Endocrine disruptor

Endocrine disruptors (sometimes also referred to as hormonally active agents) are exogenous substances that act like hormones in the endocrine system and disrupt the physiologic function of endogenous hormones. Studies have linked endocrine disruptors to adverse biological effects in animals, giving rise to concerns that low-level exposure might cause similar effects in human beings.

Background

Since the publication of Rachel Carson’s Silent Spring, there has been concern that chemicals in the environment might exert profound and deleterious effects on wildlife populations, and that human health is inextricably linked to the health of the environment.

Although researchers had studied the endocrine effects of chemicals in the past, the term endocrine disruptor was coined in 1991 at a conference at the Wingspread Conference Center in Racine, Wisconsin. This conference was chaired by Theo Colburn, then with the World Wildlife Fund and the W. Alton Jones Foundation. The term was introduced into the scientific literature with her 1993 paper. In this paper, she stated that environmental chemicals disrupt the development of the endocrine system, and that effects of exposure during development are permanent.

Endocrine disrupting compounds encompass a variety of chemical classes, including hormones, plant constituents, pesticides, compounds used in the plastics industry and in consumer products, and other industrial by-products and pollutants. Some are pervasive and widely dispersed in the environment. Some are persistent organic pollutants (POP's), and can be transported long distances across national boundaries and have been found in virtually all regions of the world. Others are rapidly degraded in the environment or human body or may be present for only short periods of time. Health effects attributed to endocrine disrupting compounds include a range of reproductive problems (reduced fertility, male and female reproductive tract abnormalities, and skewed male/female sex ratios, loss of fetus, menstrual problems, changes in hormone levels; early puberty; brain and behavior problems; impaired immune functions; and various cancers.

One example of the consequences of the exposure of developing animals, including humans, to hormonally active agents is the case of the drug diethylstilbestrol (DES), a non-steroidal estrogen and not an environmental pollutant. Prior to its ban in the early 1970s, doctors prescribed DES to as many as five million pregnant women to block spontaneous abortion, an Off-label use of this medication prior to 1947. It was discovered after the children went through puberty that DES affected the development of the reproductive system and caused vaginal cancer. The relevance of the DES saga to the risks of exposure to endocrine disruptors is questionable, as the doses involved are much higher in these individuals than in those due to environmental exposures.

Endocrine system

Main article: Endocrine system

Endocrine systems are found in most varieties of animal life. The endocrine system is made up of glands which secrete hormones, and receptors which detect and react to the hormones.

Hormones travel throughout the body and act as chemical messengers. Hormones interface with cells that contain matching receptors in or on their surfaces. The hormone binds with the receptor, much like a key would fit into a lock.

Sex steroids such as estrogens and androgens, as well as thyroid hormones, are subject to feedback regulation, which tends to limit the effects of environmental chemicals.

Theory of endocrine disruption

All communication within the human body is facilitated by the either the nervous system or the endocrine system. The nervous system transmits sensory messages to the brain and enables quick responses to sudden environmental events. Typically, these responses involve physical adjustments to avoid something harmful, such as intense heat. The endocrine system regulates adjustments through slower internal processes, using hormones as messengers. The endocrine system secretes hormones in response to environmental stimuli and to orchestrate developmental and reproductive changes. The adjustments brought on by the endocrine system are biochemical, changing the cell's internal and external chemistry to bring about a long term change in the body. These systems work together to maintain the proper functioning of the body through its entire life cycle.

The theory of endocrine disruption posits that low-dose exposure to chemicals that interact with hormone receptors can interfere with reproduction, development, and other hormonally mediated processes. Furthermore, since endogenous hormones are typically present in the body relatively tiny concentrations, the theory holds that exposure to relatively small amounts of exogenous hormonally active substances can disrupt the proper functioning of the body's endocrine system. Thus, an endocrine disruptor might be able to elicit adverse effects at a much lower doses than a toxicant acting through a different mechanism.

The timing of exposure is also presumed to be critical, since different hormone pathways are active during different stages of development. Particularly with younger individuals that are growing rapidly, interfering with the hormonal communication processes these systems provide can have profound effects on the body. Depending on the stage of reproductive development, interference with hormonal signaling can result in irreversible effects not seen in adults exposed to the same dose for the same length of time. Experiments with animals have identified critical developmental time points in utero and days after birth when exposure to chemicals that interfere with or mimic hormones have adverse effects that persist into adulthood. Disruption of thyroid function early in development may be the cause of abnormal sexual development in both males and females early motor development impairment, and learning disabilities.

