Contribution of Clinical Teratologists andGeneticists to the Evaluation of the Etiologyof Congenital Malformations Alleged to BeCaused by Environmental Agents: IonizingRadiation, Electromagnetic Fields,Microwaves, Radionuclides, and UltrasoundJOHN M. GRAHAM, JR.,1 KENNETH LYONS JONES,2 AND ROBERT L. BRENT3*1Division of Clinical Genetics and Dysmorphology, Medical Genetics Birth Defects Center, Steven Spielberg PediatricsResearch Center, SHARE’s Child Disability Center, Ahmanson Pediatric Center, UCLA University Affiliated Program,UCLA School of Medicine, Cedars Sinai Medical Center, Los Angeles, California 900482Birth Defects Center, Department of Pediatrics, UCSD Medical Center, San Diego, California 92103-84463Division of Developmental Biology, duPont Hospital for Children, Wilmington, Delaware 19899

Dr. John Graham and Kenneth Lyons Jones havebeen asked to lend their clinical expertise to evaluatethe causal relationship of various radiation exposuresto the occurrence of serious congenital malformationsand malignancy in a number children. Drs. Grahamand Jones are internationally recognized experts, hav-ing been trained as clinical pediatricians, geneticists,clinical teratologists (dysmorphologists), and basic sci-entists. Dr. Jones is best known for the modern co-description (with Dr. David Smith) of the fetal alcoholsyndrome and for his extensive experience as a clinicaldysmorphologist who established and directs one of thenation’s largest teratology counseling services. Dr. Gra-ham is best known for his research on hyperthermiaand mechanical problems as a cause of some birthdefects. Both scientists were students of Dr. David W.Smith, a world-renowned clinical dysmorphologist. Dr.Graham has also had extensive experience using ani-mal models in teratology research.

The classical approach for the evaluation of radiationrisks from in utero environmental exposures is toreview the available epidemiological studies and appro-priate animal models, and to evaluate these data fromthe standpoint of biological plausibility or biologiccommon sense (Brent, ’86).

EVALUATING THE ALLEGATIONOF TERATOGENICITY

When confronted with the question of the teratogenic-ity of certain environmental agents, the question can beposed from various vantage points:

1. Evaluating the risk of reproductive toxicity of anenvironmental agent.

2. Evaluating the suggestion that an environmentalagent was responsible for an individual child’s birthdefect or other reproductive effects.

3. Evaluating the cause of congenital malformations ina particular child or a group of children.

4. Determining whether to publish a case report of apatient or a cluster of patients with a particularcongenital malformation or a constellation of congeni-tal malformations that may be associated with anenvironmental agent (Brent, ’92).

If one wishes to answer the generic question, ‘‘Is aparticular environmental drug, chemical or physicalagent a reproductive toxicant?,’’ a formal approach isrecommended that includes a five-part evaluation, asdescribed in Table 1 (Brent, ’86).

If, on the other hand, one is concerned about thereproductive effects of an environmental agent in anindividual patient, the question may sometimes beanswered without the benefit of epidemiological stud-ies, dosimetry, or animal studies using the basic prin-ciples of teratology, reproductive toxicology, and genet-ics. Key factors in such an evaluation are having anexperienced clinician who is knowledgeable about thegenocopies that can mimic environmental teratogens,who is aware of the importance of dose or exposure, andwho is aware of the basic principles of developmentalbiology and teratology. A clinician trained and experi-enced in these fields can have a decisive role in usingthe principles of biological plausibility in evaluating theallegation that a particular environmental agent wasresponsible for a child’s congenital malformations.

Grant sponsor: Skeletal Dysplasias NIH/NICHD Program; Grantnumber: HD22657–1 1; Grant sponsor: Medical Genetics NIH/NIGMS; Grant number: GM08243; Grant sponsor: The NemoursFoundation; Grant sponsor: The Harry Bock Charities.

*Correspondence to: Robert L. Brent, Division of DevelopmentalBiology, Room 308 R/A, Box 269, duPont Hospital for Children,Wilmington, DE 19899.

TERATOLOGY 59:307–313 (1999)

r 1999 WILEY-LISS, INC.

Six cases are presented and are discussed by our twoexperts, Drs. Graham and Jones. Each of these clinicalcases eventually resulted in litigation. The clinicaldiscussion and analysis in each case is followed by theresult of the litigation.

FIRST CASE

Dr. Brent: The first patient is a 41⁄2 year old childwith microcephaly.

