How old is jacque pyles 2011

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How tall is jacque pyles? The L. Coroner's Office is investigating the death as a possible suicide. He was only 49 years old. His most recent credit was for the made-for-tv Nickelodeon musical " School Gyrls ," on which he served as an executive producer. Scott Kalvert has been found dead at the age of The director was found at his home in Woodland Hills, California on Wednesday March 5 and pronounced dead at the scene. His death is currently being investigated as a suspected suicide. Kalvert is best known for directing the movie The Basketball Diaries.

The film was an adaption of Jim Carroll 's juvenile diaries and chronicled his decline from promising basketball player, to heroin addict. Elsewhere, Kalvert took on the role of executive producer for Nickelodeon film School Gyrls , featuring Justin Bieber and Soulja Boy as themselves. In his career, Kalvert also worked on. With Justin posting pictures from a tropical location on Sept. Read on. Is it time that we start calling these two a couple?

Alright, Nick Cannon , you can do anything, we get it, stop rubbing it in our faces. Variety is reporting that multi-hyphenate actor, rapper, comedian, record producer, TV host, radio personality, Mariah Carey 's husband, dad and overall businessman is throwing his hat in the ring of movie directing for Lionsgate's "School Dance. Once his films began to flounder and a. Things may have gotten more serious between Justin Bieber and rumored girlfriend Jasmine Villegas.

After getting spotted engaging in a make-out session in the back of a car, the "Baby" hitmaker reportedly will be bringing along the year-old beauty with him to his upcoming Hawaii concerts. One insider told Us Magazine that Jasmine, who serves as his opening act on the second leg of his "My World 2. The photos were taken on September 9 in Venice,.

Lo, the sound of a million hearts crumbling! Justin Bieber , songbird of the post-Disney generation, has found love! Guess the world will find out soon!!! We present the top 10 most disturbing tweets concerning their relationship. The so-called proof of Justin Bieber 's possible romantic relationship with Jasmine Villegas has surfaced.

On Tuesday, September 21, TMZ made public the alleged photos of the rumored couple as they seemingly locked lips and got engaged in a make-out session in the back of a car.

The gossip site detailed that Justin and Jasmine were snapped in the suggestive position on September 9 in Venice, California. The photos, which fueled up even more speculation that the two are an item, were taken by some Canadian tourist who spotted the two singers. A from animal and cell culture experiments showing effects can be caused by concentrations comparable and sometimes below what is measured in humans and also the detection of NMDRCs in some of those same experiments.

In the human biomonitoring field, large databases such as the CDC's National Health and Nutrition Examination Survey NHANES have allowed researchers to make comparisons between groups of individuals with various exposure criteria; some of these studies will be addressed in detail in subsequent sections of this review. Although by definition these databases examine low-dose exposures, their use has been the subject of significant debate. This has led some to suggest that these studies as a whole should be rejected 93 , Instead, epidemiologists typically focus on a select number of comparisons that address relationships between chemicals and diseases identified a priori 96 , 97 , often because of mechanistic data obtained in laboratory animals or in vitro work with human and animal cells and tissues.

Repeated findings of links between EDC exposures and diseases in epidemiological analyses of biomonitoring data based on a priori hypotheses suggests these relationships should not be rejected as a statistical artifact and, instead, should be the basis for significant concern that low-dose effects can be detected in the general population 85 , The endocrine system is particularly tuned to respond to very low concentrations of hormone, which allows an enormous number of hormonally active molecules to coexist in circulation As a ligand-receptor system, hormones act by binding to receptors in the cell membrane, cytosol, or the nucleus.

The classical effects of nuclear hormone receptors influence gene expression directly, although rapid nongenomic actions at membrane-associated receptors are now well documented and accepted. Membrane receptors are linked to different proteins in the cell, and binding to these receptors typically changes cellular responses in a rapid fashion 99 , although the consequence of a rapid signaling event could be the activation of a nuclear transcription factor, leading to responses that take longer to detect.

