Looking for causes of neural tube defects: where does the environment fit in?

The neural tube defects anencephaly and spina bifida are important causes of infant mortality and morbidity. Recent studies suggest that many of these defects can be prevented by the periconceptional use of folic acid. At the same time, we do not know what causes most cases of neural tube defects and there is evidence to suggest that they are etiologically heterogeneous. Additional research needs to be directed toward the role of occupational and environmental exposures in the etiology of these defects. Importantly, studies need to examine embryologically and anatomically specific types of defects and develop accurate information on biologically relevant exposures. Exposures toward which attention needs to be directed include organic solvents; agricultural chemicals, including pesticides; water nitrates; heavy metals such as mercury; ionizing radiation; and water disinfection by products. We also recommend that additional attention be paid to mechanisms of neural tube closure and to the potential role of genetic heterogeneity in the absorption and metabolism of xenobiotics and in their effects on the neural tube.

Consumption of PCB-contaminated sport fish and risk of spontaneous fetal death.

Spontaneous fetal death has been observed among various mammalian species after exposure to polychlorinated biphenyls (PCBs). Our exposure-based cohort study assessed the relationship between consumption of PCB-contaminated Lake Ontario sport fish and spontaneous fetal death using 1820 multigravid fertile women from the 1990-1991 New York State Angler Cohort Study. Fish consumption data were obtained from food frequency questionnaires and history of spontaneous fetal death from live birth certificates. Analyses were stratified by number of prior pregnancies and controlled for smoking and maternal age. No significant increases in risk for fetal death were observed across four measures of exposure: a lifetime estimate of PCB exposure based on species-specific PCB levels; the number of years of fish consumption; kilograms of sport fish consumed in 1990-1991; and a lifetime estimate of kilograms eaten. A slight risk reduction was seen for women with two prior pregnancies at the highest level of PCB exposure (odds ratio = 0.36; 95% CI, 0.14-0.92) and for women with three or more prior pregnancies with increasing years of fish consumption (odds ratio = 0.97; 95% CI, 0.94-0.99). These findings suggest that consumption of PCB-contaminated sport fish does not increase the risk of spontaneous fetal death.

Acute myelocytic leukemia and prior allergies.

The relationship between prior allergies and adult acute myelocytic leukemia was investigated in a population-based case-control study. Based on data from personal interviews of 98 cases and 133 controls, a history of any type of allergy was associated with a significantly decreased risk of acute myelocytic leukemia (OR = 0.35, 95% CI = 0.20-0.60). Risk declined with the total number of specific allergies reported (p less than 0.001), and was reduced in relation to a history of prior asthma, eczema and hives. The implications of these findings in relation to natural immune surveillance against developing neoplasms are discussed.

Timing of prenatal care and risk of sudden infant death syndrome.

Sudden infant death syndrome (SIDS) is the leading cause of death during post-neonatal life. Mothers whose infants succumb to SIDS are reported to initiate prenatal care later than control mothers. Previous studies have not always controlled for socioeconomic status (SES) of mothers or other potential confounders such as gestational age or birthweight of infants. The purpose of this study was to assess whether timing of prenatal care adjusted for these potential confounders was an independent risk factor for SIDS. SIDS cases (N = 148) were identified from the Upstate New York livebirth cohort for 1974 (N = 132,948) and compared to randomly selected controls (N = 355) who were frequency-matched on maternal age, race, parity and residence and infant's birth date. Data were abstracted from matched vital certificates (97% response), hospital delivery records (89% response) and selected sample of autopsy reports (100% response). Odds ratios (OR) and 95% confidence intervals (CI) were obtained using unconditional logistic regression. A significant inverse relationship was observed for number of prenatal visits and risk of SIDS; a significant direct relationship was observed between trimester prenatal care initiated and risk of SIDS. The results suggest that timing of prenatal care is important in assessing SIDS risk even after adjusting for potential confounders of early prenatal care utilization.

Assessment of reproductive disorders and birth defects in communities near hazardous chemical sites. I. Birth defects and developmental disorders.

Members of the workgroup on birth defects and developmental disorders discussed methods to assess structural anomalies, genetic changes and mutations, fetal and infant mortality, functional deficits, and impaired fetal and neonatal growth. Tier 1 assessments for all five adverse reproductive outcomes consist of questionnaires and reviews of medical records rather than laboratory testing of biologic specimens. The work-group members noted a role for neurodevelopmental testing and for limited genetic studies, such as karyotyping in Tier 2 assessments. Emerging methodologies to identify chromosomal aberrations, DNA adducts, and repair inhibition were reserved for Tier 3.

