title: Giardia duodenalis

text: Eight genotype assemblages of "G. duodenalis" have been recognized to date (A-H). Genotyping of "G. duodenalis" isolated from various hosts has shown that assemblages A and B infect the largest range of host species, and appear to be the main (or possibly only) "G. duodenalis" assemblages that undeniably infect human subjects.


title: Giardia duodenalis

text: Frances Gillin of the University of California, San Diego, and her colleagues cultivated the entire lifecycle of this parasite in the laboratory, and identified biochemical cues in the host's digestive system that trigger "Giardia"'s lifecycle transformations. They also uncovered several ways in which the parasite evades the defences of the infected organism. One of these is by altering the proteins on its surface, which confounds the ability of the infected animal's immune system to detect and combat the parasite (called antigenic variation). Gillin's work reveals why "Giardia" infections are extremely persistent and prone to recur. In addition, these insights into its biology and survival techniques may enable scientists to develop better strategies to understand, prevent, and treat "Giardia" infections.


title: Giardia duodenalis

text: In December 2008, "Nature" published an article showing the discovery of an RNA interference mechanism that allows "Giardia" to switch variant-specific surface proteins to avoid host immune response. The discovery was made by the team working at the Biochemistry and Molecular Biology Laboratory, School of Medicine, Catholic University of Cordoba, Argentina, led by Dr. Hugo Lujan.


title: Giardia duodenalis

text: The main congress about "Giardia" is the International Giardia and Cryptosporidium Conference. A summary of results presented at the most recent edition (2019, in Rouen, France) is available.


title: Giardia duodenalis

text: The first likely description of "Giardia" was in 1681 by Antonie van Leeuwenhoek, who in a letter to Robert Hooke, described "animalcules" resembling "Giardia" trophozoites in his stool. The next known description of "Giardia" wasn't until 1859, when Czech physician Vilém Lambl published a description of the trophozoite stages he saw in the stool of a pediatric patient. Lambl termed the organism "Cercomonas intestinalis". In 1888, Raphaël Blanchard renamed the parasite "Lamblia intestinalis" in Lambl's honor. In 1915, Charles Stiles renamed the organism "Giardia lamblia" in honor of both Lambl and Professor Alfred Mathieu Giard of Paris. In 1921, Charles E. Simon published a detailed description of the parasite's morphology.


title: Endocrine disruptor

text: 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 cancerous tumors, birth defects, and other developmental disorders. 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)."


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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. Additionally, a key scientific paper, published in 1996 in the journal "Science", which helped launch the movement of those opposed to endocrine disruptors, was retracted and its author found to have committed scientific misconduct.


title: Endocrine disruptor

text: Studies in cells and laboratory animals have shown that EDCs can cause adverse biological effects in animals, and low-level exposures may also cause similar effects in human beings.


title: Endocrine disruptor

text: EDCs in the environment may also be related to reproductive and infertility problems in wildlife and bans and restrictions on their use has been associated with a reduction in health problems and the recovery of some wildlife populations.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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, 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

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


title: Endocrine disruptor

text: 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:


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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 chemical 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: In another case, phthalates in pregnant women's urine was linked to subtle, but specific, genital changes in their male infants—a shorter, more female-like anogenital distance and associated incomplete descent of testes and a smaller scrotum and penis. The science behind this study has been questioned by phthalate industry consultants. As of June 2008, there are only five studies of anogenital distance in humans, and one researcher has stated "Whether AGD measures in humans relate to clinically important outcomes, however, remains to be determined, as does its utility as a measure of androgen action in epidemiologic studies."


title: Endocrine disruptor

text: While the fact that there are chemical differences between endocrine disruptors and endogenous hormones have sometimes been cited as an argument for endocrine disruptors affecting only some (not all) of the traits that are affected by hormones, toxicology research shows that many of the effects of endocrine disruptors target the aspects of hormone effects that make one hormone regulate the production and/or degradation of the body's own hormones. These regulation effects are intertwined so that a hormone that is level affected by another hormone in turn affects the levels of multiple other hormones produced by the body itself, leaving no endogenous hormones or traits affected by them unaffected by endocrine disruptors. 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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 of the order of those to which humans are exposed.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: Critics have argued that data suggest that the amounts of chemicals in the environment are too low to cause an effect. 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 nonmonotonic dose response curves."


title: Endocrine disruptor

text: The dosage objection could also be overcome if low concentrations of different endocrine disruptors are synergistic. This paper was published in Science in June 1996, and was one reason for the passage of the Food Quality Protection Act of 1996. The results could not be confirmed with the same and alternative methodologies, and the original paper was retracted, with Arnold found to have committed scientific misconduct by the United States Office of Research Integrity.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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."


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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).


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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".


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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. 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.


title: Endocrine disruptor

text: 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."


title: Endocrine disruptor

text: 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."


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: Bisphenol S and Bisphenol F are analogs of bisphenol A. They are commonly found in thermal receipts, plastics, and household dust.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

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


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.<ref name="urlMarch/April 2001 Sierra Magazine - Sierra Club"></ref> 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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".<ref name="urlUS FDA/CDRH: FDA Public Health Notification: PVC Devices Containing the Plasticizer DEHP"></ref> Similarly, phthalates may play a causal role in disrupting masculine neurological development when exposed prenatally.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: Research on endocrine disruptors is challenged by five complexities requiring special trial designs and sophisticated study protocols:


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: "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.


title: Endocrine disruptor

text: 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".


