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Endocrine disruptor

Endocrine disruptors, sometimes also referred to as hormonally active agents, endocrine disrupting chemicals, or endocrine disrupting compounds are chemicals that can interfere with endocrine (or hormonal) systems. These disruptions can cause numerous adverse human health outcomes including, alterations in sperm quality and fertility, abnormalities in sex organs, endometriosis, early puberty, altered nervous system function, immune function, certain cancers, respiratory problems, metabolic issues, diabetes, obesity, cardiovascular problems, growth, neurological and learning disabilities, and more. Found in many household and industrial products, endocrine disruptors "interfere with the synthesis, secretion, transport, binding, action, or elimination of natural hormones in the body that are responsible for development, behavior, fertility, and maintenance of homeostasis (normal cell metabolism)."

Any system in the body controlled by hormones can be derailed by hormone disruptors. Specifically, endocrine disruptors may be associated with the development of learning disabilities, severe attention deficit disorder, cognitive and brain development problems.

There has been controversy over endocrine disruptors, with some groups calling for swift action by regulators to remove them from the market, and regulators and other scientists calling for further study. Some endocrine disruptors have been identified and removed from the market (for example, a drug called diethylstilbestrol), but it is uncertain whether some endocrine disruptors on the market actually harm humans and wildlife at the doses to which wildlife and humans are exposed. The World Health Organization published a 2012 report stating that low-level exposures may cause adverse effects in humans.

History
The term endocrine disruptor was coined in 1991 at the Wingspread Conference Center in Wisconsin. One of the early papers on the phenomenon was by Theo Colborn in 1993. In this paper, she stated that environmental chemicals disrupt the development of the endocrine system, and that effects of exposure during development are often permanent. Although the endocrine disruption has been disputed by some, work sessions from 1992 to 1999 have generated consensus statements from scientists regarding the hazard from endocrine disruptors, particularly in wildlife and also in humans.

The Endocrine Society released a scientific statement outlining mechanisms and effects of endocrine disruptors on "male and female reproduction, breast development and cancer, prostate cancer, neuroendocrinology, thyroid, metabolism and obesity, and cardiovascular endocrinology," and showing how experimental and epidemiological studies converge with human clinical observations "to implicate endocrine disruptive chemicals (EDCs) as a significant concern to public health." The statement noted that it is difficult to show that endocrine disruptors cause human diseases, and it recommended that the precautionary principle should be followed. A concurrent statement expresses policy concerns.

Endocrine disrupting compounds encompass a variety of chemical classes, including drugs, pesticides, compounds used in the plastics industry and in consumer products, industrial by-products and pollutants, heavy metals and even some naturally produced botanical chemicals. Some are pervasive and widely dispersed in the environment and may bioaccumulate. Some are persistent organic pollutants (POPs), and can be transported long distances across national boundaries and have been found in virtually all regions of the world, and may even concentrate near the North Pole, due to weather patterns and cold conditions. 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 nonsteroidal 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.

Aquatic life subjected to endocrine disruptors in an urban effluent have experienced decreased levels of serotonin and increased feminization.

In 2013 the WHO and the United Nations Environment Programme released a study, the most comprehensive report on EDCs to date, calling for more research to fully understand the associations between EDCs and the risks to health of human and animal life. The team pointed to wide gaps in knowledge and called for more research to obtain a fuller picture of the health and environmental impacts of endocrine disruptors. To improve global knowledge the team has recommended:
 * Testing: known EDCs are only the 'tip of the iceberg' and more comprehensive testing methods are required to identify other possible endocrine disruptors, their sources, and routes of exposure.
 * Research: more scientific evidence is needed to identify the effects of mixtures of EDCs on humans and wildlife (mainly from industrial by-products) to which humans and wildlife are increasingly exposed.
 * Reporting: many sources of EDCs are not known because of insufficient reporting and information on chemicals in products, materials and goods.
 * Collaboration: more data sharing between scientists and between countries can fill gaps in data, primarily in developing countries and emerging economies.

Endocrine system
Endocrine systems are found in most varieties of animals. The endocrine system consists of glands that secrete hormones, and receptors that 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. 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. Sex steroids such as estrogens and androgens, as well as thyroid hormones, are subject to feedback regulation, which tends to limit the sensitivity of these glands.

Hormones work at very small doses (part per billion ranges). Endocrine disruption can thereby also occur from low-dose exposure to exogenous hormones or hormonally active chemicals such as bisphenol A. These chemicals can bind to receptors for other hormonally mediated processes. Furthermore, since endogenous hormones are already present in the body in biologically active concentrations, additional 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 can elicit adverse effects at much lower doses than a toxicity, acting through a different mechanism.

The timing of exposure is also critical. Most critical stages of development occur in utero, where the fertilized egg divides, rapidly developing every structure of a fully formed baby, including much of the wiring in the brain. Interfering with the hormonal communication in utero can have profound effects both structurally and toward brain development. 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 interrelationships 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 develop overt or subtle lifelong health or reproductive abnormalities. Prebirth exposure, in some cases, can lead to permanent alterations and adult diseases.

Some in the scientific community are concerned 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 diethylstilbestrol (DES) in the womb due to DES used as a medical treatment.

In a 2005 publication, phthalates in pregnant women's urine was linked to subtle, but specific, genital changes in their male infants—a shorter, more female-like anogenital distance and associated incomplete descent of testes and a smaller scrotum and penis. The science behind this study was questioned by phthalate industry consultants, and back in 2008, there were only five studies of anogenital distance in humans, with one researcher stating "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 epidemiological studies." Today, it is well-established that AGD is an indicator of fetal androgen exposure, and several studies have found a correlation between AGD and the incidence of prostate cancer.

Effects on intrinsic hormones
Toxicology research shows that some endocrine disruptors target the specific hormone trait that allows one hormone to regulate the production or degradation of intrinsic hormones. As endocrine disruptors have the potential to mimic or antagonize natural hormones, these chemicals can exert their effects by acting through interaction with nuclear receptors, the aryl hydrocarbon receptor or membrane bound receptors.

U-shaped dose-response curve
Most toxicants, including endocrine disruptors, have been claimed to follow a U-shaped dose-response curve. This means that very low and very high levels have more effects than mid-level exposure to a toxicant. Endocrine disrupting effects have been noted in animals exposed to environmentally relevant levels of some chemicals. For example, a common flame retardant, BDE-47, affects the reproductive system and thyroid gland of female rats in doses similar to which humans are exposed. Low concentrations of endocrine disruptors can also have synergistic effects in amphibians, but it is not clear that this is an effect mediated through the endocrine system.

A consensus statement by the Learning and Developmental Disabilities Initiative argued that "The very low-dose effects of endocrine disruptors cannot 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 non-monotonic dose response curves."

It has been claimed that tamoxifen and some phthalates have fundamentally different (and harmful) effects on the body at low doses than at high doses.

Food
Food is a major mechanism by which people are exposed to pollutants. 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 eaten by humans. Some suspect fish consumption is a major source of many environmental contaminants. Indeed, both wild and farmed salmon from all over the world have been shown to contain a variety of man-made organic compounds. While pesticides are found in many food products, phthalates can also leech into crops, vegetables and fruits from contaminated soil and greenhouse plastic covers.

Indoor Air & Household Dust
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 houses 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 humans' PBDE body burden.

It has been shown that contaminated house dust is a primary source of lead in young children's bodies. It may be that babies and toddlers ingest more contaminated house dust than the adults they live with, and therefore have much higher levels of pollutants in their systems.