Strategies for follow-up and treatment services in state breast and cervical cancer screening programs.

This report describes strategies used to provide diagnostic follow-up and treatment services to low-income women screened through the National Breast and Cervical Cancer Early Detection Program.

Infecundity and consumption of polychlorinated biphenyl-contaminated fish.

Biologic capacity for reproduction, or fecundity, may be threatened by environmental contaminants, especially compounds capable of disrupting endocrine pathways. Telephone interviews that focused on reproductive events were conducted with female members of the New York State Angler Cohort Study who became pregnant between 1991 and 1993 and who reported known time to pregnancy (N = 895; 73%). Consumption of polychlorinated biphenyl-contaminated Lake Ontario sportfish and other factors were ascertained in 1991. The authors classified the women as follows: (a) fecund (time to pregnancy < or =12 cycles; n = 723); (b) having resolved infecundity (time to pregnancy > 12 cycles; n = 81); or (c) having unresolved infecundity (time to pregnancy > 12 cycles without pregnancy; n = 94). Adjusted odds ratios for duration of fish consumption for both resolved and unresolved infecundity were elevated (1.46 and 1.19, respectively), although confidence intervals included unity. Frequency of recent fish consumption was associated with an increased risk for select categories, although confidence intervals included one.

Screening workers for genetic hypersusceptibility: potential ethical, legal, and social implications from the Human Genome Project.

One of the potential outcomes of the Human Genome Project will be the ability to identify individuals who are at increased risk of adverse health effects following exposure to hazardous substances in the workplace because of genetic hypersusceptibility. The ability to identify such individuals is likely to lead to the inclusion of genetic screening in worker protection programs. This technology and its applications will have a number of potential ethical, legal, and social implications. In this commentary, the authors examine five broad topics relating to the use of screening for genetic hypersusceptibility in the workplace: (1) issues of risk; (2) the rationale and legal basis for screening; (3) the privacy concerns of workers; (4) the confidentiality of test results; and (5) potential discrimination. The authors close by suggesting some guidelines for developing policies regarding genetic screening.

Ethics, society and occupational reproductive hazards: fetal consequences?

Occupational exposures to agents such as lead can adversely affect fetal outcome. With the US Supreme Court decision in the Johnson Controls case regarding the legality of employer's fetal protection policies, increasing responsibility lies with women to make decisions regarding exposure to potentially hazardous agents in the workplace. What are some of the ethical issues that society needs to address with respect to this responsibility? This paper considers the ethical principles of respect for autonomy, nonmaleficence, beneficence, justice, and self interest from the perspectives of the potential mother and those concerned with protecting the fetus. Since the fetus cannot make decisions, the potential role of society in protecting fetal rights in the context of workplace exposures is explored.

Congenital malformations related to occupational reproductive hazards.

Occupational and environmental agents are the suspected cause of at least some of the approximately 60% of birth defects whose etiology is unknown. The author discusses studies of birth defects published since 1988. Studies that examine associations between congenital malformations and both maternal and paternal exposures are included.

Parental radiation exposure and children's health: are there effects on the second generation?

This paper describes the mechanisms through which parental occupational radiation exposure could affect children's health. It then goes on to review briefly some of the early work on this issue, studies based not on occupational exposures but on the Japanese atomic bomb survivors and on intrauterine x-ray exposure. Most of the discussion focuses on recent studies that have examined risks of childhood cancers and congenital malformations in the offspring of exposed workers, particularly some of the controversy engendered by recent cancer studies.

Epidemiologic approaches to the study of diseases of complex etiology.

