Document zoKpbaqkmzGvqY4vKR585JjrB

MqthodologicApproaches to Studying The Rarity Issue EnvironmentalFactors in Childhood Cancer The overall annual incidence of cancer in U.S. children 0 to 14 years of age at diag- Seymour Grufferman nosis is 143.9 per million for white males and 126.9 per million for white females. Department of Family Medicine and Clinical Epidemiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania The comparable incidence rate for black males and females is 107.2 and 107.9 per million, respectively (8).This is in contrast Little is known about environmental causes of childhood cancer. This is probably due to the relative rarity of cancer in children. In the United States, cancer incidence in adults is over 20 times greater than cancer incidencein children.The situationis compounded by the fact that two groups of cancers, leukemias and brain and spinal tumors, account for half$call chi!dhood cancers. The rarity of childhood cancer renders the conduct of most cohort studies infeasible. The m a i m of studies assessing potential environmental risk factors for childhood cancers have been case-control studies, which are highly efficient for studyng rare diseases. Casecontrol studies of childhood cancers have been greatly facilitated by using cooperative clinical trial groups for case identification. The national studies that have emerged utilize randodigit telephone dialing and telephone interviewing as feasible and economic means of identifying and interviewing controls. Other approaches such as descriptive epidemiology, ecologic studies, and studies of cancer clusters have proven to be disappointingin elucidating environmental causes of childhood cancer. to 330.4 and 277.0 per 100,000 in white males and females, respectively, of all ages (9).The comparable figures for black males and females of all ages are 351.3 and 227.1 per 100,000, respectively. Thus, adult incidence of cancer (all ages) in the United States is over 20 times greater than the cancer incidence in children 0 to 14 years of age at diagnosis. The rarity issue becomes even more salient when cne looks at the incidence of childhood cancers beyond acute leukemias and brain cancers. The Descriptive and ecologic studies provide no information on specific exposures of study subjects; U.S. annual incidence of all leukemia is rather, they use population levels as surrogates for indivldual exposure. Studies of cancer clusters 47.8 per million in white males and 29.5 have also proven to be disappointing. Although there are numerous difficulties in conducting per million in white females, and for brain research on the causes of childhood cancer, these difficulties can be remedied by using carefully and spinal tumors it is 26.4 and 23.3 in designed and conducted studies. It should be remembered that the epidemiologic approach is white male and female children, respec- probably the most likely research venue for uncovering environmental causes of childhood tively (8).Thus, leukemias account for cancer. - Environ Health Perspect lOG(Suppl 3):881-886 (1998). httpflehpnetl.niehs.nih.gov/ 51.6 and 49.5% of all cancers in 0- to 14- ~ ~ l ~ u p p ~ ~ 7 ~ ~ hftmlf e ~ a ~ a b s ~ . year-old white males and females, respec- Key words: childhood cancer, cohort studies, epidemiology, dump sites, environmental risk factors, rhabdomyosarcoma,clusters, statistical methods, case-controlstudies, cooperative clinicaltrial groups tively. Once we go beyond these two canter groups, other groups are more truly rare diseases. For example, the incidence of rhabdomyosarcoma (RMS)in children is 5.0 and 4.4 Der million in white d e s and Introduction females, andihat of osteosarcoma is 2.3 and 2.7 per million in white males and females, Relatively little is known about the causes knowledge of the etiology of childhood respectively (8).Accrual of subjects for of cancer in childhood. In the 1950s inter- canter up until the 1980s, one is struck by studies of less common subsets of an est was focused on in utrro diagnostic radi- the paucity of published etiologic studies already rare group of d~scasesbecomes di!K- ation exposure and risk of childhood relative to those of adult cancers. In large cult even through the use of large coopera- leukemia (1-3).Research interest next part, this is due to the relative rarity of tive treatment groups as sources of subjects. focused on the genetics of selected child- cancer during childhood. Difficulty in the As will be discussed, the rarity issue has hood cancers ( 4 3 . The mechanism of accrual of sufficiently large numbers of major impact on methodologic approaches transplacental carcinogenesis was demon- childhood cancer cases beyond leukemia to the study of childhood cancers. strated in the early 1970s (6).In reviewing (the type most frequent in chiidhood) has probably impeded research on the etiology ofcancers in children. More recentiy, pcd~- This paper is based on a presentationat the U.S. EPA Conference on Preventable Causes of Cancer in Children held 15-1 6 September 1997 in Arlington, Virginia. Manuscript receivedat EHP 29 December 1997;accepted 13 April 1998. Supportedby U S Public Health Service grant R01 CA-47473 from the National Cancer