JP2009114417A - Material without endocrine-disrupting action - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a chemical substance having a predetermined property of having no endocrine-disrupting action or substantially having no endocrine-disrupting action. <P>SOLUTION: The polymer material contains a plastic material comprised of an additive of a chemical substance with a molecular weight of 90-1,000 dalton and contains no endocrine-disrupting chemical substance. The chemical substance is useful for the manufacturing of a plastic material especially usable in products to be exposed to especially individuals who would suffer from the disadvantage if exposed thereto, for example, baby's bottles, baby toys, food containers, medical containers, animal cages, medical products, etc. This chemical substance is also especially useful as a food additive used in the food ingested by newborns and fragile individuals who would suffer from the disadvantage if exposed thereto. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

(Cross-reference to related applications)
This non-provisional application is filed in prior U.S. provisional patent application No. 60 / 825,021 (filing date: September 8, 2006, inventor: George Bittner), title of invention: "Materials Free of Endocrine Disruptive." Activity "), the disclosure of which is hereby incorporated by reference.

(Field)
The present invention relates generally to the plastics field, and more particularly to plastic materials that are substantially free of endocrine disrupting chemicals.

(Background of the Invention)
In mammals such as humans, naturally occurring (endogenous) sex hormones, called estrogens or androgens, are synthesized endogenously from cholesterol, as shown in FIG. Cholesterol is a progesterone precursor that has little or no estrogenic or androgenic action and has androgenic but no estrogenic action. Cholesterol has a cyclohexene (6-membered carbocyclic) group having a ketone (C═O) group and a pentane (5-membered carbocyclic) group having a methyl-carbonyl group. Progesterone is a precursor of testosterone, an androgen having a cyclohexene ring having a ketone group and a cyclopentane ring having a hydroxyl group. Testosterone is a precursor of 5α-dihydrotestosterone (DHT), a potent androgen, and 17β-estradiol (E2), a potent estrogen. Like cholesterol, testosterone, DHT, and E2 all have four carbocyclic structures consisting of three six-membered (or hexa-type) rings and one five-membered (or penta-type) ring. (Ie, the number of hydrogen groups) and the position of the carbon-carbon double bond are different. Testosterone, DHT, and E2 also differ in the number and position of hydroxyl (OH) and / or keto (C═O) groups. The number and position of groups having carbon-carbon double bonds, hydroxyl groups, keto groups, and other groups (e.g., chlorine, bromine, etc.) are such that there is a very small amount of a suitable catalyst and / or hexa Or if the pentacyclic structure is heated or otherwise energized, such as by UV light, it changes fairly easily.

Many cells interact with natural (endogenous) or exogenous (xenobiotic) endocrine disruptors at very low concentrations to activate (or block) receptor-induced responses. A sex hormone receptor. For example, the concentration of an agonistic substance, called EC50, that produces 50% of the maximal response at the receptor, or the concentration of a substance that inhibits 50% of the maximal receptor response of the standard agonist, called IC50, is typically 10 It is in the range of ⁻⁶ to 10 ⁻¹³ M.

  The Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) is a federal advisory committee established in 1996 to protect the US environment on how to develop the endocrine disruptor screening and testing program required by Congress. Make recommendations to the Agency. The Inter-Agency Coordinating Committee (ICCVAM) related to the evaluation of alternative methods is a group responsible for endorsing and recommending testing methods that do not use animals. These committees are responsible for the presence of xenobiotic (exogenous) chemicals with estrogenic, antiestrogenic, androgenic, or antiandrogenic effects that may be ingested by humans or released to the environment. We have issued a directive to regulate

(General description of endocrine disruptors)
Many chemicals that are considered endocrine disruptors are used in the manufacture of various products. These chemicals act as agonists or antagonists of androgen or estrogenic hormones, or other hormones such as thyroid hormones that are less well studied. Such endocrine disruptors can act to alter their function, production, synthesis, or degradation by binding to natural receptors. Substances that induce sex hormone-like responses are called agonists, and substances that block hormone action are called antagonists.

(General description of endrogen action)
The most common endocrine disrupting effect of sex hormones is the estrogenic effect. However, antiestrogenic, androgenic, and antiandrogenic effects are not uncommon. Endocrine disruptors of sex hormones, especially when exposed to the critical stage of development from the early stages of gestation to puberty, range from increased risk of hypospadias, retention testes, and vaginal cancer to mental developmental disorders May cause abnormal physical and / or behavioral consequences. Estrogen endocrine disruptors are the pathophysiology of the fetus, abnormal brain maturation or brain activity, reduced sperm count, immune response, enlarged prostate, ovarian and uterine dysfunction, learning disorders, and attention disorders, motivation ) It can also cause cognitive developmental disorders, including disabilities, affective disorders, and changes in sexual orientation.

  Mouse and rat in vivo data show that exposure to estrogen endocrine disruptors at various developmental stages and changes in infant and adult reproductive organs, timing of growth and sexual maturity, and aggressive behavior It has been shown that there is a relationship between Such estrogen endocrine disrupting effects can be either significant or subtle when tested in animals. Similar estrogen and androgen endocrine disrupting effects occur almost certainly in humans. This is because the basic endocrine mechanism of sex hormones has been highly conserved across all classes of vertebrates.

(Mechanism of estrogen action and anti-estrogen action)
The mechanism of estrogen and anti-estrogen endocrine disruptors is in common with natural estrogens. Synthetic endocrine disruptors present in the environment mimic endogenous hormonal action by affecting the work of the estrogen receptor and other members of the nuclear receptor superfamily. Estrogen receptor-α (ER-α) and estrogen receptor-β (ER-β) are promiscuous receptors. In other words, as shown in FIG. 2, ER-α and ER-β bind to a wide range of natural and synthetic endocrine disrupting chemicals to activate transcription of estrogen responsive genes, resulting in cell proliferation. it can. Chemicals with estrogenic action bind to ER-α and ER-β receptors and induce conformational changes. This conformational change makes the estrogen receptor an active transcriptional regulator that induces the transcription of estrogen-responsive genes from inactive proteins. In theory, antiestrogenic effects can be caused by antagonist inhibitors that bind to estrogen receptors but do not activate them, or agonists that bind strongly to estrogen receptors but do not activate as strongly as the estrogen response. In addition, selective estrogen receptor modulators (SERMs) bind to estrogen receptors, but the cellular response that is subsequently activated differs from that activated by the endogenous estrogen estradiol (E2). It is also possible for certain chemicals to reduce their effects by binding directly to endogenous E2 or other estrogen hormones. However, most chemicals that bind to the estrogen receptor have some effect on the activation of the estrogen receptor, either an estrogen effect, an anti-estrogen effect, or an effect as a SERM.