The allegation was that microcephaly and severemental retardation in this child was caused by adiagnostic radiological procedure (upper GI series)during his mother’s sixth week of pregnancy. Themother of the child did visit the emergency service ofa local hospital and had the diagnostic X-ray proce-dure. At birth the head size was normal but duringthe first few months of life the infant had repeatedrespiratory episodes necessitating visits to the emer-gency department. During his fourth month of life,he was hospitalized and he suffered a cardio-pulmonary arrest that that lasted for 20 min beforehe was resuscitated. His head size decreased fromthe 50th percentile to below the third percentileduring the year following the cardiopulmonary ar-rest. His behavioral development had been normalup until the time of the cardiopulmonary arrest. At41⁄2 years, he was a severely retarded, microcephalicchild.

Dr. Jones: Three features in this case rule out thepossibility that radiation was responsible for this child’smental retardation and microcephaly. Actually, onefeature in particular was sufficient to definitively elimi-nate intrauterine irradiation as a cause of this child’sclinical problems; namely, that he was normocephalicat birth. The second aspect of this evaluation was thatthe sensitive period of microcephaly is after the sixthweek of gestation (Otake and Schull, ’82) and the thirdcomponent is that the level of radiation from an uppergastrointestinal radiological procedure does not pro-vide enough exposure to produce severe microcephalyand mental retardation, even if it occurred during theeighth to fifteenth week of gestation. In this particularcase, the allegation of radiation-induced microcephalyis further muted by the fact that there was an obviousclinical explanation for the patients serious medicalproblem.

Result. After the deposition of the defense experts,the litigation was discontinued by the plaintiffs.

SECOND CASE

Dr. Brent: The second patient is a child withdeafness, whose mother worked with radiofrequency(RF) heat sealers during her pregnancy.

This full-term child weighed 7 lb, 6 oz at birth. By 2years of age, he was found to be deaf, although hewas otherwise physically and developmentally nor-mal. The family believed that the deafness was dueto the fact that the mother worked in a tent-makingfactory and used an RF heat sealer (27.5 MHz) toattach the tent components. It was possible for theheat sealer too exceed the maximal permissibleexposures, but this would occur for only very briefperiods. Calculations showed that there could nothave been any significant elevation of the mothersbody temperature during her working day. Examina-tion of the child revealed a normal child in everyaspect except for the isolated bilateral deafness. Hewas growing and developing normally.

Dr. Graham: Fortunately, there are features of thispatients story which make it unnecessary to review theepidemiological data pertaining to 27.5-MHz RF fre-quency exposures to pregnant populations. This isimportant in this case, because there is not a great dealof human data that pertains to this type of exposure topregnant women (NCRP report 86). While there aremany animal studies, most of the studies deal withhyperthermic exposures for relatively long periods oftime. What is important with regard to this patient’sclinical problem, is the nature of the pathology and theoverall status of the patient. Isolated, bilateral deaf-ness has been described as attributable to a geneticallytransmitted trait that can be dominant or recessive,and may also be due to a new mutation (Petit, ’96). Asignificant proportion of deafness is genetically deter-mined. More importantly, this child has isolated deaf-ness, without any other abnormalities. He had a nor-mal birth weight. He has developed normally. He has noother abnormalities, either physical or developmentalthat would fit with the suggestion that an environmen-tal exposure of any type was responsible for his disabil-ity. Even if his exposure to the RF frequency had raisedhis in utero temperature, one would not expect theradiation to produce such a specific isolated effect. Thehyperthermic effect of RF radiation or for that matterany exposure that would result in embryonic hyperther-mia would produce a constellation of developmentaleffects, not isolated bilateral deafness. As an aside, thework schedule of the pregnant mother was such thatany exposure was intermittent and never would haveresulted in hyperthermia.

Result. The defendants filed for a summary dis-missal, which was granted by the judge before the trialbegan and the court ordered the plaintiffs to pay thelitigation costs of the defendants.

TABLE 1. Evaluating the allegation of teratogenicity

Consistency of epidemiological studiesSecular trend analysisAnimal reproductive studiesDose response relationships and pharmacokinetic

studies comparing human and animal metabolismBiological plausibility

MechanismsReceptor studiesNature of the malformationsTeratology principles

308 J.M. GRAHAM ET AL.

THIRD CASE

Dr. Brent: The third child had asymmetric micro-cephaly, mental retardation, and growth retardationand whose mother was treated for breast cancer withradiation therapy and chemotherapy.

