Childhood cancer research in oxford III: The work of CCRG on ionising radiation.

BACKGROUND: High doses of ionising radiation are a known cause of childhood cancer and great public and professional interest attaches to possible links between childhood cancer and lower doses, particularly of man-made radiation. This paper describes work done by the Childhood Cancer Research Group (CCRG) on this topic METHODS: Most UK investigations have made use of the National Registry of Childhood Tumours and associated controls. Epidemiological investigations have included national incidence and mortality analyses, geographical investigations, record linkage and case-control studies. Dosimetric studies use biokinetic and dosimetric modelling. RESULTS: This paper reviews the work of the CCRG on the association between exposure to ionising radiation and childhood cancer, 1975-2014. CONCLUSION: The work of CCRG has been influential in developing understanding of the causes of 'clusters' of childhood cancer and the risks arising from exposure to ionising radiation both natural and man-made. Some clusters around nuclear installations have certainly been observed, but ionising radiation does not seem to be a plausible cause. The group's work has also been instrumental in discounting the hypothesis that paternal preconception irradiation was a cause of childhood cancers and has demonstrated an increased leukaemia risk for children exposed to higher levels of natural gamma-ray radiation.

Variation with socioeconomic status of indoor radon levels in Great Britain: The less affluent have less radon.

We demonstrate a strong correlation between domestic radon levels and socio-economic status (SES) in Great Britain, so that radon levels in homes of people with lower SES are, on average, only about two thirds of those of the more affluent. This trend is apparent using small area measures of SES and also using individual social classes. The reasons for these differences are not known with certainty, but may be connected with greater underpressure in warmer and better-sealed dwellings. There is also a variation of indoor radon levels with the design of the house (detached, terraced, etc.). In part this is probably an effect of SES, but it appears to have other causes as well. Data from other countries are also reviewed, and broadly similar effects seen in the United States for SES, and in other European countries for detached vs other types of housing. Because of correlations with smoking, this tendency for the lower SES groups to experience lower radon levels may underlie the negative association between radon levels and lung cancer rates in a well-known ecological study based on US Counties. Those conducting epidemiological studies of radon should be alert for this effect and control adequately for SES.

Infant birthweight and risk of childhood cancer: international population-based case control studies of 40 000 cases.

BACKGROUND: High birthweight is an established risk factor for childhood leukaemia. Its association with other childhood cancers is less clear, with studies hampered by low case numbers. METHODS: We used two large independent datasets to explore risk associations between birthweight and all subtypes of childhood cancer. Data for 16 554 cases and 53 716 controls were obtained by linkage of birth to cancer registration records across five US states, and 23 772 cases and 33 206 controls were obtained from the UK National Registry of Childhood Tumours. US, but not UK, data were adjusted for gestational age, birth order, plurality, and maternal age and race/ethnicity. RESULTS: Risk associations were found between birthweight and several childhood cancers, with strikingly similar results between datasets. Total cancer risk increased linearly with each 0.5 kg increase in birthweight in both the US [odds ratio 1.06 (95% confidence interval 1.04, 1.08)] and UK [1.06 (1.05, 1.08)] datasets. Risk was strongest for leukaemia [USA: 1.10 (1.06, 1.13), UK: 1.07 (1.04, 1.10)], tumours of the central nervous system [USA: 1.05 (1.01, 1.08), UK: 1.07 (1.04, 1.10)], renal tumours [USA: 1.17 (1.10, 1.24), UK: 1.12 (1.06, 1.19)] and soft tissue sarcomas [USA: 1.12 (1.05, 1.20), UK: 1.07 (1.00, 1.13)]. In contrast, increasing birthweight decreased the risk of hepatic tumours [USA: 0.77 (0.69, 0.85), UK: 0.79 (0.71, 0.89) per 0.5 kg increase]. Associations were also observed between high birthweight and risk of neuroblastoma, lymphomas, germ cell tumours and malignant melanomas. For some cancer subtypes, risk associations with birthweight were non-linear. We observed no association between birthweight and risk of retinoblastoma or bone tumours. CONCLUSIONS: Approximately half of all childhood cancers exhibit associations with birthweight. The apparent independence from other factors indicates the importance of intrauterine growth regulation in the aetiology of these diseases.

Is fluoride a risk factor for bone cancer? Small area analysis of osteosarcoma and Ewing sarcoma diagnosed among 0-49-year-olds in Great Britain, 1980-2005.

