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Endocrine Disrupting Chemicals as a Source of Environmental Stochasticity
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A New Threat to Life
 
by Christine Johnson, March 10, 2004

Abstract

 

            This paper argues that because endocrine disrupting chemicals (EDCs) have been shown to act as interfering signals with respect to biological signaling systems common to many animals, including humans, once these signals are released into the environment, they behave as a source of stochastic variation in the hormonal environment that may have significant evolutionary implications. Recent evidence suggests that the amount of variation introduced into the environment may already be exceeding the ability of some individuals within species or even all members of some species to adapt to the changing environment. Evidence is compelling in the case of many freshwater fishes, where wildlife studies have been corroborated in the laboratory. Conservation biologists may have underestimated the effects from this class of chemicals by attributing the majority of wildlife losses primarily to habitat destruction and other anthropogenic causes. The recent discovery that extremely low, environmentally relevant doses of EDCs can elicit a physiological response that alters organism development and function invalidates toxicological risk assessments upon which regulatory limits are fundamentally based; therefore the underlying epistemology of the existing regulatory framework is invalid. I conclude that government regulation based on current principles makes a number of invalid assumptions regarding the mechanisms and effects of these chemicals, requiring a policy shift towards the precautionary principle. This principle is necessary to avoid future "environmental surprises," or effects that were unpredicted and unexamined when a chemical was first approved for production and use.

 

 

 

 

 

Endocrine Disrupting Chemicals are Biologically Relevant Signals

            In 1991, a new hypothesis concerning the biological significance of certain chemicals on wildlife was formulated, now known as the endocrine disruptor hypothesis (Colborn & Clement, 1992). Based upon patterns observed in the wildlife of the Great Lakes region of the United States, Theo Colborn hypothesized that certain chemicals were accumulating in animals, behaving as the sex hormone estrogen, and causing behavioral, morphological, and reproductive problems in a large number of resident species, especially at the top of the food chain (Colborn, et. al., p. 16-20, 1990). In the last fifteen years, a significant number of studies have demonstrated that there are several classes of chemicals that can behave as biologically relevant signals, capable of altering the control of gene expression at the molecular level and interfering with homeostatic feedback loops at the developmental and functional level (Myers, et. al., 2003). A generalized hypothesis of biological signaling in ecosystems has been advanced, suggesting that any process mediated by chemical signals is a potential target for disruption, whether it occurs inside the body of an organism, between organisms, among organisms, or ecosystem-wide (McLachlan, 2001).  

            Almost all biological development unfolds as a sequence of events, orchestrated and controlled by biochemical signaling mechanisms that activate gene expression. Key among these signaling mechanisms are hormones; chemical messenger molecules that are produced in one part of the body and transported to another where they enter a cell and in concert with other intracellular complexes, initiates gene expression. Interference with any step in these signaling processes during development can result in adverse effects ranging from obvious birth defects to subtle changes that only become manifest long after exposure has occurred (Myers, et. al., 2003). High doses of endocrine disrupting chemicals (EDCs) can result in overt toxicity, such as cell death, but at lower levels, they can alter the expression of genes, resulting in endocrine system changes that become permanent during critical periods of development (Welshons, et. al., 2003). In addition, different EDCs can interfere with different signaling pathways using different mechanisms, and when combined with other chemicals in mixtures, this can result in a wide variety of possible outcomes, most of which would be difficult to detect statistically (Myers, et. al., 2003, DeGuise et. al., 2001, Weiss, 1998; Weiss, 2002).