A 44-year-old obese women was found to have breastcancer and was treated with 4.2-Gy ionizing irradia-tion and chemotherapy over a period of 6 weeks.Before her diagnosis of breast cancer, she had beenamenorrheic for more than a year, and she wasconsidered postmenopausal, but a pregnancy testwas not performed before the institution of cancertherapy. Follow-up evaluation 4 months later re-vealed no sign of local or metatstatic breast cancer.At that follow-up visit, the oncologist noted that her‘‘abdomen was soft and without masses.’’ The nextday she delivered a 4-lb, 3 oz, term, growth-retardedinfant with asymmetric microcephaly. The child re-mained below the third percentile in growth andhead size and was determined to be severely men-tally retarded.

Dr. Jones: Several features of this case were trouble-some and did not relate to the determination of thecause of this child’s clinical problems. First, a preg-nancy test was not performed in an amenorrheic womenof reproductive age before the initiation of radiationand chemotherapy. Second, pregnancy was diagnosedat term, at a time that it should have been obvious tothe physician that a fetus was present. These deficien-cies in the medical care may have had an overridinginfluence on the final resolution of the litigation, butthere is no resolution to this child’s mental retardationand microcephaly. Because the fetus received a rela-tively high dose of protracted radiation, between the13th and 19th weeks, it would be appropriate to con-sider the radiation as a likely causal factor in this case.But, chemotherapy can also be responsible for growthretardation and microcephaly. Microcephaly and growthretardation can also occur in a number of geneticsyndromes and may occur without an adequate explana-tion. There was one aspect of the case that made theradiation exposure the most likely explanation for thischild’s clinical problems. First, the radiation exposurewas high enough to produce the triad of the fetalradiation syndrome (microcephaly, mental retardation,and growth retardation) (Brent, ’94). Second, the micro-cephaly was asymmetric, which would be consistentwith a gradient exposure to the brain in a large fetus, asonly one breast was irradiated. It would be unlikelythat chemotherapy could result in asymmetrical micro-cephaly, although the chemotherapy could also havecontributed to the small head size.

Result. This case was settled out of court in favor ofthe plaintiffs before the trial was initiated.

FOURTH CASE

Dr. Brent: The fourth child had cerebral palsy andmental retardation, attributed to exposures to diagnos-

tic radiological and nuclear medicine procedures earlyin pregnancy.

A woman was seen in the emergency ward on Dec. 5with a painful swollen finger and fever. Her LMPwas Nov. 3. A chest radiograph and finger radiographfor the purpose of localizing a foreign body wasnegative. On Dec. 7 she had a xerogram of the fingerwith Technetium (Tc-99m) medronate. Although shedenied being pregnant, it was later determined thatshe had conceived on Nov. 17 and the embryo was 20days postconception on Dec. 7. The total dose to theembryo was 2.4 mSV (240 mrad). She was treatedwith six drugs, including antibiotics, during herpregnancy. Periodic ultrasound examinations re-vealed normal growth at 25 weeks. She went intolabor but was unable to reach the hospital in timeand precipitously delivered an 8-lb, 7-oz boy at termin the back seat of her car. The baby was normoce-phalic (34.5 cm) at birth, developed an intraventricu-lar hemorrhage, mental retardation, and cerebralpalsy. The allegation was that the diagnostic radia-tion studies were responsible for the child’s seriousmedical problems.

Dr. Jones: The suggestion that ionizing radiationwas responsible for this child’s clinical problems iscontradicted by the clinical facts. One of the reasonswhy this legal case was initiated is because there wasdisagreement between the plaintiffs and the defen-dants as to whether the mother was asked about thepossibility of being pregnant before the radiologicalprocedures were initiated. It was this disagreementthat was the driving force of this litigation. It had littleto do with the scientific and clinical evaluation of themerit of the allegation that diagnostic radiologicalprocedures were responsibility for this child’s clinicalproblems. There were several pieces of important find-ings that make it very unlikely that radiation hadanything to do with this child’s clinical problems. Thetriad of radiation induced teratogenesis includes micro-cephaly, mental retardation, and intrauterine growthretardation. After the radiological procedures, the babyhad several ultrasounds, which indicated that the fetuswas growing normally and, in fact, at term, the babyweighed 8 lb, 7 oz. Furthermore, the infant was notmicrocephalic in utero or at birth. Just as importantwas the fact that the total radiation exposure was farbelow the dose that could affect fetal growth and centralnervous system development. The most likely explana-tion for this child’s cerebral palsy and mental retarda-tion is the postnatal intraventricular hemorrhage, whichis associated with hypoxic episodes that may occur inprecipitous, unattended deliveries.

