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2005年10月 バロンブロッサ合意声明
環境汚染物質とヒトの不妊 情報源：Our Stolen Future New Science Vallombrosa Consensus Statement on Environmental Contaminants and Human Fertility Compromise, October 2005 PDF Version: http://www.ourstolenfuture.org/Consensus/2005/2005-1030vallombrosa.pdf Convened by: Wemen's Health@Stanford and Collaborative on Health and the Environment (CHE) バロンブロッサ会議関連ドキュメント： http://www.healthandenvironment.org/infertility/vallombrosa_documents 訳：安間 武 （化学物質問題市民研究会） 掲載日：2005年12月25日 このページへのリンク http://www.ne.jp/asahi/kagaku/pico/research/osf/05_10_Vallombrosa.html ■内容
■序言 最近の全国調査はアメリカの生殖年齢人口の12％、又は730万カップルが妊娠の困難又は／及び体外受精を経験しているということを示しいる。これは厳密には生殖障害（impaired fecundity）と命名されているが、しかし一般には不妊（infertility）と呼ばれている。 不妊の主因は広い範囲にあり、例えば、質の低下した精子又は生殖系路の異常から卵管閉塞、ホルモン／生理周期不順、無排卵まで、さらには着床困難や再発性流産などがある。ある人々は妊娠を助けるために医学的な介在を求め、そのようなことをする人の数は最近20年の間に急増している。 2002年にはアメリカでは29億ドル（約3,2000億円）が不妊治療のために使われており、毎年アメリカ人から生まれる約46,000人の赤ちゃん（又は赤ちゃん100人に1人）は最新の生殖技術（advanced reproductive technologies (ART) 訳注：妊娠を目的として卵子及び精子を体外で捜査する技術）の結果としての妊娠により生まれた。 これらのますます効果的になる医学的操作により、世界中で数十万組のカップルが妊娠に成功している。しかし、彼らはまた、精神的及び／又は金銭的な辛苦も経験しており、しばしば金銭的コストはこれらの医学的介在を必要とするカップルに手の届かない額となっている（脚注1）。 脚注1： アメリカでは、わずか14州だけが不妊治療を適用範囲とする健康保険を要求する何らかの指令を持っているが、ほとんどが部的な適用以上のものではない。 その素晴らしい望みにもかかわらず、そのような助けを求める人々にとって、必ずしも成功が保証されるわけではない。推定、治療を受けた5組に1組あるいはそれ以上がARTを受けても赤ちゃんを授からない。また、他の医学的及び／又は精神衛生条件が、カップルの不妊に関連していることがあり、（現在、治療又はARTによる妊娠に伴う健康リスクが存在するかどうかに関して、研究が行われている）。これら全ての考慮に照らして、不妊の治療とともに、避けることのできる不妊の原因を最小化することに重きが置かれるべきである。 年令、遺伝、生活習慣、潜在的疾病、生殖系感染症、栄養状態などを含む複合的相互作用要素が生物的生殖能力に影響を与えるようである。人口統計学者らは主要な要素として最初の妊娠の自主的な遅れを挙げている。しかしアメリカ疾病管理予防センターのデータは、最近20年間の生殖障害は全ての生殖年令グループで増加しているが、特に若い女性（25歳以下）で急増していることを示している。現代の広範なおびただしい数の化学物質によって引き起こされる実験動物のオス、メスの生殖関連障害を示す増加する疫学的論文と多くの実験的研究結果は、環境要素がまたヒトの不妊にも関係している可能性を示唆している。 環境と人間の健康の間の関係の科学的理解は急速に進んでいる。不妊を含む健康問題の大きな部分は10年前に考えた以上に環境的曝露によって引き起こされたかもしれない。 これらの曝露は職業的な曝露源を含むが、それに限ったものではない。実験動物又は野生生物に有害影響を与えることが知られているいくつかの環境中の化学物質について、ヒトの生殖健康への影響もまた同様に、そしてヒトが通常経験する範囲の曝露レベルにおいて、見出されつつある。 もし、非意図的な不妊が実際に増大しているなら、そして動物による研究からの洞察が実際にヒトへの影響を正確に予測するなら、不妊対処のための個人的及び社会的コストはますます耐えがたいものとなり、全ての集団のレベルにおいて生殖健康と行動様式に著しい変化が起きるであろう。このことは、公衆の健康に深く関わり、環境曝露によって引き起こされる有害影響は基本的に防止可能なのだから、もっと包括的で調整された研究課題が開発され資金が与えられなくてはならないということを強く示唆するものである。 これらの懸念に対応して、多くの分野の専門家のグループが、環境汚染、特に人工化学物質と重金属のヒトの不妊と関連する健康状態への影響について何が分かっているのかを評価するために、2005年2月27日～3月1日にカリフォルニア州メンロ・パークのバロンブロッサ・センターに集まった。ワークショップの組織者らは、この分野における重大な最近の発見が多くの興味ある科学的疑問を提起しており、患者組織と生殖医学／科学の専門的社会の中で環境リスクへの関心が脚光を浴びてきたために、この点に焦点を当てることを選択した。これは、生殖疫学、生物学、毒物学、及び臨床医学の分野の研究者らが、不妊に関連する環境健康科学の状態を見直すために、全米の関連する専門分野の代表者や不妊支援者、女性の健康と生殖保護団体らが会合した初めての会議であった。 ■会議の目的 会議の目的は：
■合意項目 会議を通じて、下記の合意が確認されたが、科学者、医学専門家、及び公衆健康推進者らがこの分野の現在の科学的理解の状態を理解するのに役立ち、さらなる進歩にとって極めて重大となるであろう重要な研究領域を特定するために、我々はそれらを提示するものである。 A. 既存の証拠に基づき、下記について確信する。
■結論 我々が検証した科学的証拠は、環境汚染はヒトの不妊の背景となる唯一の病因要素ではなさそうであるが、ある曝露は不妊の原因となる有害な生殖健康結果を引き起こす。今日、不妊のどのくらいの割合が環境的に誘引されているか深遠な人間、科学、そして公共政策の疑問である。既存の動物とヒトのデータは、一般的に認識されているもの又は科学的確実性を持って実証することができるものよりも大きい割合で環境的に引き起こされているということを示唆している。 生殖能力は人間にとって最も基本的なことである。不妊の環境的原因に関し科学的に不確実なので、ヒトの生殖健康の将来について悩ましい問題を提起すること、及び、今日までに蓄積された情報をどのように医師、患者、公衆に伝えるかについての真剣な議論を提起することが必要である。この適用は、現在、特に低レベル発達曝露に関する問題の周辺で起きている重要な不確実性を解決するために、分野間の調整と協力の下に構築され加速された研究プログラムの必要性を正当化する。一貫した強化された研究課題は、公衆健康規制機関が追求することができるものであり、個人が取る行動を通じて、不妊を防止する新たな戦略を特定するのに役に立つ。これらの調査の進展むとともに、研究によって解明される防止のための機会を明確にし促進する公式化された教育的取り組みにおいて医師、その他の健康専門家、患者、そして公衆に働きかけることの重要性がますます高まっている。 ■声明への署名者 Signatories in alphabetical order (institutional affiliation provided for identification purposes only) ■この声明で使われている用語（後日翻訳予定） Aneuploidy - The loss or gain of chromosomes in a cell due to errors in cell division, e.g. three number 21 chromosomes (or trisomy 21, also called Down syndrome) is a form of aneuploidy. Assisted reproductive technologies - The handling of eggs and sperm outside the body for the purpose of conception. The acronym ART is sometimes used imprecisely to refer to the whole range of infertility treatments, including both "lower tech" therapies, such as the use of ovulation induction drugs and intrauterine