Reproductive Hazards of the Workplace LE. Sever, Ph.D. Concern regarding adverse effects of occupational ex- posures on the reproductive health of workers is increas- ing. Several sociopolitical and legal issues influence both the regulation of worker exposure and the ability to study exposure and possible reproductive effects. Adverse repro- ductive outcomes that may be related to occupational ex- posure are discussed and some of the possible mechan- isms of action are explored. Epidemiologic approaches to the study of reproductive hazards of the workplace are considered and illustrated in this paper. Increasing attention to occupational reproductive hazards is related to a nexus of technological, sociopolit- cal and legal factors, as well as toa better understanding of the vulnerability of the human conceptus to enviror- mental insult 2+ Three relevant. major trends which have occurred during the past two decades can be identi fied 1. Millions of women have shifted to employment out- side the home 2, There isan expectation of equal employment oppor tunity 3, There is increasing knowledge about environmental health hazards. Each end has generated many issues and problems that, in turn, have spawned new laws and regulations in- tended to resolve them, Simultaneously, technological advances have led to the development of thousands of new processes and products * ‘At one time, the number of toxic substances con- sidered to be especially hazardous during pregnancy was small, as was the number of women in the work force, and women who were pregnant or of reproductive age could be excluded from occupations with potential for exposure. These conditions no longer preval, the poten- tial for male reproductive risks as well is being more wide- Iy recognized." In addition to this problem is the fact that industrial materials can be brought home in clothing, re sulting in the potential exposure of pregnant women in the households of employees. From the Energy Systems Department, Pacfle Nethwest Laboratory, Richland, WA 99352 ‘resend atthe Nowhwest Association af Occupational Melee 1980 Oe- cupational Health and Medical Conference, October 22-24 1900, n Spokane, Washington ‘This work was supported by the US. Department of Energy under Contact DBE-ACOE-76RLO 1050, Journal of Occupational Medicine/Vol. 23, No. 10/October 1981 Guidelines developed by the Equal Employment Op- portunity Commission and the Department of Labor Of- fice of Federal Contract Compliance Programs stipulate that employers consider mutagenic effects in male workers as well as teratogenic effects in females in their employment and placement policies.* An employer may exclude women workers from jobs involving exposure to 2 hazardous substance, but the employer must also con- duct research on the effects of the substance on males. ‘The research studies must be initiated, with government help if necessary, within six months and must not extend past two years, The number of occupationally related Teproductive health studies is expected to increase dramatically if these guidelines become regulations. It is important to note that at present the Occupational Safety and Health Administration (OSHA) has not com- pleted an official policy on reproductive hazards of the workplace” OSHA is, however, attempting to address comprehensively the scientific issues and policy alter- natives. Almost certainly when this policy is developed it will be received with the same interest that met the development and publication of the OSHA policy on car cinogens. ‘Of major relevance in assessing relationships between ‘occupational exposures and reproductive outcome is the ability to clearly define both exposures and outcomes of interest. This is considered from a methodological perspective later in this paper, but here the author focuses briefly on some sociopolitical and legal aspects of this problem. Needs for information relating to worker health are in- creasing concomitantly with concerns regarding privacy. The complexity of the issues involved is immense. Two examples are the recently promulgated OSHA standard regarding access to employee exposure and medical records'® and the controversy in California regarding the collection of health data as part of the birth registration process "28 The fundamental reasons for the OSHA standard, as enumerated by the agency, are that employee exposure and medical records are critically important to the detec- tion, treatment and prevention of occupational disease, and workers and their representatives need direct access to this information as well as to analyses of these records Representatives of OSHA also need access to fulfill responsibilities under the Occupational Safety and Health Act.” 685‘The most significant issue posed by OSHA access to employee records concerns a potential clash with the “right of privacy” vis-a-vis employee medical records. ‘The Privacy Protection Study Commission" report ex: plicitly struck the balance in favor of unconsented access to medical records for health research purposes. The final standard provides for OSHA access to personally iden- tifiable medical records