Cosmetics and Personal Care Products
Consumer goods are another potential source of exposure to endocrine disruptors. An analysis of the composition of 42 household cleaning and personal care products versus 43 "chemical-free" products has been performed. The products contained 55 different chemical compounds: 50 were found in the 42 conventional samples representing 170 product types, while 41 were detected in 43 "chemical-free" samples representing 39 product types. Parabens, a class of chemicals that has been associated with reproductive-tract issues, were detected in seven of the "chemical-free" products, including three sunscreens that did not list parabens on the label. Vinyl products such as shower curtains were found to contain more than 10% by weight of the compound DEHP, which when present in dust has been associated with asthma and wheezing in children. The risk of exposure to EDCs increases as products, both conventional and "chemical-free", are used in combination. "If a consumer used the alternative surface cleaner, tub and tile cleaner, laundry detergent, bar soap, shampoo and conditioner, facial cleanser and lotion, and toothpaste [he or she] would potentially be exposed to at least 19 compounds: 2 parabens, 3 phthalates, MEA, DEA, 5 alkylphenols, and 7 fragrances."

An analysis of the endocrine-disrupting chemicals in Old Order Mennonite women in mid-pregnancy determined that they have much lower levels in their systems than the general population. Mennonites eat mostly fresh, unprocessed foods, farm without pesticides, and use few or no cosmetics or personal care products. One woman who had reported using hairspray and perfume had high levels of monoethyl phthalate, while the other women all had levels below detection. Three women who reported being in a car or truck within 48 hours of providing a urine sample had higher levels of diethylhexyl phthalate, which is found in polyvinyl chloride and is used in car interiors.

Clothing
A more recent discussion around exposure to EDCs has been around clothing, following a study by Greenpeace Germany published in 2014 that found high levels of Phthalates in athletic gear. The print of a t-shirt produced in Argentine contained phthalate levels as high as 15%, while a pair of gloves contained 6% phthalates. The study also found high levels of PFAS, Nonoxynols and Dimethylformamide in shoes and boots.

In research published in 2019, Li et al. stated that dermal absorption was the main route for phthalate exposure in infants, including through clothing. It was found that laundering could not remove phthalates completely. Out of the 6 different types of phthalates that were measured, DEHP and DBP were found to be particularly present in infant clothing.

Tang et al. published research in 2019 that found all 15 different phthalates that were measured in preschoolers' clothing. Levels were largely independent of country of manufacture though they differed by garment type, fabric composition, and garment color. It was found that "when children wore trousers, long-sleeved shirts, briefs and socks at the same time, the reproductive risks exceeded acceptable level".

In a review of 120 articles published between 2014 and 2023 about phthalates in clothing, it was found that while screen printing ink, vinyl patches and synthetic leather may contain 30-60% phthalates, waterproof items such as infant mattress covers also contained very high levels of these chemicals. It was also noted that manufacturers work to replace more regulated substances, such as DEHP, with newer ones, that may not yet be as tightly regulated.

Environment
Additives added to plastics during manufacturing may leach into the environment after the plastic item is discarded; additives in microplastics in the ocean leach into ocean water and in plastics in landfills may escape and leach into the soil and then into groundwater.

Types
All people are exposed to chemicals with estrogenic effects in their everyday life, because endocrine disrupting chemicals are found in low doses in thousands of products. Chemicals commonly detected in people include DDT, polychlorinated biphenyls (PCBs), bisphenol A (BPA), polybrominated diphenyl ethers (PBDEs), and a variety of phthalates. In fact, almost all plastic products, including those advertised as "BPA-free", have been found to leach endocrine-disrupting chemicals. In a 2011, study it was found that some "BPA-free" products released more endocrine active chemicals than the BPA-containing products. Other forms of endocrine disruptors are phytoestrogens (plant hormones).

Xenoestrogens
Xenoestrogens are a type of xenohormone that imitates estrogen. Synthetic xenoestrogens include widely used industrial compounds, such as PCBs, BPA and phthalates, which have estrogenic effects on a living organism.

Alkylphenols
Alkylphenols are xenoestrogens. The European Union has implemented sales and use restrictions on certain applications in which nonylphenols are used because of their alleged "toxicity, persistence, and the liability to bioaccumulate" but the United States Environmental Protections Agency (EPA) has taken a slower approach to make sure that action is based on "sound science".

The long-chain alkylphenols are used extensively as precursors to the detergents, as additives for fuels and lubricants, polymers, and as components in phenolic resins. These compounds are also used as building block chemicals that are also used in making fragrances, thermoplastic elastomers, antioxidants, oil field chemicals and fire retardant materials. Through the downstream use in making alkylphenolic resins, alkylphenols are also found in tires, adhesives, coatings, carbonless copy paper and high performance rubber products. They have been used in industry for over 40 years.

Certain alkylphenols are degradation products from nonionic detergents. Nonylphenol is considered to be a low-level endocrine disruptor owing to its tendency to mimic estrogen.

Bisphenol A (BPA)
Bisphenol A is commonly found in plastic bottles, plastic food containers, dental materials, and the linings of metal food and infant formula cans. Another exposure comes from receipt paper commonly used at grocery stores and restaurants, because today the paper is commonly coated with a BPA containing clay for printing purposes.

BPA is a known endocrine disruptor, and numerous studies have found that laboratory animals exposed to low levels of it have elevated rates of diabetes, mammary and prostate cancers, decreased sperm count, reproductive problems, early puberty, obesity, and neurological problems. To expand on the reproductive problems faced by women exposed to BPA. Studies in the US have shown that healthy women without any fertility problems found that urinary BPA was unrelated to time of pregnancy despite a shorter luteal phase (second part of the menstrual cycle) being reported. Additional studies have been conducted in fertility centers say that BPA exposure is correlation with lower ovarian reserves. To combat this most women will undergo IVF to help with the poor ovarian stimulation response and seemingly all of them have elevated levels of BPA in the urinary tract. Median conjugation of BPA concentrations were higher in those who did have a miscarriage compared to those who had a live birth. All of these studies show that BPA can have an effect on ovarian functions and the pivotal early part of conception. One study did show racial/ethnical differences as Asian women were found to have an increased oocyte maturity rate, but all of the women had significantly lower concentration of BPA just in this study. Early developmental stages appear to be the period of greatest sensitivity to its effects, and some studies have linked prenatal exposure to later physical and neurological difficulties. Regulatory bodies have determined safety levels for humans, but those safety levels are currently being questioned or are under review as a result of new scientific studies. A 2011 cross-sectional study that investigated the number of chemicals pregnant women are exposed to in the U.S. found BPA in 96% of women. In 2010 the World Health Organization expert panel recommended no new regulations limiting or banning the use of bisphenol A, stating that "initiation of public health measures would be premature."

In August 2008, the U.S. 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 concluded that the Agency's assessment was "flawed" and had not proven the chemical to be safe for formula-fed infants. In January 2010, the FDA issued a report indicating that, due to findings of recent studies that used novel approaches in testing for subtle effects, both the National Toxicology Program at the National Institutes of Health as well as the FDA have some level of concern regarding the possible effects of BPA on the brain and behavior of fetuses, infants and younger children. In 2012 the FDA did ban the use of BPA in baby bottles, however the Environmental Working Group called the ban "purely cosmetic". In a statement they said, "If the agency truly wants to prevent people from being exposed to this toxic chemical associated with a variety of serious and chronic conditions it should ban its use in cans of infant formula, food and beverages." The Natural Resources Defense Council called the move inadequate saying, the FDA needs to ban BPA from all food packaging. In a statement a FDA spokesman said the agency's action was not based on safety concerns and that "the agency continues to support the safety of BPA for use in products that hold food."

