Ewing's Bone Sarcoma, Paternal Occupational Exposure, and Other Factors

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1 American Journal of Epidemiology Vol. 1, No. Copyright by The Johns Hopkins University School ol Hygiene and Public Health Printed in U S A. All rights reserved Ewing's Bone Sarcoma, Paternal Occupational Exposure, and Other Factors Elizabeth A. Holly, Diana A. Aston, 1 David K. Ann, 1 and Jennifer J. Kristiansen 1 To determine risk factors for Ewing's bone sarcoma, the authors interviewed mothers of patients diagnosed between January 1 and August 1 and 1 controls in the San Francisco Bay Area, California, regarding medical and occupational history of parents and other factors related to the subjects and their immediate families. Controls were selected by using random digit dial telephone methods. Adjusted relative risk estimates suggest that risks were elevated for children whose fathers were engaged in agricultural occupations during the period from months prior to conception of the subject up to the time of diagnosis for the patients or interview for the controls (relative risk (RR) =., % confidence interval (Cl) 1.-.) and for children whose fathers had occupational exposure to herbicides, pesticides, or fertilizers (RR =.1, % Cl 1.-1., p = 0.00). Prior ingestion of poison or an overdose of medication was more common in patients than in controls (RR =., % Cl 1.-1.). These and other findings should be investigated in larger population-based studies to determine specific factors that may account for the associations. Am J Epidemiol ;1:-. case-control studies; risk factors; sarcoma, Ewing's Ewing's bone sarcoma (International Classification of Diseases for Oncology code 0), although a rare tumor, is the second most common primary bone tumor in children and adolescents after osteosarcoma, with a peak incidence between ages and 0 years (1, ). It occurs with equal fre- Received for publication June 1,, and in final form October 1,. Abbreviations: Cl, confidence interval; RR, relative risk. 1 Department of Epidemiology and Biostatistics, University of California San Francisco, School of Medicine, San Francisco, CA. Department of Health Research and Policy, Stanford University, School of Medicine, Stanford CA. Northern California Cancer Center, Program in Epidemiology, Union City, CA. Repnnt requests to Dr. Elizabeth A. Holly, Department of Epidemiology and Biostatistics, University of California San Francisco, 1 Sutter Street, Suite 0, San Francisco, CA. This work was supported in part by grant RO1-CA from the National Cancer Institute, National Institutes of Health. The authors are grateful to Dr. Richard L Kempson for his review of the pathology slides and to Dr. Jordan Wilbur for his support of this study. quency in males and females until about age 1, when the incidence in males begins to predominate. These tumors are extremely unusual in American and African blacks and in Chinese (-). Ewing's bone sarcoma was originally thought to arise from endothelial cells; however, more recent evidence indicates that it derives from primitive neural tissue. It shares some characteristics with neuroepithelioma, including its rarity in black children and a unique chromosomal translocation, t( :) (). Extension from the bony cortex into the soft tissues often causes difficulty in distinguishing between a diagnosis of soft tissue tumor and Ewing's bone sarcoma, although electron microscopy and immunocytochemistry assist in accurate diagnosis. Ewing's bone sarcoma presents most often in the bones of the pelvis and the femur, although it can affect any bone. Improvements in therapy have considerably increased long-term, disease-free survival from less than 1 percent to more than 0 Downloaded from at Pennsylvania State University on May 1, 0

2 Ewings's Bone Sarcoma and Paternal Occupation percent over the past 0 years (). We conducted a case-control study to identify risk factors for this disease. MATERIALS AND METHODS Patients All patients who were diagnosed with Ewing's bone sarcoma between January 1 and August 1 and lived in the five Bay Area counties covered by the Surveillance, Epidemiology, and End Results tumor registry were eligible for this study. Fifteen additional patients were identified through a pediatric oncologist in San Francisco who specializes in treatment of this disease. Of the families that completed interviews, were identified through the Surveillance, Epidemiology, and End Results registry and resided in this geographic area at time of diagnosis. Of the 1 patients who were referred from outside the immediate Bay Area, nine resided in California, three in Oregon, and three in Nevada at time of diagnosis. Patients' pathology slides were reviewed by Dr. Richard L. Kempson of the Department of Surgical Pathology at Stanford University; only