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

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


title: Endocrine disruptor

text: 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. Working backwards through the food chain may help to identify areas to prioritize for remediation efforts. This may be extremely challenging for contaminated fish and marine mammals that have a large habitat and who consume fish from many different areas throughout their lives.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: One of the most interesting ways is the utilization of naturally occurring microbes that degrade PCB congeners to remediate contaminated areas.


title: Endocrine disruptor

text: There are many success stories of cleanup efforts of large heavily contaminated Superfund sites. A landfill in Austin, Texas contaminated with illegally dumped VOCs was restored in a year to a wetland and educational park.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: Studies suggest that bisphenol A, certain PCBs, and phthalate compounds are preferentially eliminated from the human body through sweat.


title: Endocrine disruptor

text: 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.


title: Endocrine disruptor

text: 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: Used Cars

text: Used Cars is a 1980 American satirical black comedy film co-written and directed by Robert Zemeckis. The story follows Rudy Russo (Kurt Russell), a devious salesman, working for affable, but monumentally unsuccessful used-car dealer Luke Fuchs (Jack Warden). Luke's principal rival, located directly across the street, is his more prosperous brother, Roy L. Fuchs (also played by Warden), who is scheming to take over Luke's lot. The film also stars Deborah Harmon and Gerrit Graham, and the supporting cast includes Frank McRae, David L. Lander, Michael McKean, Joe Flaherty, Al Lewis, Dub Taylor, Harry Northup, Dick Miller, and Betty Thomas.


title: Used Cars

text: Steven Spielberg and John Milius acted as executive producers on the project, while the original musical score was composed by Patrick Williams. Filmed primarily in Mesa, Arizona, the film was released on July 11, 1980.


title: Used Cars

text: Although not a box-office success at the time, it has since developed cult film status due to its dark, cynical humor and the Zemeckis style. It was marketed with the tagline, "Like new, great looking, and fully loaded with laughs." It was the only Zemeckis film to be rated R by the Motion Picture Association of America until "Flight" (2012).


title: Used Cars

text: Rudy Russo is a young and cunning car salesman in Mesa, Arizona, with aspirations of running for the state senate. He works at the struggling New Deal used car lot owned by the elderly Luke Fuchs, who agrees to invest $10,000 in Rudy's campaign if he promises to keep the business alive. Meanwhile, across the street, Luke's twin brother and arch-competitor Roy L. Fuchs is desperate to keep his used car lot from being demolished and replaced by a proposed freeway exit. Wanting to collect life insurance money and New Deal from Luke, Roy hires his mechanic, demolition derby driver Mickey, to recklessly drive Luke's pristine, hand-restored 1957 Chevrolet Bel Air around the block with Luke in the passenger's seat. Shortly after crashing the classic car into the lot, Luke dies of a heart attack, leaving Rudy with firm evidence that Roy staged the "accident". In an attempt to prevent Roy from gaining any inheritance, Rudy has his superstitious co-worker, Jeff. and mechanic, Jim, help him bury Luke on the dealership's backlot in a vintage Edsel that was once New Deal's sign ornament. When Roy comes looking for Luke the next day, they explain that Luke took the Edsel on a vacation to Miami.


title: Used Cars

text: The following night, Rudy and his friends make a live cut-in broadcast of their commercial into the middle of a major network football game. It goes awry when Jeff finds out the car on display is red (he believes all red cars are bad luck) and female model Margaret has her dress stuck on the hood ornament, which rips open and exposes her when the hood is popped open. The commercial results in New Deal receiving a massive number of new customers the next day. In one deal, Jeff cons a family into buying a station wagon by having the lot's mascot dog, Toby, fake being run over during a test drive.


title: Used Cars

text: When Roy lures customers to his lot by hiring circus animals, Rudy counters with a live stripper show. Luke's estranged daughter Barbara Jane visits the lot in hopes of reuniting with her dad, having dropped out of college more than ten years before to live on a hippie commune. Rudy conceals the truth about her father by taking her out on a date, and inadvertently convinces her to stay in town.


title: Used Cars

text: Rudy's gang broadcasts another commercial in the middle of Jimmy Carter's presidential address, destroying some of Roy's used cars in the process, most notably his prized Mercedes SL. In retaliation, Roy storms into New Deal and attacks Jeff before discovering Luke's resting place in the backlot. Roy brings the police to New Deal the next day to dig up the rearlot, but Jim has taken the Edsel out of the pit, placed Luke's corpse in the driver's seat, and rigged the car to crash into a power transformer, where it explodes as planned. Everyone believes Luke was killed in the fiery accident, and any evidence to the contrary is destroyed. Roy believes he now has possession of New Deal, but Rudy points out that Barbara, as Luke's daughter, is effectively the new owner.


title: Used Cars

text: Eventually, Barbara discovers the fiasco over her father's death and fires Rudy, Jeff, and Jim for their cover-up scheme. As a final means of shutting down New Deal, Roy has his connections in local television station KFUK re-edit Barbara's commercial to imply that she has "a mile of cars", while also pushing a trumped-up charge of false advertising.


title: Used Cars

text: Rudy's luck changes when he wins a bet on a football game, guaranteeing him enough money for his campaign. Once he discovers that Barbara is being prosecuted for false advertising, Rudy convinces her to tell the court she has a mile of cars. To avoid a charge of perjury, she must prove it in front of the judge by having more than 250 cars on her lot by 2:45 pm that afternoon. Rudy spends his investment on 250 cars bought from Mexican dealer Manuel and having 250 student drivers deliver them to New Deal's lot in less than two hours. After overcoming Roy's attempt at disrupting the resulting convoy and Jeff's superstition of driving a red car, the drivers arrive just in time. The total measurements are just long enough to equal a mile of cars, saving Barbara and the car lot. Roy's former attorney informs Rudy and Barbara that once the freeway ramp across the street is constructed, New Deal will become the largest dealership in the state.


