Document O13Vbakp9pX54vz7V3g1n4BXQ

l`7?f Uz/j-i 7ir~ O0QC/34 R&S 107515 Risks to the Offspring from Parental Occupational Exposures Joanna F. Haas, M.D., and David Schottenfeld, M.D. Risks to the offspring of workers with occupational chemical exposures may derive from mutagenic, terato genic or carcinogenic effects of industrial agents to which the parents are exposed. Evidence for impaired pregnan cies and hazards to the offspring of working populations with chemical exposures is, however, very limited. Perhaps the best documented example is increased spontaneous abortion rates in female operating room personnel who have first trimester exposure to waste anesthetic gases. Evi dence is reviewed for hazards to the offspring resulting from parental occupational exposure to vinyl chloride, benzene, chloroprene, radiation and petroleum-derived hydrocarbons. It is essential m investigating the role of occupational factors that other environmental and behav ioral factors with maior effects on pregnancy outcome be accounted for. These include smoking, alcohol, and drug exposures. An approach to surveillance for chromosomal abnormalities in offspring of occupationally exposed parents is outlined. Oerived from the Greek word "repae,"meaning a mar vel, prodigy or monster, the word "teratogenic" was used by 1857 to mean the "production of monstrous for mations or births " The term nas been refined to rerer to the biological science dealing with "the causes, mecha nisms, and manifestations of developmental deviations of either structural or functional nature An agent may act as a teratogen when administered in a number of ways, whether to the male or remale before mating, to the female during pregnancy, or to the tetus directly,' Agents m the environment mav produce alterations in the ge nome. mutations, and bv that mechanism lead to abnor malities ot development in the offspring Viral, drug or chemical agents acting through common pathways may produce indistinguishable results The outcome of such mutations may theoretically be retal detects or predis- from Cornell University Medical UoUene ana Memor^l-Sloan Kettering Cine & Center Sot bO I27"j York Av^ i or* ny 1 <>J21 n pan by a contract *ith tne American Petroleum Institute position to neoplasia. Agents-which alter the rate of growth of the fetus or are lethal to the fetus without pro ducing specific anatomic or functional anomalies are bet ter termed developmental toxins than teratogens Cancer in the offspring of individuals exposed to a car cinogen may theoretically be the result of any of three types of exposure- prezygotic, by alteration of parental germ cells, transplacental, by passage of carcinogenic substances across the placental barrier; or postnatal, by contamination of the environment with carcinogenic sub stances, primarily through ingestion (including substances excreted in human breast milk) and through inhalation. Evidence for risks to the offspring of humans occupa tionally exposed to potentially hazardous substances is reviewed in the present work. The term trans-generational carcinogenesis is used to describe the occurrence of "cancers m the offspring which can be attributed to paren tal exposures. This term is proposed to encompass not on ly the established process of transplacental carcino genesis, by which a substance administered to the mother during pregnancy results in cancer in the offspring, but also the controversial issue of preconception alterations in genetic matter resulting m increased teratogenic or cancer risk m the offspring. The latter effect could theo retically result from each ot three distinct mechanisms chromosome breakage, point mutation, or abnormalities in gametogenesis or fertilization Mutagenic and Teratogenic Characteristics of an Agent and Trans-Generational Carcinogenesis Mutagenesis, teratogenesis and carcinogenesis are re lated phenomena, but the nature of their relationship is complex and occasionally controversial. It has been argued that the "same chemical that causes abortion m the earlv stages mav produce malformations during organ development and neoplasia when exposed later in preg nancy Therefore, screening tor transplacental hazards should include, whenever possible, the entire range of fetal response, including cancers that mav develop some time after birth "4 Teratogenic, mutagenic and carcino genic activities are all demonstrable for a number ot corn- Journal of Occupational Medicine 2' Mo a/Seotember 1979 6017 i. pounds, hut transpljcent.nl carcinogenic potential. has rarely been demonstrated tor known teratogens and mu tagens, Teratogenic effects mav ret Sect a variety or ac tions involving the mother, the placenta or the feto-placental unit These effects can be indirect and mav not in volve immediate