Vallombrosa Consensus Statement on Environmental Contaminants and Human Fertility Compromise

A recent national survey indicates that 12% of the reproductive age population in the United States, or 7.3 million couples, reports experiencing difficulty conceiving and/or carrying a pregnancy to term. This is precisely termed impaired fecundity,[1] but commonly referred to, as a general experience, as infertility. Proximate causes of infertility vary widely; for example, from impaired sperm quality or reproductive tract abnormalities, to fallopian tube obstruction, hormone/menstrual cycle irregularities and anovulation, to implantation difficulties and recurrent miscarriage. Some seek medical intervention to help them conceive, and the number of people doing so has risen sharply over the last two decades. In 2002, an estimated $2.9 billion was spent on infertility treatments in the United States. Now, some 46,000 (or one in 100) babies born to Americans each year are conceived as a result of the most advanced assisted reproductive technologies (ART).

These increasingly effective medical procedures have helped hundreds of thousands of couples around the world achieve successful pregnancies. However, they can also be a hardship emotionally and/or financially, and often the financial costs place these interventions beyond the reach of couples who need them.[2] For those who can pursue such assistance, despite its great promise, success is not a given: An estimated one fifth or more of treated couples do not end up with a baby after a course of ART cycles. In addition, other medical and/or mental health conditions can be associated with infertility in the couple experiencing it (and research is ongoing as to whether there are increased health risks that attend treatment or conception via ART). In light of all these considerations, a high value should be placed on minimizing preventable causes of infertility as well as on the treatment of it.

Multiple interacting factors are likely to contribute to biological fertility challenges, including age, heredity, lifestyle, underlying disease, reproductive tract infections, and nutritional status. Demographers have identified voluntary delays in first pregnancy as a major factor. Yet, data from the U.S. Centers for Disease Control and Prevention (CDC) show that impaired fecundity over the last two decades appears to have increased in all reproductive age groups, but most sharply in younger women (younger than age 25). These data, together with a growing body of epidemiological literature and many experimental research results showing male and female fertility-related impairment in laboratory animals caused by a wide array of modern chemicals, implicate environmental factors also as possible contributors to human infertility.

Scientific understanding of the relationship between environment and human health is advancing rapidly. It reveals that a larger portion of health problems, including infertility, may be caused by environmental exposures than thought possible even a decade ago. These exposures include but are not limited to occupational sources. For some environmental agents known to have adverse effects in experimental animal studies or wildlife, impacts on human reproductive health are being found as well, and at exposure levels within the range humans commonly experience (termed “environmentally relevant”). If involuntary infertility is actually on the rise, and troubling insights from animal studies accurately predict human impacts, then the personal and societal costs of fertility compromise could become increasingly burdensome and significant shifts in reproductive health and norms at the level of whole populations could occur. This has profound implications for public health and strongly suggests that a more comprehensive, coordinated research agenda must be developed and funded-because adverse effects caused by environmental exposures are, in principal, preventable.

Responding to these concerns, a multidisciplinary group of experts gathered at the Vallombrosa Center, Menlo Park, CA, February 27 to March 1, 2005, to assess what is known about the contribution of environmental contaminants, specifically synthetic compounds and heavy metals, to human infertility and associated health conditions. Workshop organizers chose this focus because critical recent discoveries in the field have raised many new, intriguing scientific questions and heightened interest in environmental risk factors within patient organizations and reproductive medicine/science professional societies. This was the first time researchers in reproductive epidemiology, biology, toxicology, and clinical medicine convened with representatives of relevant professional societies as well as infertility support, women's health, and reproductive advocacy organizations from the United States to review the state of environmental health science as it pertains to infertility.

1 Underlined terms are defined in Appendix A (Glossary of Terms and Term Usage) specific to this document.

2 In the United States, only 14 states have any form of mandate requiring health insurers to cover or offer coverage for infertility treatments, and more often than not, such coverage is only partial at best.

APPENDIX A GLOSSARY OF TERMS AND TERM USAGE SPECIFIC TO THIS STATEMENT

Aneuploidy-The lossy or gain of chromosomes in a cell due to errors in cell division, e.g., three number 21 chromosomes (or trisomy 21, also called Down syndrome) is a form of aneuploidy.