title: Used Cars

text: The idea for "Used Cars" originated from producer John Milius, who pitched it to Gale and Zemeckis while they were writing the script for "1941" (1979), the parody film directed by Steven Spielberg. Milius said that he and Spielberg had hoped to one day write a story about a used car salesman based outside Las Vegas.


title: Used Cars

text: They had wanted to cast actor George Hamilton as Kurt Russell's character, Rudy. Universal Pictures passed on the film, leading the duo to take it to Columbia Pictures. Frank Price, the studio president at the time, had sold used cars as a young man, and he quickly said yes. According to Bob Gale, Jack Warden had initially passed on the role of Roy Fuchs, but agreed to play the role under the condition that he be able to play Luke Fuchs, since he was interested in playing the role of both brothers. John Candy was originally cast as Sam Slaton, but dropped out due to scheduling conflicts with "1941" and was replaced with Joe Flaherty.


title: Used Cars

text: The film was shot in 29 days at the working Darner Chrysler-Plymouth dealership in Mesa, Arizona, from October to November 1979. The dealership served as the setting for "Roy L. Fuchs Pre-owned Automobiles", while a vacant lot across the street served as the setting for "New Deal Used Cars". The vacant lot now has an apartment complex, while the Chrysler bankruptcy of 2009 caused the Darner dealership to lose its Chrysler affiliation. Many local police officers worked in the film in several capacities, including the "cowboy" Shotgun role. Kurt Russell produced some commercials for Darner's, inviting customers to come in and shop while the film was still being shot.


title: Used Cars

text: In the scene where Rudy and Jeff are burying the Edsel on the backlot and are confronted by Roy and Sam over Luke's whereabouts, Gerrit Graham repeated some of Kurt Russell's lines, which was not in the script. Jack Warden was so angered over the impromptu ad-libbing that he ended the scene with his own ad-libbed "What are you, a fuckin' parrot?" directed at Graham. Luke Fuch's old Edsel switches back and forth between 1958 and 1959 model years. When it is sitting on top of the pole as the car lot sign, it is a 1959 model. When it is dropped to the ground in which to bury Luke, and when it is dug-up, started, and drives across the car lot with the dead Luke behind the wheel, it is a 1958 model Edsel. When the car hits the transformer, it is again a 1959 model, with a turquoise scallop painted on the side to match the 1958 model (only 1958 model Edsels have this feature). The judge's props for the music video for Sammy Hagar's song "I Can't Drive 55" were borrowed from Zemeckis, who in turn used Hagar's song as Marty enters the alternate Hill Valley in "Back to the Future Part II"). The excerpts of President Carter's televised speech used in the film were taken from his Oval Office address on his Administration's anti-inflation program, broadcast on October 24, 1978.


title: Used Cars

text: Shout! Factory re-released "Used Cars" on Blu-ray February 26, 2019 through their Shout! Select branch. The film had been previously released by Sony Pictures Home Entertainment on January 1, 2002, as a Region 1 DVD with audio commentary by Robert Zemeckis, Kurt Russell, and Bob Gale. The film was released August 12, 2019 as a Region B Blu-ray by Eureka Entertainment Ltd., a division of their Eureka Classics product line.


title: Used Cars

text: The review aggregator website Rotten Tomatoes reported a 77% approval rating and an average rating of 6.6/10 based on 30 reviews. The website's consensus reads, "Robert Zemeckis' pitch-black satire of American culture doesn't always hit the mark, but it's got enough manic comic energy to warrant a spin." However, early reviews were mixed. "The Washington Post" Gary Arnold dubbed it "a mean, spirited farce [...] Director/co-writer Robert Zemeckis has undeniable energy and flair, but it's being misspent on pretexts and situations that seem inexcusably gratuitous and snide." A staff reviewer for "Variety" wrote that "What might have looked like a great idea on paper has been tackled by filmmakers who haven’t expanded it much beyond the one joke inherent in the premise." They too praised Zemeckis' direction as "undeniable vigor, if insufficient control and discipline." Roger Ebert of the "Chicago Sun-Times" gave the film two out of four stars, saying the film is "filled with too many ideas, relationships, and situations with plot overkill."


title: Used Cars

text: Among the positive reviews, Dave Kehr of the "Chicago Reader" found it to be a "fierce, cathartically funny celebration of the low, the cheap, the venal—in short, America." Vincent Canby of "The New York Times" wrote, "...a movie that has more laughs in it than any film of the summer except "Airplane!" It wipes out...just about every other recent comedy aimed, I assume, at an otherwise television-hooked public." Pauline Kael of "The New Yorker" described "Cars" as "a classic screwball fantasy — a neglected modern comedy that’s like a more restless and visually high-spirited version of the W. C. Fields pictures."


title: Used Cars

text: At the time, "Used Cars" received the highest ratings in test screenings in Columbia Pictures history. In 2015, film critic and historian Leonard Maltin said, "I loved "Used Cars", and I'll never understand really why that didn't become more." Zemeckis and Gale blamed the film's failure on Columbia, who moved the film up a month from its scheduled release date based on the test-screening response. It debuted with little advance marketing and was released only one week after "Airplane!"


title: Latino (demonym)

text: The masculine term Latino (), along with its feminine form Latina, is a noun and adjective, often used in English, Spanish, and Portuguese, that most commonly refers to United States inhabitants who have cultural ties to Latin America.