There are studies of cell cultures, laboratory animals, wildlife, and accidentally exposed humans that show that environmental chemicals cause a wide range of reproductive, developmental, growth, and behavior effects, and so while "endocrine disruption in humans by pollutant chemicals remains largely undemonstrated, the underlying science is sound and the potential for such effects is real." While compounds that produce estrogenic, androgenic, antiandrogenic, and antithyroid actions have been studied, less is known about interactions with other hormones.

The interrelationship between exposures to chemicals and health effects are rather complex. It is hard to definitively link a particular chemical with a specific health effect, and exposed adults may not show any ill effects. But, fetuses and embryos, whose growth and development are highly controlled by the endocrine system, are more vulnerable to exposure and may suffer overt or subtle lifelong health and/or reproductive abnormalities. Prebirth exposure, in some cases, can lead to permanent alterations and adult diseases.

There is concern by some in the scientific community that exposure to endocrine disruptors in the womb or early in life may be associated with neurodevelopmental disorders including reduced IQ, ADHD, and autism. Certain cancers and uterine abnormalities in women are associated with exposure to DES in the womb due to DES used a medical treatment. In another case, phthalates in pregnant women’s urine was linked to subtle, but specific, genital changes in their male infants – a shorter, more female-like anal-genital distance and associated incomplete descent of testes and a smaller scrotum and penis. The science behind this study has been questioned by phthalate industry consultants.

As of June 2008, there are only five studies of anogenital distance in humans, and one researcher has stated "Whether AGD measures in humans relate to clinically important outcomes, however, remains to be determined, as does its utility as a measure of androgen action in epidemiologic studies."

Scientific objection to the theory

One major objection to the theory of endocrine disruptors is the dosage effect. There is a large gap between high exposures seen in a some laboratory experiment versus the relatively low levels found in the environment. Critics argue that dose-response relationship data suggest that the amounts of the chemicals actually in the environment are too low to cause an effect. A consensus statement by the Learning and Development Disabilities Initiative rebuts this criticism arguing that "The very low-dose effects of endocrine disruptors can not be predicted from high-dose studies, which contradicts the standard 'dose makes the poison' rule of toxicology. Nontraditional dose-response curves are referred to as nonmonotonic dose response curves." Furthermore, endocrine disrupting effects have been noted in animals exposed to environmentally relevant levels of some chemicals. For example, researchers have found that a common flame retardant, PBDE-47, affects the reproductive system and thyroid gland of female rats in doses of the order of those to which humans are exposed.

The dosage objection could also be overcome if low concentrations of different endocrine disruptors were synergistic, which was asserted in a paper by Arnold. This paper was published in Science in June 1996, and was one reason for the passage of the Food Quality Protection Act of 1996. The results could not be confirmed with the same and alternative methodologies, and the original paper was retracted, and Arnold was found to have committed scientific misconduct by the United States Office of Research Integrity. Subsequent papers by other authors demonstrated that low concentrations of endocrine disruptors can have synergistic effects in amphibians, but it is not clear that this is an effect mediated through the endocrine system.

Routes of exposure

Food is a major source of pollutant exposure. Diet is thought to account for up to 90% of a person's PCB and DDT body burden. In a study of 32 different common food products from three grocery stores in Dallas, fish and other animal products were found to be contaminated with PBDE. Since these compounds are fat soluble, it is likely they are accumulating from the environment in the fatty tissue of animals we eat. Some suspect fish consumption is a major source of many environmental contaminates. Indeed, both wild and farmed salmon from all over the world have been shown to contain a variety of man-made organic compounds.

With the increase in household products containing pollutants and the decrease in the quality of building ventilation, indoor air has become a significant source of pollutant exposure.

Residents living in homes with wood floors treated in the 1960s with PCB-based wood finish have a much higher body burden than the general population. A study of indoor house dust and dryer lint of 16 homes found high levels of all 22 different PBDE congeners tested for in all samples. Recent studies suggest that contaminated house dust, not food, may be the major source of PBDE in our bodies. One study estimated that ingestion of house dust accounts for up to 82% of our PBDE body burden.

