Key concepts to consider and practical advice for choosing the safest possible drug treatments.
Bella Haruty, MPH, REHS
Los Angeles County Department of Public Health, Environmental Health Division South Los Angeles District, Los Angeles, CA
Julie Friedman, MPH, CHES
Director, Iris Cantor-UCLA Women’s Health Education and Research Center, Los Angeles, CA
Stephanie Hopp, MHS, MS
Massachusetts General Hospital, Department of Anesthesia, Critical Care and Pain Medicine
Ryane Daniels, MPHC
Tulane University, New Orleans, LA
Janet Pregler, MD
Director, Iris Cantor-UCLA Women’s Health Center, Los Angeles, CA
Address: Julie Friedman, MPH, Director, Iris Cantor UCLA Women’s Health Education and Research Center, 911 Broxton Avenue, Los Angeles, CA 90024; firstname.lastname@example.org
ABSTRACTEndocrine-disrupting chemicals (EDCs) are associated with reproductive complications such as infertility, pregnancy complications, poor birth outcomes, and child developmental abnormalities, although not all chemicals of concern are EDCs. Pregnant patients and women of childbearing age need reasonable advice about environmental contaminants and reproductive health.
A 28-year-old woman presents for routine follow-up of asthma. She has a 1-year-old son and is considering a second pregnancy. She says she read on the Internet that the US Food and Drug Administration recently banned baby bottles and “sippy” cups that contain bisphenol A (BPA), as recommended by the American Medical Association. She wonders if there are other sources of BPA and if they pose a health risk to her, her son, and possible future children.
Environmental toxins have been linked to pregnancy complications and poor birth outcomes. The past several decades have seen a significant rise in reproductive disorders such as early onset of puberty, low sperm count, and birth defects such as cryptorchidism and hypospadias.1–4 These changes may be partly explained by other trends over time, such as older maternal age, rising incidence of obesity and maternal diabetes, and demographic changes that exacerbate health disparities. However, these well-recognized factors explain only some of the wide range of reproductive health problems that have been identified.
This review focuses on emerging evidence of the adverse reproductive effects of human-produced endocrine-disrupting chemicals (EDCs).
ENDOCRINE-DISRUPTING CHEMICALS ARE UBIQUITOUS
EDCs are exogenous substances that alter normal functioning of the endocrine system and consequently have the potential to cause adverse health effects in an intact organism and its progeny.2,3,5 Substances classified as EDCs are divided into two groups:
Many human-produced EDCs are lipid-soluble. Some bioconcentrate in fat. The dietary route of exposure is the most common, primarily from fat-containing foods such as meats and seafood. Common predatory fish such as tuna and swordfish, as well as other large fish, are more likely to have high levels of EDCs accumulated from contaminated water.7 Water, air, soil, and dust in communities, schools, and workplaces may also carry EDCs.8
Some human-produced EDCs have a very long half-life and can remain in the environment for years or even decades. Because of their long half-life, some EDCs can “travel” and become part of the food chain, even in “pristine” areas where manufactured substances are not normally found.2
Nearly all pregnant women in the United States have detectable seum levels of EDCs, including BPA
Women of childbearing age and pregnant women come in contact with EDCs on a daily basis. According to the Fourth National Report on Human Exposure to Environmental Chemicals, conducted by the US Centers for Disease Control and Prevention (CDC) in 2009, nearly all pregnant women in the United States have detectable serum levels of EDCs, including BPA, perchlorates, phthalates, polybrominated diphenyl ethers, and pesticides.9 Furthermore, BPA was found in more than 90% of the urine samples tested from random subsamples of 2,500 participants in the 2009 National Health and Nutrition Examination Survey report.10
EDCs AFFECT MULTIPLE PATHWAYS
Laboratory and animal research suggests that both manufactured and naturally occurring EDCs primarily affect sex steroid hormone pathways. However, some EDCs can affect adrenal, thyroid, and other endocrine pathways.
