Document 2J0RqKR5LOqzVQ2eoLrMdeE8R

ZfUtU lt)M 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 exposures. An approach to surve/7/ance for chromosomal abnormalities in offspring of occupationally exposed parents is outlined. Derived from the Creek 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 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- fron fornlt University Med>cjl College r>d Memorial SlMn Kettering Cancer Center. Bos >. 1275 York Ave. New Vo*. NY 10021 Supported in pan by contract with the American Petroleum Institute position to nwopiasia. 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-generatioaal 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 aif 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 in the early stages may produce malformationwJuring 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."* Teratogenic, mutagenic and carcino genic activities are all demonstrable for a number of com- Journal ol Occupational Medicine/Vol. 21, No. 9/September 1979 607 * 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 feto-placentol 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 or ihe high rate of cell division, high proportion of undifferentiated cells and immaturity or immunosurveillanre mechanisms. To appreciate potential danger from an environmental exposure to offspring of the exposed organism, the outcome or all exposed pregnancies should be considered. Early fetal wastage commonly results from abnormal tetiil development At the other extreme transplacentali\ induced tumors hardly ever appear in rodent species until the animal reaches matuntv In the only docu mented example of chemical transplacental carcinogem-Ms in humans, vaginal adenoc arrmoma following di`sh\ i-tilhestrol (DES) exposure, the tumor occurs decades roilowmg exposure Thus, since tran-placemally-indueed tumor' unlike malformations, are rarelv present at birth, on*' niu't ako observe the offspring into adulthood to see the full spectrum of resulting tumor' Environmental Threats to Pregnancy Outcome Rue ogm^ed threats to pregnancy outcome are not un- c < >*nn,.!nl\ encountered in the environment and must be t-xi lud*-d when new problems are suspected Threats are posed bv biologic, chemical and physical agents, and mav derive from medical therapeutic interventions, drug ar*d 'uh'tance abuse, and env ironmental or occupational exposures to chemical agents Vcohoi -- The most widespread documented threats . to me tetus come not from the maternal physical environ- nient but from the use of tobacco and alcohol during aj. gnam v Only recently has the risk of alcohol ingestion v0 8 mpr.-nuncy been evaluated and the concept of the fetal * alccihol syndrome refined/ Of infants horn to recognized chrome alcoholic mothers, 83 3% had birth weights under * the tenth percentile, compared with 2 i% in a comparaA hie non alcoholic population * In addition to intrauterine *rowth retardation, the infants had retarded post-natal growth and intellectual development A characteristic tacies with short palpebral fissures, hypoplastic philtrum, thm vermilion line of the upper lip and retrognathia, has aUo 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 m the occurrence of congenital malformations iromrallv 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 y were further quantified by Ouellette et al.10 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 drinkers had twice the risk of having an ab normality at birth The frequency of congenital abnormal ities tn the offspring of heavy drinkers was extremely high --32% when minor abnormalities were included, 1796 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 thjt 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 habtts. should be addressed in ettorts to tie environmental exposures of the parents to the survival and integrity of the fetus Kline et al" suggest that the odds of spontaneous abortion among women who smoke are 1 & limes 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 ot 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 *ce95% 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 " Smokmg increases the-risk of spontaneous abortions bv a factor of 1 8, yet the percent age ot abortuses which are chromosomally abnormal is close to that expected. The absolute risk of a chromosomallv 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 m the first week of March, 1958, m 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 maternal 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 73 n n IJRL 19194 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 in 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 (DESX with the subsequent development of vaginal have not demonstrated measurable effects adenocarcinoma, is the prototype for transplacental on No substantial increase in leukemia risk has been de cogenesis in humans. Appreciation of 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 i0J1 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 therapeutic 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 tor estrogen analogue, was likely to have a direct effect on maternal age and pregnancy history, to he 1 73 times that the development of the target tissue at a crucial point tn of mo&hm attain not been x-rayed Oesptie 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 ot 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-ravs, the order of magnitude of the relative rok. factor?, 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 