Document Z8n7J9LqEn7Y5ekrd0zZgq10p

Risks to the Offspring from Parental Occupational Exposures Ioanna F. Haas, MX)., 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 ma/or effects on pregnancy outcome be accounted for. These include smoking, alcohol, and drug exposures. An approach to surveillance for chromosomal abnormalities m offspring of occupationally exposed parents is outlined. L/erived from the Creek word "repat."zneaning 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 1 Agents m the environment may produce alterations in the ge nome. mutations, and bv 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 mav theoretically be retal derects or precis- from Un*vfMrv weasel) Colley* and >v'#mor<4i`$lo*n Cincer Qtfitvr 3ct 1275 Yor* Av* 10021 buuoonea in parr ov a contract *nn cne America** Petroleum fnituute 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 gems ceils: transplacental, bv 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-generattona! 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 in increased teratogenic or cancer nsk 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 mav produce malformations during organ development and neoolasia when exposed later m preg nancy Therefore, screening for transplacental hazards should include, whenever possible, the entire range or fetal response, including cancers that mav develop some time after birth"* Teratogenic, mutagenic and carcino genic activities are all demonstrable tor a number ot corn- Journal of Occupational Meoicine/Voi. 21, No. 3/Sectenoer 1979 507 ucc 023919 pounds but transplacental carcinogenic potential has rarely been demonstrated tor known teratogens and mu tagens Teratogenic effects mav reflect a variety or ac tions involving the mother, the placenta or the feto-pla- cental unit. These effects can be indirect and may not in volve immediate action of the agent <jn the target retal tissue.' Transplacental carcinogens may act directly on the retal tissues which are inherently more vulnerable be cause or the high rate or 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-mduced tumors hardly ever appear in rodent species until the animal reaches maturity. In the only docu mented example of chemical transplacental carcino genesis m humans, vaginal adenocarcinoma following dh ethylstilbestrol (DE5) 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 exoosures 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 13% 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 svndrome. 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 pregnane, were further quantified bv Ouellette et al,'0 who classified women at the first prenatal visit into four categories according to alcohol consumption and jnciept-nrientk evaluated pregnanev outepme Compared to those oorn to abstinent or mocerate drinkers, mrants born to heavy drinkers had twice the risk or having an apnormalitv at Dirth The frequency- of congenital abnormalties in me nrisonny or heavy drinkers was extremely- high --32% yvhen minor abnormalities yvere included. 17% if only maior anomalies yvere considered. Multiple abnormalities yvere present in 20% of the offspring of heavy alcohol users. Maior, minor and multiple abnor malities occurred significantly less orten among abstinent or moderate drinkers. Animal models, including chicks, rats and guinea pigs, have been developed for evaluating 1 the effects of ethanol alone on offspring, and support the view that ethanol itself is a harmtul 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 al11 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.'114 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* aaon 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 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 m 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 m 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 leagues1' 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 adiustment 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. paritv. social class, area of residence and date of deiiven, did not associate maternal smoking habits with 6C3 Sisks ;o Offspring Irotfi Parental Occupational Exposures/Haas anc Scnattanfem ucc 033920 congenita! malformations in anv system '* It is possible that moderate increases in relative risk might have gone undetected. Analysis of data from a mailed survev 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 diethvlstilbestrol (DES), 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.'0-11 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 m 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 embryogenesis. 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 muitiplicity 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 fetal 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, dnnkmg, 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 dirncult to demonstrate Cohort studies of orrspring of survivors classified by radiation exposure level did not show excess mortality m 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 or 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." No substantial increase m 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." 