insemination, and "high tech" therapies, namely in vitro fertilization, gamete intrafallopian transfer, and zygote intrafallopian transfer. However, the American Society of Reproductive Medicine, the Society of Assisted Reproductive Technology and the US Centers for Disease Control and Prevention (for the purposes of their data collection) define ART as including only the "high tech" therapies. Therefore, the CDC figure for the number of babies born annually as a result of ART (46,000) excludes the number of children conceived and born as a result of lower tech therapies. Bioaccumulation - Process whereby contaminants taken up from the surrounding environment (air, food, water) are retained and concentrate in tissues at a rate faster than they can be broken down and excreted. With bioaccumulation, tissue levels of a contaminant become greater than surrounding environmental levels. Biomagnification - Process whereby the concentration of contaminants increases up the food chain due to larger organisms ingesting smaller organisms containing contaminants. Humans and other predatory organisms accumulate the highest concentrations of contaminants. Biomarker � A biological substance found in body fluids (blood, urine, breast milk) or tissues (fat) that can be measured and is associated with exposure to a contaminant. Biomarkers can help to monitor exposure to contaminants and may help to characterize individual susceptibilities to exposure. A biomarker of exposure is a measure of either the contaminant or a metabolite occurring shortly after exposure. A biomarker of effect is a persistent genetic change caused by a contaminant exposure that can be measured by changes in DNA or chromosome structures (e.g. DNA mutations). Biomarkers of effect are not necessarily specific to contaminant exposure. A biomarker of susceptibility is a gene or expression of a gene (polymorphisms) that renders an individual more vulnerable to the adverse effects of contaminant exposure. For example, due to differences in enzymes some individuals may not be able to detoxify a contaminant as efficiently as others resulting in higher levels of exposure and greater toxicity. Biomonitoring - The assessment of exposure to contaminants by measuring biomarkers of exposure in body tissues or fluids (e.g. blood, urine, breast milk, amniotic fluid, hair, adipose tissue, bone). Can be used to monitor not only exposures in populations but also to monitor changes in levels of contaminants over time. Bisphenol A - A common chemical compound that forms the building block of polycarbonate plastics and epoxy resins. Bisphenol A is used in polycarbonate plastic in food containers, water bottles, baby bottles, CD cases, eye glass lenses, the lining of food cans, and as a dental sealant. It binds with nuclear and extracellular estrogen receptors. Cell membrane receptors - A protein found on the surface of a cell that binds only specific chemical messengers, such as another protein or hormone. Binding of the specific chemical to the cell membrane receptor triggers processes inside of the cell, such as ion flux or enzyme activation. Cellular signaling - Process whereby one cell communicates with nearby cells to regulate and coordinate function. Communication can occur through direct cell-to-cell contact or through secretion of biologically active substances that inhibit or stimulate cell function. Contaminant exposure can affect cellular signaling by stimulating or inhibiting these biological signals. Cryptorchidism - Birth defect in newborn males in which one or both of the testicles has not descended into the scrotum. Cryptorchidism is a risk factor for testicular cancer later in life. Diethylstilbesterol (DES) - Synthetic estrogen given as a feed additive to livestock and prescribed for pregnant women from 1947-1971 to prevent miscarriage (experimental use began in 1941). DES has been shown to interfere with normal development of the reproductive tract resulting in fertility challenge in the sons and daughters of women