            The vast majority of the 85,000+ chemicals registered with the EPA have never been evaluated for their potential for biological signal disruption, so it is not known how many chemicals in commerce might be implicated (Landrigan, et. al., 2003). Because estrogenic effects were first identified, there was initially a focus on estrogenic chemicals but it is now known that androgens, anti-estrogens, and anti-androgens exist, as well as others (NRC, 1999). A partial list of chemical classes demonstrating endocrine disrupting properties includes: halogenated dioxins and furans, organochlorine pesticides, PCBs, phthalates, Bisphenol A, polybrominated flame retardants (PBDEs) and the breakdown products of alkylphenol polyethoxylates (Colborn, et. al., 1996). In addition to these chemicals, products intended for consumers, including pharmaceuticals, which are pharmacologically active by-design, and personal care products, many of which contain EDCs and are used in great abundance, are increasingly found in the nation's waterways (Kolpin, et. al., 1996). Many of these chemicals have been found in people at levels far above where endocrine disrupting effects are observed in animals (Houlihan, 2003).   

            Because these biologically relevant signals from outside the organism can enter the body and alter gene expression, endocrine disruptors are therefore a new source of evolutionary variation analogous to environmental stochasticity. This new form of stochasticity involves many dimensions because it acts on evolutionarily conserved signaling molecules, receptors, and processes, some of which are believed to be nearly global in nature. Estrogen, for example, is believed to be the first, and most ancient signaling molecule; consequently the estrogen receptor is widely found in the animal kingdom, including vertebrates and many invertebrates (McLachlan, 2001). Importantly, different organisms may use the same signaling molecule for different functions, making prediction of effects at the ecosystem level difficult (Stoka, 1999, Daughton & Ternes, 1999). The fundamental nature of these processes indicates that changes will occur from the level of the individual, to the community, species, population, and ecosystem. There are also indirect and non-independent effects due to multiple chemicals acting on the same pathway (Rajapaske, et. al., 2002), individual chemicals acting on multiple pathways (Frigo, et. al. 2002, Adams, et. al., 2002), bioaccumulative effects as concentration increases up the food chain (Colborn, et. al., 1993), and multigenerational effects, where the accumulated toxins are passed to offspring in utero and via lactation (Latini, et. al. 2003, Schönfelder, et. al., 2002, Foster, et. al., 2000, LaKind, et. al., 2001).

            These rapid changes introduced into the environment are historically unprecedented, as is the scale of production and use. Many, including DDT and PCB's are volatile, persistent, and can travel long distances through atmospheric circulation. Using tree bark to determine global transport of 22 organochlorine chemicals, a recent study found that all but 4 were ubiquitous globally (Simonich & Hites, 1995). The World Health Organization (WHO) recently reported that world-wide, levels of DDT and PCBs are decreasing, but PBDEs are increasing dramatically (WHO, 2002). These chemicals represent a fundamental shift in the state of the environment that is qualitatively different from other anthropogenic causes of environmental change such as habitat destruction and exploitation of wildlife; these qualitative changes necessitate a reevaluation of the relative importance of these chemicals by conservation biologists with respect to threats to biodiversity and extinction.   

            In the last several decades, studies have increasingly demonstrated a variety of developmental and reproductive problems in a range of wildlife species believed to be due to endocrine disruption. For example, researchers have found: the persistent pesticide DDT induced feminization in male gulls (Pelecanus occidentalis) offshore of Southern California (Fry and Toone, 1981), the herbicide atrazine induced hermaphroditism in leopard frogs (Rana pipiens) at levels as low as 0.1 parts per billion (ppb) throughout the midwest U.S. (Hayes, et. al., 2003), alterations in the hormone profiles of American alligators (Alligator mississippiensis) were observed in Florida due to a massive spill of the pesticides DDT and dicofol (Guillette, Jr., et. al., 1995, Gunderson, et. al, 2001), and PCBs caused alterations in reproductive hormone levels in female polar bears (Ursus maritimus) in the Norwegian arctic (Haave, et. al., 2003). Many more examples have been found in other wildlife species (Colborn et. al., 1993).

