Childhood cancer ranks high among public
concerns, evoking the public’s fear of cancer
as well as the special emotional attention
that is focused on children. Although it is rare,
its priority is elevated on the basis of years of
life lost and its prominence among life-threatening
diseases of children. Despite great success
in the treatment of childhood cancers such
as Wilms’tumor and leukemia, cancer continues
to be life threatening in children

Savitz, David A.

PubMed

Carolina Digital Repository

April 2001, Vol. 91, No. 4562 American Journal of Public Healthfidence, so histology, age at onset, and tumorbiology are all potential markers of etiologicheterogeneity. The goal of creating ever-finercase subgroups must be reconciled with theoverall rarity of cancers in children. The trade-off is between potential gains in validityachieved by creating more homogeneous casegroups and a definite loss of precision as thegroup size is reduced.Because childhood cancers are so rare,true prospective studies are virtually impossi-ble, necessitating continued reliance on case–control studies. As noted by Freedman et al.,8the 2 key challenges associated with that designare control selection and exposure assessment.Except in locations with complete birth reg-istries or population rosters (mostly in northernEurope), identifying and recruiting a sampleof the case-generating study base pose greatchallenges.Hospital-based studies make it impossibleto define the source of cases, particularly fordiseases that result in referrals from a wide ge-ographic area. Because few children are hos-pitalized for any reason, finding “exposure-neutral” diagnostic groups of children as asource of controls is even more challengingthan it is for adults. In population-based stud-ies, nonresponse is inevitable, often reachinglevels of 20% to 40% of the eligible population.As a reminder that this nonresponse is capableof distorting measures of association, virtuallyall case–control studies of childhood leukemiaEpidemiologic research into potential en-vironmental contributors to the etiology ofchildhood leukemia, brain cancer, and otherpediatric malignancies has been pursued in-tensively for over 20 years. Motivated by sci-entific interest and public concern, a number ofstudies have evaluated the role of pesticides,2ionizing radiation,3 nonionizing radiation,4,5and a wide range of occupational and envi-ronmental exposures.5–7 Dozens of epidemio-logic studies have been conducted on these top-ics, some with sophisticated designs, largepopulations, and attention to exposure assess-ment, such as the report in this issue by Freed-man et al.8 on solvent exposure and childhoodacute lymphoblastic leukemia.Scientific Challenges toIdentifying Causes of ChildhoodCancerThe scientific challenges to identifyingenvironmental contributors to the etiology ofchildhood cancer are daunting. We are uncer-tain about the relative importance of exposuresof the mother, father, and child in disease eti-ology. Although the time frame is narrowerthan the half century of potential relevance inthe etiology of adult cancer, the origins of child-hood cancer may lie anywhere between con-ception and diagnosis. The appropriate diseaseentities for study cannot be defined with con-Environmental Exposures and Childhood Cancer: Our Best May Not BeGood EnoughChildhood cancer ranks high among pub-lic concerns, evoking the public’s fear of can-cer as well as the special emotional attentionthat is focused on children. Although it is rare,its priority is elevated on the basis of years oflife lost and its prominence among life-threat-ening diseases of children. Despite great suc-cess in the treatment of childhood cancers suchas Wilms’tumor and leukemia, cancer contin-ues to be life threatening in children.For several decades, clusters of childhoodleukemia have been investigated, in a searchfirst for an infectious etiology and then for anenvironmental etiology,1 both without success.Childhood cancer clusters continue to gener-ate public concern and consume health de-partment resources, but there has been littleprogress in understanding the etiology or iden-tifying preventive measures. The focus oftenturns to the role of environmental pollutantssuch as pesticides, electromagnetic fields, andchemicals found in hazardous wastes. The ra-tionale for seeking exogenous, modifiablecauses of childhood cancer that can be avoided,leading to a reduction in the risk of disease, iscompelling.The negative consequence of suchpublic demand and support for epidemiologicresearch is the temptation to overinterpret everyshred of fallible evidence that emerges. Thepublic and media tend to place much more faiththan is warranted in isolated findings, to thedetriment