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k/ \/c Mu>n*c & /V / 5 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 in investigating the role of occupational factors that other environmental and behav ioral factors with major effects on pregnancy outcome be accounted for. These include smoking, alcohol, and drug i exposures. An approach to surveillance for chromosomal abnormalities in offspring of occupationally exposed parents is outlined. L/erived from the Creek word "repat" 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 has been refined to refer to the biological science dealing with "the causes, mecha nisms, and manifestations of developmental deviations of either structural or functional nature."1 An agent may act as a teratogen when administered in a number of ways, whether to the male or female before mating, to the female during pregnancy, or to the fetus directly * Agents in the environment may produce alterations in the ge nome, mutations, and by that mechanism lead to abnor malities of 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 fetal defects or predis- From Cornell University Medical College and M<*morul-$lo*ft Kettering Cancer Center. Bo* 60, 1275 York Ave, New York. NY 10021 Supported m part by a contract with the 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 in 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 in increased teratogenic or cancer risk in the offspring. The latter effect could theo retically result from each of three distinct mechanisms: chromosome breakage, point mutation, or abnormalities in gametogenesis or fertilization. Mutagenic and Teratogenic Characteristics of an Agent and Trans-Cenerational 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 in the early stages may produce malformations during organ development and neoplasia when exposed later in preg nancy. Therefore, screening for transplacental hazards should include, whenever possible, the entire range of fetal response, including cancers that may develop some time after birth."1 Teratogenic, mutagenic and carcino genic activities are all demonstrable for a number of corn- Journal o( Occupational Medicine/Vol. 21. No. 9/September 1979 607 ucc 035548 pounds, but transplacental carcinogenic potential has rarely been demonstrated for known teratogens and mu tagens. Teratogenic effects may reflect a variety of ac tions involving the mother, the placenta or the fetopla cental unit. These effects can be indirect and may not in volve immediate action of 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 of 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-induced tumors, unlike malformations, are rarely present at birth, one must also observe the offspring 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 infants bom to recognized chronic alcoholic mothers, 83.3% had birth weights under the tenth percentile, compared with 2.3% in a compara ble non-alcoholic population * In addition to intrauterine growth retardation, the infants had retarded post-natal growth and intellectual development. A characteristic facies, with short palpebral fissures, hypoplastic philtrum, thin vermilion line of the upper lip and retrognathia, has also been described. In addition to these features of the fetal alcohol syn drome, congenital malformations of various types occur with excess frequency. Recognition of an associated in crease in the occurrence of congenital malformations ironically re-emphasizes ancient observations and ad monitions against alcohol use during pregnancy.' The ad verse effects on the fetus of maternal alcohol abuse dur ing pregnancy were further quantified by Ouellette et al,' who classified women at the first prenatal visit into four categories according to alcohol consumption and in dependently evaluated pregnancy outcome. Compared to those born to abstinent or moderate drinkers, infants born to heavy thinkers had twice the risk of having an ab normality at birth. The frequency of congenital abnormal ities in the offspring of heavy dnnkers was extremely high--32% when minor abnormalities were included, 17% if only major 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 often 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 at'1 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.'* '* 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 al^ 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 by variation in the propor tion of chromosomally abnormal fetuses with increasing maternal age and by the fact that a large proportion of smokers are younger women." An increase in the rate of chromosomally abnormal conceptions might be masked in a proportionate-ratio analysis if 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 in the first week of 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 ef fect remained statistically significant after adjustment for maternal age. parity and social class. An investigation of congenital defects of all systems registered in South Wales from 1964 to 1966 which took into account mater nal age, parity, social class, area of residence and date of delivery did not associate maternal smoking habits with 608 Risks to Offspring from Parental Occupational Exposures/Haas and Schottenfeld ucc 035549 congenital malformations in any system.'