A program initiated by NIEHS, NTP, and the U.S. Food and Drug Administration (named CLARITY-BPA) found no effect of chronic exposure to BPA on rats and the FDA considers currently authorized uses of BPA to be safe for consumers.

The Environmental Protection Agency set a reference dose for BPA at 50 μg/kg/day for mammals, although exposure to doses lower than the reference dose has been shown to affect both male and female reproductive systems.

Bisphenol S (BPS) and bisphenol F (BPF)
Bisphenol S and Bisphenol F are analogs of bisphenol A. They are commonly found in thermal receipts, plastics, and household dust.

Traces of BPS have also been found in personal care products. It is more presently being used because of the ban of BPA. BPS is used in place of BPA in "BPA free" items. However BPS and BPF have been shown to be as much of an endocrine disruptor as BPA.

DDT

Dichlorodiphenyltrichloroethane (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 World War II, pyrethrum, an extract of a flower from Japan, had been used to control these insects and the diseases they can spread. During World War II, 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 used it to routinely dust beds, tents, and barracks all over the world.

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. Its use for agricultural purposes has since been prohibited by national legislation of most countries, while its use as a control against malaria vectors is permitted, as specifically stated by the Stockholm Convention on Persistent Organic Pollutants.

As early as 1946, the harmful effects of DDT on birds, 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. DDT is still used as anti-malarial insecticide in Africa and parts of Southeast Asia in limited quantities.

Polychlorinated biphenyls
Polychlorinated biphenyls (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 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 (Yushō disease, 1968) and Taiwan (Yu-cheng disease, 1979), 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.

PCBs in the environment may also be related to reproductive and infertility problems in wildlife. In Alaska, it is thought that they may contribute to reproductive defects, infertility and antler malformation in some deer populations. Declines in the populations of otters and sea lions may also be partially due to their exposure to PCBs, the insecticide DDT, other persistent organic pollutants. Bans and restrictions on the use of EDCs have been associated with a reduction in health problems and the recovery of some wildlife populations.

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: PBDEs are structurally very similar to Polychlorinated biphenyls (PCBs), and have similar neurotoxic effects. 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.

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 had been the dominant textile used to produce home furnishings, but now 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 in the beginning of the twentieth 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 juvenile rodents and exposure interferes with proper thyroid hormone regulation.

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, Washington state, 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. In view of the available animal data, precautions should be taken to limit the exposure of the developing male to DEHP". Similarly, phthalates may play a causal role in disrupting masculine neurological development when exposed prenatally.

Dibutyl phthalate (DBP) has also disrupted insulin and glucagon signaling in animal models.

Perfluorooctanoic acid
PFOA is a stable chemical that has been used for its grease, fire, and water resistant properties in products such as non-stick pan coatings, furniture, firefighter equipment, industrial, and other common household items. There is evidence to suggest that PFOA is an endocrine disruptor affecting male and female reproductive systems. PFOA delivered to pregnant rats produced male offspring with decreased levels of 3-β and 17-β-hydroxysteroid dehydrogenase, a gene that transcribes for proteins involved in the production of sperm. Adult women have exhibited low progesterone and androstenedione production when exposed to PFOA, leading to menstrual and reproductive health issues. PFOA exerts hormonal effects including alteration of thyroid hormone levels. Blood serum levels of PFOA were associated with an increased time to pregnancy—or "infertility"—in a 2009 study. PFOA exposure is associated with decreased semen quality. PFOA appeared to act as an endocrine disruptor by a potential mechanism on breast maturation in young girls. A C8 Science Panel status report noted an association between exposure in girls and a later onset of puberty.

Other suspected endocrine disruptors
Some other examples of putative EDCs are polychlorinated dibenzo-dioxins (PCDDs) and -furans (PCDFs), polycyclic aromatic hydrocarbons (PAHs), phenol derivatives and a number of pesticides (most prominent being organochlorine insecticides like endosulfan, kepone (chlordecone) and DDT and its derivatives, the herbicide atrazine, and the fungicide vinclozolin), the contraceptive 17-alpha ethinylestradiol, as well as naturally occurring phytoestrogens such as genistein and mycoestrogens such as zearalenone.

The molting in crustaceans is an endocrine-controlled process. In the marine penaeid shrimp Litopenaeus vannamei, exposure to endosulfan resulted increased susceptibility to acute toxicity and increased mortalities in the postmolt stage of the shrimp.

Many sunscreens contain oxybenzone, a chemical blocker that provides broad-spectrum UV coverage, yet is subject to a lot of controversy due its potential estrogenic effect in humans.

Tributyltin (TBT) are organotin compounds. For 40 years TBT was used as a biocide in anti-fouling paint, commonly known as bottom paint. TBT has been shown to impact invertebrate and vertebrate development, disrupting the endocrine system, resulting in masculinization, lower survival rates, as well as many health problems in mammals.

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 in 2009 is one-hundredth of what it was in the early 1980s. On the other hand, 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 Swedish women, and that levels in North America are doubling every two to six years.

It has been discussed that the long-term slow decline in average body temperature observed since the beginning of the industrial revolution may result from disrupted thyroid hormone signalling.

Animal models
Because endocrine disruptors affect complex metabolic, reproductive, and neuroendocrine systems, they cannot be modeled in in vitro cell based assay. Consequently, animal models are important for access the risk of endocrine disrupting chemicals.

Mice
There are multiple lines of genetically engineered mice used for lab studies, in this case the lines can be used as population-based genetic foundations. For instance, there is a population that is named Multi-parent and can be a Collaborative Cross (CC) or Diversity Outbred (DO). These mice while both from the same eight founder strains, have distinct differences.

The eight founder strains, combine strains that are wild-derived (with high genetic diversity) and historically significant biomedical research bred strains. Each genetically differential line is important in EDCs response and also almost all biological processes and traits.

The CC population consists of 83 inbred mouse strains that over many generations in labs came from the 8 founder strains. These inbred mice have recombinant genomes that are developed to ensure every strain is equally related, this eradicates population structure and can result in false positives with qualitative trait locus (QTL) mapping.

While DO mice have the identical alleles to the CC mice population. There are two major differences in these mice; 1) every individual is unique allowing for hundreds of individuals to be applied in one mapping study. Making DO mice an extremely useful tool for determining genetic relationships. 2) The catch is that DO individuals cannot be reproduced.

Transgenic
These rodents mainly mice have been bred by inserting other genes from another organism to make transgenic lines (thousands of lines) of rodents. The most recent tool used to do this is CRISPR/Cas9 which allows this process to be done more efficiently.

Genes may be manipulated in a particular cell populations if done under the correct conditions. For Endocrine disrupting chemical (EDC) research these rodents have become an important tool to the point where they can produce humanized mouse models. Additionally scientists use gene knockout lines of mice in order to study how certain mechanisms work when impacted by EDC's. Transgenic rodents are an important tool for studies involving the mechanisms that are impacted by EDC but take a long time to produce and are expensive. Additionally, the genes aimed at for knockout are not always successfully targeted resulting in incomplete knockout of a gene or off-target expression.

