African Health Sciences Makerere University Medical School ISSN: 1680-6905 EISSN: 1729-0503 Vol. 8, Num. 1, 2008, pp. 1-4

African Health Sciences, Vol. 8, No. 1, March, 2008, pp. 1-4

Editorial

Environmental causes of childhood brain tumours

^1,2Olufemi E. Idowu, ³Mopelola A. Idowu

¹Neurological Surgery Unit, Department of Surgery, Lagos State University College of Medicine (LASUCOM), Nigeria ²Lagos State University Teaching Hospital (LASUTH), Ikeja, Lagos, Nigeria ³Department of Chemistry, Rhodes University, Grahamstown 6140, South Africa.
Correspondence to: OE Idowu, Neurological Surgery Unit, Department of Surgery, Lagos State University College of Medicine (LASUCOM), Ikeja, Lagos, Nigeria. e-mail:oeidowu412@yahoo.com

Code Number: hs08001

Summary

Brain tumours hitherto said to be rare in Africans are now known to be common. They cause considerable concern due to their relatively high morbidity, mortality and enormous cost of care, especially in the developing world.

An understanding of the aetiology is particularly important in our region for planning strategies for effective prevention of brain tumours. This review endeavours to outline our current understanding of the aetiology of this disease.

Introduction

A brain tumour is one of the most devastating forms of human cancers. They cause considerable concern due to their relatively high morbidity, mortality and enormous cost of care especially in the developing world where the financial burden is carried by the poor patient and his or her relations.

Brain tumours are the second most common cancer in children, comprising about 20% of all paediatric malignancies, and the most common paediatric solid tumour. The different histological subtypes occur with different relative frequencies among children and adults¹. The most common tumours of childhood are astrocytic tumours and the primitive neuroectodermal tumors, of which the most common is medulloblastoma².

Brain tumours develop as a consequence of cellular genetic alterations that permit them to evade normal regulatory mechanisms and destruction by the immune system. These alterations may have an inherited or acquired (chemical, physical or biological neurocarcinogens) cause. Overall, only a very small proportion of brain tumours can be attributed to the effect of inherited predisposition. The various implicated and suspected environmental factors includes ionizing radiation, non-ionizing radiation, N-nitroso compounds, viral infections (JC virus, cytomegalovirus, Human immunodeficiency virus, SV-40, varicella-zoster, chicken pox), and head injury.

Ionizing radiation

Ionizing radiation in therapeutic doses is the only unequivocal acquired factor that has been identified for glial and meningeal neoplasms. Irradiation of the cranium, even at low doses, can increase the incidence of meningiomas by a factor of 10 and that of glial tumours by a factor of 3 to 7, with a latency period of 10 years to more than 20 years after exposure^3,4. The now discontinued low dose radiation treatment of tinea capitis and skin disorders in children increases the risk of brain tumours well into adulthood, as does radiotherapy for various childhood cancers and leukaemia. Survivors of the atomic bomb in Hiroshima have increased risks of meningioma in proportion to their level of exposure. In utero exposure to diagnostic radiation does not appear to significantly affect the developing foetus. Radiation doses associated with diagnostic X-rays are very small and probably pose minimal, if any, risk; but full mouth dental X- rays have been associated with meningiomas in a small number of studies.

Non-ionizing radiation

Radiofrequency (RF) signals, which fall within the microwave region of the electromagnetic spectrum, are emitted and received by mobile phone handsets. The energy levels of these waves are insufficient to damage or disrupt cellular DNA. The use of cellular telephones, exposure to high-tension wires, the use of hair dyes, head trauma, and dietary exposure to N-nitrosourea compounds or other nutritional factors have all been reported to increase the risk of brain tumours; however, the data are conflicting and unconvincing^5-10. When assessing the literature on this topic, interpretation of a small number of early studies from the USA and Sweden must be cautious. They were conducted on relatively small populations, relating to a time when analogue phones predominated and they had relatively short follow up periods with some methodological shortcomings.

The epidemiological evidence for a causal association between cancer and RF energy is weak and limited. Animal studies have provided no consistent evidence that exposure to RF energy at non-thermal intensities causes or promotes cancer. Extensive in-vitro studies have found no consistent evidence of genotoxic potential and in vitro studies assessing the epigenetic potential of RF energy are quite limited^11,12. Recent data in humans do not support the hypothesis that the use of hand-held cellular telephones causes brain tumours, but they are not sufficient to evaluate the risks among long-term, heavy users and for potentially long induction periods⁸.

Extremely low frequency magnetic fields (ELF-MF) of 50-60 Hz are used in domestic and industrial electricity supplies presenting a virtually ubiquitous exposure to the population, although levels of exposure do vary. The neurobiological basis for ELF-MF being involved in malignant transformation is not substantiated. It does not cause direct effect on disrupting cellular DNA or metabolic pathways. Overhead power cables and wiring configurations in houses affect the levels of exposure to ELF-MF in a domestic residence. Current evidence shows that at levels experienced by the general population no risk of brain tumours in children appears to be present.