* It is possible that moderate increases in relative risk might have gone undetected. Analysis of data from a mailed survey of a large num ber of professional women in medicine identified a rela tive risk of up to 1.7 for spontaneous abortion and a risk of congenital abnormalities of up to 2.3 in heavy smokers after the effects of age. parity and exposure to anesthetic gases were considered '* Drug Exposure -- In utero exposure to dietbylstilbestrol (DES1 with the subsequent development of vaginal adenocarcinoma, is the prototype for transplacental on cogenesis in humans. Appreciation of the causal role played by in utero exposure to DES followed hard upon the report of seven cases of the hithertofore exceedingly rare tumor, adenocarcinoma of the vagina, presenting in young individuals, 14 to 22 years of age.1"-11 The syndrome appears to involve not only cases of vaginal adenocar cinoma, but a spectrum of abnormalities of the vagina and cervix. Only when exposure to DES occurred during the first four months of gestation were neoplasms or ab normalities observed. The DES vaginal adenosis-adenocarcinoma relation ship is the only documented example in humans of cancer in the offspring attributable to parental environ mental chemical exposure The therapeutic agent was given in a high dose, commonly more than 10 grams in the first half of pregnancy. DES. a synthetic nonsteroidal estrogen analogue, was likely to have a direct effect on the development of the target tissue at a crucial point in embryogene5is. Since the risk to the offspring appears limited to exposures which occur during the first four months of gestation, direct exposure of the fetus is likely to be essential to the pathogenic mechanism. The long latent period, with exposure in utero and emergence of clinical sequelae in adolescence, probably reflects the im portance of pubertal endogenous estrogens as promoting factors, and is a reminder of the need for an extended period of observation following suspect trans-generational carcinogenic exposures. The association between DES and vaginal adenocarcinomas, as important as it is. does not serve as a model for preconception parental oc cupational exposures and trans-generational carcinogen esis. Teratogenic effects of a multiplicity of drugs are now documented or suspected and these will not be discussed here further except to reiterate the need to remove the potentially confounding effects of such agents in investi gations of other possible causes of impaired feta) devel opment." Given the current status of our understanding, it is essential that in the search for exogenous causes of teratogenesis and abnormal pregnancy outcomes, the poten tial confounding impacts of maternal smoking, drinking, and medication intake be taken into account. Radiation. --If preconception radiation exposure in creases cancer risk in the offspring, it would heighten con cern over other agents which produce chromosomal dam age. Chromosomal aberrations attributed to vinyl chlo ride and benzene exposure, for example, are reminiscent of those produced by radiation. While the genetic consequences of irradiation from the atomic bombings might be expected to produce some lethal mutations in the offspring of survivors, this effect has been difficult to demonstrate. Cohort studies of off spring of survivors classified by radiation exposure level did not show excess mortality in the children of the high exposure group. Neither were excess congenital malfor mations, increased infant mortality, nor impaired survival during the first ten years of life detected, regardless of ex posure level to either parent. Thus, although animal ex perience strongly suggests that such effects should be manifest in offspring of individuals exposed to ionizing ir radiation, studies of Japanese atomic bomb survivors have not demonstrated measurable effects.11 No substantial increase in leukemia risk has been de tected among offspring of survivors. Analyses having a 90% chance of detecting a four-fold increase in risk of leukemia among children of heavily exposed survivors were negative. Neither did age-at-onset of observed leukemia cases nor type of leukemia in offspring differ by level of parental radiation exposure. Despite the docu mented persistence of chromosomal aberrations in the somatic cells of adults exposed to the atomic bomb, no measurable impact on mortality, congenital malforma tions or leukemogenesis has been detected in their off spring.1* In addition to radiation exposures related to the atomic bombings, diagnostic and therapeutic medical radiation of the parents has been investigated to assess risks to the offspring. The magnitude of leukemia risk associated with previous radiation was estimated, after adjustment for maternal age and pregnancy history, to be 1.73 times that of mothers who had not been x-rayed. Despite the sugges tion of greater risk in women with higher x-ray exposure, no clear-cut dose-response gradient was demonstrated. The relative risk of leukemia in the child associated with preconception diagnostic radiation of the father (1.31) was not statistically different from unity. When both mother and father had histories of preconception diag nostic x-rays, the order of magnitude of the relative risk, 1.49, was about th4 same as that for children whose mothers alone had received radiation.11 Exposure to medical radiation has been widespread. 