Assisted reproductive technologies-The handling of eggs and sperm outside the body for the purpose of conception. The acronym ART is sometimes used imprecisely to refer to the whole range of infertility treatments, including both “lower tech” therapies, such as the use of ovulation-induction drugs and intrauterine insemination, and “high-tech” therapies, namely in vitro fertilization, gamete intrafallopian transfer, and zygote intrafallopian transfer. However, the American Society of Reproductive Medicine, the Society of Assisted Reproductive Technology, and the U.S. Centers for Disease Control and Prevention (CDC; for the purposes of their data collection) define ART as including only the “high-tech” therapies. Therefore, the CDC figure for the number of babies born annually as a result of ART (46,000) excludes the number of children conceived and born as a result of lower tech therapies.

Bioaccumulation-Process whereby contaminants taken up from the surrounding environment (air, food, water) are retained and concentrate in tissues at a rate faster than they can be broken down and excreted. With bioaccumulation, tissue levels of a contaminant become greater than surrounding environmental levels.

Biomagnification-Process whereby the concentration of contaminants increases up the food chain due to larger organisms ingesting smaller organisms containing contaminants. Humans and other predatory organisms accumulate the highest concentrations of contaminants.

Biomarker-A biological substance found in body fluids (blood, urine, breast milk) or tissues (fat) that can be measured and is associated with exposure to a contaminant. Biomarkers can help to monitor exposure to contaminants and may help to characterize individual susceptibilities to exposure. A biomarker of exposure is a measure of either the contaminant or a metabolite occurring shortly after exposure. A biomarker of effect is a persistent genetic change caused by a contaminant exposure that can be measured by changes in DNA or chromosome structures (e.g., DNA mutations). Biomarkers of effect are not necessarily specific to contaminant exposure. A biomarker of susceptibility is a gene or expression of a gene (polymorphisms) that renders an individual more vulnerable to the adverse effects of contaminant exposure. For example, due to differences in enzymes, some individuals may not be able to detoxify a contaminant as efficiently as others, resulting in higher levels of exposure and greater toxicity.

Biomonitoring-The assessment of exposure to contaminants by measuring biomarkers of exposure in body tissues or fluids (e.g., blood, urine, breast milk, amniotic fluid, hair, adipose tissue, bone). Such assays can be used to monitor not only exposures in populations but also to monitor changes in levels of contaminants over time.

Bisphenol A-A common chemical compound that forms the building block of polycarbonate plastics and epoxy resins. Bisphenol A is used in polycarbonate plastic in food containers, water bottles, baby bottles, CD cases, eye glass lenses, the lining of food cans, and as a dental sealant. It binds with nuclear and extracellular estrogen receptors.

Cell membrane receptors-A protein found on the surface of a cell that binds only specific chemical messengers, such as another protein or hormone. Binding of the specific chemical to the cell membrane receptor triggers processes inside of the cell, such as ion flux or enzyme activation.

Cellular signaling-Process whereby one cell communicates with nearby cells to regulate and coordinate function. Communication can occur through direct cell-to-cell contact or through secretion of biologically active substances that inhibit or stimulate cell function. Contaminant exposure can affect cellular signaling by stimulating or inhibiting these biological signals.

Cryptorchidism-Birth defect in newborn males in which one or both of the testicles has not descended into the scrotum. Cryptorchidism is a risk factor for testicular cancer later in life.

Diethylstilbesterol (DES)-Synthetic estrogen given as a feed additive to livestock and prescribed for pregnant women from 1947 to 1971 to prevent miscarriage (experimental use began in 1941). DES has been shown to interfere with normal development of the reproductive tract, resulting in fertility challenge in the sons and daughters of women who took DES during pregnancy. DES daughters also are at risk for a rare form of vaginal cancer.

Dioxins-A class of hundreds of related persistent chemicals, some of which are known to be highly toxic, that result from industrial combustion/incineration processes; burning of household trash or fuels such as wood, coal, and oil; chlorine bleaching of pulp/paper; and some types of chemical manufacturing. Cigarette smoke also contains dioxins.

Endocrine disruptors-Environmental compounds that interfere with the normal function of endogenous hormones. Endocrine disruptors can stimulate or block the actions of hormones, or can interfere with their metabolism. Endocrine disruptors continue to be discovered but have been recognized to include a diverse range of chemicals, including pesticides, plasticizers, flame retardants, industrial byproducts, pharmaceuticals, and plant-derived compounds.

Endogenous-Of or relating to a substance produced within the body, or a naturally occurring chemical. For example, estrogens produced by the ovary are endogenous hormones.

Endometriosis-A chronic condition affecting 5.5 million U.S. women and girls in which the tissue lining of the uterus (endometrium) grows in abnormal locations outside the uterus, such as on the fallopian tubes, ovaries, and in the abdominal/pelvic cavity. Endometriosis causes internal bleeding and thus pain, inflammation, and scarring, and is often associated with infertility.

