Hecht, S

Hesseling, P B

Preston-Martin, S

Wessels, G

South African Medical Journal (SAMJ)

October 2005, Vol. 95, No. 10  SAMJSCIENTIFIC LETTER776To the Editor: The aim of this follow-up study was to furtherinvestigate a suggested excess of childhood brain tumours(CBT) among Herero children in Namibia from 1983 to 1988.1Incidence rates of primary brain tumours among Hererochildren were found to be 4 times higher than rates amongNamibian children in any of the 10 other tribal groups oramong children of European origin.  The causes of CBTs remain largely unknown.  The onlyestablished causes are ionizing radiation and predisposinginherited syndromes.2 A particularly compelling hypothesis isthat exposure during gestation to N-nitroso compounds(NOCs) may lead to the development of CBT.  This hypothesiswas suggested by experimental work in which 100%production of nervous system (NS) tumours in rat offspringresulted from transplacental exposure to the neurocarcinogenethylnitrosourea (ENU) or to low levels of the precursorcompounds sodium nitrite and ethyl urea added to the foodand drinking water of pregnant rats.3However, when ascorbate(vitamin C) or α-tocopherol (vitamin E) were also included inthe diet, endogenous formation of ENU was blocked andtumours did not occur.3This effect was shown to occur innumerous species, from rodents to primates, with the greatestsusceptibility during gestation.4ENU precursors are readilyavailable in human diets and other common exposures.Drinking water is one possible source of nitrate, which isreadily reduced to nitrite in the presence of human saliva.When levels in water are high drinking water can be the majorsource of this NOC precursor; for example water containing >50 mg/l nitrate ion can represent 70% or more of total dietaryintake.5The first step in this follow-up investigation was to updatethe CBT incidence survey to include tumours first diagnosedfrom 1989 to 1997.  Before 1989 most Namibian children withcancer were referred to the paediatric oncology unit atTygerberg Hospital (TBH) in Cape Town.6After this datetreatment facilities in Namibia were improved, and patientswere mostly referred to TBH only for radiotherapy.6Copies ofreports of brain tumours occurring among Namibian childrenfrom 1989 to 1997 were requested from the central tumourregistry of Namibia and were reviewed by the investigators atTBH in Cape Town.  Based on the child’s surname, Hererochildren were identified from among all CBT cases.  Furtherverification of Herero ethnicity was obtained by examiningreferral patterns from the local clinic where the child firstpresented to regional medical facilities and finally to the centralpaediatric oncology ward in Windhoek.  The initial incidencesurvey found a total of 28 cases of CBT among Namibianchildren in the 6 years from 1983 to 1988; 6 of these wereamong Herero children, who comprise about 10% of thepaediatric population.  Only 1 incident of CBT occurred amongHerero children during the 9 years from 1989 to 1997 out of atotal of 24 in all Namibia.  Had the excess seen in 1983 - 1988continued, 8 new cases among Herero children would havebeen expected for the period 1989 - 1997.  In fact the number ofnew CBT cases diagnosed per year also declined among non-Herero Namibian children from 3.67/year during 1983 - 1988to 2.56/year during 1989 - 1997.Secondly, a field survey was also conducted and samples ofdrinking water were collected from sources used duringpregnancy by mothers of Herero children who had braintumours diagnosed from 1983 to 1988.  Samples were collectedwith the help of public health nurses for dipstickmeasurements of nitrite and nitrate levels along with‘convenience control’ samples from locations the investigatorvisited (Ministry of Health and Social Services (MHSS) offices)or stayed at during this survey. These dipsticks (Merck,Darmstadt) were read on location and were similar to thoseused previously in an international study of CBT and contentof maternal drinking water.5Dipstick findings were confirmedin more detailed laboratory analyses performed in the USA.At each case and control location 2 samples were used to teston site for nitrites and nitrates, and 2 additional samples werestored on dry ice and shipped on dry ice within 24 hours fromWindhoek to Minneapolis, Minnesota, USA for analysis. Labelsused on each sample ensured that the laboratory was blindedas to case or control status of the samples.   Dipstick measurements were done for 12 water samples(Table I).  The relevant water source was only available for 3 ofthe 6 CBT cases diagnosed from 1983 to 1988, although in thecase of 1 of these mothers we were only able to sample fromthe municipal supply where the woman now lives.  