patients with confirmed diagnoses of Ewing's bone sarcoma were eligible. In addition to the families that completed interviews, five families could not be located, one family lived in Iran and was unavailable for interview, and a physician indicated that there were contraindications to contacting one family. The overall interview completion rate was percent of eligible cases, although 0 percent of the families that were contacted participated in this study. Controls A total of 1 controls were frequency matched to the patients by sex and by age within 1 year of age at diagnosis. Biological mothers of controls were identified by random digit dial procedures (). To obtain controls who lived in the same geographic area as the patients, we generated telephone numbers using the area code and the first three digits of patients' telephone numbers in combination with four randomly generated numbers. These numbers were dialed up to times on weekdays and weekends at different hours of the day and evening, as needed to reach residents. There was an percent response rate for mothers of the eligible controls. Interviews Interview topics covered a range of characteristics evaluated prior to the diagnosis in the patients or to the time of interview for the controls, particularly: parental occupational history and exposure to chemicals on the job; education; height and weight; use of cigarettes, alcohol, and social drugs; maternal reproductive history, including exposure to x-rays, drugs, or other substances during ; family income; family history of birth defects and cancer; and family residence history (farm vs. nonfarm and urban vs. rural). Parents also were asked about subjects' medical history prior to the diagnosis for patients or prior to interview for controls, including medication use, congenital anomalies, childhood diseases, exposure to x-rays, length and weight at birth, height at diagnosis, and exposure to animals. Mothers of patients and controls were interviewed in person if they lived in the San Francisco Bay Area or by telephone if they lived outside the Bay Area. Ages of subjects ranged from to 1 years at the time of diagnosis for patients or at the time of mothers' interview for the controls. Analyses Unconditional logistic regression analyses were used to estimate relative risks for host and environmental factors, singly and in combination, with estimates calculated first for individual variables. Potential confounding was assessed by stratified analysis. Also computed were percent confidence intervals for estimates of the relative risk, chisquare tests for trend, and two-tailed p values (at the p = 0.0 level) (, ). An unconditional logistic model was used for final analyses to evaluate the effect of risk factors Downloaded from at Pennsylvania State University on May 1, 0

3 Holly et al. while adjusting for the influence of other variables. RESULTS A total of mothers of study subjects (1 female and male patients, female and male controls) were interviewed. As in clinical series, there were nearly twice as many male as female patients ( vs. percent). Mean age was similar for the patients at diagnosis and for the controls at interview (1. years for female patients, 1.1 years for female controls; and 1. years for the male patients, 1.1 years for the male controls; age range, -1 years). No differences between patients and controls were noted with regard to height when age-specific comparisons were made for males (p = 0.) and for females (p = 0.1). Table 1 gives unadjusted relative risk estimates and estimates adjusted for the influence of other factors. Details of only the adjusted estimates of the relative risks are presented in the text. Paternal agricultural occupation during the period of conception and prior to diagnosis was associated with an elevated risk for Ewing's bone tumors (adjusted relative risk (RR) =., percent confidence interval (CI) 1.-., p = 0.00). Separate analyses were conducted for the population-based patients and the 1 patients from outside the Bay Area (who were referred to us by the pediatric oncologist) and their respective controls to determine whether risk factor estimates differed between the two groups. Adjusted relative risk estimates were somewhat higher for paternal agricultural occupation in the population-based subjects (RR =., percent CI 1.0-., p = 0.0) when compared with those who lived outside the immediate Bay Area (RR =., percent CI , p = 0.1). Adjustment for income was included in the final analyses because a higher percentage of patients from outside the five-county Bay Area region who were referred to San Francisco for treatment had families with incomes that were greater than TABLE 1. Ewing's bone sarcoma: unadjusted and adjusted estimates of relative risks (RR) and % confidence intervals (CI), San Francisco Bay Area, California, 1-1 Paternal occupation Agriculture Construction Maternal history Thyroid hormone use during Antibiotic use during Subject's history Lived on, next to farm Exposure to cows Exposure to horses Poison or overdose of medication Mumps Vaccinated for mumps Dental radiographs Total family income (dollars) >0,000 0,000-, <0,000 Cases (n = ) No. % Controls (/> = 1) No % Unadjusted RRf % CI Adjusted* RRf % CI 1.