Hosted by the Association of Reproductive Health Professionals
September 15, 2008
ARHP Offices, 1901 L Street, NW
Washington, DC

INTRODUCTION

The Association of Reproductive Health Professionals (ARHP) convened a meeting of scientific leaders in reproductive and environmental health at ARHP’s offices in Washington, DC, on September 15, 2008 (see Appendixes A and B for participants and the day’s agenda, respectively). The purpose of the meeting was to discuss ideas to promote education and awareness of environmental effects on reproductive health. The meeting was designed to foster open discussion and the free flow of ideas about how to integrate environmental health science into the field of reproductive health in general and to find specific ways to move toward that goal.

BACKGROUND

Reproductive health professionals are increasingly being called upon to address their patients’ concerns about the negative impact of environmental contaminants on fertility and reproduction. These concerns include the safety of plastics in toys and baby bottles, fish consumption during pregnancy, toxins in breast milk, and chemicals in personal care products, among others. Reproductive health professionals are in an ideal position not only to counsel patients about these concerns but also to influence policy reform and public education efforts related to the impact of environmental exposures on reproductive health.

Many of the data on environmental impacts on reproduction are derived from animal studies and differ from the epidemiological data that are generally used to make health care decisions. For this reason, providers and patients are uncertain how to address these new and challenging issues.

In convening the September meeting, ARHP sought to bring together reproductive health experts and environmental health scientists to share findings of new research implications for patient care and education, identify barriers, and reach mutual agreement about strategies for advancing policy reform with regard to the impact of environmental exposure on reproductive health. The purpose of the meeting was to introduce the connection between environmental and reproductive health to thought and opinion leaders in the reproductive health arena who are familiar with the strongest epidemiological data that guide reproductive health practice. Also among the meeting’s aims were to present the precautionary principle¹ and to discuss the scientific foundations of the evidence relating to environmental impacts on reproductive health.

PRESENTATIONS

Presenters at the meeting underscored the latest findings on how environmental exposures may affect reproductive health. The presentations were used as a starting point for discussions about how to raise providers’ awareness and how to more fully integrate environmental issues into the field of reproductive health. The following are highlights of those presentations and discussions.

Environmental Contaminants and Reproductive Health: Science and Prevention

Tracey J. Woodruff, PhD, MPH

• The pathways of exposure to environmental contaminants are through every type of medium: drinking water, food, air, products in the home and products that people use on their bodies, and occupational exposures. Unlike pharmaceuticals, environmental contaminants unintentionally affect large numbers of people indiscriminately. Therefore, decisions need to be made in a timely fashion.
• Manufactured chemicals do not have the regulatory requirements that are imposed on pharmaceuticals. Because it is not ethically possible to conduct intentional dosing studies to identify adverse health effects with environmental contaminants, the evidence base for their effects must be evaluated differently from how this is done for pharmaceuticals, and the evidence relies more on animal data. Medicinal drugs must be shown to be both efficacious and safe through animal testing and clinical trials. There are no such requirements for manufactured chemicals, and no specific requirements for toxicity testing except for pesticides.
• Several studies have examined the concordance between perturbed developmental outcome in experimental animal studies and the human clinical experience. A report from the National Academy of Sciences concluded that “in general, there is concordance of developmental effects between animals and humans and that humans are as sensitive or more sensitive than the most sensitive animal species”:
  • ...recent research has shown that there is a remarkable degree of similarity in the developmental mechanisms of all animals. Not only individual genes and proteins but also entire pathways of signaling and response and their functions in developing embryos appear highly conserved throughout evolution. This means that, although the embryology of simpler animals might appear superficially very different from that of humans, knowledge gained from those models can often be applied directly to understanding human developmental mechanisms.
    
    On the other hand, there are important developmental and physiological attributes that can be investigated only in vertebrates, such as the adaptive immune system, or in mammals, such as placentation and lactation. Therefore, it is useful to study a representative range of model animals—from invertebrates that are only distantly related to humans but have particular experimental advantages, to rodents and other mammals that are less convenient but more closely related to humans.²
• The weight of evidence for environmental contaminants can be evaluated with a systematic review approach with a robust and objective collection of information. It would be useful to develop some criteria by which studies could be evaluated. The process used to evaluate the weight of evidence in cancer research could be applied to studies of environmental contaminants, bringing in as much information as possible while still acknowledging the uncertainties.