Social models
Experiments (gene by environment) with these relatively new rodent models may, be able to discover if there are mechanisms that EDCs could impact in the social decline in autism spectrum disorder (ASD) and other behavioral disorders. This is because prairie and pine voles are socially monogamous making them a better model for human social behaviors and development in relation to EDCs. Additionally the prairie vole genome has been sequenced making it feasible to do the experiments mentioned above. These voles can be compared to montane and meadow voles who are socially promiscuous and solitary, when looking at how different species have various forms of development and social brain structure. Both monogamous and promiscuous mice species have been used in these types of experiments, for more information studies can expand on this topic. More complex models that have systems that are as close as possible to humans are being looked at. Looking back at more common rodent models for instance the common ASD mouse are helpful but do not fully encompass what a model of the human social behaviors needs to. But these rodents will always just be models and this is important to keep in mind.

Zebrafish
The endocrine systems between mammals and fish are similar; because of this, zebrafish (Danio rerio) are a popular lab choice. Zebrafish work well as a model organism, part of which can be attributed to the fact that researchers are able to study them starting from the embryo, as the embryo is nearly transparent. Additionally, zebrafish have DNA sex markers, this allows the biologists to individually assign sex to fish, this is particularly important when studying endocrine disruptors as the disruptors can affect how, among other things, the sex organs work, so if by chance there is sperm in the ovaries later on through the testing it can then be pinned to the chemical without the chance of it being a genetic abnormality since the sex was determined by the researcher. Besides zebrafish being readily available, and easy to study through their different life stages, they have hugely similar genes to humans—70% of human genes have a zebrafish counterpart and even more fascinatingly 84% of disease genes in humans have a zebrafish counterpart. Most importantly perhaps is the fact that the vast majority of endocrine disruptors end up in water ways, and so it is important to know how these disruptors affect fish, which arguably have intrinsic value and just happen to be model organisms as well.

The zebrafish embryos are transparent, relatively small fish (larvae are less than a few millimeters in size). This allows scientists to view the larvae (in vivo) without killing them to study how their organs develop in particular, neuro development and transport of presumed endocrine disrupting chemicals (EDC). Meaning how their development is impacted by certain chemicals. As a model, they have simple modes of endocrine disruption. Along with homologous physiological, sensory, anatomical and signal-transduction mechanism similar to mammals. Another helpful tool available to scientists is their recorded genome along with multiple transgenic lines accessible for breeding. Zebrafish and mammalian genomes when compared have prominent similarities with about 80% of human genes expressed in the fish. Additionally, this fish is also fairly inexpensive to breed and house in a lab partly due to their shorter life span and being able to house more of them, compared to mammalian models.

Directions of research
Research on endocrine disruptors is challenged by five complexities requiring special trial designs and sophisticated study protocols:
 * 1) The dissociation of space means that, although disruptors may act by a common pathway via hormone receptors, their impact may also be mediated by effects at the levels of transport proteins, deiodinases, degradation of hormones or modified setpoints of feedback loops (i.e. allostatic load).
 * 2) The dissociation of time may ensue from the fact that unwanted effects may be triggered in a small time window in the embryonal or fetal period, but consequences may ensue decades later or even in the generation of grandchildren.
 * 3) The dissociation of substance results from additive, multiplicative or more complex interactions of disruptors in combination that yield fundamentally different effects from that of the respective substances alone.
 * 4) The dissociation of dose implies that dose-effect relationships use to be nonlinear and sometimes even U-shaped, so that low or medium doses may have stronger effects than high doses.
 * 5) The dissociation of sex reflects the fact that effects may be different depending on whether embryos or fetuses are female or male.

United States
The multitude of possible endocrine disruptors are technically regulated in the United States by many laws, including: the Toxic Substances Control Act, the Food Quality Protection 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. While the Food Quality Protection Act only required the EPA to screen pesticides for potential to produce effects similar to estrogens in humans, it also gave the EPA the authority to screen other types of chemicals and endocrine effects. Based on recommendations from an advisory panel, the agency expanded the screening program to include male hormones, the thyroid system, and effects on fish and other wildlife. 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. The EPA is still finding it difficult to execute a credible and efficient endocrine testing program.

As of 2016, the EPA had estrogen screening results for 1,800 chemicals.

Europe
In 2013, a number of pesticides containing endocrine disrupting chemicals were in draft EU criteria to be banned. On 2 May, US TTIP negotiators insisted the EU drop the criteria. They stated that a risk-based approach should be taken on regulation. Later the same day Catherine Day wrote to Karl Falkenberg asking for the criteria to be removed.

The European Commission had been to set criteria by December 2013 identifying endocrine disrupting chemicals (EDCs) in thousands of products—including disinfectants, pesticides and toiletries—that have been linked to cancers, birth defects and development disorders in children. However, the body delayed the process, prompting Sweden to state that it would sue the commission in May 2014—blaming chemical industry lobbying for the disruption.

"This delay is due to the European chemical lobby, which put pressure again on different commissioners. Hormone disrupters are becoming a huge problem. In some places in Sweden we see double-sexed fish. We have scientific reports on how this affects fertility of young boys and girls, and other serious effects," Swedish Environment Minister Lena Ek told the AFP, noting that Denmark had also demanded action.

In November 2014, the Copenhagen-based Nordic Council of Ministers released its own independent report that estimated the impact of environmental EDCs on male reproductive health, and the resulting cost to public health systems. It concluded that EDCs likely cost health systems across the EU anywhere from 59 million to 1.18 billion Euros a year, noting that even this represented only "a fraction of the endocrine related diseases".

In 2020, the EU published their Chemicals Strategy for Sustainability which is concerned with a green transition of the chemical industry away from xenohormones and other hazardous chemicals.

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 the body burden of these pollutants is eliminating or phasing 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.

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 bio-accumulate 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. Global efforts have been made to label the most common POPs routinely found in the environment through usage of chemicals like insecticides. The twelve main POPs have been evaluated and placed in a demographic so as to streamline the information around the general population. Such facilitation has allowed nations around the world to effectively work on the testing and reduction of the usage of these chemicals. With an effort to reduce the presence of such chemicals in the environment, they can reduce the leaching of POPs into food sources which contaminate the animals commercially fed to the U.S. population.

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 clean up 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.

Studies suggest that bisphenol A, certain PCBs, and phthalate compounds are preferentially eliminated from the human body through sweat. Although some pollutants like bisphenol A (BPA) are preferentially eliminated from the human body through sweat, recent scientific advances have been made to increase the rate of elimination of pollutants from the human body. For example, BPA removal techniques have been proposed that use enzymes such as laccase and peroxidase enzyme to degrade BPA into less harmful compounds. Another technique for BPA removal is the use of highly reactive radicals for degradation.

Economic effects
Human exposure may cause some health effects, such as lower IQ and adult obesity. These effects may lead to lost productivity, disability, or premature death in some people. One source estimated that, within the European Union, this economic effect might have about twice the economic impact as the effects caused by mercury and lead contamination.

The socio-economic burden of endocrine disrupting chemicals (EDC)-associated health effects for the European Union was estimated based on currently available literature and considering the uncertainties with respect to causality with EDCs and corresponding health-related costs to be in the range of €46 billion to €288 billion per year.

title: Endocrine disruptor


text:
U.S. Route 258

U.S. Route 258 (US 258) is a spur of US 58 in the U.S. states of North Carolina and Virginia. The U.S. Highway runs 220.15 mi from US 17 Business and NC 24 Business in Jacksonville, North Carolina north to Virginia State Route 143 (SR 143) at Fort Monroe in Hampton, Virginia. In North Carolina, US 258 connects Jacksonville with the Inner Banks communities of Kinston, Snow Hill, Farmville, Tarboro, and Murfreesboro. The U.S. Highway continues through the Virginia city of Franklin, where the highway intersects US 58, and the town of Smithfield on its way to the Hampton Roads metropolitan area. US 258 crosses the James River on the James River Bridge and follows Mercury Boulevard through Newport News and Hampton.