title: Latino (demonym)

text: Within the Latino community itself in the United States, there is some variation in how the term is defined or used. Various governmental agencies, especially the U.S. Census Bureau, have specific definitions of "Latino" which may or may not agree with community usage. These agencies also employ the term "Hispanic", which includes Spaniards, whereas "Latino" often does not. Conversely, "Latino" can include Brazilians and Haitians, and may include Spaniards and sometimes even some European romanophones such as Portuguese (a usage sometimes found in bilingual subgroups within the U.S., borrowing from how the word is defined in Spanish), but "Hispanic" does not include any of those other than Spaniards.


title: Latino (demonym)

text: Usage of the term is mostly limited to the United States. Residents of Central and South American countries usually refer to themselves by national origin, rarely as "Latino". Because of this, many Latin American scholars, journalists, and Indigenous-rights organizations have objected to the mass-media use of the word to refer to all people of Latin American background.


title: Latino (demonym)

text: In the English language, the term "Latino" is a loan word from American Spanish. ("Oxford Dictionaries" attributes the origin to Latin-American Spanish.) Its origin is generally given as a shortening of , Spanish for 'Latin American'. The "Oxford English Dictionary" traces its usage to 1946.


title: Latino (demonym)

text: Juan Francisco Martinez writes that "Latino" has its origins in the French term , coined in the mid-19th century to identify areas of the Americas colonized by Romance-speaking people and used to justify French intervention in Latin American affairs.


title: Latino (demonym)

text: By the late 1850s, with the loss of California to Anglo-Americans or the United States, owing to the Mexican-American War, the term "latino" was being used in local California newspapers such as "El Clamor Publico" by Californios writing about "America latina" and "Latinoamerica", and identifying themselves as "latinos" as the abbreviated term for their "hemispheric membership in ".


title: Latino (demonym)

text: Both "Hispanic" and "Latino" are generally used to denote people living in the United States. Marcelo M. Suárez-Orozco and Mariela Páez write that "Outside the United States, we don't speak of Latinos; we speak of Mexicans, Cubans, Puerto Ricans, and so forth." In Latin America, the term is not a common endonym and as a demonym is restricted to the Latin American-descended population of the United States, but this is not always the case. The exception is Spain where is a common demonym for immigrants from Latin America.


title: Latino (demonym)

text: Sociologist Salvador Vidal‑Ortiz and literary scholar Juliana Martínez write that after the U.S. census introduced "Hispanic" in the 1970s, "Latino" emerged as "a term of resistance to the explicit colonial relations that 'Hispanic' sets between Spain and countries in Latin America".


title: Latino (demonym)

text: The U.S. government Office of Management and Budget (OMB) has defined "Hispanic or Latino" people as "a person of Cuban, Mexican, Puerto Rican, South or Central American, or other Spanish culture or origin, regardless of race". The U.S. census uses the ethnonym "Hispanic or Latino" to refer to "a person of Cuban, Mexican, Puerto Rican, South or Central American, or other Spanish culture or origin regardless of race". The Census Bureau also explains that "[o]rigin can be viewed as the heritage, nationality group, lineage, or country of birth of the person or the person’s ancestors before their arrival in the United States. People who identify their origin as Hispanic, Latino, or Spanish may be of any race." Hence the U.S. census and the OMB are using the terms differently. The U.S. census and the OMB use the terms interchangeably, where both terms are synonyms. According to a study by the Pew Research Center, the majority (51%) of Hispanic and Latino Americans prefer to identify with their families' country of origin, while only 24% prefer the term "Hispanic" or "Latino".


title: Latino (demonym)

text: The "AP Stylebook" recommends usage of "Latino" for persons of Spanish-speaking ancestry, as well as persons "from – or whose ancestors were from – ... Latin America, including Brazilians". However, in the recent past, the term "Latinos" was also applied to people from the Caribbean region, but those from former French, Dutch and British colonies are excluded.


title: Latino (demonym)

text: Whereas "Latino" designates someone with roots in Latin America, the term "Hispanic" in contrast is a demonym that includes Spaniards and other speakers of the Spanish language.


title: Latino (demonym)

text: The term "Latino" was officially adopted in 1997 by the United States Government in the ethnonym "Hispanic or Latino", which replaced the single term "Hispanic": "Because regional usage of the terms differs – Hispanic is commonly used in the eastern portion of the United States, whereas Latino is commonly used in the western portion."


title: Latino (demonym)

text: U.S. official use of the term "Hispanic" has its origins in the 1970 census. The Census Bureau attempted to identify all Hispanics by use of the following criteria in sampled sets:


title: Latino (demonym)

text: Neither "Hispanic" nor "Latino" refers to a race, as a person of Latino or Hispanic ethnicity can be of any race. Like non-Latinos, a Latino can be of any race or combination of races: White, Black or African American, Asian American, Native American or Alaskan Native, Native Hawaiian or other Pacific Islander American, or two or more ethnicities. While Brazilian Americans are not included with Hispanics and Latinos in the government's census population reports, any Brazilian American can report as being Hispanic or Latino since Hispanic or Latino origin is, like race or ethnicity, a matter of self-identification.


title: Latino (demonym)

text: Other federal and local government agencies and non-profit organizations include Brazilians and Portuguese in their definition of "Hispanic". The U.S. Department of Transportation defines "Hispanic Americans" as: "persons of Mexican, Puerto Rican, Cuban, Dominican, Central or South American, or other Spanish or Portuguese culture or origin, regardless of race". This definition has been adopted by the Small Business Administration as well as by many federal, state, and municipal agencies for the purposes of awarding government contracts to minority owned businesses.


