Although more than 84,000 chemical compounds are in the workplace (2,000 new chemicals each year) (Endocrine Disruptor Screening and Testing Advisory Committee 1998), only about 4,000 have been evaluated for reproductive toxicity [U.S. Environmental Protection Agency (EPA) 1998]. Several NORA team members participated in the expert panel that prioritized chemical reproductive toxicants identified by the National Toxicology Program (NTP), using an objective and systematic method (Moorman et al. 2000). The method linked toxicity data with data on the population potentially at risk based on the estimated number of workers exposed and production data. Using this method, a priority matrix was developed that combined rankings for toxicity and number of workers at risk into categories of low, medium, and high. The panel found that the chemicals with the highest priority for human reproductive health studies were dibutyl phthalate, boric acid, tricresyl phosphate, and N,N-dimethylformamide. Chemicals with high/medium rankings included acrylamide, N-hydroxymethylacrylamide, 4-chloronitrobenzene, 2-butoxyethanol, oxalic acid, bisphenol A, and ethylene glycol.

Systematic prioritization of chemicals for study helps ensure efficient use of research funds. Many more chemicals remain to be studied, and the rankings should be periodically updated to incorporate new toxicity and usage data. Future priorities are likely to be affected by improved exposure information coming from biomonitoring data from the Centers for Disease Control and Prevention’s (CDC) National Health and Nutrition Examination Survey (NHANES).

Prioritized toxicants have been the focus of new studies initiated both inside and outside of NIOSH. Federal spending for occupational reproductive health research, in general, increased substantially and collaboratively during 1996–2003. For example, total NIOSH expenditures in the area of reproductive health increased from $750,000 in 1996 to > $4 million in 2004, for internal NIOSH research and for funding of research grants outside of NIOSH. As another example, an endocrine disruptor grants announcement was cosponsored by NIOSH, the National Institute of Environmental Health Sciences (NIEHS), the U.S. EPA, and the National Cancer Institute (NCI).

To promote the study of high-priority reproductive toxicants, the NORA team established a partnership with the Center for the Evaluation of Risks to Human Reproduction (CERHR). NTP and NIEHS established CERHR in 1998 to serve as an environmental health resource to the public and to regulatory and health agencies. Located in Research Triangle Park, North Carolina, the center’s staff and expert panel members represent multiple disciplines, including genetics, biology, toxicology, chemistry, industrial hygiene, biostatistics, epidemiology, and various medical specialties. The center provides scientifically based, uniform assessments of the potential for adverse effects on reproduction and development caused by agents to which humans may be exposed. This is accomplished through rigorous evaluations of the scientific literature by independent panels of scientists and through summarized reports in terms that can be understood by those who are not scientifically trained. Such evaluations encompass health effects including impaired fertility, adverse pregnancy outcomes, birth defects, and post-natal functional deficits. Nominations of chemicals to the CERHR are solicited from the public and the scientific community. Recent monographs on 1-bromopropane, 2-bromopropane, ethylene glycol, propylene glycol, and phthalates are available on the CERHR website (CERHR 2005b).

Internal NIOSH research is using field studies, exposure assessment, and laboratory biomonitoring to study several prioritized reproductive toxicants. One study is evaluating worker exposure to phthalate compounds, which are used as plasticizers and solvents in many industrial and consumer goods, such as flexible polyvinyl chloride, nail polish, fragrances, adhesives, and lacquers. In an NHANES report, phthalate levels were found to be elevated in the urine of women of reproductive age compared with levels for men (Silva et al. 2004). Several phthalates have demonstrated adverse reproductive effects, including male reproductive toxicity, in animals (CERHR 2000). There are virtually no published data available on the extent of phthalate exposures among working populations who use or are exposed to these chemicals, although thousands of workers may be exposed. Combining the field research expertise of NIOSH and laboratory expertise of the National Center for Environmental Health at the CDC, this project will measure levels of urinary metabolites of phthalates among workers in a variety of industries to identify populations for epidemiologic research.