Endpoints-In a scientific study, the outcome that is being measured. This could be a biomarker, toxic effect, disease outcome, or other measure anticipated to differ between exposed and unexposed populations.

Environmental agents-Includes synthetic chemicals, heavy metals (such as lead, mercury, cadmium), and naturally occurring compounds such as plant-derived estrogens. For the purposes of the Vallombrosa Workshop and this document, for the most part focus was limited to those agents considered synthetic contaminants in the natural environment. The phrase “environmental factors” generally refers to a broader range of possible environmental influences inclusive of alcohol, pharmaceutical use, stress, etc. Contaminants that have been identified as having toxic effects on reproductive physiology, function, or health are called reproductive toxicants.

Epidemiology-The study of the distribution and determinants of disease (and health-related) states for a human population or sample defined in time and space. Determinants of disease may include sociodemographic, geographic, behavioral, biomedical, or other environmental factors, and can be evaluated in the context of genetic factors.

Epigenetic-Refers to DNA modifications that do not involve changes in the sequence of DNA (genotype). Epigenetic changes can affect gene expression (phenotype) and can be transmitted from one generation to the next.

Estradiol-The most potent and biologically active of the estrogens produced by the ovary, it is responsible for many biological functions in the female, including breast development and development of the uterine lining during the first half of the menstrual cycle. Estradiol also can be produced by fat cells in both men and women, and can interfere with fertility in cases of obesity.

Exogenous-Of or relating to a substance produced outside of the body, or a synthetic chemical (e.g., estrogens in oral contraceptives are exogenous hormones).

Fecundity - The biologic capacity of men and women for reproduction.

Genetic signaling-Process whereby an endogenous or exogenous substance stimulates a cascade of events inside of a cell ultimately to regulate gene expression. The substance could either inhibit or stimulate gene expression through a cellular signaling pathway.

Hypospadias-Birth defect where the urinary opening (urethra) is found not at the normal location at the tip of the penis but instead on the underside of the penis. In severe cases, the urethral opening may be at the base of the penis or below the scrotum.

Infertility-Definitions and measures of infertility can vary widely, but it is typically diagnosed when a couple is unable to conceive after 6 months or 1 year of regular unprotected intercourse. Often the term is used more broadly than in its strict diagnostic sense (i.e., commensurately with impaired or subfecundity) to describe and encompass any of the range of biological challenges people may encounter in attempting to conceive and/or carry a pregnancy (including conception delay, inability to conceive, pregnancy loss or stillbirth). Primary infertility is infertility in individuals who have never had children. Secondary infertility is that experienced after already having given birth to a child or children. Fertility, in the precise sense, refers to the ability of women to give birth to a live-born infant and for men to be able to father a pregnancy resulting in a live birth. About prevalence figures: The principle source of infertility prevalence data in the United States, the periodic National Survey of Family Growth (NSFG) conducted by the National Center for Health Statistics at U.S. CDC, defines infertility as a duration of greater than 12 months exposed to the possibility of becoming pregnant, but not becoming pregnant. For this measure, the NSFG surveys only married women of reproductive age and reports a 2002 figure of 7.4%. Implicit in this measure is the desire for conception; thus those using contraception and/or not trying to conceive are not reflected. The NSFG also surveys all female respondents of reproductive age (married or not) who are not surgically sterile concerning doctor-diagnosed and self-reported impaired fecundity, and indicates that as of 2002, 11.9% of U.S. women aged 15 to 44 report impaired fecundity, compared with 10.2% in 1995 and 8.4% in 1988. Because definitions/measures of infertility vary, there is a wide range of other prevalence estimates. In a study of older women that used five definitions of the word, the age-adjusted prevalence of a history of infertility ranged from 6.1% (when the women reported a physician diagnosis) to 32.6% (unprotected intercourse for 12 months ever, based on a life-time calendar of pregnancy attempts).

Metabolomics-Metabolites are small molecules produced by biochemical processes in cells that build up and/or breakdown substances. Metabolomics, also called metabolic profiling, is the study of metabolites produced by a cell and can reveal much about the physiological state of a cell in response to a chemical exposure.

Mixtures-In this context, concerns the effects of two or more contaminants so that the outcome of exposure is different from their separate effects. The interaction could be additive (a sum of individual effects), subtractive (one substance is stimulatory and another inhibitory), or multiplicative (the effect is greater than the sum of individual effects).