Research conducted by the Environmental Working Group found that 19 out of 20 children tested had levels of PBDE in their blood 3.5 times higher than the amount in their mothers' blood. It has been shown that contaminated housedust is a primary source of lead in young children's bodies. It may be that babies and toddlers ingest more contaminated housedust than the adults they live with, and therefore have much higher levels of pollutants in their systems.

Types of endocrine disruptors

All people are exposed to chemicals with estrogenic effects in their everyday life, because endocrine disrupting chemicals are found in low doses in literally thousands of products. Chemicals commonly detected in people include DDT, Polychlorinated biphenyls (PCB's), Bisphenol A, Polybrominated diphenyl ethers (PBDE's), and a variety of Phthalates. There is a some dispute in the scientific community surrounding the claim that these chemical actually disrupt the endocrine system. Many believe that there is little evidence that the degree of exposure in humans is enough to warrant concern, while many others believe there is evidence that these chemicals pose some risk to human health.

Some researchers are investigating the health risks to children of endocrine disrupting chemicals. Bisphenol A has come under a great deal of scrutiny as it is a common component of plastic baby bottles. In March 2007, a class action lawsuit was filed in California charging that manufacturers and retailers of plastic baby bottles failed to warn consumers that their products contained Bisphenol A, a chemical that they allege poses developmental and health risks to infants and children.

DDT

Main article: DDT

Dichloro-diphenyl-trichloroethane (DDT) was first used as a pesticide against Colorado potato beetles on crops beginning in 1936. An increase in the incidence of malaria, epidemic typhus, dysentery, and typhoid fever led to its use against the mosquitoes, lice, and houseflies that carried these diseases. Before WWII, pyrethrum, an extract of a flower from Japan, had been used to control these insects and the diseases they can spread. During WWII, Japan stopped exporting pyrethrum, forcing the search for an alternative. Fearing an epidemic outbreak of typhus, every British and American soldier was issued DDT, who routinely dusted beds, tents, and barracks all over the world.

Considered safe, although little testing had been conducted, DDT was approved for general, non-military use after the war ended. It became used worldwide to increase monoculture crop yields that were threatened by pest infestation, and to reduce the spread of malaria which had a high mortality rate in many parts of the world. It's use was essentially banned worldwide, although it is permitted as a control against malaria in some regions, like Mexico, where malaria continues to be a major threat.

As early as 1946, the harmful effects of DDT on bird, beneficial insects, fish, and marine invertebrates were seen in the environment. The most infamous example of these effects were seen in the eggshells of large predatory birds, which did not develop to be thick enough to support the adult bird sitting on them. Further studies found DDT in high concentrations in carnivores all over the world, the result of biomagnification through the food chain. Twenty years after its widespread use, DDT was found trapped in ice samples taken from Antarctic snow, suggesting wind and water are another means of environmental transport. Recent studies show the historical record of DDT deposition on remote glaciers in the Himalayas.

More than sixty years ago when biologists began to study the effects of DDT on laboratory animals, it was discovered that DDT interfered with reproductive development. Recent studies suggest DDT may inhibit the proper development of female reproductive organs that adversely affects reproduction into maturity. Additional studies suggest that a marked decrease in fertility in adult males may be due to DDT exposure. Most recently, it has been suggested that exposure to DDT in utero can increase a child's risk of childhood obesity.

Polychlorinated biphenyls

Main article: Polychlorinated biphenyls

Polychlorinated biphenols (PCBs) are a class of chlorinated compounds used as industrial coolants and lubricants. PCBs are created by heating benzene, a byproduct of gasoline refining, with chlorine. They were first manufactured commercially by the Swann Chemical Company in 1927. In 1933, the health effects of direct PCB exposure was seen in those who worked in with the chemicals at the manufacturing facility in Alabama. In 1935, Monsanto acquired the company, taking over US production and licensing PCB manufacturing technology internationally.

General Electric was one of the largest US companies to incorporate PCBs into manufactured equipment. Between 1952 and 1977, the New York GE plant had dumped more than 500,000 pounds of PCB waste into the Hudson River. PCBs were first discovered in the environment far from its industrial use by scientists in Sweden studying DDT.