title: Latino (demonym)

text: The Congressional Hispanic Caucus and the Congressional Hispanic Conference include representatives of Spanish and Portuguese descent. The Hispanic Society of America is dedicated to the study of the arts and cultures of Spain, Portugal, and Latin America. Each year since 1997 the International Latino Book Award is conferred to the best achievements in Spanish or Portuguese literature at BookExpo America, the largest publishing trade show in the United States. The Hispanic Association of Colleges and Universities, which proclaims itself the champion of Hispanic success in higher education, has member institutions in the U.S., Puerto Rico, Latin America, Spain, and Portugal.


title: Latino (demonym)

text: The "American Heritage Dictionary" maintains a distinction between the terms "Hispanic" and "Latino":


title: Latino (demonym)

text: Though often used interchangeably in American English, "Hispanic" and "Latino" are not identical terms, and in certain contexts the choice between them can be significant. "Hispanic", from the Latin word for "Spain," has the broader reference, potentially encompassing all Spanish-speaking peoples in both hemispheres and emphasizing the common denominator of language among communities that sometimes have little else in common. "Latino"—which in Spanish and Portuguese means "Latin" but which as an English word is probably a shortening of the Spanish word "latinoamericano"—refers more exclusively to persons or communities of Latin American origin. Of the two, only "Hispanic" can be used in referring to Spain and its history and culture; a native of Spain residing in the United States is a "Hispanic", not a "Latino", and one cannot substitute "Latino" in the phrase "the Hispanic influence on native Mexican cultures" without garbling the meaning. In practice, however, this distinction is of little significance when referring to residents of the United States, most of whom are of Latin American origin and can theoretically be called by either word.


title: Latino (demonym)

text: The "AP Stylebook" also distinguishes between the terms "Hispanic" and "Latino". The Stylebook limits the term "Hispanic" to people "from – or whose ancestors were from – a Spanish-speaking land or culture". It provides a more expansive definition, however, of the term "Latino". The Stylebook definition of Latino includes not only people of Spanish-speaking ancestry, but also more generally includes persons "from – or whose ancestors were from – . . . Latin America". The Stylebook specifically lists "Brazilian" as an example of a group which can be considered Latino.


title: Latino (demonym)

text: There were 28 categories tabulated in the 2000 United States census: Mexican, Puerto Rican, Cuban, Dominican, Central American: Costa Rican, Guatemalan, Honduran, Nicaraguan, Panamanian, Salvadoran, Other Central American; South American: Argentinian, Bolivian, Chilean, Colombian, Ecuadorian, Paraguayan, Peruvian, Uruguayan, Venezuelan, Other South American; Other Hispanic or Latino: Spaniard, Spanish, Spanish American, All other Hispanic or Latino.


title: Latino (demonym)

text: The use of the term "Latino", despite its increasing popularity, is still highly debated among those who are called by the name. Since the adoption of the term by the U.S. Census Bureau and its subsequent widespread use, there have been several controversies and disagreements, especially in the United States and, to a lesser extent, in Mexico and other Spanish-speaking countries. Since it is an arbitrary generic term, many Latin American scholars, journalists, and indigenous-rights organisations have objected to the mass-media use of the word "Latino", pointing out that such ethnonyms are optional and should be used only to describe people involved in the practices, ideologies, and identity politics of their supporters. Journalist Rodolfo Acuña writes:


title: Latino (demonym)

text: When and why the Latino identity came about is a more involved story. Essentially, politicians, the media, and marketers find it convenient to deal with the different U.S. Spanish-speaking people under one umbrella. However, many people with Spanish surnames contest the term "Latino". They claim it is misleading because no Latino or Hispanic nationality exists since no Latino state exists, so generalizing the term "Latino" slights the various national identities included under the umbrella.


title: Latino (demonym)

text: Attempts have been made to introduce gender-neutral language into Spanish by changing the ending of "Latino", as in the terms "Latin@", "Latine", "Latino/a", and "Latinx". Both supporters and opponents of "Latinx" have cited linguistic imperialism as a reason for supporting or opposing the use of the term.


title: 16-inch/50-caliber Mark 7 gun

text: The 16"/50 caliber Mark 7 – United States Naval Gun is the main armament of the "Iowa"-class battleships and was the planned main armament of the cancelled .


title: 16-inch/50-caliber Mark 7 gun

text: Due to a lack of communication during design, the Bureau of Ordnance assumed the "Iowa" class would use the /50 Mark 2 guns constructed for the 1920 "South Dakota"-class battleships. However, the Bureau of Construction and Repair assumed that the ships would carry a compact 16-in/50 turret and designed the ships with barbettes too small to accommodate the 16-in/50 Mark 2 three-gun turret that the Bureau of Ordnance was actually working on. The new lightweight 16-in/50 Mark 7 was designed to resolve this conflict.


title: 16-inch/50-caliber Mark 7 gun

text: These guns were 50 calibers long—or 50 times their bore diameter, which makes the barrels long, from chamber to muzzle. Each gun weighed about without the breech, and with the breech. They fired projectiles weighing from at different muzzle velocities, depending on the shell. When firing armor piercing shells, their muzzle velocity was 2,500 feet per second (762 meters per second) with a range of up to . At maximum range the projectile spent almost 1½ minutes in flight. Each turret required a crew of 79 men to operate. The turrets themselves cost US$1.4 million each, to which the cost of the guns had to be added.


title: 16-inch/50-caliber Mark 7 gun

text: The turrets were "three-gun," not "triple," because each barrel could be elevated independently. The ships could fire any combination of their guns, including a broadside of all nine. The turret interiors were subdivided and designed to permit the independent loading, elevation and firing of each gun. Each turret was also installed with an optical range finder, ballistic analog computer, and a switchboard. The rangefinder and ballistic computer permitted the turret's gun captain and crew to locally engage targets, should battle damage disrupt communication with the ship's primary or auxiliary fire control centers. The firing switchboard allowed any remaining fire control computer to send data to or control the firing computers of other turrets in the event of battle damage to the primary and secondary artillery plotting rooms.


