The issue of hormone disruption is a significant environmental controversy with many emerging questions and concerns. Some scientists believe that a large number of the chemicals currently found in our air, water, soil, and food supply or added to livestock to increase growth have the ability to act as hormones when ingested by human beings and wildlife. Estrogen-mimicking growth hormones in chicken have been linked to early onset of menses and an increase in female attributes in male humans. The decrease in human sperm counts over the last 50 years may be due to hormone-disrupting chemicals. These chemicals increase profits for livestock producers and chemical manufacturers but may also increase food security and provide public health protection from other environmental risks.
I. Human Reactions to Chemicals in the Environment
II. Endocrine Disruptors: How Do They Disrupt?
III. Environmental Estrogens
IV. Environmental Thyroid Hormone Disruptors
V. Deformed Frogs: Pesticides Mimicking Retinoic Acid?
VI. Chains of Causation
VII. Human Impacts
Human Reactions to Chemicals in the Environment
There are many potentially dangerous chemicals in the environment, both human-made and naturally occurring. There is also a range of human reactions to environmental stressors such as these chemicals. The human body has many exposure vectors, such as skin absorption, ingestion, and breathing. There is a large variation in response to chemicals in heterogeneous populations such as that of the United States. This makes it very difficult to predict what dose of a chemical is safe enough for use in different applications, adding fuel to the overall controversy. Children take in more of their environment as they grow than they do when they reach adulthood.
Once in the body, chemicals travel and interact with various bodily systems before they are excreted. Throughout the body there are hormone receptor sites designed specifically for a particular hormone, such as estrogen or testosterone. Hormones are produced primarily in the pituitary gland. Once attached, the hormone controls cell maturation and behavior.
The controversy about endocrine disruption begins because many common chemicals have molecular shapes similar to the shapes of many hormones. This means that these chemicals can fit themselves into cellular receptor sites. When this happens, the chemical either prevents real hormones from attaching to the receptor or alters the cell’s behavior and/or maturation. The growth of the cell is seriously disrupted. Which chemicals have this effect, and in what dosages, is a major area of controversy. However, only about 2 percent of the chemicals sold in the United States are tested for public health safety. Even these tests are industry-controlled, critics claim, and their results are not based on vulnerability (e.g., children) or dose–response variations. Of particular concern are chemicals that contain chlorine. Chlorine-containing chemicals are themselves part of a larger class called persistent organic pollutants (POPs), which are also believed to be potential hormone disruptors. They pose a greater risk because they persist in the environment for a long time, taking longer to break down into nondangerous components. Because they take longer to break down, they increase exposure times and vectors to humans. Because exposure is increased, the risk from these chemicals, especially endocrine disruptors, is considered greater.
Endocrine Disruptors: How Do They Disrupt?
Endocrine disruptors are externally induced chemicals that interfere with the normal function of hormones. Hormones have many functions essential to human growth, development, and functioning. Endocrine disruptors can disrupt hormonal function in many ways. Here are some of them:
- Endocrine disruptors can mimic the effects of natural hormones by binding to their receptors.
- Endocrine disruptors may block the binding of a hormone to its receptor, or they can block the synthesis of the hormone. Finasteride, a chemical used to prevent male-pattern baldness and enlargement of the prostate gland, is an antiandrogen, since it blocks the synthesis of dihydrotestosterone. Women are warned not to handle this drug if they are pregnant, since it could arrest the genital development of male fetuses.
- Endocrine disruptors can interfere with the transport of a hormone or its elimination from the body. For instance, rats exposed to polychlorinated-biphenyl pollutants (PCBs; see following) have low levels of thyroid hormone. The PCBs compete for the binding sites of the thyroid hormone transport protein. Without being bound to this protein, the thyroid hormones are excreted from the body.