BACKGROUND: Artificial fluoridation of drinking water to improve dental health has long been a topic of controversy. Opponents of this public health measure have cited the possibility of bone cancer induction. The study objective was to examine whether increased risk of primary bone cancer was associated with living in areas with higher concentrations of fluoride in drinking water. METHODS: Case data on osteosarcoma and Ewing sarcoma, diagnosed at ages 0-49 years in Great Britain (GB) (defined here as England, Scotland and Wales) during the period 1980-2005, were obtained from population-based cancer registries. Data on fluoride levels in drinking water in England and Wales were accessed through regional water companies and the Drinking Water Inspectorate. Scottish Water provided data for Scotland. Negative binomial regression was used to examine the relationship between incidence rates and level of fluoride in drinking water at small area level. RESULTS: The study analysed 2566 osteosarcoma and 1650 Ewing sarcoma cases. There was no evidence of an association between osteosarcoma risk and fluoride in drinking water [relative risk (RR) per one part per million increase in the level of fluoride = 1·001; 90% confidence interval (CI) 0·871, 1·151] and similarly there was no association for Ewing sarcoma (RR = 0·929; 90% CI 0·773, 1·115). CONCLUSIONS: The findings from this study provide no evidence that higher levels of fluoride (whether natural or artificial) in drinking water in GB lead to greater risk of either osteosarcoma or Ewing sarcoma.

Cross-space-time clustering of childhood cancer in Great Britain: evidence for a common aetiology.

Previously, we identified space-time clustering in certain childhood cancers. This study aimed to determine whether there was cross-space-time clustering between different diagnostic groups. A total of 32,295 cases were diagnosed during 1969-1993. Cross-space-time clustering was analyzed by a second-order procedure based on Diggle's method. Locations were birth and diagnosis addresses. The following space-time combinations were examined: address and date of birth; address at birth and date of diagnosis; address and date of diagnosis. Cross-space-time clustering analyses considered clustering pairs of cases from two different diagnostic groups. Formal statistical significance was taken as p < 0.00067 and marginal significance 0.01 > p ≥ 0.00067. Based on address at birth and date of diagnosis, there was statistically significant cross-clustering between cases of HL and intracranial and intraspinal embryonal tumors (IIET), both aged 0-14 years (p < 0.0001). Based on address and date of birth, there was marginally significant cross-clustering between cases of lymphoid leukemia (LL) aged 5-14 years and Hodgkin lymphoma (HL) aged 0-14 years (p = 0.0019). Based on address and date of diagnosis there was marginally significant cross-clustering between cases of LL aged 1-4 years and soft tissue sarcoma (STS) aged 0-14 years (p = 0.0041). Findings from this study are consistent with possible common aetiological factors between different diagnostic groups. They suggest a common aetiology for the following pairs of diagnostic groups: HL and IIET; older cases of LL and HL; younger cases of LL and STS. The possibility of common infectious mechanisms should be explored.

Small-area analyses of bone cancer diagnosed in Great Britain provide clues to aetiology.

BACKGROUND: The aetiology of bone cancers is poorly understood. This study examined geographical patterning in incidence of primary bone cancers diagnosed in 0-49 year olds in Great Britain during 1980-2005 to provide information on factors linked with disease development. We investigated putative associations with deprivation and population density. METHODS: Data on osteosarcoma and Ewing sarcoma were obtained from national population-based registries. Negative binomial regression was used to examine the relationship between incidence rates and the Townsend deprivation score (and its component variables) and small-area population density. RESULTS: The study analyzed 2566 osteosarcoma and 1650 Ewing sarcoma cases. For females with osteosarcoma, statistically significant decreased risk was associated with higher levels of deprivation (relative risk [RR] per unit increase in deprivation score = 0.969; 95% confidence interval [CI] 0.946-0.993). For all Ewing sarcoma combined, statistically significant decreased risk was associated with greater area-level population density and higher levels of non-car ownership (RR per person per hectare increase = 0.984; 95% CI 0.976-0.993, RR per 1% increase in non-car ownership = 0.994; 95% CI 0.991-0.998). CONCLUSIONS: Higher incidence of osteosarcoma was observed for females in areas with lower deprivation levels indicating increased risk is linked to some aspect of affluent living. Higher incidence of Ewing sarcoma occurred in areas of low population density and where more people owned cars, both characteristic of rural environments. The study adds substantially to evidence associating Ewing sarcoma risk with rural environmental exposures. Putative risk factors include agricultural exposures, such as pesticides and zoonotic agents.

Immunophenotype and cytogenetic characteristics in the relationship between birth weight and childhood leukemia.