r tional 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 Exposure to medical radiation has been widespread B\ the early 1960 s. approximately 35% of a group of mothers of healthy children reported hjvmg received 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 agents in investi estimates the extent of x-ray exposures " The tendency to gations of other possible causes of impaired fetal devel substantially underreport x-ray exposure points up the dif opment." Given the current status of our understanding, it is essential that in the search for exogenous causes ot teratogenesis and abnormal pregnancy outcomes, the poten ficulty of excluding differences in prior radiation expo sure as a basis for observed differences in chromosomal aberrations Neithei is it reasonable to automatically pre 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 bv 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 Vinyl Chloride. --Chromosomal abnormalities may oc ride and benzene exposure, for example, are reminiscent cur more often than expected in persons exposed to vinyl of those produced by radiation. chloride, especially following intense exposures of long - While the genetic consequences of irradiation from the duration. The import of such abnormalities for reproduc atomic bombings might be expected to produce some tive outcome remains ill-defined. lethal mutations in the offspring of survivors, this effect Chromosomal aberrations were reported in 1975 in Journal of Occupational Medicine/Vol. 21, No. 9/September 1979 609 ~T t URL 1919 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 20-JO ppm bv 1974 The group exposed to vinyl chloride had aber rations m a total of 9 52% of all cells, compared tol 94% tor cells of three unexposed controls Differences m 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 \ m\ I chloride and the proportion of cells which were abnormal 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 or 11 men who had worked in a pol\ v inyl chloride polymerization plant and who were be lies ed to have experienced intense intermittent exposures to vinyl chloride in concentrations of over 500 ppm, as well js chronic, but unquantitated exposure for four to 28 sears (mean, 15 sear-.) Control samples were drawn from rour males in the 'air.c factors who were not known to have had vinsl chloride exposure, and from six maies from outside the factors 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 5b men who had had chronic exposure to vinyl chloride monomer m 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 celts, 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 m frequency of chromosomal aberrations between a group of 209 employees of a vinyl chloride plant (occupational exposures averaging 48 3 months) and a group or 295 individuals undergoing pre employment physicals u 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 m 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 chiwide (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 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 bv 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 fie . 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, maternal age. birth order, parity, smoking and alcohol exposure during pregnancy, mater nal infecttons. 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 so 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 r^ ported in 2 5% of all cells from exposed workers, com- 610 Risks to Offspring from Parental Occupational Exposures/Haas and Schottenfeld * 96161 W i pared to 1.0 to 1.4% for controls. Most of the excess was due to chromosomal aberrations of the unstable tvpes. 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 m 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 or 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.i( These studies and others** support the impression that exposure to benzene, particularly exposures intense enough to result in acute toxicity, can be followed bv 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 S.8% among control nurses. A similar excess of spon taneous abortion was observed for female physician anesthesiologists compared to female physicians in other specialties 40 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.*' 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 staff4< 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.** 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 male operating room personnel compared to controls 44 Questionnaires completed by 3119 married male physi cians in the United Kingdom suggested an increase in minor but not in major congenital anomalies, and no de ference in frequency of infertility, spontaneous abortion or cancer in the offspring of male anesthesiologists com pared to control physicians 45 Hydrocarbons. -- Two studies offer conflicting evi dence with respect to the risk of cancer in children ot men whose work might lead them to be exposed to petroleum-derived hydrocarbons fabia and TFruv*" re viewed death certificates in Quebec during 1965 to 1970 to identify children who had died from malignant <J*sea>e 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 or each case in the official files This effectively matched Tor season, calendar period, and province of Oirth Occupa tion of the father at the time of birth was taken from the birth certificate An industrial hygienist independent!