8y the early 1960 s, approximately 35% of a group of mothers of healthy children reported having received diagnostic radiation prior to conceiving. Similarly, about 22% of fathers of the same children reported having had some sort of diagnostic radiation at some time prior to the child's conception. Self-reporting considerably under estimates the extent of x-ray exposures.1* The tendency to substantially underreport x-ray exposure points up the dif ficulty of excluding differences in prior radiation expo sure as a basis for observed differences in chromosomal aberrations. Neither is it reasonable to automatically pre sume that medical radiation exposures have been equally present in the study and comparison groups, especially if these groups have not been matched by age or calendar period of observations. Occupational Exposures and Pregnancy Outcome Vinyl Chloride.--Chromosomal abnormalities may oc cur more often than expected in persons exposed to vinyl chloride, especially following intense exposures of long duration. The import of such abnormalities for reproduc tive outcome remains ill-defined. Chromosomal aberrations were reported in 1975 in Journal ol Occupational Medicine/Vol. 21, No. 9/September 1979 609 UCC 035550 p f Swedish vinyl chloride workers. Abnormalities appeared " in cells drawn from seven males with occupational expo sure histories of nine to 29 years (mean 16.6 years) at vinyl chloride concentrations which had declined to 2030 ppm by 1974." The group exposed to vinyl chloride had aber rations in a total of 9.52% of all cells, compared to 1.94% for 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 1.5% to 18% in the exposed workers. There was no apparent relationship between duration of exposure to vinyl chloride and the proportion of 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 in 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 four 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 in both control and study groups." No relationship could be defined between dose or duration of exposure and frequency of 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 poly vinyl chloride and compared them with 24 unexposed in dividuals." Vinyl chloride exposure of 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 of cells with chromosomal aberrations, the majority of which were breakages, was found in vinyl chloride-ex posed workers than in controls. Unstable and stable chromosomal aberrations and breaks were all signifi cantly more common in cells from exposed workers. Not all investigators have identified such changes. No differences were found in frequency of chromosomal aberrations between a group of 209 employees of a vinyl chloride plant (occupational exposures averaging 48.3 months) and a group of 295 individuals undergoing pre employment physicals." No relationship was established between duration of vinyl chloride exposure and degree of chromosomal damage. The absence of blind evalu ation in this study, as well as inclusion of individuals with minimal exposures in the exposed group, makes interpre tation difficult. This difficulty is compounded by 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 of polymerization and polyvinyl chloride (PVC) fabrication workers. " 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 only 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" 14 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 fetal 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, material 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 systems 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 in 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 reported in 2.5% of all cells from exposed workers, com- 610 Risks to Offspring from Parental Occupational Exposures/Haas and Schottenfeld 4 * < , | ; [ > ' UCC 035551 pared to 1.0 to 14% for controls. Most of the excess was due to chromosomal aberrations of the unstable types in addition to the excess of abnormal cells in the exposed group, the number of unstable alterations per abnormal cell was higher in the exposed group than in the controls." In a separate investigation, ten workers in an Italian rotogravure plant who had had sequential exposures, first to benzene and later to toluene and xylene, were studied. These workers had been subjected to concentrations of benzene ranging from 125 ppm to 532 ppm or higher. The maximal allowable concentration at the time of these ex posures had been 25 ppm. Another group of 24 workers had primarily toluene exposures except for trace contamination with xylene. These 34 workers were matched with healthy controls of similar age and sex, who had been drawn from the general population and who had no history of benzene or radiation exposure. A signifi cantly higher proportion of abnormal cells was found in the benzene-exposed individuals than in their matched controls. In the group with toluene exposure, no such ex cess was present. When the benzene and toluene groups were compared to each other, an excess of chromosome changes was present in the benzene group. Most of the excess was attributable to unstable chromosomal altera tions. ' These studies and others" support the impression that exposure to benzene, particularly exposures intense enough to result in acute toxicity, can be followed by a measurable excess of chromosomal aberrations which may persist for years. If similar effects occur in germ cells of exposed individuals, the consequences in fetal wastage, congenital anomalies and even neoplasms might be manifest in their progeny. To date no excess of such abnormalities has been reported in offspring of benzeneexposed individuals. Anesthetic Cases. -- Occupational exposures of female operating room personnel to waste anesthetic gas es have been held responsible for decreased fertility, in creased rate of spontaneous abortion, low birth weight and possibly impaired development in the offspring. An excess of spontaneous