action or the agent on the target fetal tissue.' Transplacental carcinogens may act directly on the fetal tissues which are inherently more vulnerable be cause of the high rate of cell division, high proportion of undifferentiated cells and immaturity ot immunosurveillance mechanisms To appreciate potential danger from an environmental exposure to offspring of the exposed organism, the out come of all exposed pregnancies should be considered Early fetal wastage commonly results from abnormal fetal development. At the other extreme, transplacentally*induced tumors hardly ever appear in rodent species until the animal reaches maturity In the only docu mented example of chemical transplacental carcino genesis in humans, vaginal adenocarcinoma following diethylstilbestrol (DES) exposure, the tumor occurs decades following exposure. Thus, since transplacentally-mduced tumors, unlike malformations, are rarely present at birth, one must also observe the ofrsprmg into adulthood to see the full spectrum of resulting tumors Environmental Threats to Pregnancy Outcome Recognized threats to pregnancy outcome are not un commonly encountered in the environment and must be excluded when new problems are suspected Threats are posed by biologic, chemical and physical agents, and may derive from medical therapeutic interventions, drug and substance abuse, and environmental or occupational exposures to chemical agents Alcohol -- The most widespread documented threats to the fetus come not from the maternal physical environ ment but from the use of tobacco and alcohol during pregnancy. Only recently has the risk of alcohol ingestion in pregnancy been evaluated and the concept of the fetal alcohol syndrome refined ' Of Inrants bom to recognized' chronic alcoholic mothers, 83 3% had birth weights under the tenth percentile, compared with 2 3% m a compara ble non-alcoholic population * In addition to intrauterine growth retardation, the inrants had retarded post-natal growth and intellectual development A characteristic facies, with short palpebral fissures, hvpoplastic philtrum, thin vermilion line ot the upper lip and retrognathia, has also been described In addition to these features of the fetal alcohol svn- drome, congenital malformations or various types occur with excess frequency Recognition of an associated in crease in the occurrence ot congenital malformations ironically re-emphasizes ancient observations and ad monitions against alcohol use during pregnancy 4 The ad verse etrects on the fetus ot maternal alcohol abuse dur ing pregnancx were further quantified bv Ouellette et al, " who classified women at the first prenatal visit into tour categories at cording to alcohol < cnxumption and in dependently evaluated pregnancy outcome Compared to those bom to abstinent or moderate drinkers, infants born to heavy drinkers had twice the risk ot having an ab normality at birth The frequency of congenital abnormal ities in the offspring or he.oy drinkers was extremely high -- 32% when minor abnormalities were included, 17% if only maior anomalies were considered. Multiple abnormalities were present in 20% of the offspring of heavy alcohol users. Major, minor and multiple abnor malities occurred significantly less otten among abstinent or moderate drinkers. Animal models, including chicks, rats and guinea pigs, have been developed for evaluating ' the effects of ethanol alone on offspring, and support the view that ethanol itself is a harmful agent, and that its teratogenic potential is common to several species " Smoking. --Another factor influencing pregnancy-out come, maternal smoking habits, should be addressed in efforts to tie environmental exposures of the parents to the survival and integrity of the fetus. Kline et alw suggest that the odds of spontaneous abortion among women who smoke are 1.8 times those of nonsmokers This association remains statistically significant after maternal age, and number and outcome of previous pregnancies are taken into account. The manner in which smoking affects fetal survival is controversial. Smoking results in lowered birth weight, which may or may not be related to the increased fre quency of spontaneous abortion"'4 Lowered birth weight may result from impaired maternal nutrition or fetal anoxia, neither of which produces an excess of chromosomal abnormalities in the conceptus. Alternate explanations for an association between smoking and spontaneous abortion have been proposed. Since spon taneous abortion serves as a means of selectively termi nating abnormal conceptions and since 95% of abnormal pregnancies are believed to terminate this way, an associ ation between an environmental factor and increased spontaneous abortion should always evoke suspicion of a teratogenic phenomenon " Smoking increases the risk of spontaneous abortions by a factor of 1 8. yet the percent age of abortuses which are chromosomally abnormal is close to that expected. The absolute risk of a chromosom ally abnormal fetus appears, therefore, to be higher in smoking mothers The relationship of karyotypic abnormalities in spon taneously aborted products of conception to maternal smoking habits is complicated bv variation in the propor tion of chromosomally abnormal retuses with increasing maternal age and by the tact that a large proportion of smokers are younger women,11 An increase m the rate or chromosomally abnormal conceptions might be masked in a proportionate ratio analysis it there was also an in creased loss of conceptions without demonstrable cyto genetic abnormalities Evidence for an increase in congenital malformations in children of smoking mothers is limited and conflicting. In a cohort of births occurring m the first week ot March, 1958, in England. Scotland and Wales, Fredrick and col leagues"' identified a 60% increased risk of congenital heart disease among children of women who had smoked at least one cigarette per day after the fourth month of pregnancy (7 3 vs 4 7 cases per 1000 live births) This ertect remained statistically signmcant arter adiustment for maternal age, parity and social class An investigation ot congenital defects ot all systems registered in South Wales from 1964 to 1966 which took into account mater nal age, pantv, social class, area of residence and date of delivery did not associate maternal smoking habits with 603 Risks to Offspring from Parental Occupational Exposures/Haas and Schottenfeld R&S 107516 congenital malformations in any system,'" It is possible has been difficult to demonstrate. Cohort studies of off that moderate increases in relative risk might have gone spring of survivors classified by radiation exposure level undetected did not show excess mortality m the children of the high Analysis of data from a mailed survey of a large num exposure group. Neither were excess congenital malfor ber of professional women in medicine identified a rela mations, increased infant mortality, nor impaired survival tive risk of up-to 1.7 for spontaneous abortion and a risk during the first ten years of life detected, regardless of ex of congenital abnormalities of up to 2.3 in heavy smokers posure level to either parent Thus, although animal ex after the effects of age. parity and exposure to anesthetic perience strongly suggests that such effects should be gases were considered." manifest in offspring of individuals exposed to ionizing ir Drug Exposure.-- In utero exposure to diethylstilbestrol radiation, studies of Japanese atomic bomb survivors (DES). with the subsequent development of vaginal have not demonstrated measurable effects." adenocarcinoma, is the prototype tor transplacental on No substantial increase in leukemia risk has been de cogenesis in humans Appreciation or the causal role tected among offspring of survivors. Analyses having a played by in utero exposure to DES followed hard upon 90% chance of detecting a four-fold increase in risk of the report of seven cases of the hithertofore exceedingly leukemia among children of heavily exposed survivors rare tumor, adenocarcinoma of the vagina, presenting in were negative. Neither did age-at-onset of observed young individuals, 14 to 22 years of age,i0 J1 The syndrome leukemia cases nor type of leukemia in offspring differ by appears to involve not only cases of vaginal adenocar level of parental radiation exposure. Despite the docu cinoma. but a spectrum of abnormalities of the vagina mented persistence of chromosomal aberrations in the and cervix. Only when exposure to DES occurred during somatic cells of adults exposed to the atomic bomb, no the first four months of gestation were neoplasms or ab measurable impact on mortality, congenital malforma normalities observed. tions or leukemogenesis has been detected in their off The DES vaginal adenosis-adenocarcinoma relation spring." ship is the only documented example in humans of In addition to radiation exposures related to the atomic cancer in the offspring attributable to parental environ bombings, diagnostic and therap'eutic medical radiation mental chemical exposure. The therapeutic agent was of the parents has been investigated to assess risks to the given in a high dose, commonly more than 10 grams in offspring. The magnitude of leukemia risk associated with the first half of pregnancy DES, a synthetic nonsteroidal previous radiation was estimated, after adjustment for estrogen analogue, was likely to have a direct effect on maternal age and pregnancy history, to be 173 times that the development of the target tissue at a crucial point m of mothers