Institute, Bethesda, Man/Lend. Address correspondenceto Dr. S. Grufferman, Fami& MedicinelClinicalEpidemiology, Universty of Pittsburgh School of Medicine, M200 Scaife Hall, 3550 Terrace Street, Pittsburgh,PA 15213-2500. Telephone: (412)648-8933. Fax: (412)6489114. E m d : dinepi+@pitt.edu AMmvMons used: DES, dethylstilbestrol:RMS, mabdomyosa-. atric cooperative clinical trial groups have been identified and tapped as an important m a u s for conducting etiologic research on uncus of childhood (7).This has mitigated greatly the primary problem of having suficient numbers of subjects to study childhood cancers properly. However, there remain significant problems in con- duaing research on environmental (and other) causes of cancer in children. This paper will review several methodologic issucs chat arisc in conducting rcscvch on enviFonmcntalCa~Ofchildhoodcanar. The major difficulties encountered in attempting to do epidemiologic research on childhood cncer result from the relativc rarity of individual chiidhood cancers. This becomes a particular problem if one wishes to study cancers other than acute leukemia and brain tumors in children. This fictor has perhaps played the single most important role in limiting OUT information on the causes ofchildhood cancer. Thc dative rarity of childhood cancers hu Id to the development of large multi- center cooperative d i n i d trial g r o u p for I I the conduct of cancer treatment research in children. T h e two major U.S. groups are the Children's Cancer Group (Arcadia, CA)and the Pediatric Oncology Group (Chicago, IL). A large proportion of all U.S. children with cancer is treated with protocols from the two groups. This very practical approach to dealing with the rarity issue in childhood cancer research has proven invaluable for developing new information on cancer treatment. A FurtherProblem A further problem in conducting epidemiologic research on childhood cancers, and for many adult cancers as well, is that many environmental exposures are hard to measure and validate and their links with disease are often hard to detect. This has been a particular problem in case-control research, where information is collected on a wide variety of pocsnLial environmental exposures. T h e issue is further compounded by the reliance on cases' and controls' recall of environmental exposures. Usually there are Tew, if any, means for validating exposures and even fewer biomarkers of exposure available to provide better quantification of exposures. Some ExceptionalEnvironmental ofc cancer Sometimes the astute clinical observation of the concordance of a rare form of cancer and an uncommon environmental exposure can lead to breakthroughs in knowledge of cancer causation. Little confirmation of such findings is needed when extremely strong associations are observed. An example of this is the striking c a d association between vinyl chloride exposure and angiosarcoma of the liver. The initial report of this association was the result of astute occupationai health workers observing three cases of this extremely rare cancer at manufacturing facilities producing vinyl chloride (IO).The detection of such linkages is enhanced when they are noted for extremely rare cancers associated with extremely rare exposures. For example, the rarity of both dise;lse and causal exposure led to a breakthrough finding of an association between diethylstilbestrol (DES) and clear cell vaginal adenocarcinoma in young women (6).An astute obsteuicidgynecologist observed an unusual occurrence of these rare vaginal cancers in young women in his practice (6).A case-controlstudy was conducted to assess potential exposures that might be associated with risk of these rare cancers. This classic study found a striking association between the use of DES during pregnancy and subsequent development of vaginal adenocarcinoma in the young women exposed to DES in utero (6).This observation provided considerable impetus to awareness of the mechanism of rransplacenta carcinogenesis. Unfortunately, observations such as these, which link extremely rare exposures with extremely rare malignancies, are thenuelves rare. For the vast majority of cancers, more difficult rraditional epidemiologic methods must be used to uncover new potential risk kctors. DescriptiveEpidemiology A fundamental approach frequently used to study the epidemiology of a disease is assessment of the way a disease occurs in a population. This is ofien termed descriptive epidemiology (11).One looks for unusual patterns of disease occurrence in terms of time, place, and person characteristics. For example, is there seasonal variation in the occurrence of a disease? Is there a higher incidence of a disease in some places than in others? Are women affected more than men? The answers to such questions can provide ideas (hypotheses) regarding the underlying cause of the disease. An example of the use of descriptive epidemiology for developing causal hypotheses would be the observation of an unusual occurrence of cancer cases in proximity to a hazardous waste dump site. This observation, which might well be due to chance, can lead to further epidemiologic study of associations between substances in the dump site and risk