(General explanation of androgenic action)
Androgens are important hormones for the expression of the male phenotype. Androgens have a unique role not only during male differentiation but also during the development and maintenance of secondary male sexual characteristics and during the initiation and maintenance of spermatogenesis. The two most important androgens are testosterone and 5α-dihydrotestosterone (DHT). Testosterone and DHT act through the same androgen receptor, but each have a specific role during male differentiation. That is, testosterone is involved in the development and differentiation of Wolf tube-derived structures (eg, epididymis, vas deferens, seminal vesicles, and ejaculatory tract). On the other hand, DHT, a metabolite of testosterone, is an active ligand in many other androgen target tissues such as, for example, the urogenital sinus and protuberance and structures derived therefrom (eg, prostate, scrotum, urethra, penis).

  The interaction of testosterone and DHT with the androgen receptor is different from each other. Testosterone has a 2-fold lower affinity for the androgen receptor than DHT. The rate of dissociation of testosterone from the receptor is 5 times faster than DHT. However, testosterone can compensate for “weaker” androgenic potency during sex differentiation and development of the Wolf tube structure through high local concentrations due to diffusion from nearby testis. In more terminally located structures such as the urogenital sinus and urogenital ridge, the testosterone signal is amplified via conversion to DHT.

(Mechanism of androgen action)
The effects of testosterone in humans and other vertebrates occur mainly by two mechanisms. (1) activation of androgen receptor (directly or as DHT), and (2) conversion to estradiol and activation of estrogen receptor. Free testosterone can be transported into the cytoplasm of the target tissue cell and bind to the androgen receptor in the cytoplasm or reduced to DHT by the cytoplasmic enzyme 5α-reductase. Since DHT binds to the same androgen receptor more strongly than testosterone, its androgenic potency is about 2.5 times that of testosterone. As occurs in the estrogen receptor-receptor complex, the testosterone-androgen receptor-receptor or DHT-receptor complex can move into the cell nucleus and bind directly to a specific nucleotide sequence of chromosomal DNA. The structure changes. These binding regions, called hormone response elements (HREs), affect the transcriptional activity of specific genes and cause androgenic effects.

  Like the estrogen receptor, androgen receptor is present in many different tissues in both sexes. The large differences in systemic and / or local tissue concentrations of testosterone and / or DHT throughout fetal life, puberty, and throughout life account for most of the biological differences between males and females. Bone and brain are two important tissues in humans. In these tissues, the main effect of testosterone is by aromatizing to estradiol, an estrogen. In both male and female bones, estradiol promotes cartilage to mature and become bone, resulting in closure of epiphyses and termination of growth. In the central nervous system, testosterone is also aromatized to estradiol and serves as the most important feedback signal to the hypothalamus (especially affecting LH secretion). In many mammals, embryonic or perinatal “masculinization” of the sexually dimorphic areas of the brain by testosterone-derived estradiol programs later male sexual behavior.

  In general, androgens promote protein synthesis and their tissue growth through androgen receptors. Testosterone effects are often classified as “masculinized” or “anabolic”, but the distinction is not clear because testosterone often produces both effects together. Anabolic effects typically include increased muscle mass and strength, increased bone density and strength, and stimulation for linear growth and bone maturation. Embryonic masculinizing effects typically include genital maturation, particularly the formation of the scrotum in the penis and fetus. Postnatal (usually adolescent) masculinizing effects typically include voice depression, beard growth and auxiliary hair. Many of these postnatal testosterone effects are classified as male secondary sexual characteristics.

It should be noted that many endogenous and exogenous substances have estrogen receptor or orrogen action threshold concentrations at very low EC 50 or IC 50 concentrations of 10 ⁻⁶ to 10 ⁻¹³ M and estrogenic or androgenic threshold concentrations as low as 10 ⁻¹⁵ M. Binds to and activates (or blocks) the androgen receptor. Chemicals that activate or block estrogen receptors and androgen receptors include estrogenic, antiestrogenic, androgenic, or antiandrogenic effects, respectively, typically cyclo-hexa rings (e.g., hexane rings, hexenes). Ring, benzene ring, azine ring, diazine ring, triazine ring), and one or more hydroxyl, keto, chloride, or bromide groups.

(Federal regulation of endocrine disruptors)
Experimental data from in vitro, in vivo, ecological, and epidemiological studies showing that specific chemicals or chemical formulations have varying degrees of endocrine disrupting activity are available from government agencies (EDSTAC and (Including ICCVAM), merchants, non-profit organizations, and scientific committees. In response to concerns about the endocrine disrupting effects of chemicals on humans and wildlife, the US Congress passed amendments to the Food Quality Protection Act in 1996 and the Drinking Water Safety Act in 1996. These amendments call for testing for endocrine disrupting effects of chemicals, paying particular attention to endocrine effects. To achieve this goal, the EPA has established EDSTAC to investigate whether current toxicology testing methods are sufficient to determine endocrine disrupting effects.

(Use of additives and monomers in plastics)
Many cyclohexane, cyclohexene, benzene, triazine, and other hexa ring structures make plastics and other polymers (eg, silicone, rubber, etc.), process food (eg, heat), or paper Is quite easily converted under the conditions used to produce In addition, hydroxyl, chloride, bromide, nitride and other groups can be hexanes under conditions used to make plastics and other polymers, process foods, or make paper. It is not so difficult to add to the ring, hexene ring and / or benzene ring. That is, in exogenous (xenobiotic) endocrine disrupting chemicals, the number and position of C═C, hydroxyl group, keto group, and other groups (eg, chloride group, bromide group, etc.) in the hexa ring are extremely high. A small amount of a suitable catalyst is present and / or the hexa or penta ring structure is heated or otherwise converted fairly easily if energized, for example, by UV light. Very low concentrations of such contaminants produced under the conditions as described above can have dramatic toxicological effects. This is because many cells interact with natural (endogenous) or exogenous (xenobiotic) substances at very low concentrations (10 ⁻⁶ to 10 ⁻¹³ M EC50s or IC50s) to activate estrogen receptors. This is because it includes a sex hormone receptor having a binding site to (or block).

