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.     

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.     

Childhood Cancer and Social Contact: the Role of Paternal Occupation (United Kingdom)*

Objective: To investigate the relationship between childhood cancer (particularly leukaemia) and paternal occupational social contact (a proxy for potential exposure to infections) using the UK Childhood Cancer Study. Methods: Using a national population-based case–control study, self-reported occupational data from fathers of 3596 children diagnosed with cancer between 1991 and 1996 under 15 years of age (cases) and fathers of 7011 children without cancer (controls) were analysed. Associations were assessed using odds ratios (OR) calculated by time of exposure (birth, diagnosis), diagnostic group (all cancers, leukaemia, acute lymphoblastic leukaemia (ALL), central nervous system tumours, other cancers), level of occupational social contact (high, medium, low), urban–rural status at diagnosis and occupational title. Results: From 371 occupations, 75 (20%) were classified as having high levels of occupational social contact, 31 (8%) as medium and the remaining 265 (71%) as low. No associations were apparent for fathers’ occupational social contact overall, for any time period or diagnostic group. OR for leukaemia and high levels of paternal occupational social contact at birth and diagnosis being 1.02 (95% confidence interval (CI) = 0.88–1.18) and 0.91 (95% CI = 0.79–1.06), respectively. Analyses by urban–rural status at diagnosis and by occupational title revealed no notable associations. Conclusions: The analyses of paternal occupational histories do not support the suggested association between high levels of paternal occupational social contact and an increased risk of childhood leukaemia. However, the role of participation bias should not be discounted. See Appendix 1 for Regional Investigators and Management Committee. Financial support: Leukaemia Research Fund, UK.     

Population mixing, socioeconomic status and incidence of childhood acute lymphoblastic leukaemia in England and Wales: analysis by census ward

In this population-based study of acute lymphoblastic leukaemia (ALL) diagnosed among children aged under 15 years in England and Wales during 1986-1995, we analysed incidence at census ward level in relation to a range of variables from the 1991 census, which could be relevant to theories of infectious aetiology. 'Population-mixing' measures, used as surrogates for quantity and diversity of infections entering the community, were calculated from census data on the origins and destinations of migrants in the year before the census. Incidence at ages 1-4 years tended independently to be higher in rural wards, to increase with the diversity of origin wards from which in-migrants had moved during the year before the census, and to be lower in the most deprived areas as categorised by the Carstairs index. This last association was much weaker when urban/rural status and in-migrants' diversity were allowed for. There was no evidence of association with population mixing or deprivation for ALL diagnosed at ages 0 or 5-14 years. The apparent specificity to the young childhood age group suggests that these associations are particularly marked for precursor B-cell ALL, with the disease more likely to occur when delayed exposure to infection leads to increased immunological stress, as predicted by Greaves. The association with diversity of incomers, especially in rural areas, is also consistent with the higher incidence of leukaemia predicted by Kinlen, where population mixing results in below average herd immunity to an infectious agent.     

Case–control study of paternal occupation and childhood leukaemia in Great Britain, 1962–2006

Background:

Paternal occupational exposures have been proposed as a risk factor for childhood leukaemia. This study investigates possible associations between paternal occupational exposure and childhood leukaemia in Great Britain.

Methods:

The National Registry of Childhood Tumours provided all cases of childhood leukaemia born and diagnosed in Great Britain between 1962 and 2006. Controls were matched on sex, period of birth and birth registration subdistrict. Fathers'' occupations were assigned to 1 or more of 33 exposure groups. Social class was derived from father''s occupation at the time of the child''s birth.

Results:

A total of 16 764 cases of childhood leukaemia were ascertained. One exposure group, paternal social contact, was associated with total childhood leukaemia (odds ratio 1.14, 1.05–1.23); this association remained significant when adjusted for social class. The subtypes lymphoid leukaemia (LL) and acute myeloid leukaemia showed increased risk with paternal exposure to social contact before adjustment for social class. Risk of other leukaemias was significantly increased by exposure to electromagnetic fields, persisting after adjustment for social class. For total leukaemia, the risks for exposure to lead and exhaust fumes were significantly <1. Occupationally derived social class was associated with risk of LL, with the risk being increased in the higher social classes.

Conclusion:

Our results showed some support for a positive association between childhood leukaemia risk and paternal occupation involving social contact. Additionally, LL risk increased with higher paternal occupational social class.     