of the cancers observed. O n e of the difficulties with descriptive epidemiology is that it usually does not provide us with information regarding the specific exposures of the cases. so that each shot appeared to pass through the center of the target. Clustersandthe shvpshootcrEtl&d In a random distribution of cases of cancer over a geographic area, some cases will appear to occur very close together just on the basis of random variation. The occurrence of a group of cases of a disease close together in time and place at the time of their diagnosis is called a cluster. If such a cluster is observed in relation to a suspected causal environmental factor, it often becomes a cause of concern. The usual way the cluster is investigated is that the time frame selected for study is the period between the diagnosis of the first case and the last. The geographic frame for study is often the distance between the two cases living f d e s t apart. When the incidence of the disease in these time and geographic frames is computed, it is often alarmingly high. This approach is similar to the Texas sharpshooter. In a cluster investigation, the time and space intervals become the target that is painted around the observed cluster. It is this post hoc definition of the study population and time frame that leads to spurious and often alarming reports of clusters greatly in excess of normal expectation. However, not all studies of childhood cancer clustering are done in this post hoc fashion. Excellent statistical methods have been developed for assessing whether cases occur more closely together than would be expected by chance. These approaches usually are based on analysis of all cases of a disease occurring in large defined populations selected without prior observation of clustering (13,14). The Texas Sharpshooter Meet Ecologic studies One of the fallacies in certain descriptive epidemiologic obse-eations _of clusters is termed the Texas sharpshooter effect (12). This problem can best be illustrated by the anecdote about the Texas sharpshooter. A traveler passing through a small town in Texas noted a remarkable display of sharpshooting. O n almost every barn he passed there was a target with a single bullet hole that uncannily passed through the center of the bull's-eye. He was so intrigued by this that he stopped at a nearby gas station to ask about the sharpshooter.With a chuckle, the attendant told him that the shooting was the work of Old Joe. Old Joe would first shoot at the side of a barn and then paint targets centered over his bullet holes Another type of descriptive epidemiologic a w a h e so-called ecologic study. Ecologic studies examine data on a population basis without specific assessment of individual exposures. For example, childhood cancer incidence could be assessed in counties in which there are chemical dump sites and comparison made with the incidence in counties without dump sites. T k diffi- culty with this approach is that it is not known whether cancer cases were actually exposed to the dump site and/or what their levels of exposure might have been. There is also a likelihood that children living near dump sites will differ in socioeconomic status from children living in areas without dump sites. Although ecologic studies may 882 EnvironmentalHealth Perspectives Vol 106. Supplement 3 June 1998 MITIHODS FOR CHILDHOOD CANCER STUDIES have some value in developing new hypotheses, they provide little in the way of the ability to test causal hypotheses. The Cohort study In a cohort study, subjects are defined on the basis of their exposure status ( I S ) . Usually a group of individuals who have been exposed to some environmental factor are followed over time to see whether or not they develop a disease (or diseases). A comparable group of unexposed individuals is followed similarly over time to see whether they develop the disease(s) of interest. This allows for comparison between the rates of disease occurrence in exposed and nonexposed persons. Often, general population rates of disease occurrence are used for comparison rather than control groups. Cohort studies involving childhood cancers are infrequently done. The childhood cancer cohort studies that have been done usually involve welldefined large groups of children that have had an uncommon exposure such as to ionizing radiation. Ahvanbges and Limitarions of Cohort Studies A major advantage of the cohort study approach is that it works best for evaluating the health effects of rare exposures. Selecting and following a group of people who have had a very uncommon exposure is more likely to yield meaningful results than would a case-control study. It is most unlikely that in a case-control study of usual size, many subjects will have had a history of a rare exposure. Another advantage of cohort studies is that they allow for evaluating a variety of outcomes in relationship to a particular exposure or a category of exposures. Thus, in a cohort study of an occupational exposure, many outcomes can be evaluated in relation to the exposures being studied. This is in contrast to the case-control study approach in which only a single disease is studied, but multiple potential environmental