  Plastics and other polymer products polymerize certain monomers with various additives such as smaller amounts of antioxidants, plasticizers, slip agents, fining agents, heat stabilizers, light stabilizers, colorants, etc. It is produced by. The exact concentration of monomers and various additives is called plastic (or silicone, rubber, etc.) formulation and is usually proprietary informational material. Typically, monomers and additives are made by several large chemical companies and sold to manufacturers. The manufacturer creates the product using the owner's recipe.

  In order to reliably produce acceptable polymer-based products, all chemicals used to produce such products are estrogenic, anti-estrogenic, androgenic, anti-androgenic and other It has no hormones and must not cause such hormonal effects during the manufacturing process or normal product use. In the following pages, plastic polymers are used as examples of general problems and procedures for all polymer-based products.

(Hazardous biological consequences caused by currently available polymer products)
Chemicals such as those mentioned above that have hormonal effects (most commonly estrogenic effects) are derived from plastics and other polymer products used to make baby products, food containers, microwaveable products, etc. Easily melts out. Considering that plastic products are used everywhere, estrogenic and other hormonal monomers and additives begin to dissolve in plastics in normal daily use, beginning in the fetal period, through puberty, It almost certainly gives hormonal effects that are detrimental to human health during the development process of adulthood. Hormonally active chemicals and changes in hormonal action often have a much more dramatic effect on developing organisms than adult organisms. For example, recent data have reported that the level of bisphenol A in human umbilical cords is 0.2-2 μg / kg, and it dissolves from can linings into vegetable products eaten by infants and from plastic baby bottles. Consistent with the level of bisphenol A. That is, typically, if a 7 kg infant takes 700 ml of milk formula containing 5 ppb bisphenol A from a baby bottle daily, the daily dose is 0.5 μg / kg / day, but snails, fish, In frogs and rodents, deleterious developmental changes have been reported at 0.5-2 μg / kg / day. Although randomized trials to investigate directly the harmful developmental effects of bisphenol A are unlikely in human infants, such harmful effects can also be caused in humans. This is because the basic endocrine mechanism is not significantly different between rodents and humans.

(Description of plastic monomers and additives)
Plastic is any one of a large and diverse group of materials consisting of all or part of a combination of carbon and oxygen, hydrogen, nitrogen, and other organic and inorganic elements. A substance having a large molecular weight is produced by combining these elements. Even when the final state is solid, this material is made liquid at some stage during processing and can therefore be formed into various shapes, usually by applying heat and / or pressure. Plastic products are found in almost every conceivable scene of modern life.

  Plastic is made from monomers. Monomers are typically synthesized into polymers by applying heat, pressure, and being promoted by a catalyst. The most common monomers used to make plastics are shown in Table P-1. Table P-1 also shows the general use of such plastics in the US market. With a polymer-dependent domestic market for packaging, equipment, and transportation, the United States has the largest plastic market in the world. In 1996, plastic output in the United States was 87 billion pounds, exceeding 125 billion pounds in 2000 and exceeding 200 billion pounds in 2005. Currently, about 5-10 chemical manufacturers synthesize more than 95% of the total plastic monomers and most of the commonly used additives worldwide. Therefore, they are investing heavily in the compositions currently in use.

  Polyethylene is still a plastic produced in large quantities (25% of the market in 2000 and 20% in 2005). This is because the various foams are cheap to synthesize and / or have various properties. Low density polyethylene (LDPE) and linear low density polyethylene (LLDPE) account for approximately half of total annual polyethylene production, most of which is in blown film and extruded film materials. A significant portion of this film production is used to wrap food. The other half is high density polyethylene (HDPE), most of which is used for films, plastic bottles, and plastic pipes, with use involving contact with either food or drinking water. The use of polypropylene, polystyrene, polyvinyl chloride, and polycarbonate is similarly applied. For example, many plastic containers for carbonated beverages are now made from polyethylene terephthalate (PET), a material that very well prevents carbon dioxide from escaping from the container. Bisphenol A is a monomer used to synthesize various plastics, such as PCs, epoxies, phenoxy, and polysulfone polymers (Table P-1), and is released in significant amounts when the polymers are exposed to water. (Especially when heated). Currently, PC plastics synthesized from bisphenol A, which has harmful estrogenic effects, are very commonly used in food and beverage containers, baby bottles, baby toys, microwaveable containers, and medical supplies. This is because polycarbonate plastics exhibit excellent impact strength, toughness, heat resistance, optical clarity and ease of manufacture. Since 1996, polycarbonate production has risen rapidly, reaching a market share of 15% in 2000 and about 30% in 2005. Currently, bisphenol A is one of the top 50 chemicals produced in the United States.

  Monomers used in making various plastics often exhibit deleterious estrogenic effects (eg, bisphenol A, terephthalic acid) and / or other toxic effects (eg, vinyl chloride). Here, monomers are described that probably have and / or should not have hormonal action after and / or after heating, UV irradiation or other stresses. Because the polymerization process is usually not complete, unpolymerized monomers with estrogenic action escape from the plastic, causing harmful estrogenic, androgenic, other hormonal, toxic or carcinogenic effects in humans and other species. This is because the effect can be easily caused. Although there has been no systematic investigation so far on the estrogenic effects of polyethylene degradation products, the present invention shows that the polyethylene polymer and its ethylene monomer have no known estrogenic or other harmful effects. (Provide). Furthermore, various polyethylene foams, whose properties range from “hard and compliant” to “soft and flexible”, depending on the polymerization process used, are very versatile. Polypropylene is another common monomer that should have no estrogenic, antiestrogenic, androgenic, antiestrogenic, and other hormonal effects. If all the additives do not have estrogenic and other hormonal effects, plastics made from polypropylene according to the present invention will probably not have estrogenic and other hormonal effects as well.