Population mixing and leukaemia in young people around the La Hague nuclear waste reprocessing plant

In order to investigate for an association between population mixing and the occurrence of leukaemia in young people (less than 25 years), a geographical study was conducted, for the years 1979 to 1998, in Nord Cotentin (France). This area experienced between the years 1978 and 1992 a major influx of workers for the construction of a nuclear power station and a new nuclear waste reprocessing unit. A population mixing index was defined on the basis of the number of workers born outside the French department of 'La Manche' and living in each 'commune', the basic geographical unit under study. The analyses were done with indirect standardisation and Poisson regression model allowing or not for extra-Poisson variation. Urban 'communes' were considered as the reference population. The Incidence Rate Ratio was 2.7 in rural 'communes' belonging to the highest tertile of population mixing (95% Bayesian credible interval, 95%BCI=1.2-5.9). A positive trend was observed among rural strata with increasing population mixing index (IRR for trend=1.4, 95%BCI=1.1-1.8). The risk became stronger for Acute Lymphoblastic Leukaemia in children 1-6 years old in the highest tertile of population mixing (IRR=5.5, 95%BCI=1.4-23.3). These findings provide further support for a possible infective basis of childhood leukaemia.     

Parental social contact in the work place and the risk of childhood acute lymphoblastic leukaemia

To study the possible relation between parental social contact through occupation, a marker for a child's risk of infection, and childhood acute lymphoblastic leukaemia (ALL), the parents of 294 children with ALL aged 0-14.9 years and 376 matched controls were interviewed about their jobs after their child's birth up to the age of 3 years. Job titles were assigned to a level of social contact, and an index of occupational social contact months was created using the level and the job duration. Positive interactions between this index and rural residence associated with an increased risk of childhood ALL and common ALL (c-ALL) were observed (interaction P-value=0.02 for both, using tertiles of contact months; interaction P-value=0.05 and 0.02 for ALL and c-ALL, respectively, using continuous contact months); such findings were not observed when job durations were ignored. Our data suggest that duration of parental occupation may be important when examining the association between parental social contact in the workplace and childhood leukaemia.     

Childhood leukaemia incidence and the population mixing hypothesis in US SEER data

We evaluated the infectious aetiology hypothesis of childhood leukaemia that rapid population influx into rural areas is associated with increased risk. Using data from the US SEER program, we found that in changes in rural county population sizes from 1980 to 1989 were associated with incidence rates for childhood acute lymphocytic leukaemia (ALL). The observed associations were strongest among children 0-4 years of age, born in the same state as diagnosis, in extremely rural counties, and when counties adjacent to nonrural counties were excluded. Similar analyses for brain and central nervous system (CNS) cancer in children, a disease less linked to this infectious hypothesis, provide evidence against methodologic bias. Similar evaluations for other decades were not meaningful due to limited sample sizes and, perhaps, increased population mobility.     

Leukaemia and non-Hodgkin's lymphoma in young persons resident in small areas of West Cumbria in relation to paternal preconceptional irradiation.

The results of a previous study suggested that an association between childhood leukaemia and the radiation dose received occupationally by a father before the conception of his child might provide the explanation for the marked excess of childhood leukaemia and non-Hodgkin''s lymphoma in the village of Seascale, West Cumbria. The present study identifies other small areas (electoral wards) in West Cumbria where excess cases of leukaemia and non-Hodgkin''s lymphoma in young people have occurred and determines whether a recorded dose of radiation was received occupationally by the father before the conception of each of the affected individuals. Forty-one cases of leukaemia and non-Hodgkin''s lymphoma were diagnosed during 1968-85 in young people under 25 years of age resident in the 49 electoral wards lying within the boundary of West Cumbria and the adjacent ward of Broughton. Raised incidence rate ratios (two-sided P<0.01) were found for acute lymphoblastic leukaemia among those aged 0-14 years (concentrated among those aged 0-4 years) in Seascale ward and among those aged 0-24 years (also concentrated among those aged 0-4 years) in Egremont North ward, for acute myeloid leukaemia among those aged 0-14 years in Sandwith ward, for all leukaemias among those aged 0-14 years in Broughton ward (South Lakeland) and for non-Hodgkin''s lymphoma among those aged 0-14 years in Seascale ward. For West Cumbria as a whole, incidence rates were not usual. Apart from Seascale, for none of these electoral wards has a father of an affected child been linked definitely to an occupational dose of radiation recorded before the conception of the child. Particularly striking are the excesses of acute lymphoblastic leukaemia cases among young children living in the wards of Seascale and Egremont North, situated 11 km apart. The cases in Egremont North are not associated with recorded doses of radiation received occupationally by fathers before the conception of the affected children, even though the total numbers of children associated with such doses born in Seascale and Egremont North wards are similar. This finding is further evidence against a causal role for paternal preconceptional radiation exposure in the cases of childhood leukaemia in Seascale.     