Another NIOSH internal study is evaluating the extent of exposures to 1-bromopropane, a solvent and degreaser that is proposed to replace ozone-depleting solvents in metal and electronics industries. Potential dermal and inhalation exposure to 1-bromopropane can occur during metal degreasing, precision cleaning, and use of bromopropane-containing adhesives. 1-Bromopropane was nominated by NIOSH and selected for evaluation by CERHR based primarily on documented evidence of worker exposures and published evidence of male and female reproductive and developmental toxicity in rodents (CERHR 2004), although human reproductive studies were lacking. The exposure assessment consists of walk-through surveys, company record audits, industrial hygiene assessments (personal sampling as well as area monitoring), and measurements of exhaled breath (parent compound) and urinary metabolites. Another study is examining occupational exposure to acrylamide, used in the production of polymers and gels found in a wide variety of consumer products and as a cement binder. The NTP and CERHR have concluded that there is some concern for adverse reproductive and developmental effects from occupational exposure levels of acrylamide (CERHR 2005a). Workplace exposure monitoring, reproductive and neurologic health assessments, and biomonitoring will be conducted in the NIOSH study.

Boron is ubiquitous in nature and is used in a wide array of consumer goods. However, animal reproductive toxicity data and limited epidemiologic data indicate that boric acid and borax can cause reproductive toxicity in humans, and effects on sperm development have been observed in male animals (Moore et al. 1997). With funding from a NIOSH grant under NORA, investigators at the University of California at Los Angeles are collaborating with scientists in China to conduct a study of approximately 1,400 boron-exposed workers and unexposed workers in China. Laboratory measurements for this study integrated new sperm DNA integrity measures, conventional semen quality measures, hormones, blood-urine-semen boron, and boron levels in food, drinking water, and the workplace. Currently, analysis of data and biologic specimens is continuing.

Although 3% of babies in the United States are born with a major birth defect (CDC 1995), the cause of > 40% of birth defects remains unknown (Holmes 1997). Traditionally, few etiologic studies of birth defects have addressed parental occupational exposures, even though thousands of chemicals are being used in the workplace by men and women of reproductive age. To have a sufficient sample size to conduct research on specific types of birth defects, it is important to have collaboration among multiple research sites. The CDC has established the Centers for Birth Defects Research and Prevention in Arkansas, California, Iowa, Massachusetts, North Carolina, New Jersey, New York, Texas, and Utah. These centers, along with the Metropolitan Atlanta Congenital Defects Program, have participated in the National Birth Defects Prevention Study (NBDPS), the largest case–control study of birth defects ever undertaken. NIOSH scientists are collaborating with the CDC National Center on Birth Defects and Developmental Disabilities and NCI to conduct an occupational exposure assessment using parental occupational information collected as part of the NBDPS. Parental exposures to solvents, metals, and pesticides will be analyzed, and estimated exposure among cases and controls will be compared.

The changing nature of work and the work environment and the emerging technologies in reproductive biology and exposure assessment are leading us to rethink approaches to studying exposures and traditional reproductive health outcomes. It remains important to emphasize that the spectrum of reproductive health outcomes includes not only women of childbearing potential but also all working women, all working men, and all of their potential offspring. Clinical outcomes among workers should include sexual dysfunction, infertility, pregnancy loss, male:female sex ratios of pregnancies, aberrations of fetal growth, preterm births, clinical manifestations of endocrine disruptions (e.g., early menopause and andropause), and reproductive organ and endocrine-mediated neoplasms. Outcomes among offspring include congenital malformations, developmental challenges, infant and childhood neoplasms, and potentially adult reproductive health outcomes.

An example of an emerging end point for the assessment of adverse reproductive health in women is entry into the menopausal transition. In addition to providing a marker of ovarian senescence, the transition to menopause marks the beginning of a series of hormonal changes of biologic and clinical importance. Both early and late menopause are well established as associated with chronic health challenges (Gordon et al. 1978; Lindquist et al. 1979; Trichopoulos et al. 1972). A more recent study suggests that menopause is associated with a decline in grip and pinch strength (Kurina et al. 2004). From a research perspective, a standard definition of the start of the menopausal transition would allow important comparisons across occupational health studies; some efforts have been made in this area (Lisabeth et al. 2004). Age at menarche, although a more clearly defined end point, has been found to be associated with environmental exposures, including lead (Selevan et al. 2003).