-.* ** p = 0.00; *p = t No exposure is the referent group for all dichotomous variables. t Variables in the multiple logistic model included agricultural occupation of the father, poison or overdose of medication, area of residence, year of child's birth, and income. Sex of the subject was also adjusted for in the model. Downloaded from at Pennsylvania State University on May 1, 0

4 Ewings's Bone Sarcoma and Paternal Occupation $0,000 compared with the populationbased patients. The agricultural occupations of the fathers of the seven patients ( percent) and five controls ( percent) and the time they worked at these occupations during the period from months prior to conception of the subject up to time of diagnosis of patients or time of interview for controls were as follows: cases: 1) agricultural assistant, gardener, flower grower for 0 years; ) ranch foreman (raised cattle and grains) for years; ) dairy farmer (milked cows and did field work) for years; ) mushroom grower, artichoke picker for years; ) gardener, landscaper for years; ) vegetable farmer for years; ) dairy farmer (milked cows) for 1 years; controls: 1) greenskeeper (lawns and greens) for years; ) gardener (lawns and trees) for 1 years; ) ranch manager (chickens) for years; ) ranch hand (raised cattle and hay crops) for months; and ) farm worker (grapes, pears, and crop dusting) for years. All seven fathers of patients compared with three of five fathers of controls were employed in agricultural occupations prior to and at the time of conception. Occupational exposure to herbicides, pesticides, or fertilizers was more common in the fathers of patients than in the fathers of controls (adjusted RR =.1, percent CI 1.-1., p = 0.00). All seven fathers of patients reported this exposure compared with three of five of the fathers of controls. Ewing's bone sarcoma cases whose fathers were employed in agricultural occupations did not differ from those cases whose fathers were not with regard to age at diagnosis, distribution by sex, birth weight, birth length, or primary site of Ewing's sarcoma. Paternal occupation in construction initially appeared to be associated with a higher risk of disease, although this risk diminished after controlling for other factors. Two factors related to mothers' histories showed elevated risk estimates for Ewing's bone sarcoma. The relative risk estimate associated with thyroid hormone replacement taken by mothers during with the subject decreased slightly after adjustment for other factors (RR =., percent CI 0.-1., p = 0.). Use of antibiotics during the index conveyed a somewhat elevated risk for disease after adjustment for other factors (RR =., percent CI 0.-.0, p = 0.). Subjects' histories of residence on or next to a farm or ranch and exposure to farm animals were investigated. With control for other variables, particularly paternal agricultural occupation, the risk estimates were no longer elevated. Having had cats, dogs, birds, fish, reptiles, and other pets provided relative risk estimates that were close to 1.0. Patients had ingested an overdose of medication or poisons more often than the controls (adjusted RR =., percent CI , p = 0.01). When attempts were made to control for recall bias by reanalyzing the data only on those subjects who saw a physician as a result of the poisoning episodes, the adjusted relative risk increased to. ( percent CI 1.-., p = 0.00). Substances ingested in these episodes represented a wide range of common household products (such as aspirin, cough syrup, antihistamine, Valium (Roche Laboratories, Nutley, New Jersey), diet pills, vitamins, isopropyl alcohol, various household cleaning products, paints, pesticides, and rat poison). Mothers were asked about subject's history of illnesses and birth anomalies. Only history of mumps increased risk of Ewing's bone sarcoma on univariate analysis, while vaccination against mumps initially appeared to be protective. However, since mumps vaccination was not available until and was not routinely used until 1 (), children born before 1 would have been less likely to have been vaccinated. With adjustment for just the year of the child's birth, the relative risk for history of mumps dropped to 1. ( percent CI 0.-., p = 0.). There was a tendency toward fewer patients than controls having had prior dental radiographic examinations after controlling for other factors (RR = 0., percent CI , p = 0.). No association was found between Ewing's bone sarcoma and parental educa- Downloaded from at Pennsylvania State University on May 1, 0