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 nsk of leukemia in the child associated with preconception diagnostic radiation of the father Cl.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 the same as that for children whose mothers alone had received radiation." Exposure to medical radiation has been widespread. By the early 1960's, approximately 35% of a group of mothers of healthy children reoorted 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." The tendency to substantially underreport x-ray exposure points up the dif ficulty of excluding differences m 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 Pregnancv Outcome Vinyl Chloride. --Chromosomal abnormalities mav oc cur more often than expected in persons exDosed co vinyl chloride, especially following intense exposures of long duration The import of such abnormalities for reproduc tive outcome remains ill-deimed. Chromosomal aberrations were reported in 1975 m Journal of Occupational Medicme/Voi. 21. No. 9/SeotemPer 1979 509 fjce 023921 Swedish vm\l chloride workers Abnormalities appeared m cells drawn from seven males with occupational expo sure histories or nine to 29 years (mean 16.6 years) at vmvl chloride concentrations which had declined to 20-30 ppm bv 1974 " The group exposed to vinvl chloride had aber rations in a total ot 9 52% ot all cells, compared to 1 94% tor cells or three unexposed controls. Differences m the rrequencv 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 vmvl 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 significandy 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 preemplovment physicals." No relationship was established between duration ot vinyl chloride exposure and degree or chromosomal damage. The absence of blind evalu ation in this studv. as well as inclusion of individuals with minimal exposures in the exposed group, makes interpre tation difficult. This difficulty is compounded bv the sub stantial citrerence in mean age of studv 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 bv wives or a group or polvmertzation and polyvinyl chloride (PVC) fabrication workers." '* 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 m the wives were ' derived from interviews and questionnaires administered to male workers. Participation rates for the groups queried ranged frqm 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 m the( VCM-exposed group than m 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 studv 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" " 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 0e.. spontaneous abor tion, late fetal death [stillbirth], low birth weight, neonatal death) in other settings have shown the profound 4nd sub tle effects of confounding variables such as race, socioeconomic status, maternal age, birth order, panty, 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. Ch/oroprene--Structural similarities between vinyl chloride and chioroprene have raised questions about long-term hazards resulting from chioroprene exposure. Chioroprene is mutagenic in certain systems and possiblv carcinogenic. The possibility that it has induced excessive miscarnages m the wives of male workers and led to chromosomal aberrations has been asserted but not well documented." Benzene. -- Benzene also mav. 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 re ported m 2.5% of all cells from exposed workers, com- 510 Risks ;o Offspring from Parental Occupational Exposures/Haas ano Scfioitenfalo ucc 023922 pared to 1 0 to 1 4% for controls Most or the excess was due to chromosomal aberrations or the unstable tvpes In addition to the excess of abnormal cells m 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 xviene, were studied. These workers had been suoiected 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.** 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 dunng 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.*1 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 m frequency of early spontaneous abortions, as well as low birth weight, has been reported for Finnish femaie operating room start *' Among remale phvsicians in England and Wales, greater incidence or congenital de tects, 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." The effects of paternal exposure to anesthetic gases are uncertain. Congenital anomalies were reported to be increased by 25% m 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 maie operating room personnel compared to controls.*4 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.*' 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 petraleum-denved hydrocarbons, Fabia and Thuy** 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 penod, 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 cases 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 3.1. 