The effects of acute exposure to PCBs were well known within the companies who used Monsanto's PCB formulation who saw the effects on their workers who came into contact with it regularly. Direct skin contact results in a severe acne-like condition called chloracne. Exposure increases the risk of skin cancer, liver cancer, and brain cancer. Monsanto tried for years to downplay the health problems related to PCB exposure in order to continue sales.

The detrimental health effects of PCB exposure to humans became undeniable when two separate incidents of contaminated cooking oil poisoned thousands of residents in Japan and Taiwan, leading to a worldwide ban on PCB use in 1977. Recent studies show the endocrine interference of certain PCB congeners is toxic to the liver and thyroid, increases childhood obesity in children exposed prenatally, and may increase the risk of developing diabetes.

Bisphenol A

Main article: Bisphenol A

Bisphenol A is found in some plastic water and baby bottles, plastic food containers, dental materials, and the linings of metal food and infant formula cans. It is a known endocrine disruptor, and "hundreds of studies published in the decade" have found that laboratory animals exposed to low levels of it have elevated rates diabetes, mammary and prostate cancers, decreased sperm count, reproductive problems, early puberty, obesity, and neurological problems. Some scientists believe that humans, especially infants, are currently exposed to levels that are known to cause harm in laboratory animals. The US FDA and the chemical industry maintain that it is safe, but the US Congress has taken steps to restrict the use of bisphenol A and has asked the FDA to reexamine it. Canada recently announced it plans to phase out the use of bisphenol A in baby bottles and metal formula cans. Nalgene, Playtex, and Wal-Mart have agreed to remove this substance from their products by the end of 2008.[3] In August, the FDA issued a draft reassessment, reconfirming their initial opinion that, based on scientific evidence, it is safe. However in October 2008, FDA's advisory Science Board sent FDA back to the drawing board, concluding that the Agency's assessment was "flawed" and hadn't proven the chemical to be safe for formula-fed infants.

Polybrominated diphenyl ethers

Main article: Polybrominated diphenyl ethers

Polybrominated diphenyl ethers (PBDEs) are a class of compounds found in flame retardants used in plastic cases of televisions and computers, electronics, carpets, lighting, bedding, clothing, car components, foam cushions and other textiles. Potential health concern: PBDE's are structurally very similar to Polychlorinated biphenyls (PCBs), and have similar neurotoxic effects.

In the 1930s and 1940s, the plastics industry developed technologies to create a variety of plastics with broad applications. Once World War II began, the US military used these new plastic materials to improve weapons, protect equipment, and to replace heavy components in aircraft and vehicles. After WWII, manufacturers saw the potential plastics could have in many industries, and plastics were incorporated into new consumer product designs. Plastics began to replace wood and metal in existing products as well, and today plastics are the most widely used manufacturing materials.

By the 1960s, all homes were wired with electricity and had numerous electrical appliances. Cotton and wood had been the dominant textile used to produce home furnishings, but now their home furnishings were composed of mostly synthetic materials. More than 500 billion cigarettes were consumed each year in the 1960s, as compared to less than 3 billion per year at the turn of the century. When combined with high density living, the potential for home fires was higher in the 1960s than it had ever been in the US. By the late 1970s, approximately 6000 people in the US died each year in home fires.

In 1972, in response to this situation, the National Commission on Fire Prevention and Control was created to study the fire problem in the US. In 1973 they published their findings in America Burning, a 192-page report that made recommendations to increase fire prevention. Most of the recommendations dealt with fire prevention education and improved building engineering, such as the installation of fire sprinklers and smoke detectors. The Commission expected that with the recommendations, a 5% reduction in fire losses could be expected each year, halving the annual losses within 14 years.

Historically, treatments with alum and borax were used to reduce the flammability of fabric and wood, as far back as Roman times . Since it is a non-absorbent material once created, flame retardant chemicals are added to plastic during the polymerization reaction when it is formed. Organic compounds based on halogens like bromine and chlorine are used as the flame retardant additive in plastics, and in fabric based textiles as well . The widespread use of brominated flame retardants may be due to the push from Great Lakes Chemical Corporation (GLCC) to profit from its huge investment in bromine . In 1992, the world market consumed approximately 150,000 tonnes of bromine-based flame retardants, and GLCC produced 30% of the world supply .