abortions in wives of men pro fessionally exposed to anesthetic gases has been suggest ed but not confirmed. Among operating room nurses, 29.7% of pregnancies terminated with spontaneous abortion, compared to 8.8% among control nurses. A similar excess of spon taneous abortion was observed for female physician anesthesiologists compared to female physicians in other specialties.4* Spontaneous abortions occurred two weeks earlier on the average among the operating room ex posure groups than among controls, at an average of eight rather than ten weeks of gestation. Another survey suggested that for female nurse-anesthetists who had worked during pregnancy, the frequency of birth defects in the offspring was 16.4% compared to 5.7% for pregnancies in which the mother had not worked.41 Studies from Finland and the United Kingdom also sug gested a deleterious effect on pregnancy outcome from maternal exposure to operating room environments. An increase in frequency of early spontaneous abortions, as well as low birth weight, has been reported for Finnish fe male operating room staff.44 Among female physicians in England and Wales, greater incidence of congenital de fects, lower birth weights and higher stillbirth rates, but not higher spontaneous abortion rates, were reported from pregnancies of women holding anesthesiology appointments than from those of other women physi cians.41 The effects of paternal exposure to anesthetic gases are uncertain. Congenital anomalies were reported to be increased by 25% in the offspring of male anesthesiolo gists compared to offspring of male members of the American Academy of Pediatrics, but no difference was reported for spontaneous abortion rates among wives of male operating room personnel compared to controls.44 Questionnaires completed by 5119 married male physi cians in the United Kingdom suggested an increase in minor but not in major congenital anomalies, and no dif ference in frequency of infertility, spontaneous abortion or cancer in the offspring of male anesthesiologists com pared to control physicians.4* Hydrocarbons. -- Two studies offer conflicting evi dence with respect to the risk of cancer in children of men whose work might lead them to be exposed to petroleum-derived hydrocarbons. Fabia and Thuy44 re viewed death certificates in Quebec during 1965 to 1970 to identify children who had died from malignant disease while under five years of age. For 386 of 402 such children, birth certificates were also found in the Quebec population register. A control group of 772 children (two for each cancer death) was selected using the birth registration record preceding and following that of each case in the official files. This effectively matched for season, calendar period, and province of birth. Occupa tion of the father at the time of birth was taken from the birth certificate. An industrial hygienist independently grouped the fathers into three levels of probable exposure to petroleum-derived hydrocarbons. Occupation of the father was unknown for 30 cases and 56 controls. The dis tribution of occupation of the father at birth differed for. ases and controls. Most of this difference was the result of an excess among cases of paternal occupations con sidered to be hydrocarbon-related. The relative odds of cancer in the children of men holding hydrocarbon-re lated jobs at the time of the child's birth were 31. an in crease which was unlikely to have occurred by chance. Most of the excess in exposed occupations was account ed for by motor vehicle mechanics, machinists, miners and painters. When similar analyses were conducted by the type of cancer in the child, the excess of hydrocarbonrelated occupations prevailed for the following group ings: leukemia-lymphoma, nervous system malignancy, other tumors. Fathers of four of five cases of Letterer-Siwe disease were in the hydrocarbon-related work groups No such excess was present for children with Wilms' tumor. The differences observed could not be attributed to dif ferences in parental age or in geographic residence at the time of birth. The investigation was based on deaths in children under five, and it is possible that social class bias may have been introduced in that fashion. If, of those with a childhood neoplasm, children of more affluent parents are more likely than children of poorer parents to survive beyond age five, they would not be included in the study group. This would lead to a higher proportion of children with parents of lower socio-economic status in journal of Occupational Medicine/Vol. 21, No. 9/September 1979 611 ucc 035552 the cancer death group and would bias the distribution of Surveillance of spontaneous abortions may have a father's occupation. Moreover, it was not possible to con number of advantages as a prospective means of firm that fathers in the so-called "ex[x>sod" group did, in monitoring for such effects since defective conceptions fact, have contact with hydrocarbon-derived chemicals. are aborted selectively. As a result, studies of terato- While not ideal, the death certificate probably is a valid genesis focusing on spontaneous abortions may be con source of diagnostic information for cancer deaths in siderably more efficient than those conducted in new young children. The cancer groupings employed in the borns. Because the frequency of abnormalities is higher in analysis -- "leukemias and lymphomas," "nervous spontaneous abortions, the sample size needed to system* and "others" -- were quite broad and included demonstrate a change in risk is much smaller