs for other leukaemia, lymphomas, and multiple myeloma were close to or below expectation. There was some evidence of under-ascertainment of cancer registrations, although significantly increased SRRs were shown for lung cancer and cancer of the pleura (mesothelioma). CONCLUSIONS: Many study subjects would have been exposed to carcinogens other than benzene (for example, asbestos, rubber industry fumes, foundry fumes, polycyclic aromatic hydrocarbons), and the excesses of lung cancer and mesothelioma are likely to reflect exposures to these other carcinogens. The carcinogenic effects of benzene exposure on the lymphohaematopoietic system were limited to ANLL.

Cancer in the offspring of radiation workers: an investigation of employment timing and a reanalysis using updated dose information.

An earlier case-control study found no evidence of paternal preconceptional irradiation (PPI) as a cause of childhood leukaemia and non-Hodgkin's lymphoma (LNHL). Although fathers of children with LNHL were more likely to have been radiation workers, the risk was most marked in those with doses below the level of detection. The timing of paternal employment as a radiation worker has now been examined. The previously reported elevated risk of LNHL in the children of male radiation workers was limited to those whose fathers were still radiation workers at conception or whose employment also continued until diagnosis. Children whose fathers stopped radiation work prior to their conception were found to have no excess risk of LNHL. It was not possible to distinguish between the risks associated with paternal radiation work at conception and at the time of diagnosis. A reanalysis of the original study hypothesis incorporating updated dosimetric information gave similar results to those obtained previously. In particular, the risks of LNHL did not show an association with radiation doses received by the father before conception. It seems likely that the increased risk of LNHL among the children of male radiation workers is associated with an increased exposure to some infective agent consequent on high levels of population mixing.

A case-control study of childhood leukaemia and paternal occupational contact level in rural Sweden.

In a national case-control study in Sweden, we investigated whether in rural areas (where susceptible individuals are more prevalent than in urban areas) leukaemia risk was higher among the young children of fathers with many work contacts, as the infective hypothesis has predicted. A total of 1935 cases diagnosed in 1958-1998 together with 7736 age-matched (within 1 year) population controls (of whom 970 and 3880 respectively were aged 0-4) were linked to paternal occupational details as recorded in the census closest to the year of birth. Applying the two classifications of occupational contact level used in a study of rural Scotland, the odds ratios for children aged 0-4 years in the highest contact category (which includes teachers) in the most rural Swedish counties were 3.47 (95% CI 1.54, 7.85) and 1.59 (1.07, 2.38) respectively, relative to the medium and low (reference) category; no such excess was found in urban or intermediate counties. There was also a significant positive trend at ages 0-4 in the rural counties across the three levels of increasing occupational contact (P for trend 0.02 and 0.03, respectively), but again not in the urban or intermediate counties. No such effect or trend was found at ages 5-14 in any of the three county groupings. The findings confirm those of a recent study in rural Scotland, and also suggest that unusual population mixing (as occurred in Scotland as a result of the North Sea oil industry) is not a necessary requirement for the effect, since comparable mixing has not been a feature of rural Sweden.

Paternal occupational contact level and childhood leukaemia in rural Scotland: a case-control study.

In a national Scottish study of 809 cases of leukaemia and non-Hodgkins lymphoma diagnosed in 1950-89 among children aged 0-4 years who were born in Scotland, together with 2363 matched population controls, we investigated one aspect of the infective hypothesis. This concerns whether in rural areas (where the prevalence of susceptible individuals is likely to be higher) the risk is greater among the young children of men whose work involves contacts with many different people, particularly children, as noted in certain childhood infections. A positive trend was found in rural areas across 3 levels of increasing paternal occupational contact (as recorded at birth) by each of 2 previously defined classifications; no such effect was found in urban areas. The rural trend was more marked in that part of the study period with greater population mixing, but the difference from the period with less mixing was not itself significant, leaving open whether these rural findings reflect the extreme isolation of much of rural Scotland, or the effects in such areas of a degree of population mixing. In marked contrast, among the 850 cases and 2492 controls aged 5-14, those in rural areas in the higher population mixing period showed a significantly decreasing trend with increasing paternal occupational contact level. This would be consistent with immunity produced either by earlier infection at ages 0-4 years, or directly by low doses of the infective agent that were largely immunizing at these older ages. The findings overall provide further support for infection underlying childhood leukaemia and for the role of adults.

Infective cause of childhood leukaemia and wartime population mixing in Orkney and Shetland, UK.

In Orkney and Shetland (the UK's northernmost islands), during World War II, local people were outnumbered by servicemen stationed there in case of a northern invasion. Such rural-urban population mixing promotes contact between susceptible and infected individuals. We compared childhood leukaemia mortality in wartime and postwar cohorts of Orkney and Shetland children. Childhood leukaemia increased 3.6-fold, (p=0.001) in the wartime, but not in the postwar, cohort compared with national Scottish rates. These findings add to the evidence for infection as a cause of childhood leukaemia.

Risk of breast cancer and other cancers in heterozygotes for ataxia-telangiectasia.

