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
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
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.

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 (Bern 1992). 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.

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 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.

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 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. 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
Polybrominated diphenyl ethers are 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. 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.

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. 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.

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.

Books

 * Colborn, Theo; Dianne Dumanoski; and John Peterson Myers. Our stolen future : are we threatening our fertility, intelligence, and survival? : a scientific detective story. New York : Dutton, 1996. 306 p. ISBN 0452274141


 * Sheldon Krimsky. Hormonal Chaos: The Scientific and Social Origins of the Environmental Endocrine Hypothesis Johns Hopkins University Press, 2002. 256p. ISBN 0801862795