An ecologic study of childhood leukemia and population mixing in Ontario, Canada

Objective: To examine the association between population mixing and the incidence of childhood leukemia, specifically the acute lymphocytic leukemia (ALL) subtype among young children. Methods: This ecologic study was based on incidence rates of leukemia in children aged 0–14 years. The Ontario Cancer Registry was used to identify the residence of 1394 leukemia cases between 1978 and 1992. Ecologic units were composed of census subdivisions in a 5-year period. Percent population change, determined from the Census of Canada, was employed as a measure of population mixing. The relationship between population mixing and childhood leukemia was examined separately after stratifying by the level of geographic isolation, defined according to urban–rural status. Analyses were also conducted separately in specific age groups and for the ALL subtype. Results: Population growth in rural areas was associated with an increased incidence of leukemia, particularly for the ALL subtype in children aged 0–4 years (rate ratio = 1.8, 95% confidence interval 1.1–2.8, for a greater than 20% population change relative to no increase in population). In contrast, an elevated risk due to population mixing was not observed in urban areas. Conclusions: Results from this study are consistent with results from similar studies conducted in the United Kingdom, which are suggestive of a role for an infectious agent in the etiology of childhood leukemia, as proposed in the Kinlen hypothesis.     

Incidence of childhood leukaemia in The Netherlands (1973-1980).

The childhood leukaemia incidence rate for the Netherlands was estimated at 3.11 per 100.000 children (aged 0-15 year) per year, based on a complete nation-wide childhood leukaemia registry comprising the period 1973-1980. Acute lymphocytic leukaemia (ALL) accounted for 82.4% of the patients, acute non-lymphocytic leukaemia for 13.6% and chronic myeloid leukaemia for 2.9%. ALL occurred more frequently in boys (sex ratio 1.2). The highest ALL rate was observed in the 3-4 year age group. These figures corresponded with the data of the Manchester Children''s Tumour Registry. Neither the incidence rates according to year of diagnosis nor the incidence rates according to year of birth showed a significant trend with time. The total leukaemia incidence rate in urban areas was somewhat higher than in rural areas. While the direct comparison of the incidence rate between these areas is not significant, the trend over the three categories of urbanisation is significant.     

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.     

Childhood leukaemia and population movements in France, 1990-2003

In a national study, we investigated the incidence of childhood leukaemia (CL) over a 14-year period in France in relation to several measures based on the proportion of individuals who changed address between the last two national censuses. A positive association was found with the proportion of migrants who came from a distant place. The further the migrants came, the higher was the incidence of leukaemia, particularly among children aged 0-4 years in 'isolated' communes at the time of diagnosis (RR=1.4, 95% CI: 1.1,1.8 in the highest category of migration distance). Although the role of the population density was less obvious, a more marked association was found above a certain threshold. No association with the proportion of commuters was observed.     

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.     

Quantifying the effect of population mixing on childhood leukaemia risk: the Seascale cluster.

A statistical model was developed based on Poisson regression of incidence of childhood leukaemia and non-Hodgkin's lymphoma (NHL) in relation to population mixing among all 119 539 children born 1969-1989 to mothers living in Cumbria, north-west England, (excluding Seascale). This model was used to predict the number of cases in Seascale (the village adjacent to the Sellafield nuclear installation) children, born 1950-1989 and diagnosed before 1993. After allowing for age, the incidence of acute lymphoblastic leukaemia (ALL) and NHL was significantly higher among children born in areas with the highest levels of population mixing, relative risk (RR) = 11.7 (95% confidence interval (CI) 3.2-43) and was highest among children of incomers. The model predicted up to 3.0 (95% CI 1.3-6.0) cases of ALL/NHL in children born in Seascale compared to six observed and 2.0 (95% CI 1.0-3.4) cases in children resident, but not born, in Seascale compared to two observed. Population mixing is a significant risk factor for ALL/NHL, especially in young children, accounting for over 50% of cases in Cumbria and most cases in Seascale.     