PBDEs have the potential to disrupt thyroid hormone balance and contribute to a variety of neurological and developmental deficits, including low intelligence and learning disabilities. Many of the most common PBDE's were banned in the European Union in 2006. Studies with rodents have suggested that even brief exposure to PBDEs can cause developmental and behavior problems in juveniles and exposure interferes with proper thyroid hormone regulation. Research has correlated halogenated hydrocarbons, such as PCBs, with neurotoxicity. PBDEs are similar in chemical structure to PCBs, and it has been suggested that PBDEs act by the same mechanism as PCBs.

Phthalates

Main article: Phthalates

Phthalates are found in some soft toys, flooring, medical equipment, cosmetics and air fresheners. They are of potential health concern because they are known to disrupt the endocrine system of animals, and some research has implicated them in the rise of birth defects of the male reproductive system. An overview of this paper is given in the same volume.

Although an expert panel has concluded that there is "insufficient evidence" that they can harm the reproductive system of infants, California and Europe have banned them from toys. One phthalate, Bis(2-ethylhexyl) phthalate (DEHP), used in medical tubing, catheters and blood bags, may harm sexual development in male infants. In 2002, the Food and Drug Administration released a public report which cautioned against exposing male babies to DEHP. Although there are no direct human studies the FDA report states: "Exposure to DEHP has produced a range of adverse effects in laboratory animals, but of greatest concern are effects on the development of the male reproductive system and production of normal sperm in young animals. We have not received reports of these adverse events in humans, but there have been no studies to rule them out. However, in view of the available animal data, precautions should be taken to limit the exposure of the developing male to DEHP".

Other suspected endocrine disruptors

Some examples of putative EDCs are vinclozolin, zearalenone, 17-alpha ethinylestradiol, Dioxins, PCBs, PAHs, furans, phenols and several pesticides (most prominent being organochlorine insecticides like endosulfan, DDT and its derivatives). Substances with estrogenic effects include the xenoestrogens and phytoestrogens.

Temporal trends of body burden

Since being banned, the average human body burdens of DDT and PCB have been declining. Since their ban in 1972, the PCB body burden is 1/100 of what it was in the early 1980s (Weschler 2009). Monitoring programs of European breast milk samples have shown that PBDE levels are increasing. An analysis of PBDE content in breast milk samples from Europe, Canada, and the US shows that levels are 40 times higher for North American women than for European women, and that levels in North America are doubling each year.

Legal approach

The multitude of possible endocrine disruptors are technically regulated in the United States by many laws, including: the Toxic Substances Control Act, the Federal Insecticide, Fungicide, and Rodenticide Act, the Food, Drug and Cosmetic Act, the Clean Water Act, the Safe Drinking Water Act, and the Clean Air Act.

The Congress of the United States has improved the evaluation and regulation process of drugs and other chemicals. The Food Quality Protection Act of 1996 and the Safe Drinking Water Act of 1996 simultaneously provided the first legislative direction requiring the EPA to address endocrine disruption through establishment of a program for screening and testing of chemical substances.

In 1998 the EPA announced the Endocrine Disruptor Screening Program by establishment of a framework for priority setting, screening and testing more than 85,000 chemicals in commerce. The basic concept behind the program is that prioritization will be based on existing information about chemical uses, production volume, structure-activity and toxicity. Screening is done by use of in vitro test systems (by examining, for instance, if an agent interacts with the estrogen receptor or the androgen receptor) and via the use of in animal models, such as development of tadpoles and uterine growth in prepubertal rodents. Full scale testing will examine effects not only in mammals (rats) but also in a number of other species (frogs, fish, birds and invertebrates). Since the theory involves the effects of these substances on a functioning system, animal testing is essential for scientific validity, but has been opposed by animal rights groups. Similarly, proof that these effects occur in humans would require human testing, and such testing also has opposition.