EDCs can potentially alter normal endocrine functioning by several mechanisms. They can bind to nuclear hormone receptors such as estrogen receptors, androgen receptors, progesterone receptors, thyroid hormone receptors, and peroxisome proliferator-activated receptor gamma. They can also bind to nonnuclear steroid hormone receptors (membrane estrogen receptors), nonsteroid receptors such as those for dopamine, serotonin, and norepinephrine, and orphan receptors such as aryl hydrocarbon receptor. In addition, some affect enzymatic pathways involved in steroid biosynthesis and metabolism and disrupt centralized endocrine pathways through positive and negative feedback.2 There is also evidence that EDCs have epigenetic and transgenerational effects, as they seem to be able to influence DNA methylation and histone acetylation.11
EVIDENCE OF HARM, LIMITATIONS OF EVIDENCE
In 2009, the Endocrine Society found convincing evidence that EDCs affect the male and female reproductive systems, breast health, oncogenesis, neuroendocrine function, thyroid function, metabolism, and cardiovascular health.2 The first evidence of harm from EDCs came from long-term follow-up of randomized trials of diethylstilbestrol, a synthetic estrogen used as a pharmacologic agent between 1938 and 1971 to prevent miscarriage.12
In 2013, the American College of Obstetricians and Gynecologists and the American Society for Reproductive Medicine issued a joint opinion report on exposure to toxic environmental agents. The report acknowledged that environmental toxins are ubiquitous and that they can negatively affect health from preconception through adult life. “[We] join leading scientists and other clinical practitioners in calling for timely action to identify and reduce exposure to toxic environmental agents while addressing the consequences of such exposure.”13
Because the effects of endocrine disruption can occur during fetal and embryonic development, EDC exposure before and during pregnancy is of special concern.14 Long-term effects of exposure to hazardous chemicals such as cadmium, lead, and mercury in breast milk can lead to negative consequences in adulthood.15,16
Animal studies have pointed to the negative health effects of human-produced EDCs. For example, animals exposed to BPA have aberrant breast and genitourinary development and exhibit abnormal endometrial stimulation and early puberty.2
Despite these suggestive findings, the health effects of environmental toxins on humans are difficult to determine definitively. Evidence comes mainly from epidemiologic studies showing distribution of particular medical conditions based on different levels of exposure. More research is needed on human exposure to environmental toxicants and their effects.2,17,18 The National Children’s Study, a cohort collaborative study being conducted by the Environmental Protection Agency, CDC, and National Institutes of Health, is examining the effects of environmental exposures on more than 100,000 children across the United States, following them from before birth until age 21.19
THE PRECAUTIONARY PRINCIPLE
The precautionary principle is a fairly new concept in environmental science, although clinicians have been adhering to it for a long time. As proposed in a meeting of scientists, lawyers, policy makers, and environmentalists in 1998, “When an activity raises threats of harm to human health or the environment, precautionary measures should be taken even if some cause and effect relationships are not fully established scientifically.”20
For example, studies show that breast milk in the United States commonly contains many chemicals that do not meet US Food and Drug Administration standards for baby food.15,16 Although medical ethics prohibits randomized clinical trials in humans to examine the potential harms of these chemicals, proponents of the precautionary principle advocate that it is reasonable to be concerned that these chemicals may be harmful.21–23
Without categorizing all chemicals as toxicants, nor all toxicants as worrisome for reproductive health, physicians can provide access to a growing body of information about reasonable strategies to reduce risk.
Educating patients about potential risks of exposure needs to be tempered with an appreciation of the economic and social barriers to avoiding or reducing risks. Often, people do not make conscious decisions about exposure. Rather, they are unknowingly exposed or have no access to safe, equivalent alternatives. Substituting suspected or known harmful products with potentially safer ones can be financially prohibitive. Where a patient lives and works may result in unavoidable exposure to environmental toxins.
Nevertheless, there are simple, economical alternatives that reduce or eliminate exposure to EDCs (Table 1).24–26 These include avoiding plastic and metal containers that are not marked “BPA-free,” eating locally grown fruits and vegetables, controlling pests through frequent cleaning and trapping, and avoiding pesticides.
Additionally, the flame retardant tris (1,3-dichloro-2-propyl) phosphate may be an endocrine disrupter. It is found in numerous products for infants and young children, as well as in dust, automobiles, and furniture. Flame retardants are no longer used in infant clothing but may still be found in foam products such as upholstered furniture, automobiles, and children’s nap pads.27,28
National organizations that provide resources for counseling women about human-produced EDCs as well as patient education materials are listed in Table 2.
CLINICAL CASE RESOLUTION
You counsel the patient that, although more research in humans is needed, because of safety concerns, avoiding exposing herself and her baby to BPA when possible is a reasonable approach. You review recommendations including avoiding BPA-containing plastics for food preparation (recycle code #7) and BPA-containing toys that might be mouthed by the baby, as well as minimizing the consumption of canned foods when possible. You further advise her to avoid products with flame retardants.
Key concepts to consider and practical advice for choosing the safest possible drug treatments.