exposures can be assessed. A major limitation of cohort studies is that often it is difficult to determine the exposure status of people. It is not by accident rhat most cohort studies are of occupationally exposed people, as they can be identified relatively easily and the quality and quantity of their environmental exposures can often be determined. Another problem is posed by the inefficiency of oohort&s l i r assessing rare disclses ot outcomes. To fiml enough cases of the rare disease, even if the risk is high following the exposure, extremely large cohorts of exposed individualswould have to be followed. Perhaps the greatest problem posed by cohort studies is that they allow for the assessment of associations between the studied exposures and many different diseases. By looking at a large number of potentially associated diseases, some associations will be observed purely on the basis of chance. Thus, many associations reported in the literature might be due to chance rather than to a valid association, let alone a causal association. Case-control studies are the type of epidemiologic study most frequently used by epidemiologists to assess potential causes of childhood cancer (16).In the case-control study, subjects with a disease (or health condition) are the cases. Comparisons are then made with a group of subjects without the disease-the controls. Generally, cases and controls are matched on age, gender, and race. In studies of rare diseases such as childhood cancers, casecontrol studies are efficient, as subjects are selected because they have the disease of interest. In contrast to this, in a cohort study, very large numbers of exposed individuals would have to be studied to detect an elevated risk of an extremely rare cancer. Cases and controls are usually interviewed and data are collected on a variety of exposures they might have had prior to the onset of the cases'disease. Thus, c a s e e n trol studies are retrospective. Case-control studies allow for study of many potential risk factors for disease but usually permit the study of only one disease at a time. Advantageand limitations ofCaseXontrolsbudies Case-conuol studies are most advantageous b r the s t u d y of uncommon diseases such as childhood cancers.Generally, case-control studies are relatively inexpensive because lengthy follow-up of subjects, often the case in cohort studies, is not necessary. However, most modern case-control studies of childhood cancers tend to be expensive and time-consuming because of difficulties in collecting sufKcient numbers of cases for study and then in identifying sufficient numbers of matched controls. Also,data collection usually involves personal interviews of subjects or surrogates, which adds to the apense of such studies. A key h m g e of casccontrol studies is that theg allow for the evaluation of many possible causes of a disease. By studying many potential causes, analyses can search for interactions between environmental causes and also allow for evaluation of potential confounding variables. Confounding variables are variables (exposures)that are associated both with the disease and with another exposure observed to be associated with the disease. The other exposure may appear to be associated with the disease when it is really the joint association with the confounder that is the underlying risk factor for the disease. Case-conuol studies have proven over the years to be valuable tools for the generation and testing of hypotheses regarding the causes of cancer. However, case-control studies are fraught with difficulties, as are most epi- demiologic study designs. For reasons mentioned previously, case-control studies are not efficient for evaluating the role of uncommon exposures in the etiology of a disease. Additionally, cases and controls have different levels of motivation for participating in the study and may have differential reporting or recall of exposure histories. For example, the cancer patient might be more apt to recall remote relatives that have had cancer than would a healthy community control. Part of this problem also results from the fact that when a person develops a cancer, relatives often remind that individual of other family members who have had the same or similar cancers. This is an example of selective recall. Another problem relates to the fact that in many instances, controls for we-control studies are biased subsets of the population and thus not truiy compa- rable to cases. Increasingly, in we-control studies of childhood cancer, random-digit telephone dialing is used to select controls from the same telephone area as the cases. Thus, these controls represent comparable individuals living in the same communities. However, if the telephone calls are only made during the daytime, the likelihood of bung reached for inclusion in the study could be afFected by such factors as unemployment of family members, family size, and whether or not a mother stays home to provide care for her children. As a result, in most case-control studies of childhood ~ a n ~ rean~do,m-digit dialing is done on evenings and weekcnds to avoid such p o u n d sources of bias. TheNestcdGsoGntrdStudy A hy4rid of-nml and cohort studies, the