 

Fish Species are Sensitive Indicators of Endocrine Disruption

            In the last decade, studies have increasingly identified sex-reversal of many fish species living in waters found to be contaminated with various EDCs (Jobling, et. al., 1998). The finding that 5% of roach fish (Rutilus rutilus, a common cyprinid) living downstream from a U.K. sewage treatment plant were hermaphroditic was a surprise to researchers, who noted that only two hermaphroditic roach fish had ever been reported in the literature, one in 1965 and one in 1979 (Sumpter & Jobling, 1995). Because it is known that the synthesis of vitellogenin, a liver protein used for creating egg yolks in female fish, is mainly under the control of the sex hormone 17b-estradiol, researchers suspected the presence of an estrogen of some sort in the effluent of the sewage treatment facility (Purdom, et. al., 1994). In order to test this hypothesis, they placed fish in cages directly in the effluent of 28 sewage treatment plants around the country to determine if similar results were obtained; five other control groups were placed in cages and raised in trout farms, where the water is believed to be unpolluted. For the treatment fish raised in the sewage treatment plant effluent, at 13 of the 28 sites all the fish died due to poor effluent quality, but at the other 15 sites, in all cases there was a substantial increase in vitellogenin synthesis in both males and females (Sumpter & Jobling, 1995). Because the fish vitellogenin increased dramatically, from 500 to 50,000 fold, they concluded that something in the effluent was acting as an estrogen, and thus altering development. Since female roach usually exhibit around a 1 million-fold increase in vitellogenin synthesis during the reproductive cycle, this is the basis for suggesting that fish are sensitive indicators of endocrine disrupting chemicals (Sumpter & Jobling, 1995).

            As a result of these early findings, a significant amount of further study in the U.K. has been performed, indicating that wastewater effluent from sewage treatment plants is commonly estrogenic. Purdom, et. al. (1994) initially suggested that the likely sources were birth control pills (ethynylestradiol) or alkylphenol ethoxylates, deriving from surfactants and detergents that partially break-down during the sewage treatment process. A number of studies coupled observations of increased vitellogenin synthesis with laboratory studies aimed at identifying the source of the estrogen. For example, Routledge, et. al. (1998) found that trout (Oncorhynchus mykiss) and roach fish exposed in vivo to 17b-estradiol or the alkylphenol ethoxylate 4-tert-octylphenol, at environmentally relevant concentrations similar to those measured in U.K. streams, were able to induce similar increases in vitellogenin synthesis, evidence that these chemicals are contributing factors to the widespread sexual disruption seen in these fishes (Jobling, et. al., 1998). More recent studies have confirmed these findings, providing conclusive evidence of widespread sexual disruption of fishes in the U.K. (Lye, et. al., 1999, Harris, et. al., 2001, Williams, et. al., 2003).

            Few studies have examined U.S. fish for evidence of endocrine disruption; one study that did examine the question found that 84% of genetically male fish were sex-reversed in the Hanford Reach area of the Columbia river in Washington State (Nagler, et. al., 2001). The authors suggested temperature difference or exposure to endocrine disrupting compounds may be responsible, since temperature can alter sexual differentiation in similar species, and the United States Geological Survey (USGS) has identified a number of pollutants in the water from this region (USGS, 2002). Additionally, because the Priest Rapids hatchery supplements this particular run by introducing hatchery raised fish, it is not possible to conclude that the remaining 16% of genetically male fish were not sex-reversed, because only 3% of hatchery fish are tagged by having their adipose fin clipped (Nagler, et. al., 2001). That is, the remaining 16% of males that were phenotypically normal may be hatchery produced fish.

            In 2002, the USGS published results from its first national reconnaissance of pharmaceuticals, hormones, and other organic wastewater contaminants in U.S. streams, finding that a wide range of chemicals are present in most streams, and that substantial levels of hormones, detergent metabolites (APEOs), plasticizers such as phthalates, and nonprescription drugs are common (Kolpin, et. al., 2002). The sources of these chemicals are varied, but a large contribution is made by discharge of wastewater effluent from sewage treatment facilities, particularly for chemicals such as pharmaceuticals intended for humans (Daughton & Ternes, 1999).