who had not been x-rayed. Despite the sugges embryogenesis. Since the risk to the offspring appears tion of greater risk in women with higher x-ray exposure, limited to exposures which occur during the first four no clear-cut dose-response gradient was demonstrated. months of gestation, direct exposure of the fetus is likely The relative risk of leukemia in the child associated with to be essential to the pathogenic mechanism. The long preconception diagnostic radiation of the father (1.31) latent period, with exposure in utero and emergence of was not statistically different from unity When both clinical sequelae in adolescence, probably reflects the im mother and father had histories of preconception diag portance of pubertal endogenous estrogens as promoting nostic x-rays, the order of magnitude of the relative risk, factors, and is a reminder of the need for an extended 1.49, was about the same as that for children' whose period of observation following suspect trans-genera- mothers alone had received radiation/' tional carcinogenic exposures The association between - --Exposure to medical radiation has been widespread. By DES and vaginal adenocarcinomas, as important as it is, the early 1960's, approximately 35% of a group of does not serve as a model for preconception parental oc mothers of healthy children reported having received cupational exposures and trans-generational carcinogen diagnostic radiation prior to conceiving. Similarly, about esis Teratogenic effects of a multiplicity of drugs are now 22% of fathers of the same children reported having had documented or suspected and these will not be discussed some sort of diagnostic radiation at some time prior to here further except to reiterate the need to remove the the child's conception Self-reporting considerably under potentially confounding effects of such Tgents in investi estimates the extent of x-ray exposures." The tendency to gations or other possible causes of impaired fetal devel substantially underreport x-rav exposure points up the dif- opment " ticulty or excluding differences in prior radiation expo Given the current status of our understanding, it is sure as a basis tor observed differences in chromosomal essential that in the search for exogenous causes of tera- aberrations Neither is it reasonable to automatically pre togenesis and abnormal pregnancy outcomes, the poten sume that medical radiation exposures have been equally tial confounding impacts of maternal smoking, drinking, present in the study and comparison groups, especially if and medication intake be taken into account these groups have not been matched by age or calendar Radiation-- If preconception radiation exposure in period of observations. creases cancer risk in the offspring, it would heighten con cern over other agents which produce chromosomal dam Occupational Exposures and Pregnancy Outcome age. Chromosomal aberrations attributed to vinyl chlo ride and benzene exposure, tor example, are reminiscent or those produced by radiation While the genetic consequences of irradiation from the atomic bombings might be expected to produce some lethal mutations m the offspring of survivors, this effect Vinyl Chloride. --Chromosomal abnormalities mav oc cur more often than expected in persons exposed to vinyl chloride, especiallv following intense exposures ot long duration The import ot such abnormalities for reproduc tive outcome remains ill-defined Chromosomal aberrations were reported in 1975 in R&S 107517 Journal of Occupational Medicine/Vol 21, No. 9/SeotemPer 1979 609 R&S 107518 Swedish vinyl chloride workers Abnormalities appeared m cells drawn from seven males with occupational expo sure histories of nine to 29 s ears (mean 1 fa 6 years) at vinyl chloride concentrations which had declined to 20-30 ppm by 1974 The group exposed to vinyl chloride had aber rations in a total or 9 52% of all cells, compared to 1 94% tor cells of three unexposed controls Differences in the frequency of chromatid and isochromatid breaks ac counted for most of the disparity. Considerable variation was exhibited, with cells considered abnormal ranging from 15% to 18% in the exposed workers There was no apparent relationship between duration of exposure to vinyl chloride and the proportion ot cells which were ab normal. Age, radiation exposure or other environmental factors were not evaluated, nor was it clear on what basis individuals had been selected for study In New York State, chromosomal aberrations were re ported m somatic cells of 11 men who had worked in a polyvinyl chloride polymerization plant and who were be lieved to have experienced intense intermittent exposures to vinyl chloride in concentrations of over 500 ppm, as well as chronic, but unquantitated exposure for tour to 