  Monomers that should not have estrogenic and other hormonal effects are polyethylene, polypropylene, poly (decamethylene carboxamine), poly (hexamethylene adipamide), Poly (hexamethylene sebacamide), poly (nonamethylene urea), polycaprolactam, poly (butylene glycol), poly (epichlorohydrin), poly (epichloro) Hydrin ethylene oxide), poly (ethylene oxide), polyformaldehyde (carcinogens and toxic effects), nitroso rubber, poly (tetramethylene oxide), polyimine, most inorganic polymers, polyurea-formaldehyde (polyurea-formaldehyde) ( Tolerance Not possibly have carcinogen and toxic effects), including polysaccharides, polyurethanes, most polyvinyl and polyolefin compounds, polyacetylene, and most polyacid made from short carbon chains having no cyclic structure.

(Additive)
Additives are chemicals that are introduced after the plastic is synthesized to enhance its properties. For example, antioxidants are added to extend the usable life of polyethylene and other plastics by preventing or at least minimizing degradation by oxygen. As the polymer absorbs oxygen, molecular chains are broken (chain scission), resulting in other undesirable effects such as discoloration, loss of surface gloss, surface cracking, and reduced tensile strength. In addition, plastics are typically processed into useful shapes at temperatures in excess of 150 ° C. that can cause thermo-oxidative degradation of their molecular weight, ductility, and strength. Table P-2 lists some common antioxidants. Nearly all of these antioxidants, except possibly organophosphites and thioethers, have estrogenic, carcinogenic or other toxic effects as expected. The oldest and most common antioxidants that are considered suitable for food contact use belong to a class of materials known as hindered phenols.

  Among the hindered phenols used as antioxidants, BHT is most popular (Table P-2). Since 1949, BHT has been widely used as an antioxidant food additive in edible fats, oils and fat-containing foods and cosmetics in addition to plastics. This is largely because it is considered very inexpensive and non-toxic. BHT functions by capturing and reducing free radicals related to oxidation. However, BHT has an estrogenic effect, as expected using the methods described herein. BHT has also been reported to have other toxic effects. Thus, BHT is almost certainly not suitable as an antioxidant in plastics due to its estrogenic action and very high mobility. Most antioxidants on the market today have estrogenic or other hormonal effects in their original formula, or hormonal chemicals as predicted herein. Convert easily.

  Additives other than antioxidants are often used depending on the material and its preferred application. For example, as shown in Table P-3, various pigments including lead chromate, lead molybdate, sulfadiene lead, chromium oxide, ammonium iron, ferrocyanide, carbon black, phthalo blues, etc. are polyethylene and other polymers. Used for coloring. Many of these pigments have estrogenic effects as expected herein or have other toxic effects. Other types of additives include plasticizers and stabilizers as shown in Table P-4. Adding a plasticizer to the polymer produces a flexible plastic product. For example, the most prevalent plasticizers used in PVC compounds are probably esters of phthalic acid, all of which have estrogenic effects as expected herein, and are often It has a high concentration of 4-8% of the weight of the plastic. Most plasticizers are very mobile at ambient conditions and are commonly used in children's products made of PVC, so children who "taste" the things around them have a significant amount Often take these compounds. Polyethylene is usually quite flexible so plasticizers are not usually added. On the other hand, stabilizers suppress or reduce damage to polyethylene and other polymers due to electromagnetic radiation (eg, heat, light, etc.). Thermal stabilizers used for PVC include barium-cadmium soap, organotin compounds, lead compounds, and cadmium-zinc soap. Additives containing lead and cadmium are clearly toxic. Many of the most common UV stabilizers for polyethylene, such as benzothiazole and benzophenone, have estrogenic effects and have a much lower molecular weight as expected herein. Such low molecular weight (≦ 1000 dalton) stabilizers are routinely added to polyethylene, polypropylene, and other polymeric plastics and are sufficiently mobile to escape from the plastics by diffusion into the environment.

(Federal regulation of plastics)
Due to federal regulations and commercial concerns, most monomers or additives that have carcinogenic or other lethal toxic effects (Tables P-2-4) are used in plastics that are routinely contacted by humans and in foods that are in contact with food. can not see. The FDA has long recognized the problem of chemicals (monomers and additives) escaping from plastics and other products and has severely regulated antioxidants and other agents in plastics that come into contact with food. The FDA has requested that such additives be tested for carcinogenicity and other acute toxic effects. Less toxic stabilizers such as tin-based soaps are approved by the FDA even when in contact with food, but cheaper and toxic stabilizers (barium, cadmium, and lead compounds), such as electronic components Approved for use in other applications that do not come into contact with food. Unlike the FDA regulations for carcinogenicity or other types of toxicity, the FDA does not issue regulations that define acceptable levels of estrogenic or other hormonal effects on food-contact monomers, polymers, or additives.

(Food additive)
The Food Quality Protection Act requires that chemicals be tested and regulated for endocrine disrupting effects (such as estrogenic effects). The need for safer plastics that have less impact on human health is now being sought and finally regulated because of the well-documented endocrine disrupting effects of plastics. This is because the scientific facts that were made attracted social attention.

  Currently, regulations in other developed countries or consumer interests are affecting the United States. That is, although no US federal agency has taken formal regulatory action, there are several US products that have changed significantly in response to market and social concerns. As one example, the European Union recently banned the use of phthalates and PVC plastics in children's toys under the age of three. As a result, plastic baby bottles or annular pacifiers in Europe no longer contain phthalates. In addition, in Japan and the United States, many baby products are not concerned with the harmful effects of phthalate and PVC on the health of phthalates and PVC, not by chemical manufacturers but by society and retail stores (eg Toys Us and Baby Us Us). No longer made from PVC. As a second example, the use of many polycarbonate products (eg, baby bottles and dishes) has recently decreased dramatically in Japan. This is because it has become socially known that these polycarbonates release bisphenol A, which has an estrogenic action that can have deleterious effects on human reproductive function and many other physiological systems. It is. However, almost all additives that replace phthalate or bisphenol A have an estrogenic effect, and in many cases the effect is higher than the substituted phthalate or bisphenol A. In addition, many other food-contact products used by humans (including infants) in Europe, Japan and the United States contain phthalates.

  More than 2,800 different food additives are routinely used to help maintain product freshness and quality and delay physical, chemical and biological degradation. Table A-1 lists some commonly used food additives and their intended function. Antioxidants are one of the most important and most widely used food additives. Food antioxidants are based on their function, primary antioxidants (which prevent oxidation when used alone), synergists, or secondary antioxidants (maintain or enhance the action of primary antioxidants) Compound). Primary antioxidants have varying degrees of efficacy in food systems due to many factors such as oxidation-reduction potential, degree of chemical degradation, physical loss, and solubility within the food matrix. Mixing different antioxidants often provides better protection against oxidation. This may be because the synergistic action regenerates the most reactive antioxidant.