            Another source of endocrine disruptors to aquatic environments includes the runoff from the solid precipitate of sewage treatment, originally called sewage sludge, now euphemistically known as biosolids. A number of studies have shown that biosolids contain substantial concentrations of heavy metals, phthalates, various hormones, and alkylphenol ethoxylates; when applied to agricultural fields or in forests, runoff removes a fraction of the adsorbed contaminants, thus providing a mechanism for transport to waterways (EPA, 1990, Hale, et. al., 2001, Baronti, et. al., 2000, Johnson & Sumpter, 2001, Hesselsöe, et. al., 2001, La Guardia, et. al., 2001, de Jonge, et. al., 2002, Layton, et. al., 2000). Disposing of biosolids is a recent problem, created by the Ocean Dumping Ban act of 1988 that forbid dumping municipal waste in the ocean, and thus forcing waste managers to find alternative places for disposal (EPA, 1990). At least one study indicates, however, that agricultural crops can readily uptake metals and other chemicals, thus posing a risk to consumer health (WSDA, 2001).  

            Once these chemicals are released into the environment, their fate is far from clear, however. There is evidence that many of these chemicals do not break-down into harmless compounds; evidence exists showing that: methylation of inorganic mercury is performed by microorganisms (Drexel, et. al., 2002, King, et. al., 2001), bacteria  convert non-hormonal compounds into hormonally-active substances (Panter, et. al., 1999, McLachlan, 2001), and estrogens from septic fields and high-estrogen groundwater sources migrate to marine environments (Atkinson, et. al., 2003) and that hormone breakdown is rapid under aerobic conditions, but that under anoxic condition, breakdown is much slower (Ying & Kookana, 2003).     

 

Low Dose Effects of Endocrine Disruptors

            Chemicals now believed to be endocrine disruptors were once considered only in terms of their toxicity, or ability to cause acute damage or death (Carson, 1962). Toxicity standards were first applied to chemicals in 1927 by the U.S. Department of Agriculture, when Secretary of Agriculture William Jardine set an arsenic tolerance on fruit from arsenical pesticides at 0.025gr./lb. The standard was based upon what the industry thought could be achieved with the current technology for cleaning fruits, not based on health effects (Dunlap, p. 46, 1981). In 1941, after a series of problems concerning residues, a study was performed in Wenachee, Washington, where 20-25% of U.S. apples were then grown, to determine acute health effects of arsenical pesticides; the study found that cases of poisoning were rare and not important clinically, supposedly justifying the current limits (Dunlap, p. 53, 1981). Thus, concerns about low-level exposure and the chronic effects of long-term exposure were removed from consideration entirely (Dunlap, p. 53, 1981). This pattern has been repeated for every new chemical that entered production; we now have 85,000+ chemicals in commerce, and approximately 3000 are produced in volumes exceeding 1 million pounds per year, yet fewer than 20% of these high production volume chemicals (HPVs) have been studied with respect to developmental or pediatric toxicity (Landrigan, et. al., 2003). This has resulted in a chemical-by-chemical regulatory approach that makes a number of assumptions about chemical safety that recent evidence indicates are invalid.          

            Some of the assumptions used in traditional toxicological risk assessments are discussed at length by Welshons, et. al. (2003). They make four important observations about the fundamental mechanisms of endocrine disrupting chemicals that invalidate traditional toxicological assumptions. First, they note that it is possible to predict with accuracy the low-dose hormonal mechanisms of action and physiology of delivery, both of which have been missed by traditional toxicological assessments. Second, because receptor-mediated responses are saturable (no response above 100% receptor occupancy), the assumption that it is valid to extrapolate from high test doses to low doses common in the environment is invalid. Third, the traditional toxicological assumption that "the dose makes the poison" is invalid, because observations show that the receptor-mediated responses of the endocrine system are non-monotonic, meaning that that response may be larger at lower doses than at higher doses. Fourth, the endocrine system is already physiologically active, and therefore exogenous estrogens will not exhibit threshold effects. That is, there is no lower limit which can be assumed to be without effect.