Peptide hormones can also influence gene expression directly see Refs. There are several means by which the endocrine system displays specificity of responses to natural hormones. Many hormone receptors are expressed specifically in a single or a few cell types for example, receptors for TSH are localized to the thyroid , whereas some like thyroid hormone receptors are found throughout the body For receptors that are found in multiple cell types, different effects are produced in part due to the presence of different coregulators that influence behaviors of the target genes — When the circulating levels in blood are corrected for the low fraction of the hormones that are not bound to serum binding proteins, the free concentrations that actually bring about effects in cells are even lower, for example 0.

Concentrations of active hormones will vary based on the age and physiological status of the individual i. Of course, it should be noted that active concentrations of natural hormones vary somewhat from species to species and can even vary between strains of the same species Characteristics and activities of natural hormones.

A, This schematic depicts a typical relationship of three phases of circulating hormones: free the active form of the hormone , bioavailable bound weakly to proteins such as albumin , and inactive bound with high affinity to proteins such as SHBG. These three phases act as a buffering system, allowing hormone to be accessible in the blood, but preventing large doses of physiologically active hormone from circulating.

With EDCs, there may be little or no portion maintained in the inactive phase. Thus, the entirety or majority of a circulating EDC can be physiologically active; the natural buffering system is not present, and even a low concentration of an EDC can disrupt the natural balance of endogenous hormones in circulation. B, Schematic example of the relationship between receptor occupancy and hormone concentration. Ranges of endogenous hormones in humans from Ref. There are several reasons why endogenous hormones are able to act at such low circulating concentrations: 1 the receptors specific for the hormone have such high affinity that they can bind sufficient molecules of the hormone to trigger a response, 2 there is a nonlinear relationship between hormone concentration and the number of bound receptors, and 3 there is also a nonlinear relationship between the number of bound receptors and the strongest observable biological effect.

Thus, even moderate changes in hormone concentration in the low-dose range can produce substantial changes in receptor occupancy and therefore generate significant changes in biological effects. Welshons et al. The presence of spare receptors is the basis for saying that these receptor systems are tuned to detect low concentrations that lead to occupancy of 0. Within this range of low receptor occupancy, there is high proportionality between changes in the free hormone concentration and changes in receptor occupancy, and a change in receptor occupancy by a ligand for the receptor is required to initiate changes in receptor-mediated responses There are additional reasons why natural hormones are active at low doses: 4 hormones have a strong affinity for their receptors relative to affinity for other receptors because many hormones are secreted from a single gland or site in the body but must have effects throughout the body in multiple tissues and 5 blood concentrations of hormones are normally pulsatile in nature, with the release of one hormone often controlled by the pulsatile release of another hormone , , and both the frequency and the amplitude of pulses modulate the biological response; hormones are also influenced by circadian rhythms, with dramatic differences in hormone secretion depending on the time of day , For many years, the mechanisms by which some environmental chemicals acted at low doses were not well understood.

In , the National Research Council appointed the Committee on Hormonally Active Agents in the Environment to address public concerns about the potential for adverse effects of EDCs on human health As discussed above, the endocrine system evolved to function when unbound physiologically active ligands hormones are present at extremely low doses Because of shared receptor-mediated mechanisms, EDCs that mimic natural hormones have been proposed to follow the same rules and therefore have biological effects at low doses 38 , Similarly, EDCs that influence in any way the production, metabolism, uptake, or release of hormones also have effects at low doses, because even small changes in hormone concentration can have biologically important consequences 38 , The estrogen-response mechanisms have been extensively studied with regard to the effects of endogenous estrogens and estrogenic drugs.

In classical, genomic estrogen action, when endogenous estrogens bind to ER, those receptors bind to estrogen response element sequences or to a number of other response element sites adjacent to the genes directly responsive to estrogens; this binding influences transcription of estrogen-sensitive genes Xenoestrogens produce the same reactions; these chemicals bind to ERs, which then initiate a cascade of molecular effects that ultimately modify gene expression.

Therefore, for the actions of estrogenic EDCs, molecular mechanisms and targets are already known in some detail. Similar mechanisms are induced by the binding of androgens to the androgen receptor, or thyroid hormone agonists to the thyroid hormone receptor, among others.