She hadnot previously told the public health nurse that during theFollow-up of a suspected excess of brain tumours amongNamibian childrenS Preston-Martin, G Wessels, S Hecht, P B HesselingUniversity of Southern California, Keck School of Medicine, USC/NorrisComprehensive Cancer Center, Los Angeles, USAS Preston-MartinDepartment of Paediatrics, Tygerberg Hospital and Stellenbosch University,Tygerberg, W CapeG WesselsP B HesselingUniversity of Minnesota Cancer Center, Minneapolis, Minnesota, USAS HechtCorresponding author: S Preston-Martin (spresto@usc.edu)pg 776-780  9/28/05  3:09 PM  Page 776October 2005, Vol. 95, No. 10  SAMJSCIENTIFIC LETTER778relevant pregnancy she had lived mostly on a rural Hereroreserve; there was insufficient time to visit the remote locationand no one available to show the way. Two families could notbe traced.  During her pregnancy another mother had lived in abuilding previously receiving water from a private source, butthe new building in that location was now on the municipalwater supply.  Two samples had high nitrate levels (250 and100 mg/l (ion) respectively); both were from rural watersupplies close to where case mothers had lived during theirpregnancies.  Four samples of municipal or national park waterhad no detectable nitrates, 3 had levels of only 10 mg/l, 2 hadlevels of 25 mg/l, and a rural clinic had a level of 50 mg/l.Laboratory measurements using various methods ofassaying nitrate levels conducted in the USA for 6 highestpriority samples (numbers 1 - 6 listed in Table I) in generalconfirmed dipstick findings.  Three of the 4 samples fromboreholes/wells (2 case samples and the clinic sample) fromrural water supplies showed nitrate levels at (clinic) or above(2 cases) the World Health Organization (WHO) recommendedlimit of 50 mg/l; all 3 showed these high levels on 2 or more ofthe assays used.  None of the samples from municipal suppliesor national parks had levels above 25 mg/l on any assay.Drinking water is a potential source of nitrates, which arereadily reduced to nitrites in the presence of saliva.  Whenlevels in water are high, as they were in some wells used by theHerero population, it can be the major source of this NOCprecursor,4and if the diet includes relatively low levels ofnitrosation inhibitors such as vitamins C or E, endogenousformation of carcinogenic NOC is likely to occur.2Nonetheless,the potential carcinogenic effect of this exposure is unclear, butan increased risk of CBT associated with nitrates in drinkingwater is at least plausible.4 While our results related to the dipstick measurements arenot affected by recall bias or other limitations of self-reporteddata, they do have some limitations.  Measurements wereconducted several years after women’s pregnancies; even if theresidences remained the same, water quality and content mayhave changed.  Other limitations are the semi-quantitativenature of the dipsticks, the necessary subjectivity ininterpretation of results by the rater, and the possibility thatdespite the attempt to adhere to the manufacturer’sinstructions, some interferences and inaccuracies may haveoccurred in their use.   A major limitation of our study is the very small number ofcases; both the number of incident cases among Herero andother children in Namibia from 1989 to 1997 and the number ofwater samples tested were too few to justify testing forstatistical significance.  In addition questions remain relating tothe different methods of case ascertainment during the twotime periods.  Nonetheless, a fourfold excess of a serious raredisease such as CBT represents an opportunity that warrantsinvestigation.According to the WHO and European Union maximumadmissible concentration standards, the maximum allowableTable I. Dipstick measurements of nitrates and nitrates from water samples from locations in Hereroland and central Namibiain 2000Nitrite NitriteCase Water Nitrate (mg/l) (mg/l)No. samples* (mg/l) (ion)† (ion)‡ Comments1 ca/ru 250 --- --- Mother and child deceased.  Father took us to the small settlement where the mother had lived, in order to take samples 2 ca/pu 0 --- 0 Water sampled from municipal supply where the mother now lives.During the pregnancy she had lived on a rural Herero reserve. Therewas insufficient time to visit it and no one to show us how to get there3 ca/ru 100 --- 2 Well water delivered by truck to the farm where the mother hadworked4 co/ru 10 --- 0 50 m well on guest farm5 co/pu 0 --- 0 National park guest cabin§6 co/ru 50 --- 0 Regional well supplying small clinic7 co/pu 25 --- 0 Municipal water in MHSS office8 co/pu 0 --- 0 Municipal water in MHSS office9 co/pu 0 --- 0 National park guest cabin§10 co/pu 25 --- 0 National park guest cabin§11 co/pu 10 --- 2 National park guest cabin§12 co/pu 10 --- 0 Municipal supply to residential suburb of Windhoek13 co/pu 0 --- 0 Municipal supply to residential suburb of Cape Town*Status: ca/co = case or control water sample; ru/pu = water sampled from a private rural or public source, usually in a town on municipal or other public water supply.  