  Table A-2 lists 12 common antioxidants. Some (BHA, BHT, tocopherol, TBHQ, gallate, THBP, # 1-6) are the most commonly used antioxidants. Others (# 7-12) are “natural” antioxidants isolated from plants, but are currently less common for use in food production. Most synthetic or natural antioxidants are converted to phenolic rings or chloride rings when heated in the presence of various common substances (water, table salt) by the phenolic ring or the process described herein. Contains the resulting benzene ring. Some of these natural antioxidants, carnosine (# 11), glycyrrhizic acid (# 12) often do not have a benzenephenol ring that interacts with ERs.

  Food antioxidants and other food additives that have estrogenic effects (and possibly androgenic and other hormonal effects) are almost certainly harmful hormonal effects given that they are used everywhere Are given to humans, especially during the embryonic and puberty periods. Although there is still no data that can be directly compared for food additives, recent data on plastic indicates that the level of bisphenol A in human umbilical cord is 0.2-2 μg / kg. This level is consistent with the level of bisphenol A reported to dissolve from can linings into vegetable products and from plastic baby bottles, similar to the levels of BHA and BHT in foods. BHA, BHT, and bisphenol A have similar -4 to -5 RBAs. That is, typically, if a 7 kg infant takes 700 ml of formula containing 5 ppb bisphenol A dissolved from a baby bottle daily, the daily dose will be 0.5 μg / kg / day. In snails, fish, frogs, and rodents, this is an alarming value since developmental changes have been reported at 0.5-2 μg / kg / day of bisphenol A.

  Although the estrogenic, androgenic, or other hormonal effects of food antioxidants have not yet been investigated by FDA and others, many food antioxidants are expected to exhibit estrogenic effects because they contain a phenolic ring. The Many estrogen chemicals are effective at picomolar to nanomolar levels, and antioxidants are often added to foods at micromolar to millimolar concentrations (1000 times greater, see Table A-2). Thus, such estrogen antioxidants can be a significant health hazard, especially for the developing fetus. Of the twelve antioxidants in Table A-2, BHA, BHT, tocopherol and TBHQ of antioxidants # 1 to 4 are hindered phenols, propyl gallates of # 5 and 6 and THBP is phenol. . Curcumin, catechin, sesamin, sesamorin, carnosine and glycyrrhizic acid # 7-12 are natural antioxidants, of which # 7 and 8 contain a phenol ring, and # 9 and 10 contain a benzene ring. , # 11 and 12 do not contain either a benzene ring or a phenol ring (but contain an OH group). Table A-2 shows the prediction of estrogenic / androgenic effects (yes or no) based on considerations for these 12 antioxidants. Only carnosine and glycyrrhizic acid do not contain a hexacarbocycle. Therefore, it is not expected to have an estrogenic / androgenic action, nor is it expected to easily convert to a chemical having an estrogenic / androgenic action under cooking conditions. Another acceptable food additive that lacks a phenolic ring would be ethoxyquin. However, ethoxyquin has significant cytotoxicity.

  It should be noted that many plants contain antioxidants called flavonoids that are responsible for the color of fruits (eg red and blue of grape and berry peel) and vegetables. Flavonoids include the following 12 flavones, isoflavones, flavans, flavanones, flavanols, flavanolols, anthocyanidins, catechins (including proanthocyanidins), leucoanthocyanidins, chalcones, dihydrochalcones, and aurones. Basic types (chemical types) are known. Anthocyanidins and closely related flavonoids (including proanthocyanidins) are sometimes collectively referred to as anthocyanosides. Many flavonoid antioxidants can be expected to have estrogenic or other sex hormone effects according to the present invention. That is, they often have a hexacyclic structure with hydroxyl or C = O groups, which is one of the characteristics of chemicals with estrogenic action. Such flavonoids are called phytoestrogens, but not all phytoestrogens are flavonoids.

  Lemon (husk and white mesocarp) and the white core in the middle of citrus fruits are generally rich in flavonoids in particular. Pepper's white mesocarp is rich in flavonoids as well as berry and grape skins of various colors. Some herbs (such as ginkgo biloba) are ingested partially for their flavonoid action.

(Federal regulations for food antioxidants)
For decades, food additives have been regulated by the federal for carcinogenic or other lethal toxic effects (Federal Food, Drug and Cosmetic Act (1936) (1958)). Antioxidants are food additives that are regulated in the United States in accordance with Federal Food, Pharmaceutical and Cosmetic Act Title 21 of the US Federal Regulatory Standards. In meat and poultry products, antioxidants are regulated according to meat inspection methods and poultry inspection methods. The provisions of these laws are set forth to include the following restrictions for food additives so that they can be used safely under the conditions of appropriate manufacturing methods.
(1) The amount of food additive added to the food does not exceed the appropriate amount required to obtain the desired physical, nutritional or other technical effect.
(2) As a result of use in the production, processing or packaging of food, the amount of food additives that become ingredients of food is reduced as much as possible within an appropriate range.
(3) Food additives are of a quality level appropriate for food, and are cooked and handled as food ingredients.

  The FDA accepts that food antioxidants can be added at various specific levels according to the appropriate manufacturing process. For example, ascorbyl palmitate and tocopherol acetate are lipid-soluble antioxidants, and tocopherol allows 0.002% of lipids in infant formula and 0.03% of total lipids in shellfish. Has been. Others are tolerated at higher levels (considering their higher molecular weights). For example, guaiac fat is allowed at 0.1%. For some synergists, such as citric acid, tartaric acid, and thiodiproprionic acid, no limit is set. The FDA has not yet regulated the levels of antioxidants or other food additives related to estrogens or other hormonal effects.