*, grouped the fathers into three levels or probable evprjr-iaje to petroleum-derived hydrocarbons Occupation or the father was unknown for 10 cases and 56 control-* The dis tribution of occupation of the father at birth differed *or cases and controls Most of this difference was the re-ult of an excess among cases of paternal occupation-* con sidered to be hvdrocarbon-related The relative odds of cancer m the children of men holding h\drotarbon-reiated jobs at the time of the child's birth were 11 an in crease which was unlikely to have occurred bv chance Most of the excess in exposed occupations was account ed for by motor vehicle mechanics, machinists, miner*, and painters When similar analyses were conducted bv the type of cancer in the child, the excess of hvdrocarbonrelated occupations prevailed for the following group ings. leukemia-lymphoma, nervous system malignancy, other tumors. Fathers of four of rive cases of Letterer-Siwe disease were in the hydrocarbon-related work groups No such excess was present for children with V\ilms tumor The differences observed could not be attributed to de 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 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 Journalol Occupational Medicine/Vot. 21. No. 9/September 1979 611 * .HI JI*M I IJI' 'ft"*1 rW' URL 1919? the cancer death group and would bias the distribution of father's occupation. Moreover, it was not possible to confirm that fathers in the socalled "exposed" group did, m fact, have contact with hydrocarbon-derived chemicals While not ideal, the death certificate probably is a valid source of diagnostic information tor cancer deaths in vcung children. The cancer groupings employed in the analysis -- "leukemias and lymphomas," "nervous system' and "others' -- were quite broad and included many histopathologic entities Occupational association was not restricted to specific entities within the broader < ategories Because the epidemiologic feature' of the \anous histopathologic type- of leukemias, lymphomas, and nervous system tumors are distinctive, a specific c hemical exposure or class of exposures, if assumed to be ot causal significance, would more likely be linked with specific histopathologic as well as organ system effects \ study with a similar design hut different findings was conducted m Finland J' Children under 15 years ot age vsho developed cancer were identified from the Finnish Cancer Registry. I^Vt \ Ot 1409 cancer cases so iden* tied the final sene: < nn-.s*r**<l ot JJ52 pairs for whom b;rth records which m h u!ej-father's occupation w`-re available Each case w.i- ma*< hed with a child who-*' birth date immediately preceded that of the case and w ho w as 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 hirth registration records but from records of the fren nationwide antenatal care system in operation n Finland Father's occupation was classified bv likelihood of hydrocarbon exposure in a mariner which was shown to be comparable with that t-mploved 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 m the birth certificate itself Although a large 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 vears at the time of cancer diagnosis. 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 of the two studies are not readily reconciled. Surveillance of Spontaneous Abortions as a Strategy of Environmental Monitoring The relationship between mutagenic, teratogenic and carcinogenic effects in the offspring of persons exposed to noxious environmental agents is a complex one. Surveillance of spontaneous abortions may have a number of advantages as a prospective means of monitoring for such effects since defective conceptions are aborted selectively. As a result, studies of terato* genesis focusing on spontaneous abortions may be cor> siderably more efficient than those conducted in new borns Because the frequency of abnormalities is higher in spontaneous abortions, the sample size needed to demonstrate a change in risk is much smaller than that re quired for a parallel query addressed to defects recog nized at birth The magnitude of 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 4* 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 artd'-ar gestation, and the specific measures of pregnancy outcome.4* Pater nal exposures mav act in two ways -- bv contamination of the maternal environment resulting in secondary maternal exposures, or directly bv 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 tn 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 of the Oxford English Dictionary. Oxford: Oxford University Press. 1971. cites Dunglison Medical Lex icon. 1657 2 Wilson JC Environment and BrrthDefects New York. Academic Press. 1973 3 Staples RE: Definition of teraiogenesis and teratogen, in Methods for Detection ot Environmental Agents that Produce Congenital De fects. T H Shepard et al itds ) Proceedings of the Cuadaloupe Con ference Amsterdam North Holland Publishing Company. 1975. 4 Faumeni IF.- If Tlie susceptibility of the fetus and child to chemical pollutants Chemicals m human teraiogenesis and trans placental carcinogenesis Pedutncs 53607-612. 1974 612 Risks to Offspring from Parental Occupational Exposures/Haas and Schottenleld * k. . -5. Oi Paolo IA and Kotin P. Teratogenesis-oncogenesis A study of possible relationships Arch Pathol 81 3-23. 1966 6. Rice JM An overview of transplacental chemical carcinogenesis Teratology 8113-125. 1973 7. Clarren SK and Smith DW The fetal alcohol syndrome N Engl I Med 298 1063-1067 1978 fl. 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