After failing to meet several deadlines to begin testing, the EPA finally announced that they were ready to begin the process of testing dozens of chemical entities that are suspected endocrine disruptors early in 2007, eleven years after the program was announced. When the final structure of the tests was announced there was objection to their design. Critics have charged that the entire process has been compromised by chemical company interference. In 2005, the EPA appointed a panel of experts to conduct an open peer-review of the program and its orientation. Their results found that "the long-term goals and science questions in the EDC program are appropriate", however this study was conducted over a year before the EPA announced the final structure of the screening program.

Environmental and human body cleanup

There is evidence that once a pollutant is no longer in use, or once its use is heavily restricted, the human body burden of that pollutant declines. Through the efforts of several large scale monitoring programs, the most prevalent pollutants in the human population are fairly well known. The first step in reducing our body burden of these pollutants is enacting policies that eliminate or phase out their production.

The second step toward lowering human body burden is awareness of and potentially labeling foods that are likely to contain high amounts of pollutants. This strategy has worked in the past - pregnant and nursing women are cautioned against eating seafood that is known to accumulate high levels of mercury. Ideally, a certification process should be in place to routinely test animal products for POP concentrations. This would help the consumer identify which foods have the highest levels of pollutants.

The most challenging aspect of this problem is discovering how to eliminate these compounds from the environment and where to focus remediation efforts. Even pollutants no longer in production persist in the environment, and bioaccumulate in the food chain. An understanding of how these chemicals, once in the environment, move through ecosystems, is essential to designing ways to isolate and remove them. Working backwards through the food chain may help to identify areas to prioritize for remediation efforts. This may be extremely challenging for contaminated fish and marine mammals that have a large habitat and who consume fish from many different areas throughout their lives.

Many persistent organic compounds, PCB, DDT and PBDE included, accumulate in river and marine sediments. Several processes are currently being used by the EPA to cleanup heavily polluted areas, as outlined in their Green Remediation program . One of the most interesting ways is the utilization of naturally occurring microbes that degrade PCB congeners to remediate contaminated areas.

There are many success stories of cleanup efforts of large heavily contaminated Superfund sites. A 10-acre landfill in Austin, Texas contaminated with illegally dumped VOCs was restored in a year to a wetland and educational park. A US uranium enrichment site that was contaminated with uranium and PCBs was cleaned up with high tech equipment used to find the pollutants within the soil. The soil and water at a polluted wetlands site were cleaned of VOCs, PCBs and lead, native plants were installed as biological filters, and a community program was implemented to ensure ongoing monitoring of pollutant concentrations in the area. These case studies are encouraging due to the short amount of time needed to remediate the site and the high level of success achieved.

See also

• Dose-response relationship
• Endocrine system
• Hormone
• Precautionary principle
• Theo Colborn
• Xenoestrogen
• Antimetabolite

Futher reading

• Myers, John E. B.; Colborn, Theo; Dumanoski, Dianne (1997). Our stolen future: are we threatening our fertility, intelligence, and survival?: a scientific detective story: with a new epilogue by the authors. New York, N.Y., U.S.A: Penguin Group. ISBN 0-452-27414-1.{{cite book}}: CS1 maint: multiple names: authors list (link)
• Sheldon Krimsky (2000). Hormonal chaos: the scientific and social origins of the environmental endocrine hypothesis. Baltimore: Johns Hopkins University Press. ISBN 0-8018-6279-5.

External links

• VIDEO Endocrine Disruptors: Fact vs. Fad Presentation by Ellen L. Connor, M.D., at the UW-Madison Health Sciences Learning Center.
• List of suspected or possible endocrine disruptors
• Global assessment of the state-of-the-science of endocrine disruptors published in 2002 by the World Health Organisation (WHO).
  • Scientific Facts on Endocrine Disruptors, a peer-reviewed summary of the above WHO assessment, by GreenFacts.
• The NSF sponsored Environmental Signalling Network's website
• The EU strategy on EDCs
• The US EPA (strategy) on EDCs
• Synopses of new scientific findings about endocrine disruption
• Journalist's report on endocrine disruptors (OnEarth Magazine, Winter 2006)
• PBS Frontline Interview of Dr. Theo Colborn by Doug Hamilton, 1998.
• Hormonal Chaos: The Scientific and Social Origins of the Environmental Endocrine Hypothesis by Sheldon Krimsky ISBN 0801862795
• "Sex-change chemicals in Potomac", BBC News, last updated 18 January 2007.