Result. This preliminary stages of this law suitlasted for several years. Many depositions were taken,but the lawsuit was settled before the trial. The hospi-tal, radiology department, and two attending physi-cians who cared for the mother all agreed to a signifi-cant settlement to put closure on this incident.

IONIZING RADIATION, EMFs, MICROWAVES, RADIONUCLIDES, ULTRASOUND 309

FIFTH CASE

Dr. Brent: The fifth child was diagnosed withnephroblastomatosis (Wilms’ tumor), which was al-leged to be caused by the fact that the family lived near60-Hz power lines.

This female proband was the normal-size product ofa 39-week gestation. There were no known signifi-cant teratogenic exposures. The proband was the2,863-g (25th centile) product of an uncomplicatedvertex vaginal delivery at term. She seemed welluntil approximately 7 months of age, when herfather noted that her abdomen seemed unusuallyprominent; at 10 months of age, she was admitted fora diagnostic evaluation. On examination, she hadbilateral renal masses, and ultrasound suggestedbilateral nephroblastomatosis as the most likelydiagnosis. Computed tomography (CT) scan con-firmed the diagnosis, and a chest radiograph andskeletal survey were negative for any signs of metas-tasis. Except for her renal masses, she was consid-ered to be an otherwise normal girl. Histology re-vealed bilateral diffuse nephroblastomatosis.Consultants suggested that she be treated withchemotherapy for her stage 1 Wilms’ tumor withfavorable histology. At 23 months of age, a suspiciousarea was noted on the anterior surface of her rightkidney. Follow-up ultrasound at 24 months of agedemonstrated two discrete nodular masses in theright kidney, each measuring approximately 3 cm indiameter. Two small nodules from the left kidney,and multiple large nodules from the right kidneywere biopsied, and lesions from both kidneys showedperilobar nephroblastomatosis and Wilms’ tumor.Cytogenetic analyses of multiple Wilms’ tumor nod-ules taken from both kidneys revealed that 3 of 20metaphase cells from one specimen, had replace-ment of one chromosome 7 with an isochromosome 7composed of 2 long arms. There were also somevariations noted in the length of the short arms ofchromosome 11, but these did not appear to beconsistent. Other tumor nodules appeared to have anormal chromosome complement, and her periph-eral lymphocyte karyotype was also normal. Thefamily was concerned that exposure to electomag-netic field (EMF) radiation might have caused thedevelopment of her bilateral nephroblastomatosisand Wilms’ tumor. Their home was adjacent to 60-Hzelectromagnetic power lines. Exposures were calcu-lated to range up to 20 mG.

Of all these clinical cases, this was probably the mostdifficult, because the allegation included the possibili-ties that EMF exposure affected the gonadocytes, thedeveloping embryo and or the child postnatally and theactual exposure to EMF was neither accurately deter-mined or inordinately high.

Dr. Graham: The occurrence of cancer in a child isa frightening and poorly understood circumstance formost families, and Wilms’ tumor is the most commonprimary malignant renal tumor of childhood. The world-wide incidence rate is one case per 10,000 childrenunder the age of 15 years, and Wilms’ tumor represents

about six percent of all childhood cancers in the UnitedStates (Breslow et al., ’93). This case report concernsthe occurrence of bilateral nephroblastomatosis andWilms’ tumor in a young child, whose family residednear a power line. This family believed that EMFradiation caused their child’s cancer.

This child was found to have bilateral diffuse perilo-bar nephroblastomatosis during infancy. This is consid-ered to be a disorder of renal histogenesis which has thepotential to develop into Wilms’ tumor. During normalrenal histogenesis, bifurcating ureteric ducts interactwith metanephric blastema, leaving mature nephronslocated centrally, with persistent blastema locatedperipherally in the subcapsular and intralobular areas.Nephrogenesis is usually complete by 36 weeks gesta-tion, but occasionally persistent blastemal tissue is leftbehind (Stone et al., ’90). These persistent embryonalkidney remnants are termed nephrogenic rests (NR),and they are considered precursor lesions to Wilms’tumor (Beckwith et al., ’90). Such focal arrests of renalhistogenesis can be found in 0.6% of infant autopsies,either perilobularly, intralobularly, or both (Benning-ton and Beckwith, ’75). Individual rests can regressspontaneously, or become neoplastic; hence they can besubclassified into nascent or dormant rests, maturingor sclerosing rests, hyperplastic rests, or neoplasticrests (Beckwith et al., ’90). Multiple or diffuse NRs aretermed nephroblastomatosis. Neoplastic transforma-tion of a rest into Wilms’ tumor (with the classichistological triad of blastemal, epithelial, and stromalelements) occurs in once in 10,000 live births (Breslowet al, ’93). Among 283 unilateral Wilms’ tumor speci-mens, more than 40% demonstrated associated NRs,with an equal prevalence of perilobular and intralobu-lar rests. The mean age at diagnosis for perilobularrests (36 months) was later than that for intralobularrests (16 months), or for both types combined (12months), and virtually all bilateral Wilms’ tumors occurin association with NRs (Beckwith et al., ’90).