28 years (mean, 15 years). Control samples were drawn from four males in the same factory who were not known to have had vinyl chloride exposure, and from six males from outside the factory Complex chromosomal aberra tions (rings, dicentrics, fragments) occurred significantly more frequently in the exposed than in the control group, a result which was properly interpreted with caution. The authors point out the absence of age-matched controls and the substantial age difference between study group and controls The frequency of chromosome breaks and gaps was unexpectedly high m both control and study groups.10 No relationship could be defined between dose or duration of exposure and frequency ot chromosomal aberrations Investigators reporting from the United Kingdom Studied 56 men who had had chronic exposure to vinyl chloride monomer in the course of manufacturing polyvmvl chloride and compared them with 24 unexposed in dividuals " Vinvl chloride exposure or men employed in its manufacture could not be easily quantitated, Individ uals with exposures to radiation or with recent viral infec tions or prolonged drug treatment were excluded. Samples were coded and read blindly A higher propor tion or cells with chromosomal aberrations, the maionty of which were breakages, was found in vinyl chloride-ex posed workers than in controls. Unstable and stable chromosomal aberrations and breaks were all significantlv more common in cells from exposed workers Not all investigators have identified such changes No differences were found m frequency of chromosomal aberrations between a group or 209 employees ot a vinyl chloride plant (occupational exposures averaging 48.3 months) and a group of 295 individuals undergoing preemplovment physicals w No relationship was established between duration of vinyl chloride exposure and degree or chromosomal damage. The absence or blind evalu ation m this study, as well as inclusion or individuals with minimal expo-ures in th*1 exposed group makes interpre tation difficult This difficulty is compounded bv the sub stantial difference in mean age of study and control group members Pregnancy outcome in the wives of men exposed to vinyl chloride monomer (VCM) has been said to be less favorable than that experienced by wives of a group or polymerization and polyvinyl chloride (PVC) fabrication workers 1J 14 One comparison group, the polymerization workers, was believed not to have been exposed to VCM, wheras PVC workers had low VCM exposure. Data on pregnancies and pregnancy outcomes in the wives were * derived from interviews and questionnaires administered to male workers Participation rates for the groups queried ranged from 62% to 77%. Fetal death was de fined as any known conception which did not result in a live birth and rates were adjusted by paternal age. Mater nal age was not known, but was presumed to correlate closely with paternal age, Analysis of questionnaire re sponses suggested that the number of fetal deaths per 100 conceptions was higher in the VCM-exposed group than in the comparison group This difference was reported on ly for the period following vinyl chloride exposure. Ad justments removing women who were chronic aborters eliminated statistically significant differences. While the authors felt that these observations were likely to reflect a real difference in pregnancy outcome not attributable to either interviewer or patient recall bias, the conclusions were based on indirect sources of information and could not take into account the multiplicity of maternal factors known to affect pregnancy outcome. The study design precluded documenting in even the crudest manner the validity of pregnancy histories. Without such adjustments and validation, the inferences made by Infante and col leagues" J* cannot be sustained and little light is shed on the possible association of abnormal pregnancy outcome with paternal occupational exposure to VCM. Studies of pregnancy outcome (i.e., spontaneous abor tion, late fetai death [stillbirth], low birth weight, neonatal death) in other settings have shown the profound and sub tle effects of confounding variables such as race, socioeconomic status, maternal age, birth order, parity, smoking and alcohol exposure during pregnancy, mater nal infections, and previous pregnancy outcomes These effects may readily reverse the direction of the relation ship between a suspect antecedent factor and the out come of pregnancy." Future efforts to document a rela tionship between impaired pregnancy outcome and occu pational exposures of fathers must validate information on pregnancies and take into account known con founding factors. -- Chloroprene. -- Structural similarities between vinyl chloride and chloroprene have raised questions about long-term