Nonstandard work hours may be disturbed by many physiologic functions and systems that are circadian in nature (Akerstedt 1990). Circadian rhythms normally occur in the reproductive endocrine system (Frazier and Grainger 2003). Thus, hormonal disturbances, either as a direct effect of circadian rhythm disruption or indirectly through psychosocial stress and altered sleep patterns, are suggested as a possible mechanism. The effect of shift work, and circadian rhythm disruption, on reproductive outcomes is poorly understood, although advances have been made in the development of metrics for measuring disruption of circadian rhythm in working populations. One such metric is the variability of 2-sulfoxymelatonin, the urinary metabolite of melatonin, which has been found to be correlated with travel by female flight attendants through multiple time zones (Grajewski et al. 2003).

To better understand the impact of shift work and long work hours on reproductive health, important data may be leveraged from ongoing prospective studies. In 2001, with NORA funding, NIOSH investigators initiated a collaborative study with the Harvard University Nurses’ Health Study II (NHS II) research team. This study is collecting and analyzing data from 10,000 members of the NHS II cohort. Before this study, few occupational data had been collected from the NHS II cohort. A successful, ongoing collaboration was developed between NIOSH and Harvard that will likely engender consideration of the effects of other occupational exposures on reproductive health.

One of the most promising prospective studies that will add to our understanding of reproductive health is the National Children’s Study (NCS), a multiagency landmark study of 100,000 children from preconception to adulthood (National Children’s Study 2005). NIOSH NORA team members have partnered with NCS planners to provide guidance on how to include parental occupational histories as part of the baseline metrics of the cohort. This project will allow many hypotheses to be tested regarding parental exposures and their impact on congenital anomalies, developmental delays, sexual differentiation, puberty, and subsequent fertility.

An area that merits further exploration through NCS and other studies is the relationship between parental occupational exposures, fetal growth, and distant postnatal health. For example, according to the Barker hypothesis (Khan et al. 2003; Lau and Rogers 2004), low birth weight increases the risk of obesity, hypertension, and cardiovascular disease during adulthood. Because exposure to developmental toxicants is associated with low birth weight, research is being directed at testing the Barker hypothesis with regard to toxicant-induced low birth weight. Preliminary evidence indicates that low birth weight per se (i.e., that due to controlled underfeeding during pregnancy) is not associated with adverse reproductive capacity in the offspring (Rogers et al. 2003). Continuing research will determine whether toxicant-induced low birth weight has the potential to affect reproductive capacity and other health outcomes of offspring.

Rethinking occupational exposures merits consideration of the emerging field of engineered nanomaterials [uniformly sized materials < 100 nm (1 nanometer = 10⁻⁹ meter)]. Nanotechnology is being touted as a great opportunity for technologic advancement, but the potential toxicologic hazards associated with the increasing commercial applications of nanotechnology are still being characterized (Colvin 2003). The National Nanotechnology Initiative, officially established in fiscal year 2001 (National Research Council 2002), involves 17 federal agencies, including NIOSH. The private sector is also actively involved in nanotechnology research, and applications for computer components, cosmetic products, textiles, medical imaging, and drug delivery are already in commerce or under development (Perkel 2003, 2004). Nanoscale zinc oxide and titanium dioxide, for example, are both currently being incorporated into sunscreen lotions (Royal Society and Royal Academy of Engineering 2004), and as a result, both production workers and consumers (including pregnant women) are potentially exposed to these materials. Colvin (2004) suggested that by changing the surface properties, engineered nanoparticles can cross cell membranes and potentially circulate in the blood. Hence, it is theoretically possible that nanoparticles may cross the blood–brain barrier and the placenta. Because exposures to men and women and children may already be occurring, there is a clear need to investigate the potential reproductive health risk of engineered nanomaterials (Dreher 2004).