Some children with Wilms’ tumor have associatedanomalies, which include aniridia, hemihypertrophy,cryptorchidism, and hypospadius (Miller et al., ’64).The combination of Wilms’ tumor, aniridia, genitouri-nary malformations, and mental retardation is termedthe WAGR association; it is caused by a contiguous genedeletion of 11pl3 (Riccardi et al., ’80). This finding led tothe cloning of a Wilms’ tumor gene (WTI) at this locus.Some Wilms’ tumor families and other families withDenys-Drash syndrome (male pseudohermaphroditismand nephropathy) have mutations WTI (Green et al.,’96). Both syndromes are strongly associated with thepresence of intralobular rests in the renal histology(Beckwith et al., ’90). WTI is known to code for a zincfinger transcription factor with four expressed tran-scripts and two alternate splice sites. These alternatetranscripts interact with multiple distinct targets (e.g.,one WTI transcript results in tumor suppression bydownregulating PAX2), and they all play roles in genito-urinary morphogenesis (Green et al., ’96). A second

310 J.M. GRAHAM ET AL.

Wilms’ tumor gene (WT2) has been mapped to 11p15.5based on tumor-specific loss of heterozygosity for thisregion. Unlike WT1, where loss of heterozygosity tendsto occur preferentially with the paternal allele, withWT2 the maternal allele is preferentially lost. Beckwith-Wiedemann syndrome (macrosomia, visceromegaly,macroglossia, omphalocele, and occasional hemihyper-trophy) also maps to this locus and is associated with apredisposposition to embryonal tumors, includingWilms’ tumor. In addition to an embryonal tumorsuppression gene within 11p15.5, there are three knownimprinted genes within this region (IGF2, Hl 9, andp57KIP2). Available evidence suggest that this largedomain of contiguous genes is abnormally imprinted inboth Wilms’ tumor and Beckwith-Wiedemann syn-drome (Feinberg, ’96; Chung et al., ’96; and Lee et al.,’97).

The genetics of Beckwith-Wiedemann syndrome iscomplex and includes several different genetic mecha-nisms: autosomal dominant inheritance with variablepenetrance (higher in offspring of female carriers),contiguous paternal gene duplication, and defectivegenomic imprinting, resulting in loss of the maternalallele. A major fetal growth factor gene (IGF2) is locatedwithin this region and represents a candidate gene forboth Wilms’ tumor and Beckwith-Wiedemann syn-drome. IGF2 is imprinted so that it is only expressedfrom the paternal allele. Tumor-specific loss of heterozy-gosity is associated with increased levels of IGF2 inWilms’ tumors. Similarly, when loss of the maternalallele is constitutional, it is associated with generalizedprenatal overgrowth and with a risk of Wilms’ tumor(Weng et al., ’95). Perilobular nephrogenic rests areassociated with both hemihypertrophy and Beckwith-Wiedemann syndrome (Beckwith et al., ’90). Thus,duplication of the paternal allele, or loss of the mater-nal suppressor allele is thought to result in over-expression of IGF2, cellular hyperplasia, and occa-sional neoplasia.

A third locus for Wilms’ tumor (WT3) has beenmapped to 16q based on loss of heterozygosity for thisregion in Wilms’ tumor, with no parent-specific basisfound for the loss, and an associated worse outcome(Maw et al., ’92; and Grundy et al., ’96). There areseveral large families with autosomal dominant Wilms’tumor that are not linked to either WT1, WT2, or WT3(Huff et al., ’92). Recently, Rahman et al. (’96) foundlinkage for one such family on 17ql2-q2l, and this locushas been termed WT4. In addition to these genes, thereis thought to be a Wilms’ tumor suppressor locus on 7pl1.2-pl 5, based on loss of heterozygosity for this regionin 11 sporadic Wilms’ tumors (Miozzo et al., ’96).