N-alkyl- nitrosoureas

N-alkyl-nitrosoureas (Figure 1), a category of N-nitroso compound, is the most potent neurocarcinogens yet identified in experimental studies with laboratory animals^13,14. Ethyl and methyl nitrosourea, are known transplacental carcinogens, particularly for brain tumours in rats. Their ability to cross the blood-brain barrier and their mutagenic potential makes them ideal candidates as initiators in the carcinogenic process.

Humans are exposed to N-nitroso compounds through a variety of avenues, including water, vegetables, meat products, alcohol and tobacco; certain medications, cosmetics, are also sources of exposure¹⁵. Vegetables and cured meats are major dietary sources. However, results of studies concerning N- nitroso compounds and brain tumours in humans are highly inconsistent ^{5, 16-20}.

Nitrosonornicotine has been found in unburned smoking tobacco²¹. Tobacco smoke is a known carcinogen but most of its constituents do not pass the blood-brain barrier. Smoking does not appear to be strongly linked to brain tumours either in adults who smoke themselves or via maternal smoking in pregnancy.

Viral infections

Cytomegalovirus (CMV) infection has been described in association with malignant gliomas. But recent review by Lau et al did not suggest that CMV is significantly associated with brain tumours in humans²³. At a time it was also thought that live polio vaccines contaminated with SV40 might increase the risk of brain tumours, but the initial observations were not supported by more detailed studies. Examination of brain tumour tissue for evidence of a viral cause has shown the presence of different viral DNA sequences in a proportion of cases. However, the mechanisms of how a virus might initiate malignant transformation remain unknown and more work is needed to elucidate the role of viruses in causing brain tumours.

Although more than 25 million people in sub-Saharan Africa have human immunodeficiency virus infection, little is known regarding their cancer risk²⁴. Many cancers have been reported to be increased in patients with AIDS. But only in five of these is there sufficient consistent and strong for conclusion of definite increase in risk^25,26. These cancers are Kaposi sarcoma, non-Hodgkin lymphoma, squamous cell carcinoma of the conjunctiva, Hodgkin's disease and childhood leiomyosarcoma^25,26. The role of HIV and primary brain lymphoma is well documented.

In utero infections with influenza and chicken pox (varicella) have been cited as a risk factor but the case for this is weak. Significant inverse associations of adult glioma with history of chickenpox and immunoglobulin G antibodies to varicella-zoster virus have been reported²⁷. Some recent epidemiological work on a series of children from the north west of England diagnosed with brain tumours has shown geographical distributions, which are suggestive of an infectious aetiology for some of the tumour types. Clustering in time and space and seasonality of diagnosis suggest that infections may be risk factors. Okamoto et al study provides molecular evidence of the association between JC virus and the development of certain ependymomas and choroid plexus papillomas²⁸.

Other factors

A lack of association is seen for alcohol consumption, hair dyes, hair sprays and brain tumours. There is also no association between traumatic head injury and primary brain tumours²². 

Protective factors

Some reports indicate that consumption of fruits and vegetables and of vitamins C and E might protect against the occurrence of brain tumours ^11,21. Atopic diseases such as asthma, eczema, and allergies have been said to be protective. Independent studies from different countries have suggested that atopic conditions have a "protective" possibility, particularly in the development of gliomas. Patients with gliomas report fewer symptoms of atopy compared to control subjects. This relation might indicate a role for immunologic factors in causation.

Conclusion

Relatively little is still known about the causes of most tumours of the brain. A small percentage of brain malignancies have been identified as having a genetic or familial component with a variety of environmental factors implicated to varying degrees. Ionizing radiation in therapeutic doses is the only unequivocal risk factor that has been identified for glial and meningeal neoplasms. The associations with exposure to various neurocarcinogens N-akyl-nitrosoureas, non-ionizing radiation, head trauma and infective agents are yet to be fully substantiated. Continued research into genetic, dietary, infectious and immune factors may clarify more on the aetiology of brain tumours.