without requiring individual employee consent.” ‘The report from a Workshop on Methodology for As- sessing Reproductive Hazards in the Workplace" includ- ed the recommendation that “occupational histories of both parents should be recorded on all: (e) birth certifi cates; (b) stillbirth certificates; and (c) death certificates for children to the age of 16 years." Although the concept may be admirable, this recommendation has almost no chance of materializing. A major area of privacy concern today relates to the registration of births and the birth cer- tificate. The collection of health information as part of the birth registration process was recently severely chak lenged in California. An attempt was made to make the birth certificate an instrument to register only the occur rence of the birth and to eliminate or curtail the collec- tion of health information as part of the registration pro- cess." 12 Impetus came from several sources, but the major arguments concerned invasion of privacy by data collection and also the burden placed on health care pro- viders to obtain and record data as part of the certifi: cation process. f an attempt were made to collect paren- tal occupational histories routinely and record them on the birth certificate, there is little doubt that this would ‘meet strong opposition from those concerned about pri vacy as well as from health care providers who would be required to collect the data ‘A much more logical approach to studying potentially exposed pregnancies on a large scale is to record the oc- cupation and industry of both parents on the birth cer- tificate. This is done, for example, on the new California ‘and Washington birth certificates introduced January 1, 1980. Importantly, however, in California this item is specifically excluded from mandatory reporting, It will be necessary to ascertain how completely and accurately occupations are recorded to determine the usefulness of these data. Reproductive Outcomes and Exposure Effects Turning from sociopolitical and legal concerns to biological aspects of reproductive hazards of the workplace, there exists a wide variety of possible reproductive outcomes associated with parental ex- posures. These include reduction of fertility; genetic defects; a spectrum of reproductive wastage including spontaneous abortions, congenital malformations, stilk births and neonatal deaths; intrauterine growth retarda- tion; and conditions which develop later in life, such as developmental disabilities, behavioral disorders and malignancies. These are summarized in Table 1 and re ferred to in some of the excellent reviews regarding this The variety of possible outcomes should be kept in mind as it relates to the fact that an occupational ex: posure may have reproductive effects that are not 686 “Table 1. — Reproductive Outcomes Associated with Parental Exposure, tered fertity Intrauterine growth Single gone deects retréaton Chromosomal abnormalities Neonatal deaths Spontaneous abortions Infant cuaths {at etl deaths Congenital malformations ‘ler sex rao tered gestational ength Developmental aisabiities Boavoralcsorders Chronic ciseases Malignancies manifest as gross congenital malformations or even ap- parent at birth. In addition, there are several possible methods of action on reproductive outcome. Both of these points are particularly important in designing studies of reproductive outcome. Methods of action of an occupational exposure on pregnancy outcome can be classified into one or more of the five categories shown in Table 2, Each category can involve any of several biological mechanisms. Because these methods of action determine the kinds of outcomes that require further study, they will be considered briefly. ‘The most fundamental reproductive effect an occupa tional exposure can have is on the reproductive system and, in turn, on fertility. In the female, fertility influences can be manifest as menstrual irregularities or amenor thea, Additionally, female fertility could be adversely af- fected by damage to ova, changes in reproductive system physiology such as the cervical mucous layer, or damage to the fallopian tubes. Male fertility effects include a decline in libido, as well as decreased or absent sperm production. Male fertility might also be affected by damage to the sperm-collecting network. Morphologic abnormalities of sperm, effects on sperm motility and en- zymatic abnormalities of sperm need to be considered. The development of anti-sperm antibodies in either sex could cause decreased fertility, Influences on the produc tion, regulation and action of gonadotrophic hormones are possible in both sexes. Genetic effects of environmental exposures have been realized for many years. Effects may occur at a single gene locus, which are referred to as point mutations, or abnormalities in chromosome structure or number. Because of the rarity with which point mutations occur it would be extremely difficult, if not impossible, to relate their occurrence to occupational exposures. Chromo- somal abnormalities, on the other hand, have been sug: gested as a potentially sensitive population-monitoring