Finally, at least two other genetic syndromes areassociated with overgrowth and either nephroblastoma-tosis or an increased risk of Wilms’ tumor. Perlmansyndrome (renal hamartomas, nephroblastomatosis,and fetal gigantism) is a rare perinatal lethal conditionreported by Perlman et al. (1973) in five offspring bornto second-cousin Jewish-Yemenite parents. Based on

this family and other reports of affected siblings born tonormal parents, this condition is thought to manifestautosomal recessive inheritance (Greenberg et al., ’86).

Simpson-Golabi-Behmel syndrome resembles Beck-with-Wiedemann syndrome in some respects. It is anX-linked genetic syndrome associated with a risk ofWilms’ tumor, manifesting partial expression in femalecarriers. This syndrome includes prenatal overgrowth,macroglossia, coarse face, central groove under lowerlip, heart defects, diaphragmatic defects, renal dyspla-sia, polydactyly, polythelia, and hypotonia. The gene forthis syndrome is located at Xq26 and codes for aglycoprotein, Glypican 3 (GPC3). Glycoproteins arecofactors that participate in receptor-growth factorinteractions, and GPC3 is thought to bind IGF2 (Pilia etal., ’96).

Epidemiological studies of Wilms’ tumor have shownno consistent associations with any particular paternaloccupations, known teratogens, or maternal habits.The incidence of Wilms’ tumor varies with ethnicity(increased in Blacks, decreased for Asians, and interme-diate for whites), but not with geography, and theincidence of Wilms’ tumor has remained virtually un-changed from ’74 through ’91. Because of this, Breslowet al. (1993) suggested that it is unlikely that environ-mental exposures play a major role in the etiology ofWilms’ tumor.

EMF exposure has increased steadily in recent de-cades, but this has not resulted in any increase in theincidence of Wilms’ tumor, or even any reported associa-tion between the occurrence of Wilms’ tumor and EMFexposure. Since the intensity of EMF radiation fallssharply with increasing distance from the power source,it is difficult to measure exposure in residential set-tings. Electric fields are blocked by intervening groundedobjects, but magnetic fields pass through most materi-als, hence magnetic field exposure represents the majorfocus of concern regarding possible carcinogenesis(Brent, ’93; Heath, ’96).

Since there has been no observed increase in theincidence of Wilms’ tumor over the past two decades,while exposure to EMF has increased markedly, thefamily was told that Wilms’ tumor would have occurredin their daughter even if they did not reside near apower line. They were told that there was no biologi-cally plausible evidence to suggest that EMF radiationcould promote carcinogenesis or cause mutations, eventhough the bilateral nephroblastomatosis and synchro-nous multicentric Wilms’ tumors in their daughter mostlikely represented a fresh dominant somatic mutationin one of the many Wilms’ tumor genes. This counselingwas difficult because currently there is no clinicallyavailable way to evaluate the known Wilms’ tumorgenes for mutations. The family was told that theirdaughter should return for genetic counseling andmutation analysis when she gets ready to have a familyof her own, and the parents were advised to considerprenatal diagnosis and postnatal surveillance via ultra-sound for any future pregnancies, but it was thought

IONIZING RADIATION, EMFs, MICROWAVES, RADIONUCLIDES, ULTRASOUND 311

unlikely that nephroblastomatosis would be evidentuntil close to term.

Dr. Brent: Of the six patients discussed, this child’sclinical problem is the most complex and difficult toevaluate. In the other cases two or three clinicalfindings either definitively supported or refuted theinference that some form of radiation was or was notresponsible. Several findings do not support the allega-tion that EMF was responsible: (1) EMF at these lowexposures does not have measurable mutagenic effects;(2) there is extensive literature to indicate that geneticalterations at the chromosomal and molecular level areresponsible for a high proportion of Wilms’ tumors; (3)there are no studies linking the occurrence of Wilms’tumor with EMF exposure; and (4) there has been noincrease in the incidence of Wilms’ tumor with theincreasing use and exposure of populations to EMF.

Result. The ajudication of the issues in this casewas determined by a jury trial, which resulted in adefense verdict.

SIXTH CASE

Dr. Brent: The sixth case concerns a boy who wasborn with hemimelia, but had normal headsize, intel-lect and development.