title: 16-inch/50-caliber Mark 7 gun

text: Contrary to popular belief, the ships did not move sideways noticeably when a broadside was fired; this is simply an illusion. With the enormous mass of the vessel and the damping effect of the water around the hull, the pressure wave generated by the gunfire was felt much more than the slight change in lateral velocity. The sea surface on the side of the ship to which the guns are trained is roiled by the guns' muzzle blast, which creates the illusion of motion in still photos.


title: 16-inch/50-caliber Mark 7 gun

text: The guns could be elevated from −5 degrees to +45 degrees, moving at up to 12 degrees per second. The turrets could rotate about 300 degrees at about 4 degrees per second and could even be fired back beyond the beam, which is sometimes called "over the shoulder". A red stripe on the wall of each turret, just inches from the railing, marked the limit of the gun's recoil as a safety warning to the turret's crew.


title: 16-inch/50-caliber Mark 7 gun

text: Complementing the 16-in/50 caliber Mark 7 gun was a fire control computer, in this case the Ford Instrument Company Mark 8 Range Keeper. This analog computer was used to direct the fire from the battleship's big guns, taking into account several factors such as the speed of the targeted ship, the projectile's travel time, and air resistance. At the time the was set to begin construction, the range keepers had gained the ability to use radar data to help target enemy ships and land-based targets. The results of this advance were telling: the range keeper was able to track and fire at targets at greater range and with increased accuracy, day or night. This gave the US Navy a major advantage in the latter half of WWII, as the Japanese did not develop radar or automated fire control to the level of the US Navy. With a few exceptions, such as the Japanese battleship "Yamato", Japanese warships at best used basic radar sets that were not hooked up to a fire control in any way, still relying on optical rangefinders to spot targets. Even the few Japanese warships like "Yamato" who had radar assisted guns did not directly link their fire control and radar, having to input the locations of targets spotted on radar into the fire control manually.


title: 16-inch/50-caliber Mark 7 gun

text: The 16"/50 caliber's advanced fire control was designed to allow it to fire accurately from its max range and outside of any opposing ship's effective firing range. However, this proved to be easier said than done. The US soon learned that shell dispersion was something no fire control could solve, no matter how advanced it was (this has still proven true in modern times, as modern guns equipped with radar much more advanced than the 16"/50's radar still have a max range and an effective range and cannot fire accurately from max ranges). Several live firing tests were conducted with Iowa-class battleships where the 16"/50 displayed shockingly low hit rates from the ranges it was designed to fight from even with its very advanced radar, most notably when USS "Iowa" bombarded the former battleship, then target ship "Nevada" over five days, claiming an extremely low hit rate and failing to sink the target ship. This meant that in practice, a ship wielding this gun, or multiple of them would need to close the range to within the enemy's effective firing range to fire accurately.


title: 16-inch/50-caliber Mark 7 gun

text: During their reactivation in the 1980s, the modern Mark 160 Fire Control System was used to guide the fire of the Iowa-class Battleship Mark 7 guns.


title: 16-inch/50-caliber Mark 7 gun

text: The Mark 7 gun was originally intended to fire the relatively light Mark 5 armor-piercing shell. However, the shell-handling system for these guns was redesigned to use the "super-heavy" APCBC (Armor Piercing, Capped, Ballistic Capped) Mark 8 shell before any of the 's keels were laid down. The large-caliber guns were designed to fire two different 16-inch (406 mm) shells: an armor-piercing round for anti-ship and anti-structure work, and a high-explosive round designed for use against unarmored targets and shore bombardment.


title: 16-inch/50-caliber Mark 7 gun

text: The and classes could also fire the 2,700-pound Mark 8 shell, although with a shorter range, using the 16"/45 caliber Mark 6 gun. The Mark 6 gun was lighter than the Mark 7, which helped both battleship classes to conform to the limits of the Washington Naval Treaty. However, the two treaty era battleships fired their shells at a lower muzzle velocity, which gave them superior plunging fire to the 16"/50 caliber gun.


title: 16-inch/50-caliber Mark 7 gun

text: The Mark 8 shells gave the "North Carolina", "South Dakota", and "Iowa" classes the second heaviest broadside of all battleship classes, even though the two ships were treaty battleships. Only the "Yamato"-class super-battleships could throw more weight.


title: 16-inch/50-caliber Mark 7 gun

text: The D839 propellant (smokeless powder) grain used for full charges issued for this gun was long, in diameter and had seven perforations, each in diameter with a web thickness range of between the perforations and the grain diameter. A maximum charge consisted of six silk bags–hence the term bag gun–each filled with of propellant.


title: 16-inch/50-caliber Mark 7 gun

text: The Mark 7 gun was a built-up gun and was constructed of liner, tube, jacket, three hoops, two locking rings, tube and liner locking ring, yoke ring and screw box liner. Some components were autofretted. Typical of United States naval weapons built in the 1940s, the bore was chromium-plated for longer barrel life. It had a Welin breech block that opened downwards and was hydraulically operated. The screw box liner and breech plug was segmented with stepped screw threads arranged in fifteen sectors of 24 degrees each.