Additionally, there are EDCs that act as antagonists of these hormone systems, binding to a receptor, but not activating the receptor's typical response, and preventing the binding or activity of the endogenous ligand. Finally, many EDCs bind to the receptor and trigger a response that is not necessarily the same as that triggered by the endogenous estrogens; these are termed selective ER modulators SERMs.

Ultimately, all of these actions occur at the level of the receptor. Many studies have been dedicated to the understanding of which EDCs bind to which nuclear hormone receptors and how the binding affinities compare to the natural steroid.

Thus, many of these chemicals have been classified as weak hormones. Yet studies have shown that, for example, the so-called weak estrogens like BPA can be equally potent as endogenous hormones in some systems, causing biological effects at picomolar levels 30 , 38 , 41 , Finally, EDCs have other effects that are not dependent on binding to either classical or membrane-bound steroid hormone receptors.

EDCs can influence the metabolism of natural hormones, thus producing differences in the amount of hormone that is available for binding either because more or less hormone is produced than in a typical system or because the hormone is degraded faster or slower than is normal.

Other EDCs influence transport of hormone, which can also change the amount of hormone that is available for receptor binding. And EDCs can also have effects that are independent from known endocrine actions. One example is the effect of endogenous hormones and EDCs on ion channel activity. This example illustrates how both natural hormones and EDCs can have hormonal activity via binding to nuclear hormone receptors but may also have unexpected effects via receptor-mediated actions outside of the classical endocrine system.

The various mechanisms by which EDCs act in vitro and in vivo provide evidence to explain how these chemicals induce effects that range from altered cellular function, to abnormal organ development, to atypical behaviors. Just as natural hormones display nonlinear relationships between hormone concentration and the number of bound receptors, as well as between the number of bound receptors and the maximal observable biological effect, EDCs obey these rules of binding kinetics Thus, in a way, EDCs exploit the highly sensitive endocrine system and produce significant effects at relatively low doses.

To gain insight into the effects of natural hormones and EDCs on gene expression profiles, it is possible to calculate doses that produce the same effect on proliferation of cultured cells, i.

When this is done for estradiol and EDCs with estrogenic properties, the affected estrogen-sensitive genes are clearly different However, an interesting pattern emerges: comparing profiles among only the phytoestrogens shows striking similarities in the genes up- and down-regulated by these compounds; profile comparisons between only the plastic-based estrogens also show similarities within this group.

Yet even more remarkable is what occurs when the doses are selected not based on cell proliferation assays but instead on the ability of estradiol and estrogen-mimics to induce a single estrogen-sensitive marker gene. When doses were standardized based on marker gene expression, the transcriptomal signature profiles were very similar between estradiol and estrogen mimics Taken together, these results suggest that the outcomes of these experiments are contextual to the normalization parameter and that marker gene expression and cell proliferation are not superimposable.

This indicates that the biological level at which the effects of chemicals are examined i. There are several other mechanisms by which low-dose activities have been proposed. In fact, several studies have shown that exposure to EDCs such as BPA during perinatal development can influence the response of the mammary gland to estrogen , and the prostate to an estrogen-testosterone mixture similar to the concentrations produced in aging men — There is also evidence that EDCs work additively or even synergistically with other chemicals and natural hormones in the body — Thus, it is plausible that some of the low-dose effects of an EDC are actually effects of that exogenous chemical plus the effects of endogenous hormone.

Thus, whereas only a portion of endogenous hormones are bioavailable, the entirety of a circulating EDC could be physiologically active. The effects of hormones and EDCs are dependent on dose, and importantly, low physiological doses can be more effective at altering some endpoints compared with high toxicological doses.

There are many well-characterized mechanisms for these dose-specific effects including signaling via single vs. Some of these factors will be addressed in Section III. Hormones have drastically different effects at different periods of development. In a now classical Endocrinology paper, Phoenix and colleagues showed that hormone exposures during early development, and in particular fetal development, had organizational effects on the individual, whereby the developing organs were permanently reorganized by exposure to steroids.

Permanent, nonreversible masculinization of the developing body plan by androgen exposure in utero is an example. These organizational effects are in contrast to the effects of the same hormones, at similar or even higher doses, on adults.