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.     

Incidence of Childhood Leukemia in Iraq, 2000-2019

Background: Leukemia is a major concern for children worldwide. Around 30% of malignancies in children (ages 0–14) are caused by leukemia. Objective: This study aims to explore the time trends in the incidence of childhood leukemia (aged 0-14 years) in Iraq between 2000 and 2019. Methods: Poisson regression with a log link function was used to analyze the long-term trends of incidence related to childhood leukemia cancer based on published data from the Iraqi cancer registry between 2000 and 2019. Annual estimates of the population, by 5-year age groups and by gender obtained from the United Nations, population Division. Results: A total of 8,570 cases of leukemia children in Iraq between 2000 and 2019 were recorded, the boys to girl ratio were 1.32 to 1. The most diagnosed type of leukemia was Acute lymphoblastic leukemia, accounting for about 33.56%, followed by Leukemia Not specify (NOS) (17.3%) with a relatively equal proportion of stated instances between boys and girls in these subsets. The age-standardized incidence rates, aged 0-14 years, from 2000-2019 were 3.45/100,000 for both genders. The Joinpoint regression ASRs analysis of childhood leukemia from 2000-2019 among 0 –14 age group for both genders indicate that there was an overall significant increasing trend at 1.23% per year, while no one joinpoint was identified during the entire study period. Among boys, there was an overall insignificant increasing trend at 0.77% per year. Among girls, there was an overall significant increasing trend at 1.93% per year, while one joinpoint was identified during the entire study period.  Conclusions: The overall (both genders) incidence rate of childhood leukemia has been increasing significantly in Iraq. The test for trends was insignificant among boys, while it was significant among girls. The increasing trend of leukemia requires further epidemiological studies to describe incidence by geography in Iraq.     

Cancer among children of parents with autoimmune diseases

Many different aetiologies for childhood cancer have been suggested, but few are well established. One is that parental autoimmune disease is linked with susceptibility for haematopoietic malignancies in their offspring during childhood. The present study is the first to investigate this hypothesis using a follow-up design. A cohort of 53,811 children of more than 36,000 patients diagnosed with a systemic, organ-specific or suspected autoimmune disease were followed up for cancer incidence in the Danish Cancer Registry during 1968-1993. The parents were identified through the National Registry of Patients, while their children were traced in the Central Population Register. Cancer incidence among the offspring was compared with that in the corresponding childhood population of Denmark. In total, 115 cancers were observed among children aged 0-19 years, yielding a non-significant standardized incidence ratio of 1.07. Lymphomas contributed 21 cases to the overall number of tumours, 60% more than expected (95% confidence interval (CI) 1.0-2.4); leukaemia contributed 37 cases representing an excess of 30% (95% CI 0.9-1.8). Our results give some support to the hypothesis that parental autoimmune disease is associated with childhood lymphoma and leukaemia.     

Geographical distribution of birth places of children with cancer in the UK.

Using birth addresses, we examined the geographical variation in risk for all types of childhood cancers in the UK, on a scale corresponding to the 10-km squares of the National Grid. The effects of socioeconomic and environmental factors, including natural background radiation, were investigated and their relative importance assessed using Poisson regression. Data came from a national collection of all fatal cancers between 1953 and 1980 in children aged 0-15 years and consisted of 9363 children of known place of birth from 12 complete annual cohorts born in the period 1953-64. For solid cancers, as well as for leukaemias and lymphomas, there was marked variation of cumulative mortality according to place of birth. High mortalities were associated with areas characterized as having high social class, higher incomes and good housing conditions, but also with high population densities (births per hectare). Each of these contrasting social indicators operated independently of the other, indicating complex determining mechanisms. Mortalities increased with increased radon exposure, and the relationship operated independently of the socioeconomic factors. At this scale of analysis, we found no increased mortality in industrialized areas. A population-mixing infective hypothesis, which postulates high rates of leukaemia when highly exposed urban populations are introduced to isolated rural areas, was supported by observations of high mortalities in ''growth areas'' and New Towns, but was not readily reconcilable with the high rates seen in the high-density areas. If these correlations do indeed represent an infective mechanism, then the outcomes are not limited to malignancies of the immune system alone.