system.” ‘Occupational exposures may directly affect the em- bryo or fetus as an embryotoxin, It is thought that damage during the first two weeks of human development results, either in death or in cell damage that is repaired with development subsequently proceeding normally, An em bryotoxic effect early in development could result in ‘Table 2. — Methods of Action on Reproductive Outcome, Reproductive system eltecis Genetic etlcts Embryonic ttects Teratgente eters Carcinogenic eects Reproductive Hazards of the Workplace/SeverTable 3. — Mechanisms of Teratogenesis. Inia types of changes in developing cel or tissues after tertogenic insult: ulation (gene) ‘Ohromesoral breaks, nondlsunetion, ae ‘uc interference ‘ered ele ald integrity or funtion Lack of normal precursos, substraes, et. Altered energy sources Changed memarane characteristics (smalar imbalance Enzyme inhibition ‘Adapted tom Wison®! unrecognized wastage. Similar effects later in pregnancy can result in spontaneous abortions. It has been sug- gested that monitoring the occurrence of spontaneous abortions may be one of the most sensitive methods for detecting the effects of environmental factors on reproduction.’ * Spontaneous abortions may result not, only from embryotoxic effects of environmental agents but also, among other reasons, from abnormal mor phogenesis. Abnormal morphogenesis may be due to genetic factors, both single gene and chromosomal, or to adverse effects of environmental factors on the develop- ing embryo, ic,, teratogenic effects. A teratogen is a substance, organism or physical agent which is capable of causing abnormal development. Traditionally the identification and definition of teratogenic agents were based on their ability to produce structural defects. More recently the concept of terato- genesis has been expanded to include those agents acting during embryonic or fetal development which lead to de- viation from normal morphology or function. Thus, in evaluating the potential teratogenic effects of an occupa: tional exposure, it is important to consider subtle effects such as growth retardation, developmental abnormalities and behavioral disorders, as well as structural defects. Currently one of the major areas of teratologic interest is behavioral teratology. It is questionable whether atten- tion has been paid to the possibility of prenatal exposures influencing subsequent development of chronic diseases such as diabetes. Closely related to teratogenic effects of exposures on reproductive outcome are carcinogenic effects of intra uterine exposures. There are important parallels between teratogenesis and carcinogenesis and the topic of trans placental carcinogenesis is one of considerable con- cern? "* Experience with DES and vaginal cancer presents a model for transplacental carcinogenesis similar to that regarding teratogenesis based on the thalidomide- phocomelia disaster in the 1960s. In attempting to identify-occupational exposures which may adversely affect reproductive outcome, one should consider possible relationships between teratogenesis, mutagenesis and carcinogenesis. Although it is certainly rot the case that all carcinogenic or mutagenic sub- stances are teratogenic, a number of substances have been shown on the basis of laboratory tests to be all three Hemminki and associates’ have illustrated how various manifestations, classified as teratogenic, muta genic or carcinogenic, could result from the effects of a substance on DNA Journal of Occupational Medicine/Vol. 23, No. 10/October 1981 Clearly, not all teratogenic substances act through an effect on DNA, and this is certainly not the only way an. ocucpational exposure can affect reproductive outcome. Wilson’ has summarized some of the potential mecha nisms of teratogenesis. These are shown in Table 3. Epidemiologic Approaches Reproductive Hazards Epidemiology provides the most useful approaches for studying relationships between exposures and outcomes, in human populations but limitations of epidemiologic methodology must be considered. One problem is that data are often collected without consideration of their ultimate use. For example, occupation has traditionally been used as an indicator of socioeconomic status in epidemiologic studies. This is particularly the case in perinatal studies where low socioeconomic status (SES), measured in a number of ways, has clearly been shown to, be a risk factor for low birth weight and fetal and infant, deaths, The fact that occupation has routinely been used, as an indicator of SES can be illustrated by changes in the US. standard birth certificate and the Washington State birth certificate. Prior to 1968 father's occupation was recorded on the certificate. In 1968 information on the father's occupation was deleted and replaced by the highest grade completed by both parents. In Washington, State this was dropped in 1970 and no information on, either education nor occupation routinely was collected until January 1, 1980, when information on each parent's ‘occupation began to be collected. The US. standard cer- tificate continues to recommend the collection of