Revolution in Toxicology

Pete Myers, PhD

• Traditional toxicological and epidemiological studies have been based on certain assumptions that have led to high rates of false-negative results, underestimating the effects of low doses of contaminants.
• For many environmental contaminants, low levels of exposure affect gene expression. Whereas it was once thought that only high doses are of concern, it is becoming increasingly apparent that adverse effects can occur at what used to be called “background” levels.
• The old paradigm in which diseases are under genetic control needs to be reversed. We now understand that genetic expression is vulnerable to environmental causes. In the old view, toxicity often works by overwhelming the body’s defense system. In the new view, some compounds are capable of “hijacking” gene expression. In the old paradigm, there is an immediate cause and effect of environmental contaminants. In the new model, environmental exposures are followed by long latent periods.
• High-level tests do not predict low-level impacts. Testing needs to be done at levels that are directly relevant to current human exposures. Health standards have been based on extrapolations of results from high-level testing to low-levels, but low doses are typically not tested.
• Predicted “safe” doses have not been tested. Regulations on toxicity have missed low-level impacts because of the following key assumptions used in risk assessment to establish acceptable daily intakes:
  – Assumption: Safe doses exist below a theoretical threshold.
  – Assumption: The dose-response curve is non-monotonic.
  – Assumption: High-dose testing predicts low-dose results.
  – These assumptions need to be challenged, and given population variability and background exposures, there is likely to be no “safe” level that applies in all circumstances. Therefore, dose-response analysis needs to take into account this mounting evidence.

• An example of low-dose effects is provided by the “tamoxifen flare” phenomenon. Working down the dose-response curve for tamoxifen, researchers discovered that there is a low zone in which the drug behaves as an estrogen in the system, leading to the growth of breast tumors. Such non-monotonic dose-response curves are being observed with increasing frequency.

Frederick vom Saal, PhD

• Bisphenol A (BPA) is an estrogenic compound that is an important component of polymers used to produce plastics. BPA is ubiquitous in the polycarbonates that are used in food and beverage can linings, microwave-safe food containers, dental sealants, and other products.
• More than 1 trillion pounds of plastics, all of which contain endocrine-disrupting chemicals (EDCs), are produced each year. The world’s oceans are becoming massive garbage dumps for plastics. An estimated one-quarter of polycarbonate compounds has never been used to make plastic but has been blown away from manufacturing sites.
• Polycarbonates are created by an ester bond that breaks under increasing temperatures. As they photodegrade under ultraviolet light, these compounds become particulate matter comprising a whole range of contaminants that are taken up through the food chain.
• Low-dose BPA stimulated a twofold increase in the proliferation of basal cells in mouse fetuses in an important study, leading to an increase in the number and size of dorsolateral prostate ducts and an overall increase in prostate duct volume. “It is now well known that hormones can have opposite effects at low vs. high doses. Studies that include only very high doses of drugs or chemicals can miss unique effects that are observed only within a physiologically relevant low dose range.”³
• Evidence is lacking for the safety of most environmental chemicals. Existing evidence is based on high-dose studies, which are unusable for determining the effects of low doses.

Howard M. Snyder III, MD

• In the last 50 years, there appears to have been a true rise in the incidence of hypospadias, undescended testis, and germ cell tumors of the testis. Additionally, there has been an overall decrease in male fertility even in males with completely normal descended testes. As all of these changes are related to the male endocrine system, it is plausible to think that endocrine-disrupting man-made chemicals may have a serious role in leading to these findings. Increasing experimental data support this hypothesis and point out the significance of addressing the effect of man-made chemicals on the male reproductive tract.
• The method by which environmental issues are communicated is critical , particularly for younger audiences, who are unlikely to read textbooks but are more effectively reached by small elements with large impacts. Medical information that predates Medline is unknown to many younger physicians.
• The issue of environmental effects on reproduction is no longer a debatable topic. Environmental exposures are affecting the health and welfare of the world’s population. Physicians, whose mission is to find constructive ways to improve the lot of humanity, must be called to action.