n a r d :=e-control study, has been t ci t developed (15). In this study approach, a were extremely interested in doing a case-control research. Although there has cohort study is used as a venue for con- second case-control study. Although we been much criticism of cascIontro1 studies ducting a subsequent case-control study. finally had access to large numbers of cases, regarding the assessment of so many poten- Cases who have developed a particular dis- we codd not come up with an economical tial risk ficmrs that they often generate fdse ease are i d e n t i s e d within the cohort. and feasible means of identifying controls. leads, the problem lies not in the method- Comparable d m r t members without the Our first attempt was to have case parents ologic approach but in how the analyses are disease are selected as controls for these select control families for us. This fared done and how the data are interpreted and cases. Cases and controls are compared poorly in peer review because it was felt to promulgated to the public. Simply stated, with regard to prior exposure history, labo- be likely to yield a biased (nonrandom) results from case-control studies must be ratory data, or other previously collected group af controls. Our problem was finally confirmed by other case-control studies in information. There are many efficiencies solved by the use of random-digit tele- other populations before they can be afforded by this design. First, information phone dialing to obtain controls. This accepted. Casccontrol studies are excellent on potentially causal exposures are usually technique uses a random number based on tools for developing new etiulogic hypothe- obtained well in advance of the develop- the case's telephone number. The random ses. They are as0 excellent tools for generat- ment of the disease of interest. Thus, such number is then called to see if a compara- ing chance associations that may then result information is less subject to the imperfec- ble child resides there and if the family is in misleading hypotheses. Investigators con- tions of remote memory and biased recall willing to participate. ducting case-control studies must exert PN- of information. Second, when laboratory We were then able to conduct a second, dence in their analyses and interpretation of risk factors (or markers) are assessed, they very large case-control study of over 300 their data. Good scientific investigation need only be studied in cases and controls RMS cases and a matched number of con- requires a healthy degree of skepticism for rather than in the entire cohort, thereby trols. It is likely that over 50% of all U.S. one's own as well as others' new scientific reducing c c m considerably, particularly RMS cases were in our study. We found findings. Thus, investigators should not when the laboratory studies are done on no association between fathers' (or moth- rush out and hold press conferences when previously collected biologic specimens. ers') cigarette smoking and RMS in their they find a new and sensational association E d y ExperienceUsing a Case-controlApproach children. However, when we asked about that may or may not be due to chance and smoking, we asked about several other has yet to be confirmed. The downside of exposures that also might have adverse this is that the process of doing epidemi- In response to observations in 1976 that health effects. These dummy variables were ologic research on rare cancers via case- there appeared to be an epidemic of child- used to camouflage the questions about control studies is a slow one requiring hood RMS in North Carolina, a case- cigarette smoking. Much to our surprise, testing and retesting of hypotheses. Given control study was conducted to search for we found that parents' use of recreational the rarity of most childhood cancers, the underlying causes (17).Because there was drugs (marijuana and cocaine) was strongly accrual of sufficient numbers of subjects for no state cancer registry at the time, cases associated with RMS risk in their children. study often takes years. Thus, the entire were identified through North Carolina Thus, one of our dummy variables was process from the observation of a new asso- hospitals. Thirty-three RMS cases were col- associated with risk of RMS (13). ciation to its confirmation may be a matter lected over a IO-year period. Controls were of a decade or more. Unfortunately, for identified via state birth certificates because many rare cancers, this process cannot be it was felt that hospital controls might be a accelerated;great patience is required. biased subset of North Carolina children. This study attempted to uncover some The most important lesson emerging from this experience was that cooperative clinical Recommendationsfor Future possible environmental risk factors (causes) trial groups are excellent venues for the con- Studies of Childhood Cancer for R i i I S . Because few hypotheses existed duct of case-control studies of childhood My first recommendation is that break- regarding the causes of this rare malig- cancer, particularly for the extremely rare throughs in our understanding of the nancy, information on a wide variety of cancers of childhood (7).It also demon- environmental causes of childhood cancer potential causes was collected. We asked strated that techniques for control selection are just as likely to result from studies of about smoking as well as several other expo- such as r a n d o m-dig .