(Summary of the Invention)
The present invention relates generally to the plastics field, and more particularly to plastic materials and food additives that are substantially free of endocrine disrupting chemicals. The chemical has a molecular weight of 90-1000 daltons, has a 5- or 6-membered carbon or nitrogen ring, and has protrusions that prevent interaction with the ligand binding sites of the estrogen receptor and androgen receptor. And, in the case of having one or more of the following properties, is generally not permitted for use in the manufacture of plastics that are intended to be endocrine disrupting;
For androgenic action: two anchor points corresponding to 3-keto and 17β-hydroxyl groups on DHT; trifluoromethyl and methyl groups as adjacent to the nitro group in flutamide and fenitrothion; 17β- of DHT Hydrogen bond acceptor or donor group at the position corresponding to the OH group; the distance between the hydrogen bond group corresponding to the 3-keto group and the 17β-OH group in DHT and the electrostatic interaction group is 10 Å.
For endrogenic action: benzene ring with hydroxyl, chloride or bromide; H-bond donor that mimics 17α-OH of 17β-estradiol; chemical planar and essentially hydrophobic A stereohydrophobic center that mimics the 7α and 11β conformations of 17α-estradiol with a spacing between two —OH groups at either end of 9-13Å;

  A chemical is generally a plastic that is intended to have no endocrine disrupting effects if it has a molecular weight of 90-1000 daltons and does not have any of the properties described in the subparagraphs for androgenic and endrogenic effects above. It is allowed to be used in the manufacture of

  Even if the chemical has a molecular weight greater than 1000 Daltons, which has been determined to be acceptable for use in the manufacture of plastics that are intended to have no endocrine disrupting effects, as a result of the loss of one or more side chains later It should be noted that if the property is altered or changed, such as having a reduced molecular weight and having one or more of the properties listed above, it may become unacceptable.

  Chemicals that have the acceptable properties listed above and do not bind to estrogen receptors or androgen receptors can be combined with certain plastics or food products to produce products that are substantially free of endocrine disrupting chemicals. Useful in products and applications where it is desirable to have no endocrine disrupting effects.

(Detailed description of the invention)
The present invention relates to the identification and use of monomers and additives in materials that do not contain endocrine disrupting effects. Although the term “plastic” is used herein, it should be understood that the present invention is equally applicable to other materials or products made with monomers or additives. Thus, the terms “silicone”, “rubber”, and other materials may be substituted for the term “plastic” as used herein.

  The acceptability or unacceptability of the chemicals or products described herein is defined by their ability to activate or inhibit estrogen receptors and androgen receptors. Acceptable chemicals or products that meet the criteria for not activating the estrogen receptor / androgen receptor (no endocrine disrupting properties), due to carcinogenicity, toxicity, or other harmful biological properties In some cases, general use is not allowed. Conversely, a chemical or product that is designated as unacceptable for estrogenic, androgenic, or other hormonal effects may not have other harmful biological properties. The ability to activate or inhibit the estrogen receptor and / or androgen receptor is determined by the results of an in vivo or in vivo assay, such as a sensitive, reliable and effective MCF-7 cell proliferation assay.

  The binding affinity for the two types of estrogen receptors (ER-α and ER-β) depends on the estrogen ligand, but the ligands for endogenous and exogenous estrogen receptors are typically at both receptors. Join. Both estrogen receptor types activate estrogen response elements located upstream of the promoter region of the estrogen activation gene. Chemicals that have estrogenic or anti-estrogenic effects can bind to nuclear or extranuclear receptors.

There are many physical and chemical properties of endogenous and exogenous chemicals that affect the ability of a chemical to bind to estrogen or androgen receptors. For example, the following properties of a chemical substance affect its binding ability.
A molecular weight of 90 or 160 daltons is probably the minimum limit for xenobiotics to bind to estrogen or androgen receptors, respectively. On the other hand, 1000 or 800 Dalton is probably the upper limit for binding to estrogen receptor and androgen receptor, respectively. Compounds with molecular weights greater than 800-1000 daltons are less mobile and most importantly do not bind to ER-α or ER-β or the androgen receptor. That is, chemicals that are significantly smaller or larger than the estrogen receptor binding ligand or the androgen receptor binding ligand do not bind to the estrogen or androgen receptor. However, chemicals larger than 800-1000 daltons may contain parts that are easily removed. If such degradation chemicals have the properties listed below, such degradation products can bind to the estrogen receptor or the androgen receptor.
Existing chemicals with hexa- or penta-carbon or nitrogen ring structures are less likely to bind to estrogen receptor ligands and androgen receptor ligands if they do not contain hexa- or penta-carbon or nitrogen ring structures. The androgen ring structure need not be as strict as is normally required for estrogen receptor binding.
Hydrophobic optimal log partition coefficient (P) is 4-7 for non-steroidal bonds.
The lack of protrusions that prevent interactions with the ligand binding site of the estrogen receptor and androgen receptor.

About androgen receptor binding
Chemicals lacking these anchor points presence of two anchor points corresponding to the 3-keto group and 17β- hydroxyl groups on DHT is compelling not easily bonded to the androgen receptor.
Presence of trifluoromethyl and methyl groups, such as adjacent to the nitro group in flutamide and fenitrothion. These groups can induce interaction with the hydrophobic pocket, thereby increasing androgen receptor binding.
Lack of protrusions that prevent the interaction of the estrogen receptor or androgen receptor with the ligand binding cavity.
The presence of a hydrogen bond acceptor or donor group at a position corresponding to the 17β-OH group of DHT.
For androgen receptor agonists, the distance between the hydrogen bonding group corresponding to the 3-keto group and 17β-OH group in DHT and the electrostatic interaction group is 10 Å.
For androgen receptor antagonists, a distance substantially greater than or less than 10 の 間 between the hydrogen bonding group corresponding to the 3-keto group and the 17β-OH group and the electrostatic interaction group.