hazards resulting from chloroprene exposure Chloroprene is mutagenic in certain svstems and possibly carcinogenic The possibility that it has induced excessive miscarriages in the wives of male workers and led to chromosomal aberrations has been asserted but not well documented. " Benzene -- Benzene also may. cause chromosomal aberrations following heavy occupational exposures Twenty males working m a factory in which benzene had been used as a solvent were studied for chromosomal aberrations Members of this group had one to 20 years of benzene exposure; 14 were known to have previously been neutropenic Chromosomal abnormalities were re ported in 2 5% of all cells from exposed workers, com- 610 Risks to Offspring from Parental Occupational Exposures/Haas and Schottenfald  pared to 1 0 to 1 4% tor controls Most of the excess was England and Wales, greater incidence of congenital de due to chromosomal aberrations or the unstable tvpes In fects, lower birth weights and higher stillbirth rates, but addition to the excess of abnormal cells m the exposed not higher spontaneous abortion rates, were reported group, the number of unstable alterations per abnormal from pregnancies of women holding anesthesiology cell was higher in the exposed group than in the appointments than from those of other women physi controls.17 cians,41 In a separate investigation, ten workers in an Italian The effects of paternal exposure to anesthetic gases rotogravure plant who had had sequential exposures, first are uncertain. Congenital anomalies were reported to be to benzene and later to toluene and xylene, were studied. increased by 25% in the offspring of male anesthesiolo These workers had been subiected to concentrations of gists compared to offspring of male members or the benzene ranging from 125 ppm to 532 ppm or higher The American Academy of Pediatrics, but no difference was1 maximal allowable concentration at the time of these ex* reported for spontaneous abortion rates among wives of posures had been 25 ppm. Another group of 24 workers male operating room personnel compared to controls " had primarily toluene exposures except for trace Questionnaires completed by 5119 married male physi contamination with xylene. These 34 workers were cians in the United Kingdom suggested an increase in matched with healthy controls of similar age and sex, who minor but not in major congenital anomalies, and no dif had been drawn from the general population and who ference in frequency of infertility, spontaneous abortion had no history of benzene or radiation exposure A signifi or cancer in the offspring of male anesthesiologists com cantly higher proportion of abnormal cells was found in pared to control physicians.49 the benzene-exposed individuals than in their matched Hydrocarbons. -- Two studies offer conflicting evi controls. In the group with toluene exposure, no such ex dence with respect to the risk of cancer in children of cess was present. When the benzene and toluene groups men whose work might lead them to be exposed to were compared to each other, an excess of chromosome petroleum-derived hydrocarbons. Fabia and Thuy44 re changes was present in the benzene group. Most of the viewed death certificates m Quebec during 1965 to 1970 excess was attributable to unstable chromosomal altera to identify children who had died from malignant disease tions.1* while under five years of age. For 386 of 402 such These studies and others19 support the impression that children, birth certificates were also found in the Quebec exposure to benzene, particularly exposures intense population register A control group of 772 children (two enough to result in acute toxicity, can be followed by a for each cancer death) was selected using the birth measurable excess of chromosomal aberrations which registration record preceding and following that of each may persist for years. If similar effects occur in germ cells case in the official files. This effectively matched for of exposed individuals, the consequences in fetal season, calendar period, and province of birth. Occupa wastage, congenital anomalies and even neoplasms might tion of the father at the time of birth was taken from the be manifest in their progenv. To date no excess of such birth certificate An industrial hygienist independently abnormalities has been reported m offspring of benzene- grouped the fathers into three levels of probable exposure exposed individuals to petroleum-derived hydrocarbons Occupation of the Anesthetic Cases, -- Occupational exposures of father was unknown for 30 cases and 56 controls. The dis female operating room personnel to waste anesthetic gas tribution of occupation of the father at birth differed for es have been held responsible for decreased fertility, in cases and controls. Most of this difference was the result creased rate of spontaneous abortion, low birth weight of an excess among cases of paternal occupations con- and possibly impaired development in the offspring An -sidered to be hydrocarbon-related The relative odds of excess of spontaneous abortions in wives of men pro cancer in the children of men holding hydrocarbon-re fessionally exposed to anesthetic gases has been suggest lated jobs at the time of the child's birth were 3 1, an in ed but not confirmed. crease which was unlikely to have occurred by chance Among operating room nurses. 