The effects of steroids on individuals after puberty have been termed activational, because the effects on target organs are typically transient; withdrawal of the hormone returns the phenotype of the individual to the preexposed state , although this is not always the case One of the most striking examples of the ability of low doses of hormones to influence a large repertoire of phenotypes is provided by the study of intrauterine positioning effects in rodents and other animals.

The rodent uterus in particular, where each fetus is fixed in position along a bicornate uterus with respect to its neighbors, is an excellent model to study how hormones released from neighboring fetuses can influence the development of endocrine-sensitive endpoints Importantly, differences in hormonal exposures by intrauterine position are relatively small see Fig.

Thus, even a small magnitude in differences of hormonal exposures is sufficient to generate effects on behavior, physiology, and development. Intrauterine position produces offspring with variable circulating hormone levels. Fetuses are fixed in position in the bicornate rodent uterus, thus delivery via cesarean section has allowed for study of the influence of intrauterine position on behaviors, physiology, and organ morphology.

Illustrated here are the differences in estradiol E2 and testosterone T concentrations measured in male and female fetuses positioned between two male neighbors 2M , two female neighbors 2F , or neighbors of each sex 1MF.

Direction of blood flow in the uterine artery dark vessel and vein light vessel is indicated by an arrow The earliest studies of intrauterine position compared behavioral characteristics of females relative to their position in the uterus — ; male behavior was also affected by intrauterine position , — Subsequent studies of intrauterine position showed that position in the uterus influenced physiological endpoints , — , — as well as morphological endpoints in female rodents , , , , — Male physiology and morphological endpoints were similarly affected by intrauterine position , , — The endocrine milieu of the uterine environment has been implicated in these effects because differences in hormonal exposure have been observed based on intrauterine position Fig.

The production of testosterone in male mice starting at approximately d 12 of gestation allows for passive transfer of this hormone to neighboring fetuses , , Thus, fetuses positioned between two male neighbors have slightly higher testosterone exposures compared with fetuses positioned between one male and one female or two female neighbors , — These data indicate that very small differences in hormone exposures during fetal development are capable of influencing a variety of endpoints, many of which become apparent only during or after puberty.

Furthermore, small differences in hormone exposures may be compounded by other genetic variations such as those normally seen in human populations. Intrauterine effects have been observed in animals with both large litters and singleton or twin births including ferrets, pigs, hamsters, voles, sheep, cows, and goats , , But perhaps the most compelling evidence for intrauterine effects comes from human twin studies.

From these studies, many authors have concluded that testosterone from male fetuses influences developmental parameters in female twins; typically, male same-sex twins do not display altered phenotypes for these endpoints. Yet importantly, limited studies indicate that female twins can influence their uterine pairs, with some behaviors affected in male co-twins ; breast cancer incidence in women and testicular cancer in men have also been shown to be influenced by having a female co-twin 83 , , Although the mechanisms for these intrauterine effects are not completely understood, very small differences in hormone exposures have been implicated, making the effects of twin gestations a natural example of low-dose phenomena.

In the human fetus, the adrenals produce androgens that are converted to estrogen by the enzyme aromatase, specifically in the placenta. In a human study designed to compare hormone levels in the amniotic fluid, maternal serum, and umbilical cord blood of singleton male and female fetuses, significant differences were observed in the concentrations of testosterone, androstenedione A4 , and estradiol Specifically, amniotic fluid concentrations of testosterone and A4 were approximately twice as high in male fetuses, whereas estradiol concentrations were slightly, but significantly, higher in female fetuses.

Yet, interestingly, there were no differences for any of the hormones in maternal serum, similar to findings in mice that litters with a high proportion of males or females did not impact testosterone, estradiol, or progesterone serum levels in mothers In umbilical cord serum, concentrations of A4 and estradiol were higher in males compared with females , although it must be noted that these samples were collected at parturition, long after the fetal period of sexual differentiation of the reproductive organs.

Several studies have specifically compared steroid hormone levels in maternal and umbilical cord blood samples collected from same-sex and opposite-sex twins. Male twins, whether their co-twin was a male or a female, had higher blood concentrations of progesterone and testosterone compared with female twins Furthermore, for both sexes, dizygotic twins had higher levels of these hormones, as well as estradiol, compared with monozygotic twins.