title: 16-inch/50-caliber Mark 7 gun

text: Off of Truk Atoll on 16 February 1944, "Iowa" and "New Jersey" engaged the at a range of and straddled her, setting the record for the longest-ranged straddle in history (although not a single hit was claimed). Some reports indicated the near misses caused splinter damage and casualties to the crew. "Nowaki" was able to escape due to the range and her speed. The action against "Nowaki" was part of Operation Hailstone. This is the only surface engagement that "Iowa"-class battleships are known to have engaged in. In the action, "Iowa" sank the Japanese training cruiser "Katori", while "New Jersey" helped to sink destroyer "Maikaze", and the auxiliary cruiser "Akagi Maru".


title: 16-inch/50-caliber Mark 7 gun

text: The gun was also used as the basis for Project HARP, an experimental gun-based space-launch research program.


title: Homicide statistics by gender

text: According to the data given by the United Nations Office on Drugs and Crime, worldwide, 78.7% of homicide victims are men, and in 193 of the 202 listed countries or regions, men were more likely to be killed than women. In two, the ratio was 50:50 (Switzerland and British Virgin Islands), and in the remaining seven – Tonga, Iceland, Japan, New Zealand, South Korea, Latvia, and Hong Kong – women were slightly more likely to be victims of homicides compared to males. A 2000 global study on homicide by the United Nations Office on Drugs and Crime found that men accounted for about 98 percent of all homicide perpetrators worldwide and 79% of the victims (see the chart below).


title: Solifenacin

text: Solifenacin, sold as the brand name Vesicare among others, is a medicine used to treat overactive bladder and neurogenic detrusor overactivity (NDO). It may help with incontinence, urinary frequency, and urinary urgency.


title: Solifenacin

text: Common side effects include dry mouth, constipation, and urinary tract infection. Severe side effects may include urinary retention, QT prolongation, hallucinations, glaucoma, and anaphylaxis. It is unclear if use is safe during pregnancy. It is of the antimuscarinic class and works by decreasing bladder contractions.


title: Solifenacin

text: Solifenacin was approved for medical use in the United States in 2004. In 2020, it was the 266th most commonly prescribed medication in the United States, with more than 1million prescriptions.


title: Solifenacin

text: It is used to treat overactive bladder. It may help with incontinence, urinary frequency, and urinary urgency.


title: Solifenacin

text: It is also used to treat neurogenic detrusor overactivity (NDO), a form of bladder dysfunction related to neurological impairment, in children ages two years and older. NDO is a dysfunction of the bladder that results from disease or injury in the nervous system. NDO may be related to congenital conditions (often-inherited conditions beginning at or before birth), such as spina bifida (myelomeningocele), or other conditions such as spinal cord injury. With NDO, there is overactivity of the bladder wall muscle, which normally relaxes to allow storage of urine. The bladder wall muscle overactivity results in sporadic bladder muscle contraction, which increases pressure in the bladder and decreases the volume of urine the bladder can hold. If NDO is not treated, increased pressure in the bladder can put the upper urinary tract at risk of harm, including possible permanent damage to the kidneys. In addition, spontaneous bladder muscle contractions can lead to unexpected and frequent leakage of urine with symptoms of urinary urgency (immediate urge to urinate), frequency (urinating more often than normal) and incontinence (loss of bladder control).


title: Solifenacin

text: Solifenacin is contraindicated for people with urinary retention, gastric retention, uncontrolled or poorly controlled closed-angle glaucoma, severe liver disease (Child-Pugh class C), and hemodialysis.


title: Solifenacin

text: Long QT syndrome is not a contraindication although solifenacin, like tolterodine and darifenacin, binds to hERG channels of the heart and may prolong the QT interval. This mechanism appears to be seldom clinically relevant.


title: Solifenacin

text: Solifenacin is not to be used in people with gastric retention (reduced emptying of the stomach), uncontrolled narrow angle glaucoma (fluid buildup in the eye which raises eye pressure) or hypersensitivity (allergic reaction) to solifenacin or any of its components. Solifenacin is also not recommended for use in people with severe liver failure, clinically significant bladder outlet obstruction in the absence of clean intermittent catheterization, decreased gastrointestinal motility (slowed intestinal contractions), or at high risk of QT prolongation (an electrical disturbance where the heart muscle takes longer than normal to recharge between beats), including people with a known history of QT prolongation and people taking medications known to prolong the QT interval.


title: Solifenacin

text: The most common side effects of solifenacin are dry mouth, constipation and urinary tract infection. As all anticholinergics, solifenacin may rarely cause hyperthermia due to decreased perspiration. Somnolence (sleepiness or drowsiness) has been reported. Severe allergic reactions, such as angioedema (swelling beneath the skin) and anaphylaxis, have been reported in people treated with solifenacin succinate and may be life-threatening.


title: Solifenacin

text: Solifenacin is metabolized in the liver by the cytochrome P450 enzyme CYP3A4. When administered concomitantly with drugs that inhibit CYP3A4, such as ketoconazole, the metabolism of solifenacin is impaired, leading to an increase in its concentration in the body and a reduction in its excretion.


title: Solifenacin

text: As stated above, solifenacin may also prolong the QT interval. Therefore, administering it concomitantly with drugs which also have this effect, such as moxifloxacin or pimozide, can theoretically increase the risk of arrhythmia.


title: Solifenacin

text: Solifenacin is a competitive cholinergic receptor antagonist, selective for the M receptor subtype. The binding of acetylcholine to these receptors, particularly M, plays a critical role in the contraction of smooth muscle.


title: Solifenacin

text: By preventing the binding of acetylcholine to these receptors, solifenacin reduces smooth muscle tone in the bladder, allowing the bladder to retain larger volumes of urine and reducing the number of micturition, urgency and incontinence episodes. Because of a long elimination half life, a once-a-day dose can offer 24-hour control of the urinary bladder smooth muscle tone.