29 7% of pregnancies Most of the excess m exposed occupations was account terminated with spontaneous abortion, compared to ed for by motor vehicle mechanics, machinists, miners 8 8% among control nurses A similar excess of spon and painters When similar analyses were conducted by taneous abortion was observed for female physician the type of cancer in the child, the excess of hydrocarbon- anesthesiologists compared to female physicians in other related occupations prevailed for the following group specialties Spontaneous abortions occurred two weens ings leukemia-lymphoma, nervous system malignancy, earlier on the average among the operating room ex other tumors Fathers of four of five cases of Letterer-Siwe posure groups than among controls, at an average of disease were in the hydrocarbon-related work groups No eight rather than ten weeks of gestation Another survey such excess was present for children with Wilms' tumor suggested that tor female nurse-anesthetists who had The differences observed could not be attributed to dif worked during pregnancy, the frequency of birth defects ferences in parental age or in geographic residence at the in the orrspnng was 16 4% compared to 5 7% tor time of birth The investigation was based on deaths m pregnancies in which the mother had not worked *' children under five, and it is possible that social class bias Studies from Finland and the United Kingdom also sug may have been introduced in that fashion If, of those gested a deleterious ertect on pregnancy outcome from with a childhood neoplasm, children of more attluent maternal exposure to operating room environments An parents are more likely than children or poorer parents to increase in frequency or earlv spontaneous abortions, as survive beyond age five, they would not be included in well as low birth weight, has been reported for Finnish fe the study group This would lead to a higher proportion of male operating room start `` Among female physicians m children with parents ot lower socio-economic status in R&S 107519 Journal of Occupational Medicme/Vol. 21, No. 9/September 1979 611 I I I 37 (/> o -nJ rcon fo -1 t t 1I -f i * *t i i: i - 11! Hii the cancer death group and would bias the distribution o; father s occupation Moreover, it was not possible to con firm that fathers in the so-called " exposed" group did, in fact, have contact with hvdrocarbon-denved chemicals While not ideal, the death certificate probably is a valid source or diagnostic information for cancer deaths in young children The cancer groupings employed in the analysts -- "leukemias and Ivmphomas," "nervous system" and "others" -- were quite broad and included many histopathologic entities Occupational association was not restricted to specific entities within the broader categories. Because the epidemiologic features of the various histopathologic types of leukemias, lymphomas, and nervous system tumors are distinctive, a specific chemical exposure or class of exposures, it assumed to be of causal significance, would more likely be linked with specific histopathologic as well as organ system effects A study with a similar design but different findings was conducted in Finland 47 Children under 15 years of age who developed cancer were identified from the Finnish Cancer Registry, 1959-1968. Of 1409 cancer cases so iden tified, the final senes consisted of 852 pairs for whom birth records which Included fathers occupation were available Each case was matched with a child whose birth date immediately preceded that of the case and who was born m the same maternity welfare district This procedure matched effectively by calendar period, season and domicile at the time of birth. Father's occupa tion was drawn not from birth registration records but from records of the free, nationwide antenatal care system in operation in Finland Father's occupation was classified by likelihood of hydrocarbon exposure in a manner which was shown to be comparable with that employed in the study done m Quebec No excess risk for hydrocarbon-exposed fathers was detected tor any class of neoplasms either for children whose cancers occurred under five or under 15 years of