Jacksonville to Kinston
US 258 begins at a directional intersection with US 17 Business and NC 24 Business in Jacksonville. The business routes head east together as Marine Boulevard toward downtown Jacksonville; US 17 Business heads southwest along Wilmington Highway to meet up with US 17 along the freeway bypass of Jacksonville that also carries NC 24 and leads to Marine Corps Base Camp Lejeune. US 258 and NC 24 Business run concurrently along Richlands Highway, a five-lane road with center turn lane, west to the western terminus of the freeway, a four-way intersection at which NC 24 begins to run concurrently with US 258; the west leg of the intersection is NC 53 (Burgaw Highway). The U.S. Highway and state highway parallel the New River through a junction with the southern end of NC 111 (Lake Catherine Road) to just south of Richlands, where the highways cross the river and pass through that town. The highways head west out of the town as Kinston Highway. West of Richlands NC 24 continues west as five-lane Beulaville Highway toward Beulaville while US 258 curves north along Kinston Highway, which reduces to two lanes.

US 258 briefly passes through Jones County, where the highway intersects NC 41 at Hargetts Crossroads before entering Lenoir County. The U.S. Highway crosses the Trent River and passes through Woodington prior to its junction with US 70 and NC 58 (New Bern Road) just south of the Neuse River in Kinston. The roadway continues straight as Queen Street, which carries NC 58, US 70 Business, and US 258 Business across the river into downtown Kinston. US 258 runs concurrently northwest along the US 70 four-lane divided highway; the two U.S. Highways have an intersection with NC 11 and NC 55 (Old Pink Hill Road) before crossing the river and meeting the other end of the highways' business routes, which follow Vernon Avenue. US 258 and US 70 follow Vernon Avenue a short distance west to where US 258 turns north. The U.S. Highway has an at-grade crossing with the North Carolina Railroad and meets the western end of NC 148 (C.F. Harvey Parkway), which serves Kinston Regional Jetport and the North Carolina Global TransPark.

Kinston to Tarboro
US 258 crosses Wheat Swamp into Greene County. The U.S. Highway intersects NC 58 (Kingold Boulevard) again south of Snow Hill, which the highway enters along 2nd Street. In the center of town, US 258 turns onto Greene Street and crosses Contentnea Creek, then has a four-way intersection with US 13, NC 91, and NC 903. The roadway continues north as NC 91; US 258 begins to run northeast concurrently with US 13 and NC 903. NC 903 diverges from the two U.S. Highways west of Maury; the U.S. Highways intersect NC 123 in the hamlet of Lizzie. US 258 and US 13 diverge north of Sandy Run. US 258 crosses Middle Swamp into Pitt County and intersects US 264 Alternate south of Farmville. US 258 and US 264 Alternate briefly run together east for 0.2 mi before US 258 heads north again. US 258 comes to a diamond interchange with I-587 and US 264 (John P. East Memorial Highway) and Wesley Chapel Road northeast of the center of Farmville. US 258 joins the I-587 and US 264 freeway west for about 3 mi before exiting at another diamond interchange northwest of town. The former routing of the highway through Farmville is now U.S. Route 258 Business.

US 258 intersects NC 222 (Wilson Street) in Fountain before entering Edgecombe County. The U.S. Highway intersects NC 124 in Crisp and NC 42 and NC 43 east of Pinetops, then parallels the Tar River to Tarboro. South of downtown Tarboro, the U.S. Highway has a partial cloverleaf interchange with the US 64 freeway and Western Boulevard, which features US 64 Alternate, NC 111, and NC 122. US 258 and the two state highways cross the Tar River on the freeway, then exit US 64 onto Mutual Boulevard at a partial interchange on the east side of the river in Princeville. There is no access from southbound US 258 to eastbound US 64 or from westbound US 64 to northbound US 258. The missing movements are provided via NC 33, which the three highways intersect in the center of town. A short distance to the east, NC 111 diverges on Greenwood Boulevard. US 258 and NC 122 parallel the river north before the two routes diverge northeast of Tarboro.

Tarboro to Franklin
US 258 intersects NC 97 in the hamlet of Lawrence before the highway enters Halifax County. The U.S. Highway crosses Deep Creek before becoming the Main Street of Scotland Neck. US 258 becomes concurrent with NC 125 at the south edge of the town and with NC 903, which enters from the east on 9th Street, in the center of town. NC 125 and NC 903 exit town to the west on 12th Street. US 258 has a junction with NC 561 north of Scotland Neck; the two highways cross the Roanoke River into Northampton County. The two highways meet the northern end of NC 308 just before entering Rich Square as Main Street. In the center of Rich Square, US 258 intersects NC 305 (Jackson Street), which exits town to the east with NC 561. The U.S. Highway has an at-grade crossing of the North Carolina and Virginia Railroad southwest of Woodland, where the highway, marked as Main Street, has a concurrency with NC 35 between Spruce Street and Linden Street.

North of Woodland, US 258 crosses Potecasi Creek and parallels the Northampton–Hertford county line north to Murfreesboro. The U.S. Highway joins US 158 east into Hertford County on its four-lane divided southern bypass of the town while the roadway continues straight as US 158 Business (Main Street). Southeast of the town, US 258 leaves US 158 and joins NC 11 on Beechwood Boulevard, which the two highways follow to NC 11's northern terminus at US 158 Business. US 258 leaves Murfreesboro on Virginia Boulevard, which crosses the Meherrin River and heads northeast through Como to the state line, where the highway enters Southampton County, Virginia. The U.S. Highway, now named Smiths Ferry Road, uses the General Vaughan Bridge to cross the Nottoway River a short distance north of its confluence with the Blackwater River to form the Chowan River.

US 258 meets the western end of SR 189 (Quay Road) before reaching its diamond interchange with US 58 (Southampton Parkway) south of the independent city of Franklin. US 258 joins US 58 on a four-lane freeway heading east while the roadway continues north into the city as US 258 Business (South Street). US 258 and US 58 head southeast through a widely spaced partial cloverleaf interchange with SR 714 (Pretlow Street) before crossing the Blackwater River into the city of Suffolk. East of the river, the U.S. Highways have a partial cloverleaf interchange with SR 189, which joins US 58 heading east toward Norfolk while US 258 exits the freeway and heads north, becoming Great Mill Highway on entering Isle of Wight County southeast of Franklin. When Great Mill Highway continues north toward an industrial area on the east side of Franklin, US 258 veers northeast on Camp Family Highway, crosses over Norfolk Southern Railway's Franklin District, and meets the northern end of US 258 Business at its intersection with US 58 Business (Carrsville Highway) just north of its grade crossing of CSX's Portsmouth Subdivision rail line and just south of Franklin Municipal-John Beverly Rose Airport.

Franklin to Hampton
US 258 continues northeast as Walters Highway through the hamlet of Walters to the town of Windsor, where the highway is named Prince Boulevard, has a grade crossing of Norfolk Southern's Norfolk District rail line, and intersects US 460 (Windsor Boulevard). The U.S. Highway continues north as Courthouse Highway through the county seat of Isle of Wight to the town of Smithfield. US 258 enters the town as Main Street before joining SR 10 on the town's bypass; Main Street continues as US 258 Business. The two-lane bypass has a diamond interchange with Fairway Drive, then crosses Cypress Creek and collects the northern end of US 258 Business, which runs concurrently with SR 10 Business on Church Street. US 258 and SR 10 continue southeast on four-lane divided Benns Church Boulevard to Benns Church, where US 258 leaves SR 10 and joins SR 32 on Brewers Neck Boulevard. The U.S. Highway and state highway follow that boulevard to Carrollton, where the highways join US 17 on Carrollton Boulevard. The three highways curve northeast and cross the James River on the James River Bridge.

