Chemicals that Interfere with the Body's Natural Hormones
Chemicals used in everyday products—plastics, cleaning products, cosmetics—and industrial processes—manufacturing, waste disposal—can affect the body’s development, growth and hormone balance by mimicking, blocking or disrupting the body’s natural hormones.
Breast development is a process guided by naturally occurring hormones, minuscule amounts of which exert striking effects in breast tissue at the critical stages of prenatal development, puberty and pregnancy. These two features of naturally occurring hormones—that they exert extreme effects in small amounts and that they have the strongest effects at specific developmental stages—also characterize endocrine-disrupting compounds.
Endocrine-disrupting compounds (EDCs) are synthetic chemicals that have been developed because of their useful properties in many common products, including plastics, pesticides and herbicides, personal care products, household cleaning products, flame retardants, and so on. Secondary, often unanticipated properties of these chemicals include their dispersal into our soil, dust, water resources and air, and their subsequent uptake into wildlife and human bodies, where they exert effects that disrupt the delicate balance of the endocrine system.
EDCs can mimic, antagonize or complexly disrupt particular endocrine pathways, often interacting with hormone receptors and altering the balance of cellular responses. Although most of the current research on EDCs focuses on mechanisms by which EDCs interrupt the interactions of hormones with traditional steroid receptors (ER, PR, AR), it is important to recognize that there are multiple ways thatthe EDCs may exert their effects. Emerging research suggests many EDCs affect more than one of these pathways.
EDCs Alter Hormone Receptors
The most well-studied pathway by which EDCs affect the body is by direct interaction with hormone receptors. Hormone receptors are protein receptors in the cells that bind to a specific hormone, as a form of chemical communication within the body. Once a hormone binds to a receptor, a series of changes can occur in the cell, to bring about a physiological state in the body. Everything from sexual development, to metabolism, to brain development is affected by this process. EDCs can alter this process in several ways. They can bind to the receptors meant for naturally occurring hormones, thereby setting off a series of physiological changes in the body. Many EDCs only bind partially to these receptors, but they can still affect the endocrine system. EDCs can also block the receptors, so that the body’s natural hormone messengers cannot reach their target receptors.
In addition to the steroid hormone receptors described above, there is another class of proteins that are called estrogen-related receptors (ERRs) because they are structurally very similar to ERs. These ERRs, especially ERRγ, serve as binding sites for several endocrine-disrupting compounds including bisphenol A (BPA) and diethylstilbestrol (DES) (Takayanagi et al., 2006). On the other hand, the natural estrogen, estradiol, does not bind to ERRs (De Coster and van Larebeke, 2012). Therefore the ERRγ-regulated pathway provides an alternative mechanism for some EDCs to affect cellular activity beyond their interruption of normal estradiol pathways. ERRγ pathways may regulate metabolic activity in cells, including cancer cells, as well as proliferation of cells and tumor progression (Bianco et al., 2012).
EDCs Direct Interactions with Molecules and Influence on Epigenetics
There are several other ER-independent mechanisms by which EDCs may alter cell activities, including in breast cells, resulting in changes that may alter risk for development of cancer. Examples include direct interactions with molecules involved regulating cell proliferation, effects on enzymes involved in the metabolism of hormones including aromatase, epigenetic changes that alter regulation of gene expression without causing direct mutations in gene signaling, altering feedback between hormone secreting cells and the brain structures that normally maintain homeostasis (balance) in hormone levels over time (De Coster and van Larebeke, 2012). Some of these overlap with systems affected by the natural estrogens; others are completely independent.
When exposure to EDCs occurs during early (especially fetal) development, consequences can be severe, increasing the probability of later negative health outcomes including cancers, neurodevelopmental and neurodegenerative diseases, metabolic disorders, asthma and immune disorders. Substantial evidence of the fetal origin of disease (Barker, 1994) and the influence of EDCs has been documented in human studies and supported by hundreds of articles from experimental animal studies (Vandenberg et al., 2012; Schug et al., 2011). A particularly extensive literature supports the hypothesis that early developmental exposures to EDCs including (but not limited to) diethylstilbestrol, bisphenol A, phthalates, atrazine and other pesticides and herbicides, heavy metals including cadmium, and so on can increase risk for later development of breast cancer. This theme is explored extensively in the Chemicals Linked to Breast Cancer section of this site.
Two important characteristics of EDCs make them different from many non-endocrine toxicants associated with the development of various disease states: (a) low-dose effects, and (b) non-monotonic response curves.
These are critical properties for understanding the scientific literature linking EDCs to disease, including breast cancer. They also are at the center of controversies related to the interpretation of certain studies, especially those that examine low-dose, early-life exposures to EDCs and their subsequent effects on health.
Except in cases of accidental or occupational exposures, most exposures to EDCs are at “very low doses.” In 2001, a panel of expert scientists convened by the National Toxicology Program defined “low-dose effects” as “biological changes that occur in the range of human exposures or at doses lower than those typically used in the standard testing paradigm of the U.S. Environmental Protection Agency for evaluating reproductive and developmental toxicity” (Melnick et al., 2002, p. 427). Most toxicology studies look at higher doses of chemicals and their effects on well-established experimental endpoints, and then extrapolate down to lower doses, assuming a linear relationship between dose and negative health outcomes. Yet many EDCs have been shown to exert important biological effects, often different from those studied in traditional toxicology experiments, at very low doses of chemicals. These low-dose effects are especially prevalent in early developing tissues, before the time that complex hormonal regulation is established and during the developmental period when even minuscule levels of naturally occurring hormones have been shown to have significant effects on developing organs, including the breast (see Vandenberg et al., 2012 for review).
Nevertheless, much of the “he said/she said” public argument about whether scientific findings really demonstrate that low doses of EDCs are associated with negative health outcomes in human and animal models, often revert to whether a “low dose” can have a significant biological effect. We argue strongly, along with scores of other scientists and scientific organizations, that low-dose effects of EDCs have been demonstrated broadly, repeatedly and in many tissues and models (Vandenberg et al., 2012; Diamanti-Kandarakas et al., 2009; Welshons et al., 2003; PCP, 2010).
A linear dose-response relationship is a consistent straight line.
When considering dose-response relationships, often with the goal ultimately of determining the “lowest observed adverse effect level” (LOAEL), traditional toxicology and regulatory science assumes that a higher dose will have greater impact on health outcomes than will low doses, and that in simple terms, the relationships will be fairly linear (Vandenberg, 2012). Using this logic, risk assessors often infer the effects of low doses based upon tests conducted at higher doses. According to these models, high doses have great effects, and the dose-response curve has a consistent slope, whether positive or negative.
Not all relationships between exposures and responses are linear.
Yet this assumption of a consistent slope sign (positive or negative), or monotonicity, is inappropriate when studying EDCs. Instead, non-monotonicity, or changes in slope directions on dose-response curves might best be used as models for dose-response curves when studying EDCs. A recent extensive review of the literature on EDCs (Vandenberg et al., 2012) concluded that non-monotonic dose-response curves “are not the exception, but should be expected and [are] perhaps even common” (p. 27).
If dose-response curves are non-monotonic, and therefore the slopes of the dose-response curve can change significantly over the range of doses, then one cannot draw conclusions about low-dose effects by extrapolating from higher-dose effects, nor can one assume safety or lack of response at doses below those often studied in traditional toxicology studies (Vandenberg et al., 2012).
This issue is critical in supporting the call above for addressing seriously and rigorously the increasing literature demonstrating low-dose response to EDCs, especially at developmentally sensitive times. Additionally, the fact of non-monotonicity has serious repercussions for regulatory policy and practice.