Another challenge in consideration of occupational reproductive health is assessment of multiple exposures. If workers are exposed to multiple compounds that act by the same mechanism, effects may be additive or synergistic, even though no single exposure occurs above occupational exposure limits (NIOSH 2005). This concern is supported by toxicologic studies showing additivity of adverse reproductive effects from solvent mixtures (Brown-Woodman et al. 1994), anti-androgenic fungicides (Nellemann et al. 2003), metals and chlorinated hydrocarbons (Roegge et al. 2004), and other mixtures. For this reason, it has been standard industrial hygiene practice to use a mixture formula to calculate a lower acceptable occupational exposure level when multiple exposures occur in the work-place [American Conference of Governmental Industrial Hygienists (ACGIH) Worldwide 2004]. More research is needed on mechanisms of toxicity to determine when this risk assessment procedure should be applied. Even more challenging may be consideration of the effects of physical hazards in concert with chemical hazards; for example, whole-body vibration can affect androgen levels just as chemical toxicants can (Cardinale and Pope 2003). Interpreting available information on additive and synergistic effects of exposures remains a challenge for employers, especially small businesses with limited access to industrial hygiene and toxicologic specialists. It is incumbent on occupational health researchers and policy makers to address these challenges to better protect all workers.

Developing and providing effective communication is a major challenge within the public health and occupational health communities. Workers in multiple industries need clear, quickly accessible information that can advise men and women on risks to their reproductive health. The NIOSH NORA RHRT has collaborated with the Hazardous Drug Working Group to update written instructions and label warnings for certain hazardous drugs. The RHRT is also interested in finding ways to improve the quality of material safety data sheets (MSDSs), with special interest in improving the quality of reproductive health information.

Reproductive risk communication research is needed for the development of effective ways to communicate with workers about occupational reproductive hazards. For men, the extent of risk minimization (the belief that men are not susceptible to reproductive hazards) needs to be determined. Among women, methods are needed to improve communication about the importance of exposure reduction in the preconception and periconception periods.

Effective hazard communication programs translate technically complex terms from reproductive health research into language that workers can easily understand (“plain language”). Despite extensive literature on the comprehensibility of educational materials for topics such as nutrition, smoking cessation, and cancer treatment, there is little published research on the comprehensibility of materials used for workplace hazard communication. In one study, 100 workers from manufacturing industries were asked to read several MSDSs written at the 12th grade reading level (Kolp 1993), and then their understanding of this information was tested. Of a possible score of 100 points, comprehension scores were in the range of 60–67, suggesting that a third of the MSDS health and safety information was incomprehensible to workers. One-fourth of the adult population in the United States has limited literacy skills (American Medical Association 1999), and it is recommended that health education materials should be written at the 5th to 8th grade reading level (National Work Group on Literacy and Health 1998). The American National Standards Institute (ANSI) devotes several pages of its revised standard on MSDS preparation to communication principles, providing good general guidelines on techniques to enhance comprehensibility of these important documents (ANSI 2004). The NORA RHRT conducted a session on MSDS communication at the 2005 Society of Toxicology Meeting to help improve reproductive hazard communication.

Also needed is consensus building on how best to classify reproductive hazard data for occupational health communication. This could assist occupational health and safety professionals to use best practices when writing MSDSs or designing occupational hazard communication programs. To account for different levels of evidence, the Globally Harmonized System of Classification and Labeling of Chemicals provides three classification categories for reproductive toxicants—known, presumed, or suspected reproductive or developmental hazards—and also a category to designate effects on, or via, lactation (Silk 2003; UN Economic Commission for Europe 2003). Detailed methods for interpreting toxicologic and epidemiologic research are provided, and concentration limits trigger classification of a mixture into each hazard category. For each of these categories, a hazard statement written in nontechnical language is provided. This initiative emphasizes the importance of testing communication materials for comprehensibility (Silk 2003). Development of risk-based classification information is preferable to a category approach but will take consensus efforts to implement. Future research needs to apply methods such as these to ascertain the perceptions of workers with varying levels of literacy and differences in cultural experiences and to determine their effectiveness in promoting safe work practices.