than that re many histopathologic entities. Occupational association quired for a parallel query addressed to defects recog was not restricted to specific entities within the broader nized at birth. The magnitude of this difference can be categories. Because the epidemiologic features of the dramatic. If chromosomal defects diagnosable on the ap various histopathologic types of leukemias, lymphomas, pearance of the newborn are considered alone, the sam and nervous system tumors are distinctive, a specific ple size required may be hundreds of times that required . chemical exposure or class of exposures, if assumed to be in an investigation examining prevalence of chromosomal of causal significance, would more likely be linked with anomalies in early abortion.4* In addition to sample size specific histopathologic as well as organ system effects. considerations, study of spontaneously aborted concep A study with a similar design but different findings was tions offers a lead time of at least six months over studies conducted in Finland.4' Children under 15 years of age of live births. The abortion specimen can be studied with who developed cancer were identified from the Finnish care and thoroughness, permitting detection of anomalies Cancer Registry, 1959-1968. Of 1409 cancer cases so iden lethal to the fetus which might escape detection in tified, the final series consisted of 852 pairs for whom studies of live births. birth records which included father's occupation were The problem of power and sample size is only one of available. Each case was matched with a child whose the issues which beleaguer investigators of associations birth date immediately preceded that of the case and between exposures to parents and outcomes of pregnan who was born in the same maternity welfare district. This cy. Related factors are the timing of the exposure, mater procedure matched effectively by calendar period, nal or paternal, in relation to conception and/or gestation, season and domicile at the time of birth. Father's occupa and the specific measures of pregnancy outcome.44 Pater tion was drawn not from birth registration records but nal exposures may act in two ways -- by contamination from records of the free, nationwide antenatal care of the maternal environment resulting in secondary system in operation in Finland. Father's occupation was maternal exposures, or directly by affecting paternal ger classified by likelihood of hydrocarbon exposure in a minal tissue. Since spermatogenesis is a continuous pro manner which was shown to be comparable with that cess, paternal exposures occurring shortly before concep employed in the study done in Quebec. No excess risk for tion are those requiring the most investigative attention. hydrocarbon-exposed fathers was detected for any class Cumulative or delayed effects are more likely to be of im of neoplasms either for children whose cancers occurred portance in maternal exposures. By focusing on early under five or under 15 years of age. pregnancy wastage, particularly if the frequency of The two studies differed primarily in the source of in chromosomal abnormalities in the aborted product of formation on father's occupation. For the Finnish study, . conieptions can be determined, the objectives of study that information was drawn from antenatal records com are better focused and achieved with reduced sample piled for the most part in the first trimester of gestation. size, and the confounding effects of the maternal in utero This may be a better index of exposure at the time of con ception than information recorded at the time of birth in environmental factors are minimized. In conclusion, while the potential clearly exists for tera- the birth certificate itself. Although a large number of " togeriesis and trans-generational carcinogenesis in the off pairs were discarded in Finland because father's occupa spring of workers exposed to mutagenic and carcinogenic tion was not recorded, these came from a circumscribed agents, such effects have been difficult to demonstrate calendar period. Since a matched pairs design was main conclusively in humans. Future investigations must take tained throughout the analysis, removal of these cases into account a variety of environmental and behavioral should not influence the result. The Finnish study used in factors which can affect fetal development if causal cident cancer cases and looked at age groups up to 15 associations between occupational exposures and years at the time of cancer diagnosis. The Quebec group pregnancy outcome are to be identified. identified only cancer deaths up to five years of age. Variation in terminology of occupational classification might also contribute to the differences, although efforts References 1 O E D The Compact Edition of the Oxford English Dictionary were made to establish their comparability. At present, the contradictory findings of the two studies are not readily reconciled. Oxford Oxford University Press. 1171, cite* Dunglison Medical Lex icon. 1ftS7 2 Wilson |C Environment and Birth Defects. New York Academic Press. 1973 1 Staples RE. Definition of teratogenesis and teratogen, in Methods Surveillance of Spontaneous Abortions as a Strategy of Environmental Monitoring The relationship between mutagenic, teratogenic and carcinogenic effects in the offspring of persons exposed for Detection of Environmental Agents that Produce Congenital De fects. T. H Shepard et al (Eds) Proceedings of the Cuadabupe Con ference. 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