Developmental toxicology and endocrine disruption are relatively new fields of research. Although traditional toxicology has pursued the environmental causes of death, cancer, and genetic damage, developmental toxicology/endocrine disruptor research has focused on the roles that environmental chemicals may have in altering development by disrupting normal endocrine function of surviving animals.
There is probably no bigger controversy in the field of toxicology than whether chemical pollutants are responsible for congenital malformations in wild animals, the decline of sperm counts in men, and breast cancer in women. One of the sources of these pollutants is pesticide use. Americans use some two billion pounds of pesticides each year, and some pesticide residues stay in the food chain for decades. Although banned in the United States in 1972, DDT has an environmental half-life of about 100 years. Recent evidence has shown that DDT (dichloro-diphenyl-trichloroethane) and its chief metabolic by-product, DDE (which lacks one of the chlorine atoms), can act as estrogenic compounds, either by mimicking estrogen or by inhibiting the effectiveness of androgen. DDE is a more potent estrogen than DDT and is able to inhibit androgen-responsive transcription at doses comparable to those found in contaminated soil in the United States and other countries. DDT and DDE have been linked to such environmental problems as the decrease in the alligator populations in Florida, the feminization of fish in Lake Superior, the rise in breast cancers, and the worldwide decline in human sperm counts. Others have linked a pollutant spill in Florida’s Lake Apopka (a discharge including DDT, DDE, and numerous other polychlorinated biphenyls) to a 90 percent decline in the birth rate of alligators and reduced penis size in the young males.
Dioxin, a by-product of the chemical processes used to make pesticides and paper products, has been linked to reproductive anomalies in male rats. The male off spring of rats exposed to this planar, lipophilic molecule when pregnant have reduced sperm counts, smaller testes, and fewer male-specific sexual behaviors. Fish embryos seem particularly susceptible to dioxin and related compounds, and it has been speculated that the amount of these compounds in the Great Lakes during the 1940s was so high that none of the lake trout hatched there during that time survived.
Some estrogenic compounds may be in the food we eat and in the wrapping that surrounds them, for some of the chemicals used to set plastics have been found to be estrogenic. The discovery of the estrogenic effect of plastic stabilizers was made in an unexpected way. Investigators at Tufts University Medical School had been studying estrogen-responsive tumor cells. These cells require estrogen in order to proliferate. The studies were going well until 1987, when the experiments suddenly went awry. That is, the control cells began to show high growth rates, suggesting stimulation comparable to that of the estrogen-treated cells. Thus it was if someone had contaminated the medium by adding estrogen to it. What was the source of contamination? After spending four months testing all the components of their experimental system, the researchers discovered that the source of estrogen was the plastic tubes that held their water and serum.
The company that made the tubes refused to tell the investigators about its new process for stabilizing the polystyrene plastic, so the scientists had to discover it for themselves. The culprit turned out to be p-nonylphenol, a chemical that is also used to harden the plastic of the plumbing tubes that bring us water and to stabilize the polystyrene plastics that hold water, milk, orange juice, and other common liquid food products. This compound is also the degradation product of detergents, household cleaners, and contraceptive creams. A related compound, 4-tert-pentylphenol, has a potent estrogenic effect on cultured human cells and can cause male carp (Cyprinus carpis) to develop oviducts, ovarian tissue, and oocytes.
Some other environmental estrogens are polychlorinated biphenyls (mentioned earlier). These PCBs can react with a number of different steroid receptors. PCBs were widely used as refrigerants before they were banned in the 1970s, when they were shown to cause cancer in rats. They remain in the food chain, however (in both water and sediments), and have been blamed for the widespread decline in the reproductive capacities of otters, seals, mink, and fish. Some PCBs resemble diethylstilbesterol (DES) in shape, and they may affect the estrogen receptor as DES does, perhaps by binding to another site on the estrogen receptor. Another organochlorine compound (and an ingredient in many pesticides) is methoxychlor. This can severely inhibit frogs’ fertility, and it may be a component of the worldwide decline in amphibian populations.