Private rurallocations got water from boreholes.  †Nitrite level from dipstick with two strips, one for nitrites and one for nitrates.‡Nitrite level from dipstick with single strip to measure nitrites only.§Each national park location was distinct.  Included are samples from guest cabins in Waterberg, Daan Viljoen, and two locations in Etosha - Namutoni and Okaukuejo.MHSS = Ministry of Health and Social Services (water was sampled from the MHSS regional offices in Otjwarango and Gobabis).pg 776-780  9/28/05  3:10 PM  Page 778October 2005, Vol. 95, No. 10  SAMJSCIENTIFIC LETTER780nitrate level for drinking water is 50 mg/l nitrate ion.  In mostcountries drinking water from private sources such asboreholes is less closely regulated than water from publicsupplies.  Homes with water from local boreholes are alsomore likely to be located in agricultural areas with thepossibility of exposure to various infectious and chemicalagents from sources other than drinking water; informationwas not collected on such possible exposures from farmanimals or agricultural chemicals.  Furthermore, drinkingwater with high nitrate levels frequently also includes othercontaminants, such as pesticides and metals,5which were notmeasured in this study. In summary, our study showed that the previously observedapparent excess incidence of primary brain tumours amongHerero children from 1983 to 1988 did not continue after 1989.Further, our study demonstrated that the extraordinaryhelpfulness of the public health workers in Namibia madefollow up of families of these children possible even after 15 ormore years since last contact   Water sampling suggests thatnitrate levels may be high in boreholes in some rural areas ofHereroland; however, water from municipal supplies inNamibia appears to contain low levels.Dr Preston Martin’s involvement in this project was supportedby grant number 1FO6TW02352 from the Fogarty InternationalCenter.Before its initiation, this investigation was approved by theEthical and Scientific Review Board of the Faculty of HealthSciences at Stellenbosch University in the Western Cape and by theNamibian Ministry of Health and Social Services in Windhoek.We thank Drs Ali, Ithindi, Khomas, Makame, Omaheke, andOtjozandjupa for their interest in our study. We are especiallygrateful  for the help in planning and conducting this study thatwe received from public health nurses and administratorsincluding Mrs Dierghardt, Mrs Hausiku, Mrs Lottering, and MrsTjongarero. We are also grateful for the advice and hospitality of Dr and MrsStefan Kuit.Analyses of water samples were conducted in the AqueousGeochemistry Laboratory, Department of Geology and Geophysics,University of Minnesota on a Dionex DX-500 ion chromatograph,with a CD 20 detector, a GP 40 pump, and 2 AS4A anion exchangecolumns eluted with carbonate/bicarbonate at a flow rate of 2.1ml/minute.Beth Mueller and Susan Nielsen provided helpful guidance andcomments.1. Wessels G, Hesseling PB. Unusual distribution of childhood cancer in Nambia. PediatrHematol Oncol 1996: 13: 9-20.2. Baldwin R, Preston-Martin S.  Epidemiology of brain tumors – a review.  Toxicol ApplPharmacol 2004, 199: 118-131.3. Dietrich M, Preston-Martin S, Buffler P, Pogoda J, Block G. Dietary and endogenously formedN-nitroso compounds and risk of childhood brain tumors. Cancer Causes Control 2005; 16:619-635.  4. Rice JM, Ward JM. Age dependence of susceptibility to carcinogenesis in the nervous system.Selikoff IJ, Hammond EC, eds. Brain Tumors in the Chemical Industry. New York: New YorkAcademy of Sciences, 1982.5. Mueller BA, Searles-Nielsen S, Preston-Martin S, et al. Household water  source and the riskof childhood brain tumors: Results from the SEARCH International Brain Tumor Study.  Int JEpidemiol 2004, 33: 1-8.6. Hesseling PB, Wessels G, van Riet FA. The Tygerberg Hospital Children's Tumour Registry1983 - 1993. Eur J Cancer 1995; 31A: 1471-1475.pg 776-780 q5  9/28/05  3:11 PM  Page 780

Follow-up of a suspected excess of brain tumours among Namibian children

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Follow-up of a suspected excess of brain tumours among Namibian children

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