            The authors of this study provide an elegant example of the effects of low-dose exposure, showing how a lack of positive controls can lead researchers to falsely conclude that a given chemical is not an endocrine disruptor. Using MCF-7 breast cancer cells with estrogen receptors, and a line of cells called C4-12-5 that do not express estrogen receptors, they showed that cells with receptors that are exposed to estrogen respond in two regions: first, response to estrogen is increased in the low-dose range and it stays at this level for over 5 orders of magnitude difference in concentration, until the concentration is high enough to induce toxic effects, and the cell dies. (Fig. 1) C4-12-5 cells without estrogen receptors do not exhibit effects in the low-dose range, but still exhibit cell death at approximately the same concentration as the MCF-7 cells. Finally, if the estrogen receptor expressing MCF-7 cells are contaminated with 3 parts per trillion (ppt) of diethylstilbestrol (DES), a synthetic estrogen, the response in the low-dose range is obscured, but the toxic effects at high concentrations are still observed. From this, they conclude that many experiments that have concluded negative findings with respect to low-dose exposures to endocrine disruptors may be due to a lack of positive controls and inadvertent contamination of the sample by an estrogenic substance. (Figure 1 follows the references) 

            These findings of effects at doses that are environmentally relevant demonstrates that risk assessments considering chemicals in isolation and using invalid assumptions regarding mechanisms of action are inappropriate for setting regulatory limits. These findings at the mechanistic level coupled with observations of endocrine disruption in wildlife exposed to environmentally relevant doses indicates that a major shift in chemical regulation is necessary in order to protect a wide variety of species that depend upon a stable chemical environment for reproduction, including humans. Because conservation biologists have mainly considered only the toxic effects of chemicals, they may have underestimated the effects from this class of chemicals by attributing the majority of wildlife losses primarily to habitat destruction and other anthropogenic causes, rather than considering the impact of EDC exposure.

            The recent discovery that extremely low, environmentally relevant doses of EDCs can elicit a physiological response that alters organism development and function invalidates toxicological risk assessments upon which regulatory limits are fundamentally based; therefore the underlying epistemology of the current regulatory framework is entirely invalid. As a result of these epistemological problems, scientists interested in public policy have been examining these problems and attempting to formulate an alternative to the chemical-by-chemical regulatory approach. The most promising of these approaches is the precautionary principle.

 

The Precautionary Principle and Public Policy

            Sandra Steingraber’s book Living Downstream: A Scientist’s Personal Investigation of Cancer and the Environment is emblematic of an unfolding paradigm shift that is providing a simple, albeit contested, solution to increasing rates of vexing health problems. Rather than assuming that chemicals released into the environment are safe until proven harmful, Steingraber joins a growing number of environmental scientists and advocacy groups who have suggested the opposite approach – that advocates of chemical use should bear the burden of demonstrating safety (Steingraber, 1998) While regulatory proscriptions like those of the precautionary approach have historically been attacked vehemently by the chemical industry (CMA, 1979), the principle offers a method that can integrate scientific and ethical rationality, and because it emphasizes public disclosure of safety test results, it encourages democratic decision-making rather than decisions based solely upon privately-held expert knowledge.

            As articulated in principle 15 of the Rio Declaration on Environment and Development in 1992, the precautionary principle was originally defined as follows:

In order to protect the environment, the precautionary approach shall be widely applied by States according to their capabilities. Where there are threats of serious or irreversible damage, lack of full scientific certainty shall not be used as a reason for postponing cost-effective measures to prevent environmental degradation (UNEP, 1992).

            There are three major problems with this definition: first, the phrase “according to their capabilities” leaves a significant amount of room for delay, particularly in cases where endpoints are multigenerational or difficult to measure using current techniques (Colborn, et. al. p. 263, 1996) Second, “cost-effective measures” are ill-defined because the time frame for calculating these costs is not specified, encouraging economic discounting of the future (Baumol & Blinder, p. 547, 1985) Also, because industries can inflate their estimated losses using worst-case loss scenarios and by ignoring possible benefits deriving from innovation, the inclusion of cost-effectiveness into the equation weakens the principle as defined. Third, the definition requires scientific demonstration of harm and there are a number of cases where harm has not yet been definitively linked to chemical exposures even though it is clearly possible that there is a relationship, such as dropping sperm counts (Sharpe & Skakkebæk, 1993, Cheek, et. al., 1998) This bias results in type-II errors, or errors that result in a risk to the public, because science requires funds to perform experimentation and significance typically requires a demonstrable statistical difference between cases and controls in order to demonstrate an effect, but statistical significance is exactly what is unachievable for detecting subtle, chronic effects (Schettler, et. al., p. 24, 2000, Weiss, 1998, Weiss, 2002, Schrader-Frechette & McCoy, p. 157, 1993)