National Children's Study - Led by a consortium of U.S. government agencies (http://nationalchildrensstudy.gov), this study aims to examine prospectively the effects of environmental factors on the health and development of more than 100,000 children from before birth to age 21 years.

Nonmonotonic dose-response curve-A traditional dose-response curve in toxicology assumes that the response to exposure will increase with increasing dose. This is known as a monotonic curve (i.e., one in which the slope of the dose-response curve does not change from positive to negative or vice versa). In a nonmonotonic dose-response (NMDR) curve, the slope of the dose-response curve changes sign as the level of exposure increases. Some NMDR curves are shaped like a U, others are shaped like an inverted U. NMDR curves are important from a public health perspective because in dose-response curves that are nonmonotonic, low-dose effects cannot be predicted from high-dose testing. The traditional assumption that higher doses cause greater harm (“the dose makes the poison”) is used in standard risk assessment studies to identify the level of a chemical exposure beneath which contamination should cause no effect. This old assumption may be true for many chemicals and for many classic health effects, but it can be misleading for exposures that have a NMDR curve.

Nuclear hormone signaling-A type of genetic signaling whereby a hormone (e.g., estrogen or thyroid hormone) binds to its receptor in the nuclear membrane inside a cell and triggers expression of genes associated with the hormone. Endocrine disruptors can interfere with normal hormone signaling to either stimulate or inhibit normal hormone action.

Octyl/nonyl phenols-Chemicals that belong to a broader class of compounds known as alkylphenol ethoxylates (APEs). APEs are high-volume chemicals that have been used for more than 40 years as detergents, emulsifiers, and wetting and dispersing agents. Some uses include as ingredients in spermicides, cosmetics, and detergents; and as inert ingredients in pesticides. Some are endocrine disruptors. Several are noted contaminants in aquatic environments.

Perfluorinated compounds (PFCs)-Persistent, bioaccumulative chemicals found in a wide array of products including stain-resistant coatings for carpets and clothing (Gore-Tex), nonstick cookware (Teflon), and insecticides. Widespread contamination of human tissues has been documented, with some of the highest levels found in U.S. populations.

Persistence-Refers to the stability of a contaminant in the environment. Persistent contaminants are characterized by their ability to resist natural degradation so that they build up in the environment with time. Persistent contaminants often are globally transported on currents of wind or water.

Phthalates - Chemicals added to personal care products to enhance penetration and hold scent/color, and as plasticizers in rigid plastics such as polyvinyl chloride to create flexibility. Phthalates are found in numerous and diverse consumer products including, for example, vinyl flooring, plastic shower curtains, cosmetics and fragrances, shampoos and lotions, toys, pharmaceutical and herbal pill coatings, and in hospital equipment including intravenous bags and tubing.

Polybrominated diphenyl ethers (PBDEs)-Persistent, bioaccumulative chemicals added to electronics, upholstery foam, textiles, and numerous other materials to make them more flame resistant. PBDEs have a chemical structure very similar to PCBs and have been rapidly accumulating in wildlife and human tissues.

Polychlorinated biphenyls (PCBs) - Persistent, bioaccumulative compounds banned in the United States in the late 1970s, although widespread contamination still exists. PCBs were used in hundreds of commercial and industrial applications, including as lubricants, plasticizers, insulators for electrical applications, caulking, and paint.

Polycystic ovarian syndrome (PCOS)-A medical condition in which the ovaries produce an excess of male hormones (androgens), develop many small cysts, and do not release an egg on a monthly basis. This condition affects 5 to 10% of women of reproductive age and is a leading cause of infertility. Symptoms include irregular and heavy periods, excessive hair growth, acne, and obesity.

Polymorphisms-Variations in DNA sequence (genes) found in a large portion of the population. Polymorphisms may or may not render an individual more susceptible to the toxicity of a contaminant exposure or be linked to a specific form or disease.

Premature ovarian failure (POF)-Occurs in 1 to 4% of U.S. females, and is characterized by depletion or dysfunction of a woman's eggs-or ovarian function-prematurely, before the age of 40. In extreme cases, POF can occur as early as the teen years.

Proteomics - The study of the structure and function of proteins that are produced by genes inside of a cell and the ways these proteins interact with one another inside of the cell. Exposure to contaminants may affect protein expression and can be studied as a biomarker of exposure.

Transcription factors-A protein that binds to DNA and regulates gene expression.

Toxicogenomics-The study of how genes/gene expression changes in response to exposure to a toxic substance.