title: Solifenacin

text: Peak plasma concentrations are reached three to eight hours after absorption from the gut. In the bloodstream, 98% of the substance are bound to plasma proteins, mainly acidic ones. Metabolism is mediated by the liver enzyme CYP3A4 and possibly others. There is one known active metabolite, 4"R"-hydroxysolifenacin, and three inactive ones, the "N"-glucuronide, the "N"-oxide and the 4"R"-hydroxy-"N"-oxide. The elimination half-life is 45 to 68 hours. 69% of the substance, both in its original form and as metabolites, are excreted renally and 23% via the feces.


title: Solifenacin

text: Like other anticholinergics, solifenacin is an ester of a carboxylic acid containing (at least) an aromatic ring with an alcohol containing a nitrogen atom. While in the prototype anticholinergic atropine the bicyclic ring is tropane, solifenacin replaces it with quinuclidine.


title: Solifenacin

text: The compound was studied using animal models by the Yamanouchi Pharmaceutical Co., Ltd. of Tokyo, Japan. It was known as YM905 when under study in the early 2000s.


title: Solifenacin

text: Solifenacin was approved for medical used in the United States in 2004 with an indication to treat overactive bladder in adults 18 years and older.


title: Solifenacin

text: In May 2020, solifenacin was approved for medical use in the United States with an indication to treat neurogenic detrusor overactivity (NDO), a form of bladder dysfunction related to neurological impairment, in children ages two years and older.


title: Solifenacin

text: The efficacy of solifenacin to treat neurogenic detrusor overactivity (NDO) was established in two clinical trials with a total of 95 pediatric NDO participants, ages two to 17 years old. The studies were designed to measure (as a primary efficacy endpoint) the maximum amount of urine the bladder could hold after 24 weeks of treatment. In the first study, 17 participants ages two to less than five years old were able to hold an average of 39 mL more urine than when the study began. In the second study, 49 participants ages five to 17 years were able to hold an average of 57 mL more urine than when the study began. Reductions in spontaneous bladder contractions, bladder pressure and number of incontinence episodes were also observed in both studies. The approval of Vesicare LS was granted to Astellas Pharma US, Inc.


title: Solifenacin

text: The INN is solifenacin. It is manufactured and marketed by Astellas, GlaxoSmithKline and Teva Pharmaceutical Industries.


title: Solifenacin

text: A 2006 cost-effectiveness study found that 5 mg solifenacin had the lowest cost and highest effectiveness among anticholinergic drugs used to treat overactive bladder in the United States, with an average medical cost per successfully treated patient of $6863 per year. By 2019, with the introduction of generics, the retail cost of a month's supply was down to $20 in the US.


title: Carlo Ponti (conductor)

text: Carlo Ponti Jr. (born 29 December 1968) is an Italian orchestral conductor working in the United States. He is the son of late film producer Carlo Ponti Sr. and Italian actress Sophia Loren, and the older brother of film director Edoardo Ponti.


title: Carlo Ponti (conductor)

text: Born in Geneva, Switzerland, Ponti worked at the Conductor's Institute in Connecticut, under the direction of Harold Farberman from 1994–96, worked with Mehli Mehta, Zubin Mehta, and Andrey Boreyko in Los Angeles from 1997-99, and furthered his musical studies in Austria at the Vienna Musikhochschule from 1999 to 2001 under Leopold Hager and Erwin Acel.


title: Carlo Ponti (conductor)

text: He has guest conducted internationally and was the recipient of various awards for fostering the growth of young musical talent through music education. Ponti has been associate conductor of the Russian National Orchestra from 2000 to 2018 and was music director and principal conductor of the San Bernardino Symphony from 2001 to 2013. In 2013 he founded the Los Angeles Virtuosi Orchestra, an ensemble emphasizing music's educational value of which he is artistic and music director. The Los Angeles Virtuosi Orchestra is currently performing its eight concert season (2022–2023) in Los Angeles.


title: Carlo Ponti (conductor)

text: Ponti has released two recordings with the Russian National Orchestra on the Pentatone label and his work and performances have been featured on ABC, CBS, NBC/Universal, NPR, PBS, ORF, Sky News, Spectrum, KTLA, Fox News, Leonard Lopate, Dennis Miller, "Symphony Magazine", Classical KUSC, the Associated Press, American Public Media's "Performance Today" and "America's Music Festivals".


title: Mount Katahdin

text: Mount Katahdin ( ) is the highest mountain in the U.S. state of Maine at . Named Katahdin, which means "Great Mountain", by the Penobscot Native Americans, it is within Northeast Piscataquis, Piscataquis County, and is the centerpiece of Baxter State Park. It is a steep, tall massif formed from a granite intrusion weathered to the surface. The flora and fauna on the mountain are typical of those found in northern New England.


title: Mount Katahdin

text: Katahdin was known to the Native Americans in the region and was known to Europeans at least since 1689. It has inspired hikes, climbs, journal narratives, paintings, and a piano sonata. The area around the peak was protected by Governor Percival Baxter starting in the 1930s. Katahdin is the northern terminus of the Appalachian Trail and is near a stretch known as the Hundred-Mile Wilderness.


title: Mount Katahdin

text: The mountain is commonly called just "Katahdin", though the official name is "Mount Katahdin" as decided by the US Board on Geographic Names in 1893.


title: Mount Katahdin

text: Katahdin is in Baxter State Park, which is in east central Piscataquis County, about northwest of Millinocket. It is on the drainage divide between the East and West branches of the Penobscot River.