About estrogen receptor binding
The presence of one phenol (or hydroxyl triazine) ring with a benzene ring having a hydroxyl radical (phenol), chloride radical, or bromine radical is much more important than any other structural or physico-chemical feature. The 3-OH group mainly acts as an H-bond donor, but may also act as an acceptor. The H-donor capacity of 3-OH groups is particularly affected by the nature of the directly adjacent (ortho) group. The H-bond donor capacity for some ortho-substituted phenols shows the following trend: phenol> 2-methylphenol = 2-tert-butylphenol>2,6-dimethylphenol> 2,6-di-tert-butylphenol. Among them, 2,6-di-t-butylphenol is not an H-bond donor because 4,4'-methylenebis (2,6-di-t-butylphenol) (4,4'-methylenebis (2, Consistent with the lack of binding effect observed for 6-di-t-butylphenol)). Chemicals with a phenolic structure tend to bind to ER, but the degree of efficacy depends on the presence of key structural features described in 4-7 below. Although a xenobiotic has a benzene ring without an —OH group, it can still bind to the ER, but the binding potential largely depends on the presence of important structural features described in 6-7 below. To do. Furthermore, OH, Cl, Br and other groups having the appropriate properties described in 6-7 below are easily added to the hexane ring, hexene ring, or benzene ring.
H-linked donor that mimics 17α-OH of 17β-estradiol.
Containing chemicals by the spacing between the two -OH groups are one 9~13Å phenol group or a chloride group at either end of the plane and essentially, to hydrophobic chemicals, weak against ER ~ Medium affinity. Most strong to moderate ER ligands contain two —OH or Cl groups with an O—O distance range of 9-13 Å.
The exact steric size and orientation of the sterically hydrophobic central hydrophobic group that mimics the 7α and 11β configurations of 17α-estradiol is as important as 17α-OH. A chemical that contains a phenol ring that is separated from another benzene ring having 0 to 3 bridge atoms is very likely to be an ER ligand. The volume of the ER ligand-binding pocket (450 ³ ) is approximately twice that of 17α-estradiol (245 ³ ). The length and width of the 17β-estradiol skeleton is in good agreement with the ligand binding pocket geometry, but there are large unoccupied depressions at the 7α and 11β-positions of 17β-estradiol. The location of these depressions is very important for a variety of exogenous estrogens, some of which do not have a benzene ring or OH group, as they allow the steric groups of a given size to fit. It is.
Ligand-binding pockets identified by X-ray crystallography of increased ERs overall chemical hydrophobicity are mainly hydrophobic at the central and vertical ends, and polar groups are located at the ends of the horizontal depressions, It has a three-dimensional “cross” -like shape. When many of the above properties are held constant, increasing direct hydrophobicity usually indicates greater ER affinity if a direct comparison is possible. Exogenous estrogens with groups lacking the most effective OO distance are greater to achieve the same binding affinity as exhibited by 17α-estradiol or exogenous estrogens with 3α- and 17β-OH groups Hydrophobicity is necessary.

Applying the above to the selection of chemicals that are acceptable for use in the production of plastics that are substantially free of endocrine disrupting activity, have a molecular weight of 90-1000 daltons, have a 5- or 6-membered carbon or nitrogen ring, and are hydrophobic A chemical having a sex logarithmic distribution coefficient of about 4 to about 7, having no protrusions that prevent interaction with the ligand binding site of estrogen receptor and androgen receptor, and having one or more of the following properties: It can be seen that the chemical is unacceptable for use in the manufacture of plastics that are substantially free of endocrine disrupting effects.
For androgenic action: two anchor points corresponding to 3-keto group and 17β-hydroxyl group on DHT; trifluoromethyl group and methyl group as adjacent to nitro group in flutamide and fenitrothion; on 17β-OH group of DHT The hydrogen bond acceptor or donor group at the corresponding position; the distance between the hydrogen bond group corresponding to the 3-keto group and 17β-OH group in DHT and the electrostatic interaction group is 10 Å.
For endrogenic action: benzene ring with one or more hydroxyl, chloride, or bromide groups; H-bond donor that mimics 17α-OH of 17β-estradiol; chemical planar and essentially hydrophobic Stereohydrophobic center that mimics the 7α and 11β conformations of 17α-estradiol with a spacing between two —OH groups at either end of 9-13 Å.

  A chemical is generally a plastic that is intended to have no endocrine disrupting effects if it has a molecular weight of 90-1000 daltons and does not have any of the properties described in the subparagraphs for androgenic and endrogenic effects above. It is allowed to be used in the manufacture of

  Even if the chemical has a molecular weight greater than 1000 Daltons, which has been determined to be acceptable for use in the manufacture of plastics that are intended to have no endocrine disrupting effects, as a result of the loss of one or more side chains later It should be noted that if a property is altered or changed, such as having a reduced molecular weight and having one or more of the properties listed above, it may not be acceptable.

(Examples of chemicals identified as having endrogenic and / or androgenic properties)
Many chemicals with cyclohexane, cyclohexene, benzene, or carbon hexacycles with hydroxyl or ketone groups can interact with estrogen receptors and androgen receptors. The same applies to some ring structures having 1 to 3N having a chlorine group or substituted 1 to 3C in azine, or the other ring structures. These chemicals can be used to make products from various polymers (plastics, silicones, rubbers and various additives), additives to food (antioxidants, colorants, etc.), or paper Often found in wood fibers, emulsifiers, colorants, etc.

Listed below are examples of synthetic chemicals that exhibit unintended estrogenic and / or androgenic properties because they bind to estrogen receptors and / or androgen receptors. Many of these chemical substances have a benzene ring (see the following items # 1 to 12), but some do not (see, for example, the following items # 13 to 17). One has a hexacycle containing three nitrogen groups (see item # 17 below). Some have chlorine groups instead of hydroxyl groups (see items # 3, 10-17 below). Some of these xenobiotic chemicals have a structure having a benzene ring (see, for example, items # 1 to 11 below), and others have a structure having a non-benzene ring (see items # 12 to 17). ).
1. p-nonylphenol (by-product from PVC products and detergents and spermicides)
2. Paraben (Lotion)
3. Phenosulfothiazine
4). Phthalate (plastic softener)
5. 4-Methylbenzylidine camphor (4-MBC) (sunscreen lotion)
6). Hydroxy-anisole butyrate (food storage)
7). Bisphenol A (food preservation, plasticizer)
8). DEHP
9. Erythrosine, red coloring No. 3 DDT (insecticide)
11. Polychlorinated biphenyl (PCB) s (lubricants, adhesives, paints)
12 Methoxychlor (insecticide)
13. Endosulfan (insecticide)
14 Heptachlor 15. Dieldrin 16. Keepon 17. Atrazine (herbicide)

All acceptable chemicals used to produce acceptable plastics, silicones, rubbers, food additives, or paper products are detected for estrogenic, anti-estrogenic, androgenic, anti-androgenic, or other hormonal effects Do not be. Furthermore, it should not be easily converted into or produced by chemicals where such effects are detected. As described herein, detectable amounts of estrogenic, antiestrogenic, androgenic, antiandrogenic, or other hormonal effects are sensitive, reliable, and effective, 17β -Means that the estrogenic action of estradiol can be detected by in vitro or in vivo assays such as the MCF-7 cell proliferation assay which can be detected at ^10-14 to ^10-15M .