of sound policy and the credibilityof researchers.10. Chemical Manufacturers Association. Sum-mary Report: Baselines for Improvement, Pub-lic Perceptions of the Chemical Industry, 1989–1990. Toledo, Ohio: National Family Opinion;1991.11. Baxter R. Some public attitudes about healthand the environment. Environ Health Perspect.1990;86:261–269.12. Greenberg M, Chess C. Communicating envi-ronmental risk through the mass media. PublicManager. Fall 1992:45–48.13. Statistical Abstract of the United States: 1999.119th ed. Washington, DC: US Bureau of theCensus; 1999:tables 348, 649, 680, 682.14. Deconstructing Distrust: Americans View Gov-ernment. Washington, DC: Pew Research Cen-ter for People and the Press; 1998.15. Kotchian S. Perspectives on the place of envi-ronmental health and protection in public healthagencies. Annu Rev Public Health. 1997;18:245–259.16. Brown MJ, Gardner J, Sargent J, Swartz K, HuH, Timperi R. Effectiveness of housing policiesin reducing children’s lead exposure. Am J Pub-lic Health. 2001;91:618–620.17. Eckel W, Rabinowitz M, Foster G. Discoveringunrecognized lead-smelting sites by historicalmethods. Am J Public Health. 2001;91:625–627.18. Greenberg M, Lee C, Powers C. Brownfieldsand public health: reviving the past to protectthe future. Am J Public Health. 1998;88:1759–1760.19. US Environmental Protection Agency, ScienceAdvisory Board. Toward Integrated Environ-mental Decision-Making. Washington, DC: En-vironmental Protection Agency; 2000. Publica-tion EPA-SAB-EC-00-011.20. Heloma A. The short-term impact of nationalsmoke-free workplace legislation on active andpassive smoking among employees. Am J Pub-lic Health. In press.21. Freedman MD, Stewart P, Kleinerman RA, etal. Household solvent exposures and childhoodacute lymphoblastic leukemia. Am J PublicHealth. 2001;91:564–567.22. Savitz DA. Environmental exposures and child-hood cancer: our best may not be good enough.Am J Public Health. 2001;91:562–563.23. Smulian JC. New Jersey’s electronic birth cer-tificate program: variations in data sources. AmJ Public Health. In press.24. M Soobader, FB LeClere, W Hadden, and BMaury. Using Aggregate Geographic Data toProxy Individual Socioeconomic Status: DoesSize Matter? Am J Public Health. 2001;91:632–636.April 2001, Vol. 91, No. 4 American Journal of Public Health 563in the United States, including the study byFreedman et al., have found higher risk in thelower social classes, despite there being an es-tablished, though modest, positive correlationbetween higher social class and risk for childcancer5 on the basis of registry information.The overrepresentation of upper-social-classcontrols relative to lower-social-class controls,stronger than the corresponding trend amongcases, appears to be the source of this effect,replicated across studies. Adjustment for so-cial class can be made, but this consistent ob-servation suggests that other aspects of nonre-sponse (particularly among controls) may wellhave more insidious effects.The second consequence of conductingcase–control studies is the loss of informationassociated with retrospective exposure assess-ment. Until the cancer is identified (or the con-trol child reaches the equivalent age), we can-not ascertain exposure and are thus faced withreconstructing exposure throughout the po-tential etiologic period. Studies that identifythe cases as they are diagnosed, as was done byFreedman et al.,8 avoid the additional time delayassociated with recruiting cases diagnosed be-fore the initiation of data collection, but thereis still a limit to the accuracy of exposure as-sessment for periods extending back as far as15 years. Biological markers of exposure areclearly not applicable, and direct measurementof environmental agents in the physical loca-tions of interest is of uncertain relevance owingto the passage of time. We are forced to relyon memory, which itself is limited in accuracyand objectivity with regard to the importantdetails about workplaces and the home envi-ronment that can affect exposure.Solvents and ChildhoodLeukemiaRecognizing all these limitations, the re-port by Freedman et al. reflects the “state ofthe art” in childhood cancer epidemiology withregard to study size (640 cases included in theanalysis), homogeneity of disease classifica-tion (all acute lymphoblastic leukemia), methodof control selection (random-digit dialing), andapproach to exposure assessment (structuredquestionnaire addressing frequency and dura-tion of exposure). As would be predicted, thegreatest concerns with bias arise from nonre-sponse and exposure misclassification. Only64% of eligible controls were enrolled, and de-spite some evidence against the available mea-sures of social class being associated with