            Indeed, the Chemical Manufacturers Association (CMA) has seized upon these ambiguities and has interpreted the Rio definition of the precautionary principle to require the public to demonstrate scientifically that a given product actually causes harm; further, they believe that a body of scientific evidence is required, rather than just an indication of harm (CMA, p.3, 1996). In cases where harm is likely, they advocate risk management techniques to determine the appropriate response given the estimated economic costs (CMA, p.5-6, 1996). That is, they are advocating the same exact position they have maintained for the entire history of chemical regulation. Because a large number of scientists receive funding directly or indirectly from the CMA (Tye, 1998), this raises questions of expert control over chemical usage, and diverts attention away from the necessity of releasing basic toxicity data. These conditions contradict the tenets of democracy, and instead encourage a kind of totalitarian decision-making process performed by so-called “experts" (Gaventa, p. 27, 1993). This process is readily apparent in the realm of agriculture, where the dominance of “experts” has resulted in narrowly defined objectives based on food production criteria that routinely ignores social costs such as ecological degradation and other risks to the public (Raina & Sangar, p.118, 2002).

            Despite these impediments, scientists like Steingraber are following the path forged by Rachel Carson and are instead appealing to the public directly and bypassing the rigid institutionalized structures that have heretofore dominated decision-making that ultimately affects both human and ecosystem health. Groups such as the Science and Environmental Health Network (SEHN) are vigorously advocating for a form of the precautionary principle that eschews the dominance of vested experts in decision-making processes and encourages the public to re-engage in these debates by providing information that integrates science, ethics, and policy (SEHN, 2003). Like Steingraber, groups such as SEHN are promoting the idea of reverse onus – that the advocates of chemical use must bear the burden of proof when the safety of their products are challenged; they and other groups are now demanding credible scientific evidence of safety prior to their widespread use (Tickner, et. al., p. 5, 2003)

            The battle lines that have been drawn between the two sides in this debate follow the classical model of a scientific revolution outlined by Kuhn over thirty years ago, in the sense that increasing health and wildlife problems are creating a crisis that cannot be resolved through the methods of normal science (Kuhn, p.94, 1962[1996]) Recent developments seem to indicate that the precautionary paradigm is gaining momentum, as recently the European Union has moved to implement a new program known as Registration, Evaluation and Authorization of Chemicals (REACH), which would require that all chemicals marketed in excess of one ton per year to be evaluated along the lines suggested by the precautionary principle (European Commission, 2003). Thirty-three organizations have come forward in support of the program, suggesting that it represents both a model for U.S. regulatory changes as well as an opportunity to educate the public on the paucity of data provided by chemical companies regarding the safety of their products (Environmental Media Services, 2003). Perhaps a threshold is approaching, a “tipping point” in the chemical use paradigm (Gladwell, p. 21, 2002). Like the unfolding of an epidemic, the tipping point of this paradigmatic change may be brought about by those individuals and groups who are now taking a stand by suggesting that the more radical idea is not to change current practices – but that in actuality, the more radical idea may be to follow a paradigm that insists on flirting with disaster.

 

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welshons_chart.jpg

Figure 1: Dose-response curves of MCF-7 and C4-12-5 cells. A) estrogen responsive cells exposed to estradiol, B) estrogen non-responsive cells exposed to estradiol, and c) a positive control showing that 3 ppt of DES is capable of obscuring low-dose effects of estradiol. Source: Welshons, et. al. (2003)

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