5 Holly et al. tion; use of cigarettes, alcohol, or medications taken at any time; or weight of the parents. Maternal occupations, chemical exposures, and reproductive history, including x-ray exposures or medications taken during, other than those already mentioned, conveyed no increased risk. No association was noted with the subjects' birth length or weight or with the subjects' medical history, with the exception of overdose of medication or accidental ingestion of poison. There also was no evidence that family history of birth defects or cancer was related to Ewing's bone sarcoma. Because the number of patients in this study was limited, it is important to note that the risk estimates for most of the factors just mentioned were all quite close to 1.0 both before and after adjustment for other relevant variables. A summary of other findings, all with values greater than 0.01, is presented in table as a guide for future research. DISCUSSION Paternal history of agricultural occupation; paternal history of occupational exposure to herbicides, pesticides, or fertilizers; and overdose of medication or ingestion of poison by subjects were statistically significant risk factors for Ewing's bone sarcoma in this study after adjustment for other factors. Numerous statistical tests were conducted in this study, and statistical power to detect associations was limited by the number of patients with the disease. Factors with elevated relative risks such as use of maternal thyroid hormone replacement and antibiotic use during need further evaluation in larger population-based data sets. An association between Ewing's bone sarcoma and paternal agricultural occupation, using data from the Intergroup Ewing's Sarcoma Study with 0 patients, has been reported. Results showed an elevated risk of.0 for paternal agricultural occupation when using a population-based control group for comparison (). In an interim analysis from this same study that included patients and controls, the relative risk for paternal agricultural occupation was.0. The differences between the two sets of study results were not noted by the authors (). They concluded that more in-depth studies to address specific environmental exposures and developmental anomalies are needed. In addition to finding an association between Ewing's sarcoma and agriculturerelated occupation of the subject's father, the Intergroup Ewing's Sarcoma Study reported a greater use of tranquilizers by mothers during with the subject, greater postnatal exposure of subjects to x- rays, and a high incidence of all hernias in subjects. We were unable to confirm these associations. The relative risk for hernias present at birth or evidenced during the first years after birth were elevated on univariate analysis. However, after adjustment for other relevant factors, the risk estimate was substantially reduced. In our study, patients had had fewer dental and other radiographic examinations than did controls. Dental radiographs had a statistically significantly lower unadjusted relative risk that was no longer present when adjusted for other factors, as shown in table 1. The mechanism that relates Ewing's bone sarcoma in the child to environmental exposure of the father is unknown. However, herbicides and pesticides have been found to be associated with soft tissue sarcoma (- 1). Buckley et al. () noted an association between paternal occupational pesticide exposure and acute nonlymphoblastic leukemia in children. In our study, herbicide and pesticide exposures related to the agricultural occupation of the father also were more common in the fathers of patients than in the fathers of controls. In a case series from Western Australia, historical information was gathered on six patients diagnosed within years with histologically proven Ewing's bone sarcoma (1). These cases were unusual as they were older (average age, years) than the average Ewing's patient in the Western Australia Bone Tumor Registry, had all lived near each other in rural areas, and had all been exposed to farm animals for extended periods (three were farmhands). No mention Downloaded from at Pennsylvania State University on May 1, 0