A male infant weighing 7 lb, 14 oz was born withassymetrical hemimelia and a nasofrontal capillaryhemangioma. Several months after birth he wastreated for hip dysplasia and several years later hewas diagnosed with bilateral inguinal hernias. Hisintrauterine and extrauterine growth had been abovethe 50th percentile, and his parents and doctorsdescribed him as having normal intelligence. Themother was the employee of a large corporation andwas the operator of an X-ray diffractometer that wasused to orient silicon crystals. During her employ-ment, the mother wore ring badges that revealedexposures below the maximum permissible expo-sure. In fact, most of the exposures were zero.Exposure was possible only for the first 50 days ofpregnancy, as she no longer used the X-ray diffractom-eter after that time. The diffractometer sat on atable, the X-ray beam projected 180 degrees from theoperator and was only several millimeters wide andhigh. There is no way that she could operate themachine and be in the beam on the other side of thetable. Even if someone else operated the machineand she stood in the direct line of the beam, herabdomen would be below the level of the table andwould therefore receive no radiation. Furthermore,even if the abdomen could be placed in the beam, shewould have to remain in one position to expose theembryo. This bizarre circumstance would result inan abdominal exposure of thousands of rads beforethe embryo would receive an embryotoxic exposure.This is partly due to the fact that this X-ray diffrac-tometer had a copper anode and, therefore, had apredominant X-ray energy of 9 kV.

Dr. Graham: There is no information in this casethat supports the allegation that ionizing radiation

caused this child’s congenital malformations. The dosim-etry and exposure data indicate that the embryo did notreceive significant amounts of radiation. In fact, it isunlikely that the embryo received an exposure that wasgreater than the background exposure. One can actu-ally ignore the radiation exposure data and concludethat there was no causal association between themother’s job and the congenital malformations in herson, because a significant exposure to ionizing radiationthat resulted in a severe congenital malformation,would affect the central nervous system and the growthpotential of the fetus and child and this child grewnormally in utero and had normal intelligence. Further-more, this type of unilateral limb defect could never beproduced by a cytotoxic agent that has no specificity.This child’s defect is a congenital amputation and iscaused by developmental problems that do not includeionizing radiation at any exposure.

Result. Depositions were taken from both the plain-tiff and defense experts. During jury selection, the newsmedia provided extensive coverage of the allegationthat the defendant-company was responsible for achild’s congenital malformation.. The officers of thecompany made a corporate decision to settle the casewith the plaintiff.

SUMMARY

Analysis of these six clinical problems demonstratesthe value of a complete clinical evaluation of a childwith congenital malformations by an experienced andwell-trained physician who is familiar with the fields ofdevelopmental biology, teratology , epidemiology, andgenetics. Too often, the entire emphasis is placed onepidemiological data that may be meager or insufficientfor a rational conclusion when clinical findings that arereadily available can provide definitive answers withregard to the etiology of a child’s malformations or themerits of an environmental etiology.

LITERATURE CITEDBeckman DA, Fawcett LB, Brent RL. 1997. Developmental toxicity. In:

Massaro EJ, editor. Handbook of human toxicology. New York: CRCPress. p 1007–1084.

Beckwith JB, Kiviat NB, Bonadio JF. 1990. Nephrogenic rests, nephro-blastomatosis, and the pathogenesis of Wilms’ tumor. Pediatr Pathol10:1–36.

Bennington JL, Beckwith JB. 1975. Tumors of the kidney, renal pelvisand ureter. In: Atlas of tumor pathology. Series 2, fasc12. Washing-ton, DC: Armed Forces Institute of Pathology.

Brent RL, Beckman DA, Jensh RP. 1986. The relationship of animalexperiments in predicting the effects of intrauterine effects in thehuman. In: Kriegel H, Schmah, W, Gerber GB, Stieve FE, editors.Radiation risks to the developing nervous system. New York: GustavFisher. p 367–397.

Brent RL. 1986a. Effects and risks of medically administered isotopesto the developing embryo. In: Fabro S, Scialli AR, editors. Drug andchemical action in pregnancy. New York: Marcel Dekker. p 427–439.

Brent RL. 1986b. Methods of evaluating the alleged teratogenicity ofenvironmental agents. In: Sever JL, Brent RL, editors. Teratogenupdate: Environmentally induced birth defect risks. New York: AlanR Liss. p 199–201.

Brent RL. 1993. Congenital malformation case reports: The editor’sand reviewer’s dilemma. Am J Med Genet 47:872–874.

312 J.M. GRAHAM ET AL.

Brent RL. 1994. The effect of embryonic and fetal exposure to X-ray,microwaves, ultrasound, magnetic resonance, and isotopes. In:Barron WM, Lindheimer MD, editors. Medical disorders duringpregnancy. 2nd edition. St. Louis, MO, Mosby-Yearbook. p 487–518.

Brent RL, Gordon WE, Bennett WR, Beckman DA. 1993. Reproductiveand teratologic effects of electromagnetic fields. Reprod Toxicol7:535–580.