BACKGROUND: High birth weight increases the risk of childhood acute lymphoid leukemia (ALL) through unknown mechanisms. Whether this risk is specific to ALL subtypes is unknown, and low case numbers have prevented investigation of the rarer leukemias. Here we address these associations using a large population-based dataset. PROCEDURE: Using the National Registry of Childhood Tumors, birth weights of 7,826 leukemia cases, defined by immunophenotype and cytogenetic subgroup, were compared with those of 10,785 controls born in England and Wales between 1980 and 2007. RESULTS: The risk for overall leukemia increases 7% with each 0.5 kg increase in birth weight (OR 1.07, 95%CI 1.04-1.10). This risk is limited to the lymphoid leukemias (OR 1.08, 95%CI 1.05-1.12) diagnosed between 1 and 9 years of age. Analysis by cytogenetic feature reveals that there appears to be association with specific chromosomal abnormality: the risk of tumors with high hyperdiploid karyotypes increases 12% per 0.5 kg increase in birth weight (OR 1.12, 95%CI 1.05-1.20), and t(1;19) tumors show an increased risk of 41% per 0.5 kg increase (OR 1.41, 95%CI 1.09-1.84). The risk of acute myeloid leukemia is elevated in high and low birth weight babies. There is no significant risk relationship to other leukemias or myeloproliferative diseases. CONCLUSIONS: Birth weight is a risk factor for ALL and AML. Other subtypes of the disease are not significantly affected. There appears to be association with specific chromosomal abnormality, which may aid our understanding of the development of childhood leukemia in utero.

Spatial clustering of childhood cancer in Great Britain during the period 1969-1993.

The aetiology of childhood cancer is poorly understood. Both genetic and environmental factors are likely to be involved. The presence of spatial clustering is indicative of a very localized environmental component to aetiology. Spatial clustering is present when there are a small number of areas with greatly increased incidence or a large number of areas with moderately increased incidence. To determine whether localized environmental factors may play a part in childhood cancer aetiology, we analyzed for spatial clustering using a large set of national population-based data from Great Britain diagnosed 1969-1993. The Potthoff-Whittinghill method was used to test for extra-Poisson variation (EPV). Thirty-two thousand three hundred and twenty-three cases were allocated to 10,444 wards using diagnosis addresses. Analyses showed statistically significant evidence of clustering for acute lymphoblastic leukaemia (ALL) over the whole age range (estimate of EPV = 0.05, p = 0.002) and for ages 1-4 years (estimate of EPV = 0.03, p = 0.015). Soft-tissue sarcoma (estimate of EPV = 0.03, p = 0.04) and Wilms tumours (estimate of EPV = 0.04, p = 0.007) also showed significant clustering. Clustering tended to persist across different time periods for cases of ALL (estimate of between-time period EPV = 0.04, p =0.003). In conclusion, we observed low level spatial clustering that is attributable to a limited number of cases. This suggests that environmental factors, which in some locations display localized clustering, may be important aetiological agents in these diseases. For ALL and soft tissue sarcoma, but not Wilms tumour, common infectious agents may be likely candidates.

Space-time clustering of childhood cancer around the residence at birth.

Previously, we identified space-time clustering in certain childhood cancers around diagnosis residence. These findings provided support for the involvement of environmental agents in etiological processes occurring close to diagnosis. We have reanalyzed the same British population-based dataset. The aim of the study was to determine whether there was space-time clustering around the residence at birth in relation to time of birth and separately from time of diagnosis. A total of 29,553 cases, diagnosed during the period 1969-1993, were examined by a second-order procedure based on K-functions. Locations were birth addresses, but separately, both dates of birth and diagnosis were analyzed. There was statistically significant space-time clustering for Hodgkin lymphoma (HL) and central nervous system (CNS) tumors (p=0.047 and 0.01, respectively, based on birth date) and for total leukemia at ages 1-4 years only, Non-Hodgkin lymphoma (NHL) and Wilms tumor (p=0.01, 0.02 and 0.006, respectively, based on diagnosis date). These results, interpreted together with other epidemiological evidence, suggest an etiological role for environmental factors focused around birth address for certain childhood cancers. For HL and CNS tumors, findings suggest that etiological exposures occurred at similar ages or in utero. For leukemia, NHL and Wilms tumor there is support for exposures occurring at similar times before diagnosis. For leukemia, HL, NHL and CNS tumors, but not Wilms tumor, the findings are consistent with infectious hypotheses.