Mortality from cancer among 178 parents and 236 grandparents of 95 British patients with ataxia-telangiectasia was examined. For neither parents nor grandparents was mortality from all causes or from cancer appreciably elevated over that of the national population. Among mothers, three deaths from breast cancer gave rise to a standardized mortality ratio of 3.37 (95% confidence interval (CI): 0.69-9.84). In contrast, there was no excess of breast cancer in grandmothers, the standardized mortality ratio being 0.89 (95% CI: 0.18-2.59), based on three deaths. This is the largest study of families of ataxia-telangiectasia patients conducted in Britain but, nonetheless, the study is small and CIs are wide. However, taken together with data from other countries, an increased risk of breast cancer among female heterozygotes is still apparent, though lower than previously thought.

Pregnancy and menstrual hormone levels in mothers of twins compared to mothers of singletons.

This study examined the hormonal differences between premenopausal mothers of twins and other premenopausal parous women during and after pregnancy. Serum concentrations of oestradiol and testosterone between 6 and 20 weeks of gestation were measured for 11 mothers of twins and 115 mothers of singletons selected from the controls in a case-control study of cryptorchidism. Serum concentrations of oestradiol, progesterone, testosterone, follicle stimulating hormone and sex hormone-binding globulin during the menstrual cycle were measured for 25 mothers of twins and 38 mothers of singletons recruited as a part of a prospective study of breast cancer risk. During pregnancy, women carrying twins had a 58% higher geometric mean oestradiol concentration (p = 0.02) and a 50% higher testosterone concentration (p = 0.03) than women carrying singletons. Women who had previously had twins demonstrated a 49% higher mean concentration of follicle stimulating hormone (p = 0.02) and a 42% higher concentration of sex hormone-binding globulin (p = 0.03) than women who had singletons only, but no significant differences in oestradiol, progesterone and testosterone concentrations. The increased concentrations of follicle stimulating hormone during the menstrual cycle of mothers of twins, which has also been reported in two previous studies suggests that follicle stimulating hormone level may be an important determinant of dizygotic twinning.

Cancer in the offspring of radiation workers: a record linkage study.

OBJECTIVES: To test the "Gardner hypothesis" that childhood leukaemia and non-Hodgkin lymphoma can be caused by fathers' exposure to ionising radiation before the conception of the child, and, more generally, to investigate whether such radiation exposure of either parent is a cause of childhood cancer. DESIGN: Case-control study. SETTING: Great Britain. SUBJECTS: 35,949 children diagnosed as having cancer, together with matched controls. MAIN OUTCOME MEASURES: Parental employment as radiation worker as defined by inclusion in the National Registry for Radiation Workers and being monitored for external radiation before conception of child; cumulative dose of external ionising radiation for various periods of employment before conception; dose during pregnancy. RESULTS: After cases studied by Gardner and colleagues were excluded, fathers of children with leukaemia or non-Hodgkin lymphoma were significantly more likely than fathers of controls to have been radiation workers (relative risk 1.77, 95% confidence interval 1.05 to 3.03) but there was no dose-response relation for any of the exposure periods studied; indeed, the association was greatest for those with doses below the level of detection. No increased risk was found for fathers with a lifetime preconception dose of 100 mSv or more, or with a dose in the 6 months before conception of 10 mSv or more. There was no increased risk for the group of other childhood cancers. Mothers' radiation work was associated with a significant increase of childhood cancer (relative risk 5.00, 1.42 to 26.94; based on 15 cases and 3 controls). Only four of the case mothers and no controls were radiation workers during pregnancy. CONCLUSIONS: These results do not support the hypothesis that paternal preconception irradiation is a cause of childhood leukaemia and non-Hodgkin lymphoma; the observed associations may be chance findings or results from exposure to infective or other agents. If there is any increased risk for the children of fathers who are radiation workers, it is small in absolute terms: in Britain the average risk by age 15 years is 6.5 per 10,000; our best estimate, using all available data, is that the increase is 5.4 per 10,000. For mothers, the numbers are too small for reliable estimates of the risk, if any, to be made.

High-contact paternal occupations, infection and childhood leukaemia: five studies of unusual population-mixing of adults.

The hypothesis has been tested that, among excesses of childhood leukaemia associated with extreme population-mixing, the incidence is higher for the children of men in occupations involving contact with many individuals (particularly children), as noted in certain childhood infections. Data on childhood leukaemia were examined from five previous studies of the author in which significant excesses had been found associated with population-mixing involving adults. Occupational titles were categorized according to the estimated level of work contacts as medium, high, very high or indeterminate. Occupations involving frequent contact with children were categorized as having a very high contact level given the high frequency of exposure to the infection postulated as underlying childhood leukaemia. There was a significant positive trend (P < 0.001) in childhood leukaemia risk at ages 0-14 years across the occupational contact categories from the reference group (comprising the medium and low plus indeterminate categories) through high to very high (i.e. high-child) contact categories in the combined data from the author's five studies of adult population-mixing; this significant trend also applied at ages 0-4 (P < 0.001) and 5-14 (P < 0.01) years. The excess in the high category was mainly because of paternal occupations connected with the construction industry and transport, suggesting a broader definition of the 'very high' contact category. No sign of these excesses was found in a limited examination of the question outside areas of population-mixing using mortality data for childhood leukaemia in the general population of England and Wales. The findings represent the first individual-based support for infection underlying childhood leukaemia that is promoted by population-mixing, as well as further support for the role of adults in transmission of the infection.