age. The two studies differed primarily in the source of in formation on father's occupation For the Finnish study, that information was drawn from antenatal records com piled for the most part in the first trimester of gestation. This mav be a better index or exposure at the time or con ception than information recorded at the time or birth in the birth certificate itself Although a large number of pairs were discarded in Finland because fathers occupa tion was not recorded, these came from a circumscribed calendar period Since a matched pairs design was main tained- throughout the analysis, removal ot these cases should not mrluenre the result 7b-` Finnish study used in cident cancer cases and looked at age groups up to 15 years at the time of cancer diagnosis The Quebec group identified only cancer deaths up to rive years or age Variation in terminology or occupational classification ringht also contribute to the differences, although ertorts were made to establish their comparability At present the contradictory findings or the two studies are not readilv, reconciled Surveillance of Spontaneous Abortions as a Strategy of Environmental Monitoring The relationship} between mutagenic, teratogenic and carcinogenic effects in the ot!spring or persons exposed to rovio-.e environmental a,,-_-or- is a complex one Surveillance of spontaneous abortions mav have a number of advantages as a prospective means or monitoring for such effects since defective conceptions are aborted selectively As a result, studies of teratogenesis focusing on spontaneous abortions may be con siderably more efficient than those conducted m new borns Because the frequency of abnormalities is higher m spontaneous abortions, the sample size needed to demonstrate a change in risk is much smaller than that re quired tor a parallel query addressed to defects recog nized at birth. The magnitude or this difference can be dramatic. If chromosomal defects diagnosable on the ap pearance of the newborn are considered alone, the sam ple size required may be hundreds of times that required in an investigation examining prevalence of chromosomal anomalies m early abortion ia In addition to sample size considerations, study of spontaneously aborted concep tions offers a lead time of at least six months over studies of live births The abortion specimen can be studied with care and thoroughness, permitting detection of anomalies lethal to the fetus which might escape detection in studies of live births. The problem of power and sample size is only one of the issues which beleaguer investigators of associations between exposures to parents and outcomes of pregnan cy. Related factors are the timing of the exposure, mater nal or paternal, in relation to conception and/or gestation, and the specific measures of pregnancy outcome.4' Pater nal exposures may act in two ways -- by contamination of the maternal environment resulting in secondary maternal exposures, or directly by affecting paternal ger minal tissue. Since spermatogenesis is a continuous pro cess, paternal exposures occurring shortly before concep tion are those requiring the most investigative attention Cumulative or delayed effects are more likely to be of im portance m maternal exposures. By focusing 'on early pregnancy wastage, particularly if the frequency of chromosomal abnormalities in the aborted product of conceptions can be determined, the objectives of Study are better focused and achieved with reduced sample size, and the confounding effects of the maternal in utero environmental factors are minimized. In conclusion, while the potential clearly exists for teratogenesis and trans-generational carcinogenesis in the off spring of workers exposed to mutagenic and carcinogenic agents, such effects have been difficult to demonstrate conclusively in humans Future investigations must take into account a variety of environmental and behavioral ractors which can affect fetal development if causal associations between occupational exposures and pregnancy outcome are to be identified. References 1 O F D The Compact Edition or the Qvtord English Dictionary Orrord Ostord University Press 1071 cites Dunglison Medical Lex icon. Pis' Wilson 1C Environment and Birth Delects New York Academic Press 1471 ) staple'RE Definition or reMtogenesis and teratogen in Methods to: Detection or Lnvironment.it Xgenty thit Produce Congenital Or tint' T H Shepard et il (Eds I Proceedings or the Cuadaloupe Con- ferenr e Vms'erdam Norm Holland Publishing Company l^'s a faumeni IF Ir rh susceptibility ot the retus and child to chemical pollutants Chemicals m human teratogenesij and tran>- la cental carcmogene-is Pediafriry 53/.lil'-hl a. 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Vo1 21 `io 9'Sootember 1979 613