US 258, US 17, and SR 32 enter the city of Newport News on Mercury Boulevard. The six-lane highway has a partial cloverleaf interchange with US 60 (Warwick Boulevard) and crosses CSX's Peninsula Subdivision rail line before reaching SR 143 (Jefferson Avenue), where SR 32 has its northern terminus. US 17 turns north onto Jefferson Avenue while US 258 continues east on Mercury Boulevard into the city of Hampton. At Newmarket Drive south of the former Newmarket North Mall, the U.S. Highway expands to eight lanes and passes through a heavily commercialized area. East of SR 415 (Power Plant Parkway), US 258 meets Interstate 64 at an interchange featuring a pair of flyover ramps. The U.S. Highway heads east from the Interstate concurrent with SR 134 as the highway passes between Peninsula Town Center to the north and the Hampton Coliseum to the south. At the eastern end of the heavily commercialized area, US 258 has intersections with the eastern end of SR 152 (Cunningham Drive) and Armistead Avenue, which heads south as SR 134.

US 258 crosses Newmarket Creek just west of the highway's partial cloverleaf interchange with La Salle Avenue. The U.S. Highway reduces to six lanes at its diamond interchange with SR 278 (King Street), which serves Langley Air Force Base. US 258 becomes four lanes at its northern intersection with SR 169, which heads north as Fox Hill Road. The U.S. Highway crosses the Hampton River and curves south toward its terminus. US 258 intersects SR 351 (Pembroke Avenue) and Woodland Avenue, which leads to I-64 and downtown Hampton and where the highway reduces to a four-lane undivided street. The U.S. Highway has another junction with SR 169 (Mallory Street) in the Phoebus neighborhood of Hampton. At the east edge of Phoebus, US 258 crosses the Mill Creek estuary on a causeway and reaches its northern terminus at an intersection with the southern terminus of SR 143 (Ingalls Road) at the entrance to Fort Monroe. Ingalls Road continues south onto the former military base at Old Point Comfort that was decommissioned in September 2011.

Kinston business route
U.S. Route 258 Business (US 258 Business) is a business route of US 258 through Kinston, North Carolina. The highway runs 4.77 mi entirely concurrent with US 70 Business from US 258, US 70, and NC 58 on the south side of Kinston to US 70 and US 258 on the west side of Kinston. US 258 Business and US 70 Business run concurrently with NC 58 across the Neuse River into downtown Kinston, in the center of which the highways intersect NC 11 and NC 55 (King Street). North of downtown, the business routes turn west onto Vernon Avenue while NC 58 continues north on Queen Street. US 258 Business and US 70 Business pass the exhibited remains of the CSS Neuse before they reach their common terminus at a directional intersection with US 258 and US 70.

Snow Hill truck route
U.S. Route 258 Truck (US 258 Truck) is a truck route of US 258 bypassing east of downtown Snow Hill, North Carolina. The truck route travels 2.8 mi, overlapping NC 58, NC 903, and US 13.

Farmville business route
U.S. Route 258 Business (US 258 Business) is business route of US 258 that passes through Farmville, North Carolina. The route is the former mainline routing of US 258 through the town before it was routed onto the US 264 freeway north of the town. US 258 Business begins at the intersection of US 264 Alternate and US 258 within the town limits of Farmville. The route heads north on Main Street to the center of town where it reaches NC 121 (Wilson Street). The two highways form a concurrency and travel west along Wilson Street. After 0.48 mi, US 258 Business makes a right turn onto May Boulevard and exits the town. It ends at the US 264's exit 63 which is also where US 258 ends its concurrency with US 264 and returns to surface roads. In October 2022, AASHTO approved a request to eliminate this route.

Franklin business route
U.S. Route 258 Business (US 258 Business) is a business route of US 258 through Franklin, Virginia. The highway runs 3.74 mi from US 258 and US 58 south of Franklin to US 258 and US 58 Business east of Franklin. US 258 Business begins at a diamond interchange with the US 58 freeway in Southampton County; the highway immediately enters the city of Franklin as South Street. The business route passes to the south of the Franklin campus of Paul D. Camp Community College on its way to the downtown area. Just west of the Blackwater River, US 258 Business curves north onto Main Street, which crosses over CSX's Portsmouth Subdivision rail line. The business route turns east at Second Street and becomes concurrent with US 58 Business at Mechanic Street. The two business routes exit the city of Franklin by crossing the Blackwater River into Isle of Wight County. US 258 Business and US 58 Business continue east as Carrsville Highway through an industrial area. The business routes parallel the Portsmouth Subdivision and pass under Norfolk Southern Railway's Franklin District before reaching US 258 Business's northern terminus at US 258. US 58 Business continues east through Carrsville and Holland.

Smithfield business route
U.S. Route 258 Business (US 258 Business) is a business route of US 258 through Smithfield, Virginia. The highway runs 3.07 mi between intersections with US 258 and SR 10 on the west and south sides of Smithfield. US 258 Business begins at the junction of US 258 and SR 10; the two highways head south along the bypass of the town while the business route heads into the center of town as Main Street. The business route joins SR 10 Business on Church Street; the two highways parallel the Pagan River to its junction with Cypress Creek and provide access to Windsor Castle. After crossing Cypress Creek, US 258 Business and SR 10 Business curve south and expand to a five-lane road with center turn lane that the highways follow to their southern junction with US 258 and SR 10.

Smithfield alternate route
U.S. Route 258 Alternate (US 258 Alternate) is an alternate route of US 258 Business through Smithfield, Virginia. The highway starts at the southwest end of Grace Street at US 258 Bus on the west side of Smithfield, continues to Church Street, then turns right down Church Street before ending at US 258 Business in downtown Smithfield.

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: U.S. Route 258


text:
U.S. Route 159

U.S. Highway 159 (US 159) is a 83.6 mi auxiliary route of US 59. It travels from Nortonville, Kansas at US 59 to New Point, Missouri, also at US 59. The highway permits through traffic on US 59 to bypass the cities of Atchison, Kansas and Saint Joseph, Missouri, traveling instead through Falls City, Nebraska and Hiawatha, Kansas (assuming the bridge over the Missouri River is open).

Route description

 * KS
 * 52.3 mi
 * NE
 * 13.86 mi
 * MO
 * 17.424 mi
 * Total
 * 83.584 mi
 * }
 * Total
 * 83.584 mi
 * }
 * }

Kansas
The southwestern end of U.S. Route 159 is in Nortonville, Kansas. It joins with U.S. Route 73 in Horton, Kansas. The two highways overlap and passing through Hiawatha, Kansas and Reserve, Kansas, stretching to the Nebraska border. The highway provides an important connection between Falls City, Nebraska and Hiawatha, Kansas, providing Nebraska residents with an alternative connection to St. Joseph, Missouri when there is a problem with the Rulo bridge.

Nebraska
U.S. Route 159 enters Nebraska through its southern border in Richardson County. It enters south of Falls City, Nebraska concurrently with U.S. Route 73. After coming up through the south end of Falls City, the U.S. Route 159 turns east (with Route 73 continuing north). After the eastbound turn, U.S. Route leaves the state at the Missouri River bridge in Rulo, Nebraska.