Breslow N, Oishan A, Beckwith JB, Green DM. 1993. Epidemiology ofWilms’ tumor. Med Pediatr Oncol 21:172–181.

Chung WY, Yuan L., Feng L, Hensie T, Tycko B. 1996. Chromosome15pl 5.5 regional imprinting—comparative analysis of KIP2 andH19 in human tissues and Wilms’ tumors. Hum Mol Genet 5:1101–1108.

Feinberg AP. 1996. Multiple genetic abnormalities of 1 1 pl 5.5 inWilms’ tumor. Med Pediatr Oncol 27:484–489.

Green DM, D’Angio GJ, Beckwith JB, Breslow NE, Grundy PE,Ritchey ML, and Thomas PRM. 1996. Wilms’ tumor. CA Cancer JClin 46:46–73.

Greenberg F, Stein F, Gresik MV, Finegold MJ, Carpenter RJ, RiccardiVM, Beaudet AL. 1986. The Perlman familial nephroblastomatosissyndrome. Am J Med Genet 24:101–110.

Grundy P, Telzerow P, Moksness J, Breslow NE. 1996. Clinicopatho-logic correlates of loss of heterozygosity in Wilms’ tumor a prelimi-nary analysis. Med Pediatr Oncol.27:429–433.

Hardell L, Holmberg B, Malker H, Paulsson EE. 1996. What is theetiology of human brain tumors? Cancer 77:1006–1008.

Heath CW. 1996. Electromagnetic field exposure and cancer: A reviewof epidemiological evidence. CA Cancer J Clin 46:29–44.

Huff V, Reeve AE, Leppert M, Strong LC, Douglass EC, Geiser CF, LiFP. 1992. Nonlinkage of 16T markers to familial predisposition toWilms’ tumor. Cancer Res 52:6117–6120.

Lee MP, Hu RJ, Johnson LA, Feinberg AP. 1997. Human KVLQTLgene shows tissue-specific imprinting and encompasses Beckwith-Wiedemann syndrome chromosomal rearrangements. Nature Genet15:181–185.

Maw MA, Grundy PE, Millow LJ, Eccles MR, Dunn RS, Smith PJ,Feinberg AP, Law DJ, Paterson MC, Telzerow PE. 1992. A thirdWilms’ tumor locus on chromosome 16q. Cancer Res 52:3094–3098.

McCann J, Dietrich F, Rafferty C, Martin AO. 1993. A critical review ofthe genotoxicity potential of electric and magnetic fields. Mutat Res297:61–95.

Miller RW, Fraumeni JF, Manning MD. 1964. Association of Wilms’tumor with aniridia, hemihypertrophy and other congenital malfor-mations. N Engl J Med 270:922–927.

Miozzo M, Perofti D, Minolefti F, et al. 1996. Mapping of a putativetumor suppressor locus to proximal 7p in Wilms’ tumors. Genomics37:310–315.

Murphy JC, Kaden DA, Warren J, Sivak A. 1993. Power frequencyelectric and magnetic fields: A review of genetic toxicology. MutatRes 296:221–240.

NCRP report no. 86. Biological effects and exposure criteria forradiofrequency electromagnetic fields. National Council on Radia-tion Protection and Measurements, Washington, DC, April 2, 1986.386 p.

Petit C. 1996. Genes responsible for human hereditary deafness: Asymphony of thousand. Nature Genet 14:385–391.

Pilia G, Hughes-Benzie RM, MacKenzie A, Baybayan P, Chen EY,Huber R, Neri G, Caok, Forabosco A, Schlessinger D. 1996. Muta-tions in GPC3, a glypican gene, cause the Simpson-Golabi-Behmelovergrowth syndrome. Nature Genet 12:241–247.

Rahman N, Arbour L, Tonin P, et al. 1996. Evidence for a familialWilms’ tumor gene (FWTl) on chromosome 17ql2–q2l. Nature Genet13:461–463.

Riccardi VM, Hiftner HM, Francke U, et al. 1980. The aniridia–Wilms’tumor association: The critical role of chromosome band 1 1 pl 3.Cancer Genet, Cytogenet. 2:131–137.

Robert E. 1996. Teratogen update: Electromagnetic fields. Teratology54:305–313.

Weng EY, Mortier GR, Graham JM Jr. 1995. Beckwith-Wiedemannsyndrome: An update and review for the primary pediatrician. ClinPediatr 34:317–326.

IONIZING RADIATION, EMFs, MICROWAVES, RADIONUCLIDES, ULTRASOUND 313