-..- i t _dia-lin g -re-n-d e ~~ r the rare cancers as from studies of more com- sures that also have adverse health effects. conduct of national case-control studies mon cancers. Thus, studies of diseases that The most important finding emerging from feasible. T h e reason for the conduct of may be of little public health impact can this study was a strong association between studies that are national in scope and use yield important knowledge regarding the fathers' cigarette smoking and RMS in their subjects from cooperative clinical trial causation of childhood cancer. children. There was no association between groups is that it allows for the accession of Over the years there has been great mothers' smoking and RMS in their chil- suficiendy large numbers of subjects with interest in studying unusual clusters of dis- d e n . A biologically based hypothesis was extremely rare cancers to allow for proper ease, particularly clusters of cancer. Almost developed to explain the finding and there statistical analyses. It also yields a relatively all of the clustering studies done have failed seemed to be an important need to confirm representative group of cases. to yield new knowledge about the environ- or refute it (18). This experience also illustrates that m e n d causes of chil&ood cancer. The post Because Rh4S is such a rare disease, we case- control studies can assess many hoc nature of most cluster investigationshas searched for ways to identify larger num- potential causes of a disease and some of yielded results suggestingstriking excesses of bers of cases. We contacted the Intergroup the suspected risk factors will prove to be cancers in certain locales. However, these Rhabdomyosarcoma Study (Omaha, NE), associated with the disease merely on the reports generally tend to be meaningless and a cooperative clinical trials group, and they basis of chance-the Achilles heel of serve to alarm the public unnecessarily. 1 884 1 Environmental Health Perspectives * Vol 106, Supplement 3 * June 1998 METHODS FOR CHILDHOODCANCER STUDIES There has also been increasing interest in conducting ecologic studies of environmen- tal factors in childhood cancer. Such studies might look at the relationship between residence near a dump site and the occurrence of childhood cancer in its immediate vicinity. These studies suffer from a lack of specific exposure data for the subjects involved. They are also likely to be confounded by socioeconomic and other factors. Thus,it is highly unlikely that useful information can be obtained on environmental causes from such studies. Cohort studies of environmental causes of chiidhood cancer would be extremely difficult and unlikely to yield important new information other than in special situations. Usually, it is very difficult to identify a large enough cohort of children with a common set of exposures for study. It should be remembered that childhood cancers are extremely rare and thus huge cohorts would have to be assembled to generate sufficient numbers of children with the cancer at issue to derive meaningful results. Cohort studies of parents' occupational exposures and risk of cancer in their children should only be done when specific exposure data are available. Numerous such studies have been published (20).However, these studies have tended to be lacking in information on the type, dose, and timing of the parents' occupational exposures. Thus, if further studies are to be done and not add to the confusion in the literature, they should only be done in situations in which precise exposure information can be obtained. Traditional case-control studies that rely predominantly on interview data are unlikely to yield new information on environmental causes of childhood cancer. Most childhood cancers have already been studied in this manner. Well-designed large case-control studies that involve biologic information or that validate exposure information are likely to yield important new information. Such studies should be multidisciplinary and large in size to allow for proper evaluation of causal interactions and potential confounding variables. Such studies would be relatively expensive because of their increased complexity; however, this expense would be well justified.