Linda Giudice, MD, PhD

• Fairly good data exist on the effects of occupational exposures to EDCs on infertility. Regional differences have been found, including in more industrialized parts of Europe and greater infertility rates in Superfund sites versus reference populations.
• Data show that EDC exposure leads to changes in the sex ratio of offspring to favor females. These changes have been confirmed among some Arctic villages, some of which have no boys. EDCs in the mothers’ blood have been correlated with the higher ratio of girls to boys born in these villages.
• Critical windows of susceptibility to EDCs exist during the preconception (gamete), periconception (blastocyst), prenatal (embryo and fetus), and postnatal (infant) periods, as well as childhood and adolescence.
• Endometriosis is an estrogen-dependent phenomenon that is linked to enhanced sensitivity to estradiol in the adult woman. Uterine fibroids are also linked to estrogen exposure. It is reasonable to consider the possibility that environmental exposures to EDCs may be contributing to an increase in incidence of endometriosis and uterine fibroids.
• Next steps must be toward education, policy, and research. Science is not always directly translatable into policy, but gaps in knowledge should not prevent advocacy for policy that will prevent exposure to chemicals for which there is strong evidence that exposure is harmful to the public’s health.
• Existing evidence is sufficient to justify policies to prevent harm. In fact, the UK, Japan, and Canada have all passed legislation restricting the manufacture and marketing of several endocrine-disrupting chemicals. Organizations that can come together to reach policy recommendations include the American College of Obstetricians and Gynecologists (ACOG), the American Society for Reproductive Medicine (ASRM), the Association of Reproductive Health Professionals (ARHP), the Endocrine Society, the Society for Gynecologic Investigation, and the Society for the Study of Reproduction.

OPEN DISCUSSION

After the presentations, the group engaged in extensive discussion about the studies that have been conducted on the relationship between environmental exposures and reproductive health, as well as how to evaluate the evidence from these studies. A high level of scientific exchange took place during this part of the group’s deliberations. The discussion then moved toward larger issues related to policy and education efforts.

• Epidemiological methods have thus far not made a large contribution to the clarity of discussions around environmental exposures and reproductive health. Better measures of physiological exposures will be needed before the field can move on to classical epidemiological studies. The debate regarding epidemiology has included attempts to use a composite analysis to evaluate biological data. Various groups have made some efforts toward building epidemiological models around biology, but these attempts have yet to come together in a meaningful way. Epidemiological studies do have a place, however, in that the discovery of strong associations prompts searches for the mechanism behind that association.
• Epidemiological studies are hindered by small sample sizes and low doses of exposure. New statistical techniques may help sort out these problems.
• The National Health and Nutrition Examination Survey (NHANES) may provide a promising database for this effort, though it would not yield developmental data. A group in Korea led by Lee, working with NHANES data, examined the relationship between type 2 diabetes and exposure to six organic pollutants.⁴
• A number of mechanistic and laboratory studies have shown these pollutants to be involved in endocrine regulation. Using a simplistic model giving the overall estimate of exposure to all six pollutants at once, Lee et al. found that the odds ratio was as high as 37. However, within the lowest quartile of subjects, who were exposed only to background levels, no relationship was found between obesity and type 2 diabetes. This study is an example of efforts to factor in mixtures in examining the health effects of environmental exposures.
• From prior experiences with DDT, we know that the right policy decisions can have huge society-wide effects. Policies can affect how clinicians talk to patients about specific environmental exposures and periconceptual planning and health, reproductive outcomes, and prenatal and postnatal development.
• Effective changes can be made in populations through public health campaigns. Examples of this fact can be seen in the effects of promoting reduction in caffeine intake among pregnant women.
• To affect policy, begin doing systematic instead of narrative reviews. Systematic reviews are clearly superior. They should be conducted through a dogged search through the literature and using a transparent search strategy to assess the quality of the information obtained. The information from these studies can be rated according to the strength of the evidence and the recommendations that could be made as a result.
• We need to find a way to view the scientific evidence so that we don’t jump to inaccurate conclusions but also don’t dismiss the volume of evidence about potential effects. We also need to convey information about what is and is not known to educate medical students, incorporate existing knowledge about EDCs into the medical curriculum, and educate patients without unnecessarily alarming them.
• The study of epigenetics needs to be incorporated into medical school curricula. Part of the paradigm shift that is needed is an understanding of how animal studies relate to human health. Also needed is a shift away from explaining rare outcomes to looking at common, low levels of exposure that are affecting a substantial portion of the population.
• Experiments on environmental exposures need to use the levels that humans are actually exposed to , rather than models, extrapolations, or estimates.
• The issue of environmental effects on reproduction is a public health issue that requires thinking and planning now. It is possible to make effective changes through public health campaigns, but we need to decide what the message should be.
• The Collaborative on Health and the Environment (CHE) Toxicant and Disease Database is looking at levels of evidence for certain conditions and environmental exposures. It focuses primarily on human studies, although there are some regulations based on animal studies. This database has been peer reviewed by the Centers for Disease Control and Prevention, the U.S. Environmental Protection Agency, and others. It includes information on reproductive health as well as neurobehavioral disorders and cancer. The database is available online at http://database.healthandenvironment.org.