References

1. Schoenberg BS, Christine BW and Whisnant JP: The descriptive epidemiology of primary intracranial neoplasms: the Connecticut experience. Am J Epidemiol 1976; 104:499-510.
2. Rorke LB: The cerebellar medulloblastoma and its relationship to primitive neuroectodermal tumors. J Neuropathol Exp Neurol 1983; 42:1-15.
3. Pollak L, Walach N, Gur R, Schiffer J. Meningiomas after radiotherapy for tinea capitis — still no history. Tumori 1998; 84:65-68.
4. Walter AW, Hancock ML, Pui CH, et al. Secondary brain tumors in children treated for acute lymphoblastic leukemia at St Jude Children's Research Hospital. J Clin Oncol 1998;16:3761-3767.
5. Kaplan S, Novikov I, Modan B. Nutritional factors in the etiology of brain tumours: potential role of nitrosamines, fat, and cholesterol. Am J Epidemiol 1997;146:832-841.
6. Salvatore JR, Weitberg AB, Mehta S. Nonionizing electromagnetic fields and cancer: a review. Oncology (Huntingt) 1996;10:563-574.
7. Inskip PD, Mellemkjaer L, Gridley G, Olsen JH. Incidence of intracranial tumours following hospitalization for head injuries (Denmark). Cancer Causes Control 1998; 9:109-116.
8. Inskip PD, Tarone RE, Hatch EE, et al. Cellular-telephone use and brain tumours. N Engl J Med 2001; 344:79-86.
9. Tomenius L: 50-Hz electromagnetic environment and the incidence of tumours in Stockholm County. Bioelectromagnetics 1986; 7:191-207.
10. Savitz DA, Wachtel H, Barnes FA, et al.: Case-control study of childhood cancer and exposure to 60-Hz magnetic fields. Am J Epidemiol 1988; 128:21-38.
11. Moulder JE, Foster KR, Erdreich LS, McNamee JP. Mobile phones, mobile phone base stations and cancer: a review. Int J Radiat Biol. 2005; 81(3):189-203.
12. Shirai T, Kawabe M, Ichihara T, Fujiwara O, Taki M, Watanabe S, Wake K, Yamanaka Y, Imaida K, Asamoto M, Tamano S. Chronic exposure to a 1.439 GHz electromagnetic field used for cellular phones does not promote N-ethylnitrosourea induced central nervous system tumors in F344 rats. Bioelectromagnetics. 2005; 26(1):59-68.
13. Kleihues P, Lantos PL and Magee PN: Chemical carcinogenesis in the nervous system. Int Rev Exp Pathol 1976; 15:153-232.
14. Magee PN: N-nitroso compounds and related carcinogens. In Chemical carcinogens. ACS Monograph 173 (C.E. Searle, ed.). Washington, DC: American Chemical Society, 1976; 491-625.
15. Preston-Martin S and Henderson BE: N-nitroso compounds and human intracranial tumours. IARC Scientific Publications1984; 57:887-894.
16. Preston-Martin S., Yu MC, Benton B, et al.: N-nitroso compounds and childhood brain tumours: a case-control study. Cancer Res 1982; 42:5240-5245.
17. Howe GR, Burch JD, Chiarelli AM, et al.: An exploratory case-control study of brain tumours in children. Cancer Res 1989; 49:4349-4352.
18. Bunin GR, Kuijten RR, Buckley JD, et al.: Relationship between maternal diet and subsequent primitive neuroectodermal brain tumours in young children. N Engl J Med 1993; 329:536-541.
19. Bunin GR, Buckley JD, Boesel CP, et al.: Risk factors for astrocytic glioma and primitive neuroectodermal tumor of the brain in young children: a report from the Children's Cancer Group. Cancer Epidemiol Biomarkers Prev 1994b; 3:197-204.
20. Sarasua S and Savitz DA: Cured and broiled meat consumption in relation to childhood cancer: Denver, Colorado (United States). Cancer Causes Control 1994; 5:141-148.
21. Hoffman D, Hecht SS, Ornaf RM, Wydner EL. N-nitrosonornicotine in tobacco. Science. 1974; 186: 265-267
22. Nygren C, Adami J, Ye W, Bellocco R, af Geijerstam JL, Borg J, Nyren O. Primary brain tumors following traumatic brain injury—a population-based cohort study in Sweden.Cancer Causes Control. 2001; 12(8):733-737.
23. Lau SK, Chen YY, Chen WG, Diamond DJ, Mamelak AN, Zaia JA, Weiss LM. Lack of association of cytomegalovirus with human brain tumors. Mod Pathol. 2005; 18(6):838-43. 
24. Mbulaiteye SM, Katabira ET, Wabinga H, Parkin DM, Virgo P, Ochai R, Workneh M, Coutinho A, Engels EA. Spectrum of cancers among HIV-infected persons in Africa: The Uganda AIDS-Cancer Registry Match Study. Int J Cancer.2006; 118: 985 -990
25. Chokunonga E, Levy LM, Bassett MT, Mauchaza BG, Thomas DB, Parkin DM. Cancer incidence in the African population of Harare, Zimbabwe: Second results from the cancer registry 1993-1995. Int J Cancer. 2000; 85: 54 -59
26. Beral V, Newton R. Overview of the Epidemiology of Immunodeficiency-Associated Cancers. Journal of the National Cancer Institute Monographs. 1998; 23:1-6.
27. Wrensch M, Weinberg A, Wiencke J, Miike R, Sison J, Wiemels J, Barger G, DeLorenze G, Aldape K, Kelsey K. History of chickenpox and shingles and prevalence of antibodies to varicella-zoster virus and three other herpesviruses among adults with glioma and controls. Am J Epidemiol. 2005; 161(10):929-38.
28. Okamoto H, Mineta T, Ueda S, Nakahara Y, Shiraishi T, amiya T, Tabuchi K. Detection of JC virus DNA sequences in brain tumors in pediatric patients. J Neurosurg. 2005; 102(3 Suppl):294-8.  

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