Fetal sex had no effect on maternal concentrations of testosterone, progesterone, or estrogen, suggesting that any differences observed in fetal samples are due to contributions from the fetuses' own endocrine systems and the placental tissue Yet an additional study conducted in women carrying multiple fetuses more than three indicates that both estradiol and progesterone concentrations in maternal plasma increase with the number of fetuses, and when fetal reduction occurs, these hormone levels remain elevated It has been proposed that low-dose effects seen in different intrauterine positions in litter-bearing animals could be an evolutionary adaptation, whereby the genotypes of the fetuses are relatively similar but a range of phenotypes can be produced via differential hormone exposures , For example, female mice positioned between two females are more docile and thus have better reproductive success when resources are plentiful, but females positioned between two males are more aggressive and therefore are more successful breeders under stressful conditions , , In this way, a mother produces offspring with variable responses to environmental conditions, increasing the chances that her own genetic material will continue to be passed on.

Yet although there is evidence to suggest that a variable intrauterine environment is essential for normal development , intrauterine positional effects appear to have little effect on offspring phenotypes in inbred rodent strains , This result may be related to the link between genetic diversity and hormone sensitivity , , suggesting that outbred strains are the most appropriate for studying endocrine endpoints and are also most similar to the effects of low doses of hormones on human fetuses.

Finally, it has been proposed that similar mechanisms are used by the developing fetus in response to natural hormones via intrauterine position and EDCs with hormonal activity To this end, several studies have examined the effects of both exposure to an EDC and intrauterine position or have considered the effect of intrauterine position on the response of animals to these chemicals , , , , For example, one study found that intrauterine position affected the morphology of the fetal mammary gland, yet position-specific differences were obliterated by BPA exposure Additional studies suggest that prostate morphology is disrupted by 2,3,7,8-tetrachlorodibenzo- p -dioxin TCDD exposure in males positioned between two females, but this chemical does not affect prostate morphology in males positioned between two males Finally, male rodents positioned between two males have higher glucose intolerance than males positioned between two females, yet when these males are given a diet high in phytoestrogens, glucose tolerance is dramatically improved in the males positioned between two males, whereas their siblings positioned between two females do not benefit What is clear from these studies is that low doses of natural hormones are capable of altering organ morphology, physiology, and reproductive development, similar to the effects of EDCs.

C—F , clearly indicate that the fetal endocrine system cannot maintain a so-called homeostasis and is instead permanently affected by exposures to low doses of hormones. In , the NTP acknowledged that there was evidence to support low-dose effects of DES, genistein, methoxychlor, and nonylphenol 2. Specifically, the NTP expert panel found that there was sufficient evidence for low-dose effects of DES on prostate size; genistein on brain sexual dimorphisms, male mammary gland development, and immune responses; methoxychlor on the immune system; and nonylphenol on brain sexual dimorphisms, thymus weight, estrous cyclicity, and immune responses.

Using the NTP's definitions of low dose i. For example, if a chemical blocks the synthesis of a hormone, blood levels of the hormone are expected to decline, and the downstream effects should then be predicted from what is known about the health effects of low hormone levels. In contrast, if a chemical binds a hormone receptor, the effects are expected to be very complex and to be both tissue specific and dose specific.

Finally, most EDCs interact with multiple hormone pathways, or even multiple hormone receptors, making the expected effects even more complex and context specific — Table 3 summarizes a limited selection of chemicals that have evidence for low-dose effects, with a focus on in vivo animal studies.

As seen by the results presented in this table, low-dose effects have been observed in chemicals from a number of classes with a wide range of uses including natural and synthetic hormones, insecticides, fungicides, herbicides, plastics, UV protection, and other industrial processes. Furthermore, low-dose effects have been observed in chemicals that target a number of endocrine endpoints including many that act as estrogens and antiandrogens as well as others that affect the metabolism, secretion, or synthesis of a number of hormones.

It is also clear from this table that the cutoff for low-dose effects is not only chemical specific but also can be effect dependent. And finally, although this table is by no means comprehensive for all EDCs or even the low-dose effects of any particular chemical, the affected endpoints cover a large range of endocrine targets. EDC action indicates that for some chemicals, an effect is observed i. Low-dose cutoff means the lowest dose tested in traditional toxicology studies, or doses in the range of human exposure, depending on the data available.