who took DES during pregnancy. DES daughters also are at risk for a rare form of vaginal cancer. Dioxins - A class of hundreds of related persistent chemicals, some of which are known to be highly toxic, that result from industrial combustion/incineration processes; burning of household trash or fuels such as wood, coal and oil; chlorine bleaching of pulp/paper; and some types of chemical manufacturing. Cigarette smoke also contains dioxins. Endocrine disruptors - Environmental compounds that interfere with the normal function of endogenous hormones. Endocrine disruptors can stimulate or block the actions of hormones, or can interfere with their metabolism. Endocrine disruptors continue to be discovered but have been recognized to include a diverse range of chemicals including pesticides, plasticizers, flame retardants, industrial byproducts, pharmaceuticals and plantderived compounds. Endogenous - Of or relating to a substance produced within the body, or a naturally occurring chemical. For example, estrogens produced by the ovary are endogenous hormones. Endometriosis - A chronic condition affecting 5.5 million US women and girls in which the tissue lining of the uterus (endometrium) grows in abnormal locations outside the uterus, such as on the fallopian tubes, ovaries, and in the abdominal/pelvic cavity. Endometriosis causes internal bleeding and thus pain, inflammation and scarring, and is often associated with infertility. Endpoints - In a scientific study, the outcome that is being measured. This could be a biomarker, toxic effect, disease outcome, or other measure anticipated to differ between exposed and unexposed populations. Environmental agents - Includes synthetic chemicals, heavy metals (such as lead, mercury, cadmium), and naturally occurring compounds such as plant-derived estrogens. For the purposes of the Vallombrosa Workshop and this document, for the most part focus was limited to those agents considered synthetic contaminants in the natural environment. The phrase "environmental factors" generally refers to a broader range of possible environmental influences inclusive of alcohol, pharmaceutical use, stress, etc. Contaminants that have been identified as having toxic effects on reproductive physiology, function or health are called reproductive toxicants. Epidemiology - The study of the distribution and determinants of disease (and health-related) states for a human population or sample defined in time and space. Determinants of disease may include sociodemographic, geographic, behavioral, biomedical, or other environmental factors and can be evaluated in the context of genetic factors. Epigenetic - Refers to DNA modifications that do not involve changes in the sequence of DNA (genotype). Epigenetic changes can affect gene expression (phenotype) and can be transmitted from one generation to the next. Estradiol - The most potent and biologically active of the estrogens produced by the ovary, it is responsible for many biological functions in the female, including breast development and development of the uterine lining during the first half of the menstrual cycle. Estradiol also can be produced by fat cells in both men and women and can interfere with fertility in cases of obesity. Exogenous - Of or relating to a substance produced outside of the body, or a synthetic chemical (e.g. estrogens in oral contraceptives are exogenous hormones). Fecundity - The biologic capacity of men and women for reproduction. Genetic signaling - Process whereby an endogenous or exogenous substance stimulates a cascade of events inside of a cell to ultimately regulate gene expression. The substance could either inhibit or stimulate gene expression through a cellular signaling pathway. Hypospadias - Birth defect where the urinary opening (urethra) is found not at the normal location at the tip of the penis but instead on the underside of the penis. In severe cases, the urethral opening may be at the base of the penis or below the scrotum. Infertility - Definitions and measures