Examples of acceptable and non-acceptable monomers and additives for use in the manufacture of plastics, food and paper (herein denoted as “A” and “N / A”, respectively) are provided in Table A. Note that N / A chemicals often dissolve out of the product, and even very low concentrations of constituents or contaminants may have significant deleterious effects. Because many cells interact with natural (endogenous) or exogenous (xenobiotic) substances at very low concentrations of EC ^-6 or IC 50 of 10 ^-6 to 10 ^-13 M, estrogen receptor- or androgens This is because it includes estrogen receptors and / or androgen receptors having binding sites that activate (or block) receptor-induced responses.

As mentioned above, in order to produce an acceptable product, all acceptable chemicals used to produce that product are estrogenic, antiestrogenic, androgenic, antiandrogenic, or other hormonal Must not be detected. Furthermore, it should not be easily converted into or produced by chemicals where such effects are detected. A detectable amount of estrogenic, antiestrogenic, androgenic, antiandrogenic or other hormonal activity is a sensitive, reliable and effective estrogenic effect of 17β-estradiol of 10 ⁻¹⁴ to 10 ^−10. Means that it can be detected by an in vitro or in vivo assay such as an MCF-7 cell proliferation assay that can be detected at ^-15 M. It should be noted that chemicals that are considered unacceptable often dissolve out of the product, and even very low concentrations of constituents or contaminants can have significant deleterious effects. Because many cells interact with natural (endogenous) or exogenous (xenobiotic) substances at very low concentrations of EC 50 or IC 50 of 10 ⁻⁶ to 10 ⁻¹³ M, estrogen receptor or orrogen This is because it includes estrogen receptors and / or androgen receptors having binding sites that activate (or block) receptor-induced responses.

  Although the present invention has been disclosed in terms of preferred embodiments, those skilled in the art will appreciate that other embodiments are also possible. Although the above discussion is directed to specific embodiments, it is understood that other configurations are possible. In particular, the expressions “in one embodiment” or “in another embodiment” are used herein, but these terms are meant to generally refer to the possibilities of an embodiment and It is not intended to be limited to any particular embodiment configuration. These terms refer to the same or different embodiments, and unless otherwise specified, may be combined as a collection of embodiments. Unless otherwise specified, “a”, “an”, and “the” mean “one or more”.

  When one embodiment is described herein, it is readily understood that more than one embodiment can be used in place of one embodiment. Similarly, as more than one embodiment is described herein, it is readily understood that that one device can be replaced by one embodiment.

  Given the wide range of possible endocrine disrupting chemicals, the above detailed embodiments are intended to be exemplary only and should not be construed to limit the scope of the invention. Rather, what is claimed as the invention is all that comes within the spirit and scope of the following claims and their equivalents.

  Nothing in the specification should be construed as referring to any required element, step, or function that must be included in the claims. The scope of patented subject matter is defined only by the claims granted and their equivalents. Unless otherwise stated, other aspects of the invention as described herein do not limit the scope of the claims.

FIG. 1 shows the synthesis of estrogen or androgen from cholesterol. FIG. 2 shows the binding of endocrine disrupting chemicals that activate transcription of estrogen responsive genes that lead to cell proliferation.

Claims (11)

A polymer material substantially free of endocrine disrupting chemicals,
A polymeric material that is substantially free of endocrine disrupting chemicals, comprising a plastic material comprising an additive, wherein the additive comprises a plastic material comprising a chemical having a molecular weight of 90 to 1000 Daltons. 2. The chemical substance according to claim 1, wherein the chemical substance does not have a 5- or 6-membered carbon ring or a nitrogen ring and / or has no protrusion that prevents interaction with a ligand binding site of an estrogen receptor and an androgen receptor. Polymer material. The polymeric material of claim 2, wherein the chemical does not have two anchor points corresponding to a 3-keto group and a 17β-hydroxyl group on DHT. The polymer material according to claim 2, wherein the chemical substance has no trifluoromethyl group and no methyl group. The polymeric material of claim 2, wherein the chemical does not have a hydrogen bond acceptor or donor group at a position corresponding to a 17β-OH group of DHT. The polymer material according to claim 2, wherein the chemical substance has a distance between a hydrogen bonding group corresponding to a 3-keto group and a 17β-OH group in DHT and an electrostatic interaction group is not 10 angstroms. The polymeric material of claim 2, wherein the chemical does not have a benzene ring having one or more hydroxyl, chloride, or bromide groups. The polymeric material of claim 2, wherein the chemical does not have an H-bond donor that mimics the 17α-OH of 17β-estradiol. 3. The polymeric material of claim 2, wherein the chemical is not 9 to 13 inches apart between two -OH groups at the planar surface of the chemical and at either end that is essentially hydrophobic. The polymeric material of claim 2, wherein the chemical does not have a steric hydrophobic center that mimics the 7α and 11β configuration of 17α-estradiol. A polymer material substantially free of endocrine disrupting chemicals,
A plastic material having an additive with a molecular weight greater than 1000 Daltons, having a 5- or 6-membered carbocyclic or nitrogen ring and / or a hydrophobic log partition coefficient of about 4 to about 7 and / or an estrogen receptor and A polymeric material that does not have protrusions that prevent interaction with the ligand binding site of the androgen receptor and / or is substantially free of endocrine disrupting chemicals, including a plastic material having one or more of the following properties;
For androgenic action: two anchor points corresponding to 3-keto group and 17β-hydroxyl group on DHT; trifluoromethyl group and methyl group as adjacent to nitro group in flutamide and fenitrothion; on 17β-OH group of DHT Hydrogen bond acceptor or donor group at the corresponding position; the distance between the hydrogen bond group corresponding to the 3-keto group and the 17β-OH group in DHT and the electrostatic interaction group is 10 Å, and for the endrogen action: phenol ring An H-bond donor that mimics the 17α-OH of 17β-estradiol; the spacing between the two —OH groups at the chemical plane and at either end of essentially hydrophobic is 9-13Å; 17α- Stands that mimic the 7α and 11β conformations of estradiol Body hydrophobic center.

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