In this preparation I have discussed some of the concepts and methods of epidemiologic studies of diseases of complex etiology. I have pointed out some of the relationships between epidemiology and genetics and examined briefly the relatively new field of genetic epidemiology. Epidemiology is a comparative science and is based on asking questions about the who, where, and when of disease occurrence in an attempt to understand "why." As a comparative science, it is necessary to have measures that can be meaningfully compared between places and times. In epidemiology, the measures we use are rates, and we have examined some of the commonly used types and kinds of rates and the information that is necessary for their generation. To a large degree, epidemiology is concerned with determining if there is an association between a characteristic or exposure and a disease. Epidemiologic reasoning involves an iterative process of hypothesis generation and testing. I described some of the study designs that are used in attempting to identify etiologic factors in diseases of complex etiology. I noted that we usually begin with descriptive studies and then move on to analytic studies where associations between exposure and disease are examined. In discussing study designs, I pointed out that studies can be based on examination of associations at either the group or individual level. I discussed the basic aspects of four epidemiologic study designs: ecologic studies, cross-sectional studies, case-control studies, and cohort studies. Illustrative examples of the study designs were presented from the literature. In addition, some of the basic statistical approaches were noted that are used to determine if the association between exposure and outcome is greater than that expected to occur by chance alone. Some of the strengths and weaknesses of various study designs were commented on briefly.

An epidemiologic study of neural tube defects in Los Angeles County II. Etiologic factors in an area with low prevalence at birth.

Epidemiologic characteristics of neural tube defect (NTD) births occurring in Los Angeles County, California, residents during the period 1966-1972 are presented. The prevalence at birth was 0.52/1000 births for anencephalus, 0.51/1000 for spina bifida, and 0.08/1000 for encephalocele, rates considered to be low for a predominantly white population. We hypothesized that environmental (nongenetic) factors are of less etiologic importance in a low-prevalence population than in areas or time periods with high prevalence. We tested that hypothesis by examining epidemiologic characteristics of NTDs in Los Angeles County and comparing them with high-prevalence populations. The data did not support a major etiologic role for environmental factors: (1) no significant differences between rates by month of birth or conception; (2) no significant association with maternal age or parity for anencephalus; for spina bifida a significant maternal age effect (P less than 0.01) and for encephalocele a parity effect (P less than 0.02); and (3) no significant relationship with father's occupational class for either anencephalus or encephalocele but a marginally significant (P less than 0.05) inverse association for spina bifida when a statistic based on ordinal relationships was used. Findings supporting the importance of genetic factors in etiology included: (1) a high percentage of males; (2) a higher twin concordance rate than in high-prevalence populations; and (3) an anencephalus rate among blacks comparable with rates for blacks in other United States populations. Our findings in conjunction with those from other areas and times of low prevalence suggest environmental factors play a relatively insignificant role in the etiology of NTDs in such populations.

Reproductive hazards of the workplace.

Concern regarding adverse effects of occupational exposures on the reproductive health of workers is increasing. Several sociopolitical and legal issues influence both the regulation of worker exposure and the ability to study exposure and possible reproductive effects. Adverse reproductive outcomes that may be related to occupational exposure are discussed and some of the possible mechanisms of action are explored. Epidemiologic approaches to the study of reproductive hazards of the workplace are considered and illustrated in this paper.

Childhood cancers associated with parental occupational exposures.

Statistics suggest that environmental and occupational exposures may be at least partially responsible for an increased incidence of cancer in children. The authors describe the latest findings in this area of research and look at the methodologic concerns that arise and how they affect the derivation of causal inferences from such studies.

Overall design considerations in male and female occupational reproductive studies.

Epidemiologic studies are extremely useful for examining the possible relationships between occupational exposures and reproductive outcomes in occupational populations. In this paper, we examine some of the major epidemiologic design considerations in male and female occupational reproductive studies. An important consideration in all epidemiologic studies is to choose appropriate outcome variables. One of the unique characteristics of reproductive studies is the wide range of potential outcome variables: from problems of infertility, through fetal development, and into childhood diseases and diseases of young adulthood. Usually, it is infeasible to look at all possible outcomes. By omitting certain outcomes, however, important associations between exposure and outcome may remain undetected. Epidemiology relies on observations of populations. Factors in data availability, collection, and analysis, and in study design often limit the inferences that may be drawn. The "exposed" or "at risk" groups are not likely to be randomly selected and the investigator has little control over the exposures of the study population. Unlike experimental investigations, epidemiologic observations are made on individuals exposed to a variety of hazards during their lives. The size of the population available for study is critical. Bias from potential confounding factors can be minimized through the use of appropriate matching and/or statistical techniques. Many of the topics discussed here will be expanded in subsequent chapters. Although this paper is designed to assist in planning occupational epidemiologic studies, we strongly recommend that, when attempting to conduct such studies, professional guidance from epidemiologists and biostatisticians be obtained.