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 m children under five, and it is possible that social class bias may have been introduced m 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 mcludea in the study group. This would lead to a higher proportion of children with parents of lower socio-economic status in ,,aurnai :f Occupational Medicme/Vol. Zi. No. 9/Septemoer i 979 5lf ucc 023923 the cancer death group ana would bias the distribution or father s occupation. Moreover, it was not possible to con firm that fathers m the so-called "exposed" group did m fact, hose contact with hydrocarbon-derived chemicals, while not ideal, the death cemncate probablv is a valid source ot diagnostic Information for cancer deaths m young children The cancer groupings employed in the analysis -- "leukemias and Umphomas," "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, if 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.*7 Children under 15 years of age who developed cancer were identified from the Finnish Cancer Registry. 1959-1963. Of 1 409 cancer cases so iden tified. the final series consisted of 352 pairs for whom birth records which included father's occupation were available. Each case was matched with a child whose birth date immediately preceded'that of the case and who was born in 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 in Quebec. No excess risk for hydrocarbon-exposed fathers was detected for 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 may be a better index of exposure at the time of con ception than information recorded at the .time of birth in the birth certificate itself. Although a targe number of pairs were discarded in Finland because father s occupa tion was not recorded, these came from a circumscribed calendar period. Since a matched pairs design was main tained throughout the analysis, removal of these cases should not influence the result The Finnish study used in cident cancer cases and looked at age groups up to 15 years at the time of cancer aiagnosis. The Quebec group identified only cancer deaths up to five years of age. Variation in terminology of occupational classification might also contribute to the differences, although efforts were made to establish their comparability. At present, the contradictory findings or the two studies are not readily, reconciled. Surveillance of Spontaneous Abortions as a Strategy of Environmental Monitoring The relationship betwee" mutagenic, teratogenic and carcinogenic effects m the onsDnng or persons exoosed o en\ironmenrai agents * a complex one RlS'rS 10 Surveillance ot spontaneous abortions may have a number of advantages as a prospective means or monitoring for such effects since defective conceptions ate aborted selectively As a result, studies of teratogenesis focusing on spontaneous abortions mav be con siderably more efficient chan those conducted in new borns 8ecause the frequency of abnormalities is higher m spontaneous abortions, the sample size needed to demonstrate a change m risk is much smaller than that re quired for a parallel query addressed ro 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 mav be hundreds of times that required in an investigation examining prevalence of chromosomal anomalies in early abortion ** 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.** Pater nal exposures may act in pwo 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 in 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 factors which can affect fetal development if causal associations between occupational exposures and pregnancy outcome are to be identified. References 1 O E D. The Compact Edition ot the Oxtord English Dictionary Oxford*. Ovoid University Press, 1971, cites Oungluon Medical Lex icon 185* 1 Wilson 1C. Environment and 8tfth Detects. Mew toils Academic Press 1973 3 St.ioies RE Definition oi teratogenevs and teratogen, m Merhods :or Detection 01 Environmental Agents that "roduce Congenital De tect* 7 H SheoJfd e'jJ ,Eds! Proceedings or the Cuacaioune Con-e-ence Amsterdam Morin Hoilanc P-johshing Comnanv i"5 a Ejuinenr ]F 1r The njscnp-:btiit\ or *he retu< and cni<d *2 chemical oollutanrs Chemicals .n human teratogeneso and tr.-mv ciacentai carcmogene-.- 3nd.jrr,cs 53 807-511 1*-i r.nrn 75o:=i Ccc'jpp-'.'Cpz! gxscsuras-'Haas ar.c Schocs-ve'c ucc 023924 5 D'P.iO'O !A jnd kckn 0 T-r,itrc*-ni-'w-oncog-n...i. A -:i..d\ ?u posaole 'eliHion>.iiD, Aren Pjri'Oi1 81 3-23. I1-"*) n Rice IM An overview or M\in-.ni.ictrni.sl cHemic.il CtifCmog-ne-i> Fe-Jioioci 811 M25. 19'3 7 Clorren Sr- and Smith DM1 The teial alcohol -vndrome \ mri / Med 298 Inn 1*1067 1973 8 Llleidnd CN The orr.nnng or alcoholic mothers Ann M \cjd So 197 167-1 o9 1971. 9 lonei Kl ond Smith DM Recognition or the retoi Alcohol -vn- drome in eori\ miancv Lancet 2V"9-1U01. 1973 10 Ouellette Em Rosett HI Rosmen PN end Weiner L, Adverse et- recti on oitspnng or maternal alcohol aouie during pregnanes v Engl / Med 297 528-530, 1977 11 Kronick IB Teratogenic errecu or ethvl alcohol admmutered to pregnant mice. Am / Qbstet Cvnecol 124676-680, 1976 12. Kline I. Stem ZA. Suiser M. and Warburton D Smoking, A risk factor ror spontaneous abortion \ Eng; / Med 297 793-796, 1977 13 Rush 0 and Kass Maternal smoking-A reassessment or the as sociation with perinatal mortality Am I Epidemiol 96 183-1% 1972 14 Mever MB. lonas BS. and Tonascia IN Perinatal events as sociated with maternal smoking during pregnancy Am I Epidemiol 103 464-476. 