paren- tal education with no provision currently for information ‘on occupation For identifying potential occupational reproductive hazards, data recorded on the birth certificate are seldom specific enough to identify particular exposures However, occupational information collected in. past epidemiological studies, as well as data currently being collected, need to be evaluated for associations between, ‘occupational groups and adverse outcomes. Some studies of neural tube defects» and oral clefts,” ™ showing statistically significant associations with parental ‘occupations, indicate the need for increased research. “This brief consideration of obtaining occupational in- formation from the birth certificate introduces the prob- lem of determining cause-and-effect relationships in epi- demiologic studies. There are at least three fundamental problems which relate to obtaining information on expo sure, and also to the identifying of and controlling for confounding factors, which can be used to support causal hypotheses. The first of these problems is that occupational popula- tions often have combined exposures. It is seldom the case that a worker is exposed to only a single potentially hazardous substance, Many radiation workers, for exam- ple, have had chemical exposures in addition to their ex: posure to ionizing radiation. Combined chemical ex- posures are common in some industries. ‘The second problem is that itis often difficult to deter mine and quantify exposures. Of particular interest to the National Institute for Occupational Safety and Health, (NIOSH), for example, are studies where dose-effect rela- 687 to the Evalu ofRETROSPECTIVE (CASE-CONTROL) STUDIES - DISEASE PRESENT | ABSENT (cases) | (CONTROLS) EXPOSED NOT EXPOSED PROSPECTIVE (COHORT STUDIES - EXPOSURE Fig 1. — Epldominogc study designs to examine th essocation betwoen expasure and ls tionships are identified or determined.” Even when ex: posure levels can be determined through industrial hygiene monitoring, it is often impossible to determine the dose received by an individual worker. This problem becomes even greater when attempts are made to deter- mine exposures historically. Longo' has suggested that Tong-term exposure to low concentrations of various compounds probably poses the greatest threat to the pregnant mother and her fetus. tis exactly this kind of ex: posure that is most difficult to quantify in epidemiologic studies. The final point that needs to be stressed regarding ex: posure is the necessity to control for nonoccupational ex: posures. Both smoking” and alcohol consumption"* have been clearly shown to influence pregnancy outcome. If ‘occupational groups differ from referent groups in terms of smoking or drinking habits, this can lead to spurious results regarding association of an exposure with an adverse outcome, There are also problems associated with identification and definitions of outcomes in epidemiologic studies, By careful study design these problems are potentially more easily resolved than are those of exposure. Sources of case ascertainment and the definition of what constitutes, a case must be clearly established in protocol develop- ment. Verification of outcomes is a major consideration, and must be incorporated into the plan. Of fundamental importance is the selection of a con- trol or referent population, For reproductive outcome in an exposed population to be interpreted meaningfully, it must be compared to information derived from a similar, but nonexposed, population. In many epidemiologic, studies it is more difficult to identify appropriate control groups than exposed or case populations. It is paramount that if an occupational exposure causes some abnormal reproductive outcome; then ex: posure must have preceded the outcome in time. The temporal relationship between an exposure and an out come must be clearly established for a study to have any, scientific relevance. From a study design point of view, however, it is not always feasible to approach a problem by looking first at an exposed population and waiting to see if the outcome of interest occurs with increased fre- quency, As Fig1 illustrates, there are two major ways of examin- ing a relationship between exposure and outcome in epi- demiologic studies. One way is in observing groups of in- 688 dividuals who differ in exposure and determining if they differ in the occurrence of the outcome of interest, This, can be seen in Fig 1 by reading horizontally and is most commonly referred to as a prospective or cohort study. The other approach is to select groups which differ in the presence of the outcome variable of interest, cases and controls, and determine if they differ in terms of ex. posure, This is shown in Fig 1 by reading vertically and is, Teferred to as a retrospective or case-control approach Statistical analysis is required in both instances to deter- mine if an association between exposure and outcome differs from what would be expected by chance. ‘There are many important considerations that enter in- to making decisions regarding the appropriate study design for use in a specific instance, Of