6 Ewings's Bone Sarcoma and Paternal Occupation TABLE. Ewing's bone sarcoma: unadjusted estimates (except as noted) of relative risks (RR) and % confidence intervals (Cl) for negative results,* San Francisco Bay Area, 1-1 Mother smoked during Father smoked during Mother consumed alcohol during Mother's kin with cancer Mother's kin with birth defects Father's kin with cancer Father's kin with birth defects Professional pest extermination in home during Professional pest extermination in home during subject's childhood Medical problems of mother during Spotting or cramping Severe nausea, vomiting Eclampsia, toxemia High blood pressure Procedures performed during Radiography General anesthesia Cesarean section Medication taken by mother during For vomiting, nausea Diuretics Sleeping pills Pain relievers Tranquilizers Subject's medical history Chicken pox Measles Rubella Rubella, adjusted! Infectious mononucleosis Hyperactive Hernias (all types) Hernias present at birth or evidenced during first years of life Hernias, adjustedt Fractures or diseases bones Disorders of the heart Urinary tract disorders Disorders of male organs No. of males No. with disorder Eye/ear disorder Disorder of digestive tract Radiographs other than dental Took vitamins and/or minerals Cases (" = ;) No % Controls 1) e» = No % RR % Cl * These variables are not included in table 1. t These variables were adjusted for agricultural occupation of the father, poision or overdose of medication, area of residence, year of child's birth, and income. P Downloaded from at Pennsylvania State University on May 1, 0

7 Holly et al. was made of parental occupations or of pesticide exposures. The authors suggested the possibility of an infectious etiologic agent, such as an oncogenic virus transmitted by farm animals (1). Another report of Ewing's bone sarcomas in two brothers noted that the father had always worked in agriculture and that the boys had had contact with farm animals (1). The brothers, aged and 1 years, were diagnosed within a few months of each other. No studies were conducted to determine whether chromosomal translocations were present in the tumors of the affected brothers. Studies of Ewing's bone sarcoma have yielded conflicting results regarding an association with height. Fraumeni (1) reported that patients were significantly taller than controls (p < 0.0). The effect appeared to be related primarily to males. Another study noted that females with Ewing's bone tumors were significantly shorter than were population controls, while there was no difference in the height of the males (0). Others have reported no association with height (, 1). In our study, there were no differences in height when patients were compared with controls by each year of age and by sex. Although medication overdose or poison ingestion was more common in the cases, the time sequence from event to occurrence of disease in the cases and interview in the controls was the same in both groups. We suspect that the association between Ewing's bone sarcoma and medication overdose or poison ingestion may be an indication of a confounding factor not measured in this study. This supposition is supported by: 1) the similar time sequence just mentioned; ) the comparable nature of the substances ingested by the patients and the controls; ) similar mean age at poisoning for patients and controls; ) the diversity in the substances themselves; and ) the absence of other reports of this association. However, potential toxicologic effects of acute exposure of some of these substances on the target tissue cannot be ruled out without further study. Response bias is unlikely to provide an explanation for the association with agricultural occupation of the father for several reasons. First, the participation rate of subjects was high in both patient and control families, and parents were contacted at all times of the day and evening and on weekends to avoid selecting only those who were home during the day. Second, the relative risk for the association with agricultural occupation of the father was high, at., and third, an elevated risk for this factor was also reported by the Intergroup Ewing's Sarcoma Study (, ). Fourth, the risk was elevated both in the population-based patients (RR =.) and in the subjects who were referred from outside the Bay Area when compared with their respective geographically matched controls (RR =.). The somewhat, but not statistically significantly, diminished effect for paternal agricultural occupation in the subjects from outside the Bay Area may have been related to families with higher incomes having been more likely to travel long distances to seek specialists, with fewer families with agricultural occupations able to afford the numerous journeys to San Francisco. Because we excluded non-english-speaking families and those without telephones, we were less likely to have migrant farm laborers, who could have had high pesticide exposure. This underrepresentation would most likely bias the estimates of risk toward 1.0. Fifth, there were no systematic differences in patient and control responses to the vast majority of questions on exposures and medical history. Sixth, the random digit dial procedures used in this study have been shown by others to yield random samples of individuals in a population and to have good response rates (). Random digit dial procedures were also used to obtain controls for the case-control study that included Intergroup Ewing's Sarcoma patients (, ). A strong association of agricultural occupation of the father with Ewing's bone sarcoma has now been noted in two studies of this childhood tumor. This study did not provide data to address how paternal occupational exposure might affect a child. Pos- Downloaded from at Pennsylvania State University on May 1, 0