Some scientists, however, say that these claims are exaggerated. Tests on mice have shown that litter size, sperm concentration, and development were not affected by concentrations of environmental estrogens. However, recent work has shown a remarkable genetic difference in the sensitivity to estrogen among different strains of mice. The strain that had been used for testing environmental estrogens, the CD-1 strain, is at least 16 times more resistant to endocrine disruption than the most sensitive strains, such as B6. When estrogen-containing pellets were implanted beneath the skin of young male CD-1 mice, very little happened. However, when the same pellets were placed beneath the skin of B6 mice, their testes shrank and the number of sperm seen in the seminiferous tubules dropped dramatically. This wide range of sensitivities has important consequences for determining safety limits for humans. This is sometimes known as the variance in the dose response to a given chemical.
Environmental Thyroid Hormone Disruptors
The structure of some PCBs resembles that of thyroid hormones, and exposure to them alters serum thyroid hormone levels in humans. Hydroxylated PCB was found to have high affinities for the thyroid hormone serum transport protein transthyretin, and it can block thyroxine from binding to this protein. This leads to the elevated excretion of the thyroid hormones. Th yroid hormones are critical for the growth of the cochlea of the inner ear, and rats whose mothers were exposed to PCBs had poorly developed cochleas and hearing defects.
Deformed Frogs: Pesticides Mimicking Retinoic Acid?
Throughout the United States and southern Canada there is a dramatic increase in the number of deformed frogs and salamanders in what seem to be pristine woodland ponds. These deformities include extra or missing limbs, missing or misplaced eyes, deformed jaws, and malformed hearts and guts. There is speculation that pesticides (sprayed for mosquito and tick control) might be activating or interfering with the retinoic acid pathway. The spectrum of abnormalities seen in these frogs resembles the malformations caused by exposing tadpoles to retinoic acid.
Chains of Causation
Whether in law or science, establishing chains of causation is a demanding and necessary task. In developmental toxicology, numerous endpoints must be checked, and many different levels of causation have to be established. For instance, one could ask if the pollutant spill in Lake Apopka was responsible for the feminization of male alligators. To establish this, one has to ask how the chemicals in the spill might contribute to reproductive anomalies in male alligators and what would be the consequences of that happening. After observing that the population level of the alligators had declined, unusually high levels of estrogens in the female alligators, unusually low levels of testosterone in the males, and a decrease in the number of births among the alligators were reported. On the tissue and organ level, the decline in birth rate can be explained by the elevated production of estrogens from the juvenile testes, the malformation of the testes and penis, and the changes in enzyme activity in the female gonads. On the cellular level, one sees ovarian abnormalities that correlate with unusually elevated estrogen levels. These cellular changes, in turn, can be explained at the molecular level by the finding that many of the components of the pollutant spill bind to the alligators’ estrogen and progesterone receptors and that they are able to circumvent the cell’s usual defenses against overproduction of steroid hormones.
It is a matter of debate now as to how to prove the effects of environmental compounds on humans. Scientists claim that genetic variation in the human species, the lack of controlled experiments to determine the effect of any particular compound on humans, and a large range of other multiple intervening factors make any causality difficult to prove. Evidence from animal studies suggests that humans and natural animal populations are at risk from these endocrine disruptors. It may be that the damage is greater than thought because most risk assessments do not compute cumulative effects. Because of the many exposure vectors of chemicals, the cumulative impacts and risks could be far greater and have far-reaching effects on many people.
As chemical emissions accumulate in the environment and bioaccumulate in humans, more controversy will ensue. Loss of fertility, cancer, and other health issues may not be worth the price of increased profits for industries that use or manufacture these chemicals. As more of these chemicals are used and more of their effects become known, this controversy will escalate.
Robert William Collin
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- Wittcoff , Harold A., Jeffery S. Plotkin, and Bryan G. Reuben, Industrial Organic Chemicals. Hoboken, NJ: Wiley, 2004.