sol-vent exposure, that level of nonparticipationleaves open the possibility of distorted results.Relative to an ideal measure of actual solventexposure, as might be obtained through per-sonal monitoring, the effectiveness of the ex-posure assessment questions is uncertain. Theinvestigators focus on differential error, whichcould contribute to elevated measures of asso-ciation, but nondifferential misclassification ismore certain to be present and can be invokedas an argument that observed associations aremore likely to be underestimates of any un-derlying causal association.This study advances the hypothesis thatsolvent exposure may contribute to the etiol-ogy of childhood leukemia, moving it from aplausible hypothesis with no direct epidemio-logic support to one with very limited epide-miologic support. The total evidence support-ing the hypothesis that household solventexposures cause childhood leukemia never-theless remains weak but deserving of furtherstudy. Perhaps the most disconcerting chal-lenge posed by the study is how to makeprogress in evaluating the hypothesis further.The very strengths of the study by Freedmanet al. make it difficult to suggest improvements.Certainly, pure replication, assessing whetherthe same study design generates the same re-sults in other settings, would be welcome.There is clearly some room for refinements inthe approach to exposure assessment, withmore detailed query pertaining to exposuredeterminants. Those who are already engagedin such studies would do well to include per-tinent questions regarding household solventexposure. However, given the rarity of the dis-ease and the expense associated with studies ofthis size, it is difficult to advocate initiatingnew studies with household solvent exposureas a primary justification.Even though the epidemiologic studiesdirectly tackle the exposure and disease of in-terest, more insight may be generated by strongfindings of indirect relevance than by moreweak findings of direct relevance. Researchthat addresses the impact of self-reported ac-tivities on measured solvent exposure wouldbe highly beneficial to interpreting this studyand could lead to improved methods of retro-spective exposure assessment. Toxicologicstudies of implicated agents, such as methylenechloride and benzene, focusing on animal mod-els of childhood leukemia may help in the in-terpretation of these results. For a possible pa-ternally mediated pathway linking solventexposure to childhood leukemia, further workon sperm-mediated genetic alterations associ-ated with solvent exposures could be contrib-utory. With regard to childhood exposure, focusmight shift to endpoints that can be measuredprospectively in modest populations, ideally,biomarkers of early effect such as cytogeneticdamage. If we are to attain the conclusive re-sults pertaining to solvent exposure (or pesti-cides, nonionizing radiation, etc.) and leuke-mia (or other childhood cancers)—an elusivegoal so far—it is very unlikely to come throughsheer weight of replicated findings from con-ventional epidemiologic studies.David A. Savitz, PhDRequests for reprints should be sent to David A.Savitz, PhD, Department of Epidemiology, CB#7400, University of North Carolina, Chapel Hill,NC 27599-7400 (e-mail: david_savitz@unc.edu).This editorial was accepted November 24,2000.AcknowledgmentsI would like to thank Dr Andrew Olshan for his re-view and helpful comments on the manuscript.References1. Alexander FE. Clusters and clustering of child-hood cancer: a review. Eur J Epidemiol. 1999;15:847–852.2. Daniels JL, Olshan AF, Savitz DA. Pesticidesand childhood cancers. Environ Health Perspect.1997;105:1068–1077.3. Laurier D, Bard D. Epidemiologic studies of leu-kemia among persons under 25 years of age liv-ing near nuclear sites. Epidemiol Rev. 1999;21:188–206.4. Ahlbom A, Day N, Feychting M, et al. Apooled analysis of magnetic fields and child-hood leukaemia. Br J Cancer. 2000;83:692–698.5. Little J. Epidemiology of Childhood Cancer.Lyons, France: International Agency for Re-search on Cancer; 1999. IARC Scientific Publi-cation 149.6. McBride ML. Childhood cancer and environ-mental contaminants. Can J Public Health.1998;89:S53–S62.7. Colt JS, Blair A. Parental occupational expo-sures and risk of childhood cancer. EnvironHealth Perspect. 1998;106:909–926.8. Freedman DM, Stewart P, Kleinerman RA, etal. Household solvent exposures and childhoodacute lymphoblastic leukemia. Am J PublicHealth. 2001;91:564–567.

Environmental exposures and childhood cancer: our best may not be good enough

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Environmental exposures and childhood cancer: our best may not be good enough

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