------ -~-__ ~- - Because it is often the case that the specific level of exposure of a child to a suspected environmental risk factor is unknown, it would be highly desirable to have some biologic measure of past exposure. Unfortunately, few biomarkers of exposure levels are currently available. Biomarkers of cancer risk following environmental exposures would be high on many epidemiologists' wish lists. The availability of inexpensive, reliable, and valid laboratory measures of environmental exposures, cancer risk, or individual susceptibility would greatly strengthen epidemiologic studies of environmental risk factors for childhood cancer (21).It would particularly facilitate ecologic and case-control studies. Development of such biomarkers should be a priority area for future research. It is likely that genetic factors (i.e., hereditary susceptibility)play an important role in the etiology of many cancers of childhood. Children with a genetic predisposition for cancer may be particularly sensitive to environmental carcinogenic exposures. The Knudson two-mutation hypothesis of familial cancer occurrence is consistent with this notion ( 4 ) .Thus, it should be fruitful in future epidemiologic research on childhood cancer to consider genetic-environmental interactions. The difficulty in conducting such research hinges on the rarity of most genetically related cancers of childhood. Again, the availability of a useful and economical laboratory measure of genetic susceptibility to childhood cancer would be a boon to epidemiologic research. - Another area for future research is the role of environmental factors in the causation of second malignancy in cancer patients. As treatment of childhood cancer becomes more successful, many patients will survive into adulthood. Some of these patients will develop second cancers, most of which are believed to be due to cancer therapy effects or to genetic predisposition. The question arises as to whether a cancer survivor's risk of second cancer might be increased further by environmental factors such as occupational exposures. This is a potentially fruitful area for new research. In summary, there are numerous dificulties in conducting research aimed at elucidating the causes of childheod cancer. However, these difficulties a~ not insurmountable and can be remedied by :he conduct of carefully designed and conducted studies. I t must be remembered that the epidemiologic approach is probably the most likely research venue for uncovering the causes of childhood cancer. REFERENCESAND NOTES 1. Stewart A, Webb J, Giles D, Hewitt D. Malignant disease in childhood and dugnostic radiation in m.h m 2447 (1956). 2. Stewart A, Webb J, Hewitt D. A survey of childhood mdignancies. Br Med J 1:1495-1508 (1958). 3. MacMahon B. Prenatal x-ray exposure and childhood cancer. J Natl Cancer Inst 28:1173-1191 (1962). 4. Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68:820-823 (1971). 5. Li FP, Fraumeni JF Jr. Prospective study of a family cancer syndrome. JAMA2472692-2694 (1 982). 6. Herbst AL, Ulfelder H, Poskanzer DC.Adenocarcinoma of the vagina: association of maternal stilbestrol therapy with tumor appearance in young females. N Engl J Med 284878-881 (1971). 7. Grufferman S, Delzell ES, DcLong ER. An approach to conducting epidemiologic rcscarch within cooperative clinical trials groups. J Uin OncoI2:670-675 (1984). 8. Austin DF. Flaunely J, Greenberg R Isaaaon P, Key C, Kdond LN,PlaaC, Swanson GM,Thomas D, West D,aaL The SEER Program 1973-1982. In: International Inddena ofchildhood Cancer (Parkin DM, Stiller CA,Bicher CA,Draper GJ, Terracini B, Young JL, eds). JARC Sd Publ No 87. Lyon:lnternational Agency for Research on Cancer,1988;lOl-107. 9. Parkin DM, Muir CS, Whelan SL,Gao Y-T,Ferlay J, PoweU J, eds. Cancer Incidence in Five Continents, Vol VI. IARC Sci Publ No 120. Lyon:Internationd Agency for Research on Cancer, 1992. 10. Creech JL Jr, Johnson MN. Angiosarcoma of liver in thp manufacture of polyvinyl chloride. J Occup Med 16:150-151 (1974). 1 1 . Esteve J, Benhamou E, Raymond L. Sta:istical Methods in Cancer Research. Vol IV.Descriptive Epidemiolo LARC Sci Publ No 128. Lyon:Internationd Agency for research on Cancer, 1994. 12. Grufferrnan S. Clustering and aggregation of exposure; in Hodglun's disease. Cancer 391829-1833 (1977). 13. Alexander FE, Williams J, ~aisonneuveP, Boylc P, eds. The simulated data sets. In: Methods for Investigating iocillized Clustering of Disease. IARC Sci Publ Vol 135. Lyon: ~ntcmationaAl gency for Rcseud,on Cancer; 1996;21-27. t i 14. Kncg EG.G k EA Spatial dwcringof miLlkvvl anceca in Great Britain. J Epidemid CommunityH a W W313-319 (1996). 15. Brrdow NE, Day NE. S d c a l Methods in Gaca Rrsarrh. Vd XI: The Design and Anal+ of Cohort Sadia.URC Si Pub1 No 82. Lyon:International Agency for Research on Cancer, 1987. 2716. &B NE NE. Statistical Methods in GKcr Raatch. Vol I: T h e ysis of Case-ConPol Studies. LARC Sci Pub1 No 32. Lyon:International Agcncy for Research on Cancer, 1980. 17. G d e r m a n S, Wang HH, DeLong ER Kmi SYS,DcLell ES,F?UenaJM.Environmental ficto~in Ja? etio ofrhab- domyosarcoma in childhood. J Nad Cancer Inst%l@7-113 (1982). 18. Grufferman S, Delzell ES,M d e MC, Michalopoulos G. Parents' ci arette smoking and childhood cancer. Med Hypochesaf217-2O (1983). 19. Grufferman S, Schwartz AG, Ruymann FB. Maurer HM. chi$en.Parenu' use of cocaine and mari'uana, and increased risk of rhabdomvosarcoma in Cancer GW Control 4:217-222 (1993). 20. Chow W-H, Linct MS,Liff JM,Greenberg RS. Cancers in children. In: Cancer Epidemiology and Prevention. 2nd cd (Schottcnfeld D. Fraumcni IF Jr, eds). New York:Oxford Uni-i Press, 19%,1331-1%9. 21. Toniolo~B, ofka P, &S D, RothmvlN, H u h B,Pevce 5N. e&. Ap liation of Biomarkcn in Cancer E idemiolo IARC Sci ubl No 142. Lyon:InternationafAgcncy Rcsarch on Cancer, 1997. - i B 886 1 Environmental Health Perspectr.ves ~Vol106.SuPplement3~June1998