Missouri
U.S. Route 159 enters the state of Missouri crossing the Missouri River near the Rulo bridge south of Big Lake, Missouri. It crosses Interstate 29 near Fortescue, Missouri before ending at US-59 near New Point. Its total length in Missouri is approximately 16 mi.

History
When the route was commissioned in 1934, U.S. Route 159 only went between Nortonville, Kansas and Horton, Kansas. In 1945, it was extended north to Craig, Missouri via Falls City, Nebraska. After 1975, the route in Missouri was altered to go east from the Fortescue area to what is now its current terminus near New Point, Missouri. The old route which went to Craig is now Route 111.

In 2013, a new bridge over the Missouri River, located about 650 feet south of the old Rulo Bridge, opened to traffic. In April 2019, a large portion of this route was closed for several months because of flooding of the Missouri River. The bridge and the road between Rulo, Nebraska and Missouri Route 111 was reopened in September 2019, and the remainder of the route to Interstate 29 was reopened in late October.

title: U.S. Route 159


text:
Spellbound (2002 film)

Spellbound is a 2002 American documentary that was directed by Jeffrey Blitz. The film follows eight competitors in the 1999 Scripps National Spelling Bee. The film received positive reviews and won several awards, including a nomination for the Academy Award for Best Documentary Feature.

Spellers
The spellers were Neil Kadakia, Emily Stagg, Ashley White, April DeGideo, Harry Altman, Angela Arenivar, Nupur Lala and Ted Brigham. As they appear from left to right on the DVD's cover:

Neil Kadakia
Neil (as speller # 139) missed "hellebore" as "helebore" in the bee to get ninth place. Other words Neil spelled include: encephalon, desecration, mercenary, Darjeeling, and hypsometer. He was sponsored by the Orange County Register. Neil is a graduate of UC Berkeley. He is currently the COO of Greens Global, a real estate company based out of San Clemente, CA. On July 3, 2011, he married Archana Sheth, also a UC Berkeley graduate. He is also an avid chess player, and has earned over 15 chess trophies in his life. His grandfather paid 1000 people in India to pray for him.

Emily Stagg
Emily Stagg (speller # 148) was sponsored by the New Haven Register in New Haven, Connecticut and spelled: seguidilla, disclaimant, kookaburra, viand, apocope, brunneous, clavecin (spelled incorrectly as "clavison"). She came in 6th place. In 2006, as a junior in Carleton College, she wrote an op-ed article for the New York Times questioning the usefulness of the National Spelling Bee.

Ashley White
Ashley White (speller 149) represented The Washington Informer in Washington, DC in the spelling bee, spelling "lycanthrope" before misspelling "ecclesiastical" in the third round. Following Ashley's teenage pregnancy (she was 18), a marketing consultant who had seen the movie managed to rally support from other viewers of the documentary to help Ashley into Howard University. The proctor of the Washington Informer regional spelling bee featured in the film is Mac McGarry.

April DeGideo
April DeGideo, who lives in Ambler, Pennsylvania, participated in the 1998 and 1999 bees, in the latter of which she placed third, representing the Times Herald of Norristown, Pennsylvania. April graduated in 2007 from New York University with a degree in Journalism. She then went on to get a second degree in creative writing and later went on to publish two books. The study guide, and Where to start.

Harry Altman
Many critics who reviewed Spellbound singled out Altman (speller # 8) as its most interesting "character". Roger Ebert wrote that he "has so many eccentricities that he'd be comic relief in a teenage comedy... He screws his face up into so many shapes while trying to spell a word that it's a wonder the letters can find their way to the surface." He spelled "cephalalgia" and "odyssey" over the course of the bee. In a prolonged clip, Altman was eliminated in the fourth round, on the word "banns", which he spelled "bands". He later appeared in the 2001 Bee, but was again eliminated in the fourth round. Altman went to the Academy for Engineering and Design Technology (now Bergen County Academies) in Hackensack, New Jersey. In autumn 2005, he enrolled in the University of Chicago. In 2014 Harry completed a PhD in Mathematics from the University of Michigan, focusing on integer complexity.

Angela Arenivar
Angela Arenivar represented the Amarillo Globe-News in the 1998 and 1999 bees, being eliminated in the latter during the third round. Angela graduated from Texas A&M University in 2007 with a bachelor's degree in Spanish and earned a master's in Spanish from the University of New Mexico in 2009. She has taught Spanish in Texas public high schools. Angela now attends Texas A&M University pursuing her Ph.D. in Hispanic Studies.

Nupur Lala
Nupur Lala was the champion of the 1999 Scripps National Spelling Bee (as speller # 155), spelling "logorrhea" to win. Nupur won the bee against David Lewandowski, a speller from Indiana who misspelled "opsimath." She turned down an MTV reality show that would have followed her college years. In 2003, she entered University of Michigan at Ann Arbor to study brain and cognitive sciences and pre-medical studies and graduated in 2007 with a degree in Brain, Behavior and Cognitive Science. In the fall of 2014 she entered the College of Medicine at the University of Arkansas for Medical Sciences. She also appeared in the 2020 documentary Spelling the Dream.

Ted Brigham
Ted Brigham was speller # 1. He represented the Rolla Daily Record of Rolla, Missouri. One of the more notable stories from his experience is the congratulations posted by students on the marquee in front of his high school in which "champ" was misspelled (presumably as an ironic joke) as "chapm". Ted misspelled "distractible" in the second round, becoming the first of the eight spellers eliminated. Ted attended medical school in Kansas City, Missouri until his death in December 2007. His family chose not to disclose the circumstances of his death.

Other notable spellers

 * George Thampy was speller # 245 in the bee and was mentioned several times within the film. He misspelled "kirtle" as "curtle" for third place, tying with April DeGideo. Thampy eventually won the 2000 national bee.
 * David Lewandowski finished second place in the spelling bee, spelling "opsimath" as "opsomath". After David's mistake, Nupur spelled "logorrhea" to win the competition.
 * Allyson Lieberman was originally slated to be featured as one of the spellers in the documentary, but her clips were ultimately left out of the film; the scene involving her can be found in the special features of the DVD. The youngest contestant in the entire 1998 bee, she misspelled "purblind".
 * Frances Taschuk and Ann Foley are shown in the final set of scenes prior to the last round of the spelling bee. Frances misspells "acoelous" and Ann "quinquevir".
 * Vinay Krupadev is in a scene involving Harry's mother feeling "sorry for the boy from Texas who got 'yenta'". She was referring to Vinay, who is actually from Marietta, Ohio, and his pronunciation of "yenta," shown in the film. He eventually spelled it "yente".
 * Jess Altman was mentioned in a scene by Harry Altman for being a terrific speller and that he was disappointed she didn't make the Nationals.
 * Sonia Nagala won the North Dakota bee with the word "butyraceous", but was eliminated in the second round of the Nationals. She completed her MBA at Harvard Business School in 2018.
 * Frank Neuhauser, winner of the first National Spelling Bee, held in 1925, also appears in the film.

Reception
Spellbound opened to positive reviews from critics. Rotten Tomatoes gives the film an approval rating of 97%, based on reviews from 139 critics, and an average rating of 8.27/10. The website's critical consensus states, "A suspenseful, gripping documentary that features an engaging cross section of American children". Metacritic gives the film a weighted average score of 80% based on reviews from 34 critics, indicating "generally favorable reviews".