Affected endpoint means at least one example of an endpoint that shows significant effects below the low-dose cutoff dose. This list is not comprehensive, and the lack of an endpoint on this table does not suggest that low doses do or do not affect any other endpoints.

Several EDCs have been well studied, and the number of publications focusing on low-dose effects on a particular developmental endpoint is high; however, other chemicals are less well studied with fewer studies pointing to definitive low-dose effects on a given endpoint.

In fact, there are a significant number of EDCs for which high-dose toxicology testing has been performed and the no observed adverse effect level NOAEL has been derived, but no animal studies in the low-dose range have been conducted, and several hundred additional EDCs where no significant high- or low-dose testing has been performed see Table 4 for examples.

Balancing the large amount of data collected from some well-studied chemicals like BPA and atrazine with the relative paucity of data about other chemicals is a difficult task.

Select examples of EDCs whose potential low-dose effects on animals remain to be studied. These chemicals were identified in the s as part of the dirty dozen, 12 chemicals that were acknowledged to be the worst chemical offenders because of their persistence in the environment, their ability to accumulate through the food chain, and concerns about adverse effects of exposures to wildlife and humans. These chemicals were banned by the Stockholm convention and slated for virtual elimination.

WoE approaches have been used in a large number of fields to determine whether the strength of many publications viewed as a whole can provide stronger conclusions than any single study examined alone. Historically, risk assessors have used qualitative approaches i. Whatever the method used, when EDCs are being assessed, it is important to use the principles of endocrinology to establish the criteria for a WoE approach. We do this in Section II. B , identifying three key criteria for determining whether a study reporting no effect should be incorporated into a WoE approach.

For some well-studied chemicals, there are large numbers of studies showing both significant effects, and additional studies showing no effects, from low-dose exposures.

In these cases, extensive work is needed to deal with discordant data collected from various sources; studies showing no effect of low-dose exposures must be balanced in some way with those studies that do show effects. This can lead to problems including those encountered by the NTP expert panel, which found that there was some evidence for low-dose effects of BPA on certain endpoints but mixed findings for other endpoints.

For example, the panel noted that some studies found low-dose effects of BPA on the prostate, but other studies could not replicate these findings. In Section II. B , we address criteria that are needed to accept those studies that are unable to detect low-dose effects of chemicals; these criteria were not used by the NTP in , but they are essential to address controversies of this sort and perform WoE analyses using the best available data.

In the sections that follow, we employed a WoE approach to examine the evidence for low-dose effects of single chemicals on selected endpoints or tissues, also paying attention to when in development the EDCs in question were administered. Over the past decade, a variety of factors have been identified as features that influence the acceptance of low-dose studies 69 , 71 , 76 , 77 , 90 , , , In fact, the NTP low-dose panel itself suggested that factors such as strain differences, diet, caging and housing conditions, and seasonal variation can affect the ability to detect low-dose effects in controlled studies 2.

In particular, three factors have been identified; when studies are unable to detect low-dose effects, these factors must be considered before coming to the conclusion that no such effects exist. Although all scientific experiments should include negative untreated controls, this treatment category is particularly important for EDC research.

When a study fails to detect low-dose effects, the observed response in control animals should be compared with historical untreated controls; if the controls deviate significantly from typical controls in other studies, it may indicate that these animals were, in fact, treated or contaminated in some way or that the endpoint was not appropriately assessed 77 , , For example, if an experiment was designed to measure the effect of a chemical on uterine weight, and the control uteri have weights that are significantly higher than is normally observed in the same species and strain, these animals may have been inadvertently exposed to an estrogen source, or the uteri may not have been dissected properly by the experimenters.

In either case, the study should be examined carefully and likely cannot be used to assess low-dose effects; of course, untreated controls should be monitored constantly because genetic drift and changes in diet and housing conditions can also influence these data, thus explaining changes from historical controls. Importantly, several types of contamination have been identified in studies of EDCs including the leaching of chemicals from caging or other environmental sources , , the use of pesticide-contaminated control sites for wildlife studies and contaminated controls in laboratory studies 76 , and even the use of food that interferes with the effects of EDCs , It is also important to note that experiments must consider the solvent used in the administration of their test chemical, and thus good negative controls should test for effects of the solvent itself.