of infertility can vary widely, but it is typically diagnosed when a couple is unable to conceive after six months or one year of regular unprotected intercourse. Often the term is used more broadly than in its strict diagnostic sense, i.e. commensurately with impaired or sub-fecundity, to describe and encompass any of the range of biological challenges people may encounter in attempting to conceive and/or carry a pregnancy (including conception delay, inability to conceive, pregnancy loss or stillbirth). Primary infertility is infertility in individuals who have never had children. Secondary infertility is that experienced after already having given birth to a child or children. Fertility, in the precise sense, refers to the ability of women to give birth to a live born infant and for men to be able to father a pregnancy resulting in a live birth. About prevalence figures: The principle source of infertility prevalence data in the US, the periodic National Survey of Family Growth conducted by the National Center for Health Statistics at US CDC, defines infertility as a duration of greater than 12 months exposed to the possibility of becoming pregnant, but not becoming pregnant. For this measure, the NSFG surveys only married women of reproductive age and reports a 2002 figure of 7.4%. Implicit in this measure is the desire for conception; thus those using contraception and/or not trying to conceive are not reflected. The NSFG also surveys all female respondents of reproductive age (married or not) who are not surgically sterile concerning doctordiagnosed and self-reported impaired fecundity, and indicates that as of 2002 11.9% of US women aged 15-44 report impaired fecundity, compared to 10.2% in 1995 and 8.4% in 1988. Because definitions/measures of infertility vary, there is a wide range of other prevalence estimates. In a study of older women that used five definitions of the word, the age-adjusted prevalence of a history of infertility ranged from 6.1% (when the women reported a physician diagnosis) to 32.6% (unprotected intercourse for 12 months ever, based on a life-time calendar of pregnancy attempts). Metabolomics - Metabolites are small molecules produced by biochemical processes in cells that build up and/or breakdown substances. Metabolomics, also called metabolic profiling, is the study of metabolites produced by a cell and can reveal much about the physiological state of a cell in response to a chemical exposure. Mixtures � In this context, concerns the effects of two or more contaminants so that the outcome of exposure is different from their separate effects. The interaction could be additive (a sum of individual effects), subtractive (one substance is stimulatory and another inhibitory), or multiplicative (the effect is greater than the sum of individual effects). National Children' Study - Led by a consortium of US government agencies (http://nationalchildrensstudy.gov), this study aims to examine prospectively the effects of environmental factors on the health and development of more than 100,000 children from before birth to age 21. Non-monotonic dose response curve - A traditional dose-response curve in toxicology assumes that the response to exposure will increase with increasing dose. This is known as a monotonic curve, i.e. one in which the slope of the dose-response curve does not change from positive to negative or vice versa. In a non-monotonic dose-response curve, the slope of the dose response curve changes sign as the level of exposure increases. Some NMDR curves are shaped like a U, others are shaped like an inverted U. NMDR curves are important from a public health perspective because in dose-response curves that are non-monotonic, low dose effects cannot be predicted from high dose testing. The traditional assumption that higher doses cause greater harm ("the dose makes the poison") is used in standard risk assessment studies to identify the level of a chemical exposure beneath which contamination should cause no effect. This old assumption