NEXT STEPS

At the conclusion of the meeting, there was consensus that reproductive and environmental health clinical and scientific leadership should collaborate to advance knowledge on reproductive environmental health. As part of a grant received by ARHP to develop an umbrella program on environment and reproductive health, two slide set curricula will be developed. The slide presentations will be developed with input from an advisory committee to be co-chaired by Dr. Michael J. Thomas and Dr. Tracey J. Woodruff. These curricula will be presented to audiences at national and regional meetings of professional societies, via webinar, and will be integrated into ARHP’s Curriculum Organizer for Reproductive Health Education (CORE) tool, an open access slide library for building scientific presentations on the full spectrum of reproductive health topics.

Following are other projects decided upon by the group.

• Launch a Web resource center on ARHP’s Web site dedicated to reproductive and environmental health.
• Produce a joint editorial in Contraception, co-authored by several of this group’s members, and possibly a series of editorials written over time. Place similar jointly authored articles and editorials in additional journals (ASRM’s Fertility and Sterility, ACOG’s Obstetrics and Gynecology) to raise awareness of the reproductive health implications of exposure to EDCs and the need for sound public policy.
• Use information in the CHE database to serve as the basis for a print and Web-based toolkit for patients, with stickers and posters indicating what exposures should be avoided at what developmental milestones.
• Under the leadership of the University of California, San Francisco’s FASTEP (From Advancing Science to Ensuring Prevention) Program, work collaboratively to develop criteria and methodology to assess and disseminate the growing body of evidence in the reproductive environmental health field.
• Work collaboratively with ACOG to develop Clinical Practice Guidelines and a supplement in ACOG’s journal, Obstetrics and Gynecology, on reproductive environmental health.
• Establish a cadre of reproductive and environmental health spokespeople who are prepared to speak jointly about these exposures, their impact on the public’s health, and the wisdom of a public policy that promotes prevention of harmful exposures.

CONCLUSION

In convening this meeting, ARHP began the process of creating bridges between experts in environmental health research and clinical and biological scientists. A challenge in the endeavor to disseminate information about environmental exposures will be to base this information on rigorous science. Increased efforts will also be needed to network with experts who have different perspectives but who share the common overall goal of increasing awareness and improving public health.

FUNDER ACKNOWLEDGMENT

The Reproductive and Environmental Health Scientific Leadership Meeting was made possible by a grant from the Passport Foundation.

APPENDIX A: List of Participants

APPENDIX B: Agenda

References

1. The precautionary principle is a moral and political principle applied to scientific evidence and policy making. The principle states that, in the absence of scientific consensus on whether a chemical exposure might cause severe or irreversible harm to the public or the environment, the burden of proof that it will not do so rests with industry and government.
2. National Academy of Sciences. Scientific Frontiers in Developmental Toxicology and Risk Assessment. Washington, DC: NAS, 2000.
3. Timms BG, Howdeshell KL, Barton L, et al. Estrogenic chemicals in plastic and oral contraceptives disrupt development of the fetal mouse prostate and urethra. Proc Natl Acad Sci USA 2005;102(19):7014–19.
4. Lee DH, Lee IK, Song KE, et al. A strong dose-response relation between serum concentrations of persistent organic pollutants and diabetes: results from the National Health and Nutrition Examination Survey. Diabetes Care 2006;29:1638–44.