Using solvent negative controls helps prevent false positives as well as the possibility that the vehicle could mask the effects of the chemical being studied. Many studies do not include a positive control, either because of the size and cost of the experiment when including an additional treatment or because an appropriate positive control has not been identified for the endpoint being examined. However, if the study fails to detect low-dose effects of a test chemical, no convincing conclusion can be made; in this case, a positive control is required to demonstrate that the experimental system was capable of detecting such effects 71 , 75 , 77 , Several issues must be considered when addressing whether the positive control confirms the sensitivity of the assay.

First, an appropriate chemical must be selected, and it must be administered via the appropriate route, i. Second, the positive control chemical must be examined, and effective, at appropriately low doses. Thus, if the test chemical is times less potent than the positive control, a dose of the positive control times lower than the test compound must produce effects 69 , 71 , For example, studies that report effects of ethinyl estradiol only at doses that are hundreds of times higher than the dose that is effective in contraceptives are not capable of detecting low-dose effects of test chemicals.

Without appropriate and concurrent positive and negative controls, studies that fail to detect low-dose effects of test chemicals should be rejected. An analysis of the BPA literature clearly showed that many of the studies that failed to detect effects of low doses used the Charles River Sprague-Dawley rat 75 ; this strain was specifically bred to have large litters , and many generations of inbreeding have rendered the animal relatively insensitive to estrogens The NTP expert panel noted the lack of effects of BPA on Sprague-Dawley rats and concluded that there were clear differences in strain sensitivity to this chemical 2.

Importantly, this may not be true for Sprague-Dawley rats that originate from other vendors, indicating that animal origin can also influence EDC testing. Many studies in mice , , , — and rats , — have described differences displayed between two or more animal strains to a natural hormone or EDC. Often these differences can be traced to whether a strain is inbred or outbred. Genetically diverse strains are generally found to be more sensitive to estrogens Importantly, well-controlled studies demonstrate that strain differences in response to estrogen treatment may be organ dependent or may even differ between levels of tissue organization within the same organ.

For example, the Sprague-Dawley rat is more sensitive to ethinyl estradiol than other strains when measured by uterine wet weight. However, when other endpoints were measured, i.

Additionally, there are data to indicate that strain differences for one estrogen may not be applicable for all estrogenic chemicals. Attempts have been made, at times successfully, to map the differences in strain response to genetic loci However, it appears that strains with differences in response that manifest in some organs do not have divergent responses in other organs, a phenomenon that is not explained by genetic differences alone.

For these reasons, the NTP's recommendation that scientists use animals that are proven responsive to EDCs 2 must be observed. Additional factors have also been identified as influential in the ability or inability to detect low-dose effects in EDC studies. Although these factors must be considered when interpreting studies and using a WoE approach, some issues that were previously identified as essential factors in the design of studies i.

The first factor is the use of good laboratory practices GLP in the collection of data. Because GLP guidelines are designed only to control data collection, standards for animal care, equipment, and facility maintenance, and they do not ensure that studies were designed properly with the appropriate controls, it has been argued that the use of GLP methods is not appropriate or required for EDC studies GLP studies are typically large, with dozens of animals studied for each endpoint and at each time point.

Thus, it has been concluded that these studies are better simply because they are larger. Yet small studies designed with the use of power analysis, statistical tools that allow researchers to determine a priori the number of animals needed to determine significant differences based on effect size, are equally capable of detecting effects while reducing the number of animals used GLP studies also typically but not necessarily rely upon standardized assays, which are not generally considered contemporary tools and are often shown to be incapable of detecting adverse effects on endpoints that employ modern tools from molecular genetics and related disciplines.

Finally, there is no published evaluation of whether studies performed under GLP are more capable of providing accurate results. The priority given to GLP studies therefore does not appear to have been justified based on any comparative analysis. Thus, as long as studies include appropriate measures of quality assurance, they need not be performed under GLP standards to provide reliable and valuable information, and many GLP studies are inadequate to assess important and relevant endpoints.