may be true for many chemicals and for many classic health effects, but it can be misleading for exposures that have a non-monotonic dose-response curve. Nuclear hormone signaling - A type of genetic signaling whereby a hormone (estrogen or thyroid hormone, e.g.) binds to its receptor in the nuclear membrane inside a cell and triggers expression of genes associated with the hormone. Endocrine disruptors can interfere with normal hormone signaling to either simulate or inhibit normal hormone action. Octyl/nonyl phenols - Chemicals that belong to a broader class of compounds known as alkylphenol ethoxylates (APEs). APEs are high-volume chemicals that have been used for more than 40 years as detergents, emulsifiers, and wetting and dispersing agents. Some uses include: as ingredients in spermicides, cosmetics and detergents; and as inert ingredients in pesticides. Some are endocrine disruptors. Several are noted contaminants in aquatic environments. Perfluorinated compounds (PFCs) - Persistent, bioaccumulative chemicals found in a wide array of products including stain-resistant coatings for carpets and clothing (Gore-Tex), non-stick cookware (Teflon), and insecticides. Widespread contamination of human tissues has been documented, with some of the highest levels found in US populations. Persistence - Refers to the stability of a contaminant in the environment. Persistent contaminants are characterized by their ability to resist natural degradation so that they build up in the environment with time. Persistent contaminants often are globally transported on currents of wind or water. Phthalates - Chemicals added to personal care products to enhance penetration and hold scent/color, and as plasticizers in rigid plastics such as PVC to create flexibility. Phthalates are found in numerous and diverse consumer products including, e.g. vinyl flooring, plastic shower curtains, cosmetics and fragrances, shampoos and lotions, toys, pharmaceutical and herbal pill coatings - and in hospital equipment including IV bags and tubing. Polybrominated diphenyl ethers (PBDEs) - Persistent, bioaccumulative chemicals added to electronics, upholstery foam, textiles and numerous other materials to make them more flame resistant. PBDEs have a chemical structure very similar to PCBs and have been rapidly accumulating in wildlife and human tissues. Polychlorinated biphenyls (PCBs) - Persistent, bioaccumulative compounds banned in the US in the late 1970s, although widespread contamination still exists. PCBs were used in hundreds of commercial and industrial applications, including as lubricants, plasticizers, insulators for electrical applications, caulking and paint. Polycystic ovarian syndrome (PCOS) - A medical condition in which the ovaries produce an excess of male hormones (androgens), develop many small cysts and do not release an egg on a monthly basis. This condition affects 5-10% of women of reproductive age and is leading cause of infertility. Symptoms include irregular andheavy periods, excessive hair growth, acne and obesity. Polymorphisms - Variations in DNA sequence (genes) found in a large portion of the population. Polymorphisms may or may not render an individual more susceptible to the toxicity of a contaminant exposure or be linked to a specific form or disease. Premature ovarian failure (POF) - Occurs in 1- 4% of US females, and is characterized by depletion or dysfunction of a woman' eggs - or ovarian function - prematurely, before the age of 40. In extreme case, POF can occur as early as the teen years. Proteomics - The study of the structure and function of proteins that are produced by genes inside of a cell and the ways these proteins interact with one another inside of the cell. Exposure to contaminants may affect protein expression and can be studied as a biomarker of exposure. Transcription factors - A protein that binds to DNA and regulates gene expression. Toxicogenomics - The study of how genes/gene expression changes in response to exposure to a toxic substance. |