1976 15 Stein Z. Sasset M. and Warburton 0: Spontaneous abortion as a screening device. The ertect of tetal survival on the incidence of birth detects Am / Epidemiol 102:275-290. 197S 16. Alberman . Creasy M. Elliott M et al Maternal tactors associated with fetal chromosomal anomalies in spontaneous abor tions Sr I Obstet Cynaecol 83 621-627 1976 17 Fredrick I. Alberman ED. and Goldstein H Possible teratogenic effect of cigarette smoking. Nature 231 529-530. 1971 18 Richards IDC Congenital malformations and environmental in fluence in pregnancy Sr I Prev Soe Med 23 218-225. 1969. 19 Himmelberger DU. Brown BW, |r, and Cohen EN Cigarette smoking during pregnancy and the recurrence of spontaneous abor tion and congenital abnormality Am I Epidemiol 108.470-479 1978. 20. Herbst AL and Scullv RE: Adenocarcinoma of the vagina in adolescence1 a report of 7 cases including 6 dear-cell carcinomas (so called mesonephromasL Cancer 25 745-757, 1970, .21. Herbst AL. Ulfeider h. and Poskanaer DC: Adenocarcinoma of the vagina Associabon o< maternal stilbestrol therapy with tumor ap pearance m vOung women. N Engl I Med 284 875-881, 1971 22. Herbst al K unman Rl. Scullv RE. and Poskanaer DC. Clear cell adenocarcinoma of the genital tract in young females. N Engl I Med 287:1259-1264. 1972. 23. Herbst AL. Poskanaer DC. Robboy SI, et al: Prenatal exposure to stilbestrol A prospective companson of exposed female offspring With unexposed controls N Engl J Med 292:334-339. 1975. 24. Hemonen OP: Birth Defects and Drugs m Pregnancy. Littleton. Mass: PSC Publ. Co.. 1977 25. Kato H. Schull w|. and Neel IV a cohort-type study of survival in the children or parents exposed to atomic bombings. Am / Hum Cenet 18 339-373. 1966. 26. Hoshino T. Kato H. Finch SC. and Hrubec Z' Leukemia m off spring of atomic bomb survivors Stood 30719-729, 1967 27. Craham S. Levin ML, Lilienreld AM. et al: Preconception, in trauterine. and postnatal irradiation as related to leukemia. Naif Cancer Inn Monogr 19:347-371. 1966. 28. Craham $. Levin Ml. lilienfeki AM. et al: Methodological prob lems and design of the tristate leukemia survey Ann nv Acad 5cr . 107j5*-5of 1%.' 29 Funv--C-AviOIO F I.in-.w: II L.nna.r- 1 ,ii i :-wi,,, .lOe-rniion- :n wor-ers ^ifio-r-d ;o \;r,\. . m-r Oil"-*-1 i- - :975- 111 Ducatman A H:r-cnorn K .1116 >v(1,nir !| kir.i - .. ..-I.w posure ,md human chrome.om* -Pi-- -r-o-- '..L.'.ir -To- 11 it,1 1 VI75 31 Pj,-chase IFK Runarrtion CR aori A-s-r.nn D C- jnd dummant ierhal cm--::-or-.'ns: cnionc:- la-ccr 2 al-'-a : 32 Picr.iano Dl FLke RE Cat PC jnrl K:li.sn Di V m. cv rog-ne;ics / 0CCL0 \.'-*d 19 52* 530 l'A" 33 inran-.e PF, Wagonr- Ik. McMxhari Al tm\I chloride Lancer 1 7J4-7)?, i?"o al C-meric n-1 34 Intante PF Wagoner IK. McMichaci Al et al Cenetic m*. or vinyl chloride Lancet 1 1289-1290 1976 35 Dalmg |R and Emanuel I1 Induced abortion and -ubsecuencome or pregnancy in a senes or American women *-" / '.'ed 297 1241-1245 1977 36 Inrante Pc Wagoner IK and lours Rl Chloroyrene Ob--na tions of carcinogenesis and mutagesesn. in Origins or Human Cancer Book A Incidence of Cancer in Humans H H Hurt, I D Wa-jon, and T. A. Wmsten lEds l Coldspring Harbor Laboratory. 1977 pp 205-217. 37, Tough im and Court Brown vvm Chromosome aberrations and exposure to ambient benzene Lancet 1 684 1975 38 Form a, Pacirico E. and Limonta A. Chromosome studies in workers exposed to benzene or toluene or both Arch fnveon Health 22 373-378.1971 39 Form AM. Capoellim A Packtico E. and Vigilant EC. Chromosome changes and rhetf evolution in subiects with past ex posure to benzene. Arch Environ Health 23.385*391. 1971. 40 Cohen EN. Beilville |W, and Brown BW Anesthesia, pregnancy and miscarriage: A studv of operaong room nurses and anesthetists , Anetthetiokfv 35 343-347.1971. 41. Corbett TH. Cornell RC. Endres IL and Leding K: Birth defects among children ot nurse-anesthetists Anesthesiology 41:341-344, 1974 42 Rosenberg P and Kirves A: Miscarriages among operating room theatre staff Act* Amesthese! Stand iSueei) 533741^97-1.^ Mr 43 Pharoah POD. Alberman . and Dovle P: Outcome or oreg- '*** nanev among women in anesthetic practice Lancer 1 34-36. 1977 44 Cohen EN. Brown BW. |r,, Bruce DL. et al Occupational disease among ooeranng room personnel A national study Aneethesio-'Ogv 41-321-340,1974 - -v.-.x. 45. Kmll-iones RP Newman Bl. and Spence aa. .Anaesthetic prac tice and pregnancy. Controlled survey of male anesthetists in the United Kingdom Lancet 2:807-809 1975, n&tMgfc*. 46. Fabia I and Thuv TD. Occupation of father at time of birth of children dying or malignant diseases Sr I Prev Soc Med 28 98-100, 1974 47 Hakulinenen T Salonen T, and Tepoo L. Cancer in the offsonng of fathers in hvdrocarbon-related occupations 8r / Prev Joe Med 30:138-140. 1976 ... 48. Kline I. Stein Z. Stroomo B. et al. Surveillance of spontaneous abortions: Power in environmental monitoring- Amafcjpidemio/ .106 345-350.1977. V - 49. Strobmo BR. Kline I. and Stem Z. Chemical and physical ex posures of parents: Effects an human reproduction and offspring. Ear ly Hum Develop 1 371-399. 1978. .r'r.b--'- * \-L Joc"*a( cf OccuDationa! Medcine'VdI 2i . Mo, 9/Seotember 197.9 1 UCC 023925