8 Ewings's Bone Sarcoma and Paternal Occupation sible mechanisms include chemicals or viruses brought home by the fathers and transferred to the children, direct exposure of the children who accompanied their fathers to work, or agricultural chemicals that could have caused a germ cell mutation prior to conception. The rapid growth of the fetus during renders it susceptible to mutagenesis, chromosomal aberrations, and carcinogenesis (-), with tumors developing in the progeny after in utero carcinogenic exposures (). Work with rats has shown tumor development in progeny of male rats exposed to chemical carcinogens prior to mating (). Larger populationbased epidemiologic investigations need to obtain detailed information about exposures of parents and children to pesticides, herbicides, and animals; any poisoning episodes in children; maternal drug use during ; and factors found by others (, ) that may provide further clues to the etiology of this often fatal disease primarily of children and adolescents. REFERENCES 1. Cutler SJ, Young JL Jr, eds. Third National Cancer Survey: incidence data. Natl Cancer Inst Monogr 1;1:l-.. Pizzo PA, Horowitz ME, Poplack DG, et al. Solid tumors of childhood. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: principals and practice of oncology. Vol.. Chap.. Philadelphia, PA: JB Lippincott, 1:-0.. Fraumeni JF Jr., Glass AG. Rarity of Ewing's sarcoma among U.S. Negro children. (Letter). Lancet ;l:-.. Jensen RD, Drake RM. Rarity of Ewing's tumor in Negroes. (Letter). Lancet ; 1:.. Li FP, Tu JT, Liu FS, et al. Rarity of Ewing's sarcoma in China. (Letter). Lancet ;l:.. Waksberg J. Sampling methods for random digit dialing. J Am Stat Assoc 1,:0-.. Breslow NE, Day NE. Statistical methods in cancer research. Vol. 1. The analysis of case-control studies. IARC scientific publication no.. Lyon: International Agency for Research on Cancer,.. Dixon WJ, Brown MB, Engelman L, et al., eds. Biomedical computer programs. Berkeley, CA: University of California Press, 1.. Mumps United States, 1-1. MMWR 1;:1-.. Daigle A, Winn D, Robison L, et al. The etiology of Ewing's sarcoma (ES): a case-control study. Proc Am Soc Clin Oncol 1;:1.. Daigle AE. Epidemiologic study of etiologic factors in Ewing's sarcoma. Vols. I and II. Dissertation Abstracts International 1;:1-B.. Eriksson M, Hardell L, Berg NO, et al. Soft-tissue sarcomas and exposure to chemical substances: a case-referent study. Br J Ind Med 11;:-. 1. Hardell L, Eriksson M. The association between soft tissue sarcomas and exposure to phenoxyacetic acids: a new case-referent study. Cancer 1;: Eriksson M, Hardell L, Adami HO. Exposure to dioxins as a risk factor for soft tissue sarcoma: a population-based case-control study. J Natl Cancer Inst ;: Zahn SH, Blair A, Holmes FF, et al. A case-referent study of soft-tissue sarcoma and Hodgkin's disease: farming and insecticide use. Scand J Work Environ Health 1; 1:-0.. Buckley JD, Robison LL, Swotinsky R, et al. Occupational exposures of parents of children with acute nonlymphocytic leukemia: a report from the Childrens Cancer Study Group. Cancer Res 1; : Holman CDJ, Reynolds PM, Byrne MJJ, et al. Possible infectious etiology of six cases of Ewing's sarcoma in Western Australia. Cancer 1;: Zamora P, deparedes MG, Baron MG, et al. Ewing's tumor in brothers. Am J Clin Oncol 1; : Fraumeni JF Jr. Stature and malignant tumors of bone in childhood and adolescence. Cancer ; 0:-. 0. Pendergrass TW, Foulkes MA, Robison LL, et al. Stature and Ewing's sarcoma in childhood. Am J Pediatr Hematol Oncol 1;:-. 1. Pui CH, Dodge RK, George SL, et al. Height at diagnosis of malignancies. Arch Dis Child 1; :-.. Hartge P, Brinton LA, Rosenthal JF, et al. Random digit dialing in selecting a population-based control group. Am J Epidemiol 1; 0:-.. Tomatis L, Hilfrich J, Turusov V. The occurrence of tumors in Fl, F, and F descendants of BD rats exposed to iv-nitrosomethylurea during. Int J Cancer 1;1:-0.. Rice JM. Perinatal period and : intervals of high risk for chemical carcinogens. Environ Health Perspect 1;:-.. Tomatis L, Cabral JR, Likhachev AJ, et al. Increased cancer incidence in the progeny of male rats exposed to ethylnitrosourea before mating. Inr J Cancer 1!;:-.. Nomura T. Parental exposure to X-rays and chemicals induces heritable tumors and anomalies in mice. Nature 1;:-. Downloaded from at Pennsylvania State University on May 1, 0