Awards
The film was nominated for the Academy Award for Best Documentary Feature; Yana Gorskaya's editing won the ACE Eddie award for best editing of documentary. Spellbound won the Emmy Award for Cultural/Artistic Programming and Jeffrey Blitz was nominated for directing.

In 2007, it was included as #4 of the "IDA's Top 25 Documentaries" of all-time by the members of the International Documentary Association.

title: Spellbound (2002 film)


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Sean Burke

Sean Burke (born January 29, 1967) is a Canadian former professional ice hockey goaltender and the current director of goaltending for the Vegas Golden Knights, with whom he won the Stanley Cup with in 2023. He played 18 seasons in the National Hockey League (NHL) for the New Jersey Devils, Hartford Whalers, Carolina Hurricanes, Vancouver Canucks, Philadelphia Flyers, Florida Panthers, Phoenix Coyotes, Tampa Bay Lightning and Los Angeles Kings between 1988 and 2007. He was born in Windsor, Ontario, but grew up in Toronto, Ontario.

Playing career
As a youth, Burke played in the 1980 Quebec International Pee-Wee Hockey Tournament with the St. Michael's minor ice hockey team from Toronto.

Burke attended St. Michael's college high school and played junior B hockey for the St.Michael's Buzzers in the 1983-84 season. He was taken in the 3rd round of the OHL draft by the Toronto Marlboros where he would play for the next two seasons.

Burke was drafted by the New Jersey Devils in the second round of the 1985 NHL Entry Draft. He earned national attention from his international play, backstopping the Canada men's national junior ice hockey team to a silver medal in the 1986 World Junior Ice Hockey Championships and a fourth-place finish for the men's national team at the 1988 Winter Olympics in Calgary.

Burke transitioned directly from Canada's Olympics national team to the Devils. He started 11 games for the Devils in the 1987–88 season, including an overtime victory against the Chicago Blackhawks on the final night of the season that qualified the Devils for their first Stanley Cup playoff series.

Dubbed a "rookie sensation", Burke helped the Devils go on a strong playoff run, defeating the division-leader New York Islanders in the first round in six games and then the Washington Capitals in seven games. The Devils were one game away from the Stanley Cup Finals but lost in Game 7 of the Wales Conference Finals to the Boston Bruins. Burke's play was widely heralded, with The Hockey Digest stating, "Burke is now the franchise for the Devils, and to whatever heights he rises, the Devils will rise with him," and in December 1988, Burke became the first Devil to appear on its cover.

Because he played just 11 games in the 1987–88 regular season, Burke maintained his rookie status for the 1988–89 season. That season, he was named to the 1989 All-Star Game.

Burke played for the Devils through the 1990–91 season, then sat out the 1991–92 season requesting a trade. Instead, he joined coach Dave King and played for the Canadian national team in the Winter Olympics for a second time, backstopping Canada to a silver medal. Teammates on the 1992 Olympic team included future NHL players Eric Lindros and Joe Juneau.

On August 28, 1992, Burke was traded to the Hartford Whalers in exchange for Bobby Holík, a second-round pick in the 1993 NHL Entry Draft (used to select Jay Pandolfo) and future considerations. He played there (and with the relocated Whalers team, the Carolina Hurricanes) for six seasons. He was voted Whalers' team MVP from 1993 to 1997. Burke then played with several teams, including the Philadelphia Flyers, Vancouver Canucks and Florida Panthers. He subsequently signed with the Phoenix Coyotes and played there for five seasons, where he was a finalist for the Vezina Trophy and third finalist for the Hart Memorial Trophy in the 2001–02 season.

Burke was selected to represent the Arizona Coyotes in the 2000-01 and 2001-02 NHL All Star games.

After that, Burke played for the Philadelphia Flyers (for the second time) recording his 300th career NHL win (the 20th goaltender to reach this milestone), and the Tampa Bay Lightning. Burke was placed on waivers by Tampa Bay before the 2006–07 season but was not picked up. He then played for Tampa Bay's American Hockey League (AHL) affiliate, the Springfield Falcons. Burke was placed on waivers by the Lightning and picked up off re-entry waivers by the Los Angeles Kings.

Burke announced his retirement from professional hockey on September 18, 2007. Burke currently sits #15 on the list of all time games played for NHL goaltenders (820) #30 all time wins (324) #50 all time shutouts (38) and #5 all time penalty minutes for goaltenders (310)

International play
Burke played in 11 games for the Canadian national team in the 1988 and 1992 Winter Olympics. He served as the back-up goaltender in the 1991 Canada Cup and has also played in 130 games for other Canadian national teams from 1985 through 2003.

The 130 games that Burke has played for Team Canada represent the most games any goaltender has played Internationally for Canada

In 2020, Burke was named into the IIHF All-Time Canada Team along with Scott Niedermayer, Chris Pronger, Wayne Gretzky, Mario Lemieux and Sidney Crosby.

Post-NHL career
On March 4, 2008, the Phoenix Coyotes hired Burke to become its director of prospect development. He was also the assistant to the general manager and Coyotes' goaltending coach.

In 2015 Burke was part of the management group along with General Manager Jim Nill, George McPhee and Pat Verbeek that led Canada to a gold medal at the IIHF World Championships. Canada went undefeated in the tournament held in Prague, Czech Republic beating Russia 6 t0 1 in the gold medal game.

In 2016 Burke joined General Managers Brad Treliving and George McPhee as part of the management group for the IIHF World Championships in Moscow and Saint Petersburg, Russia. Canada won the gold medal defeating Finland 2 to 0 in the final game.

In 2017 Burke co managed Team Canada at the IIHF World Championships along with Ron Hextall in Cologne, Germany and Paris, France. Canada took home the silver medal after being defeated 2 to 1 in a shootout by Sweden.

Burke was the General Manager for Team Canada at the Spengler Cup in 2016, 2017 and 2019 taking home gold medals. In 2018 he managed the team along with Ron Francis taking home the silver medal.

In September 2016, Burke joined the Montreal Canadiens as a professional scout. He also spent the 2020-21 season as the full time goaltending coach with the Canadiens as the team made it to the Stanley Cup finals losing to the Tampa Bay Lightning in 5 games. On July 25, 2017, he was announced as the general manager of Canada's men's team for the 2018 Winter Olympics in Pyeongchang. where Team Canada went on to win the bronze medal. That same season he co managed the IIHF World Championships with Martin Brodeur and Scott Salmond held in Copenhagen and Herning, Denmark.

In March 2021, Burke was appointed as the director of goaltending for the Montreal Canadiens.

On June 25, 2022, Burke was appointed as director of goaltending for the Vegas Golden Knights. Even with the Golden Knights losing their previous season's starting goaltender Robin Lehner for the entire season due to injury and off-sesason surgery, and rotating through a total of five other goaltenders due to various injuries (by numbers of regular season games started, Logan Thompson, Adin Hill, Laurent Brossoit, Jonathan Quick, and Jiří Patera), Burke was able to help coach the Golden Knights to the Stanley Cup in 2023 (Burke's first Stanley Cup win).

Burke is a member of the International Ice Hockey Federations Players Committee where he has served on the committee since 2016.

Personal life
Burke and his wife Christy have one son together. Burke has two children from a previous marriage.

On November 2, 1997, Burke and his then-wife were both charged with assault following an alleged altercation at their home. Despite the incident, the Carolina Hurricanes chose not to suspend Burke. In January 1998, Burke was fined $200, sentenced to 18 months probation, and required to complete an educational program on domestic violence after pleading guilty to the assault charge.

title: Sean Burke