particular impor- tance are the expected frequencies of both the exposures and the outcomes of concern, Some basic texts in epide- miology discuss the relative merits of alternate study designs” How these basic study designs could be used in studies of reproductive outcome by considering a hypothetical set of studies of a worker population exposed to some factor of interest is illustrated further in this paper. Such studies could be carried out on occupational populations for which employment rosters and exposure data were available. A case-control study is discussed, since concep- tually it is the simplest design. The case-control study begins with the selection of a group of cases, consisting of ‘outcomes of interest, and a group of controls. The cases in this example consist of babies with congenital anomalies and fetal and infant deaths where at least one parent was a plant worker. For each an appropriate con- trol birth or births would be obtained. The purpose of the study would be to determine if the parents of the babies, constituting the case group have greater cumulative or gestational exposure to the factor of concern than do the parents of the babies constituting the control group. The study is initiated with groups which differ in terms of out- comes and ascertains whether they differ in terms of ex- posure to the factor of interest. Two of many possible cohort studies might also be significant. In both, groups which differ in terms of their exposure are taken and it is determined if they have similar reproductive outcomes, The easiest type of cohort study to visualize is one in which groups of interest are identified today and followed through time. Studies of this type require long-term commitment of resources — both personnel and funds. Given these constraints, one ‘can modify this design and conduct a nonconcurrent or a historical prospective study. With this approach it is necessary to trace identified groups of interest which dif fer in exposure, and follow them to the present. One must be able to identify the population of interest, ascertain their exposures and trace them to determine the distribu tion of the outcomes of interest. This study would be designed to examine specific pregnancy outcomes in workers who differ in terms of exposure. The first of these proposed studies would be that of the reproductive performance of a cohort that entered the employee population during a defined time period. Female employees and wives of male employees with varying levels of exposure would be identified, traced, and asked to complete a detailed reproductive history Reproductive Hazards of the Workplace/Severand exposure questionnaire. Information on occupational exposures would be obtained from employee records. ‘Among the specific aims of this study design would be to determine: (1) f rates of spontaneous abortion differ for women exposed or wives of men exposed to varying levels of the factor; (2) if there are reported differences in, “fertility” for women exposed or wives of men exposed to varying levels of the factor; (3) the exposure-associated risk of cancer or birth defects diagnosed at any time in offspring of exposed workers; and (4) the effect of ex posure on other pregnancy outcomes such as perinatal mortality or prematurity Through the questionnaire approach one can identify spontaneous abortions and disturbances in fertility which could not be ascertained using other study designs. Its also possible to determine exposures to other potentially hazardous substances and to alcohol and cigarettes. ‘A second type of cohort study would involve looking at the population of births occurring within the defined population during a specified period of time. Births would be identified from vital and hospital records and grouped according to the degree of parental exposure. Compari- sons would then be made between exposure groups for variables such as sex ratio, birth weight, gestational age, ‘Apgar scores and congenital malformation rates. This study would provide a defined population of births upon which incidence rates could be based. Appropriate statis- tical analysis would be used to compare exposure groups, and determine if there were significant differences be- tween groups in these outcome variables. ‘As a substudy of a birth cohort study, a particular group of these births could be identified and followed in- to childhood. A questionnaire would be administered to the mothers, focusing on various aspects of the children’s development in an attempt to identify birth defects, de- velopmental disabilities, behavioral abnormalities, growth disturbances and childhood neoplasms, Question- naire data would need to be augmented and verified by the use of medical records Conclusion Some of the issues related to the design and conduct of studies of reproductive hazards in the workplace have been examined. Some of the sociopolitical and legal issues involved, reproductive outcomes of concern and mechanisms relating to them, and some fundamentals of the epidemiologic approach to the problem have been considered. 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