|
EHP2005年10月号 Mini-Monograph
全米子ども調査のための教訓 −国立環境健康科学研究所／米環境保護局の 子どもの環境健康と疾病防止研究から− 情報源：Environmental Health Perspectives Volume 113, Number 10, October 2005 Lessons Learned for the National Children's Study from the National Institute of Environmental Health Sciences/ U.S. Environmental Protection Agency Centers for Children's Environmental Health and Disease Prevention Research http://ehp.niehs.nih.gov/members/2005/7669/7669.html 訳：安間 武 （化学物質問題市民研究会） 掲載日：2005年10月12日 はじめに この小論文中の一連の六つの記事は、全米子ども調査の設計と実施のために役に立つ方法で、子どもの環境健康と疾病防止研究センター（以後、子どもセンター）での共同体験から得たものを学びたいとの思いから書かれた。子どもセンターは、国立環境健康科学研究所（NIEHS）と米環境保護局（EPA）によって共同主催されており、病因の観察調査と教育活動調査の両方を実施している。子どもセンターが調査したいくつかの曝露と結果は全米子ども調査にとって興味あるものである。この小論文は子どもセンターの研究の経験をハイライトし、その記事が全米子ども調査のための教訓の入門書として役立つことを意図している。それらの記事はいくつかのトピックスに関する考えの統合を表している。長期的出生コホート調査実施の方法論的問題点（Eskenazi et al. 2005）及び地域参加研究（Israel et al. 2005）及び大気汚染の測定における問題（Gilliland et al. 2005）、農薬曝露I(Fenske et al. 2005)、ぜん息（Eggleston et al. 2005）、及び神経行動毒性（Dietrich et al. 2005）。現時点で子どもセンターの統合経験を要約することは、全米子ども調査の計画とプロトコール開発について通知し、多様な人種及び民族グループの子どもたちの都市及び田舎での曝露を調査する時に何が実施され何が実施されていないかに関する情報を提供する機会を与えるものである。 全米子ども調査 全米子ども調査のアイディアは、1997年4月21日にクリントン大統領によって署名された大統領令13045に基づき、1997年に設立された”子どもたちへの環境健康リスクと安全リスクに関する大統領タスクフォース”の発達障害作業部会から出されたものである。”環境健康リスク及び安全リスクからの子どもたちの保護”という名のこの大統領令（Clinton 1997）は、関連する活動に関与する連邦政府諸機関に子どもに健康の脅威を及ぼす可能性のある特別な環境要因を考慮することを要求した。1999年後半、タスクフォースは、”両親と子どもに与える環境影響の長期コホート調査”（後に、”全米子ども調査”と改名）の実施可能性調査を承認した。引き続き、2000年10月に議会が満場一致で採択した”子ども健康法（2000年）”はこの調査の計画立案と実施を承認した。 子ども健康法は、子どもの健康と発達に与える環境影響の国家長期調査を計画し実施するために、国立健康人間発達研究所／国立健康研究所の所長に対し、米EPA、疾病管理予防センター、その他適切な諸機関を含む政府機関とコンソーシアムを形成するよう求めた。国立環境健康科学研究所（NIEHS）は直ぐに第4番目の主導的パートナー機関となった。子ども健康法は、物理的、化学的、生物学的、及び心理社会学的要素を含む環境を広範囲に定義した。さらに、この法は、発達障害の基本的メカニズムと健康に有害な及び健康を促進する双方の環境要素の調査を要求した。 全米子ども調査の計画は妊婦をできるだけ早い妊娠時機に登録し、また妊娠前のコホートのサブ集団を登録することとしている。現在の計画では、10万の出生児を成人(21歳)になるまで追跡し、調査期間を通じて所定の時点でデータと結果を収集することとなっている。この調査の二つの主要な目標は、曝露とその後の時点で生じる結果（すなわち、曝露はその後に生じる結果よりも数ヶ月又は数年先んずるかもしれない）とを関連付けルためのひとつの手段として長期設計を用いること、及び遺伝的特性を含む様々な要素の中での相互作用を探索することである。一般設計及び管理上の構造は全米子ども調査機関間調整委員会（2003年）及び調査計画（National Children's Study 2005）によって記述されている。 この大規模調査は、多くの手法開発調査、特に手間とコストがなるべくかからない曝露評価手法の開発の取り組みとともに2000年中頃に始まった（U.S. EPA 2004a）。他の取り組みとして、曝露と結果のバイオマーカーの分析のための非侵襲的（noninvasive）手法に関するラボ研究（Rockett et al. 2002）、動物研究における曝露−結果の関連性のさらなる探索を可能とする子どもとラボ動物モデルにおいて適用できる手法の開発（Sharbaugh et al. 2003）、及び会員補充と維持の問題を調査するために焦点を絞ったグループを用いるフィールド調査、などがある。データ検索のための先端技術の評価、子どもの健康の結果に及ぼす環境要素影響の主導的仮説の検証、及び調査における考慮のための主導的サンプリング戦略の検証などを含む多くの検証と白書の発行がなされた。さらに、曝露と結果のバイオマーカーに関するリソース・データベースが開発された（U.S. EPA 2004b）。もっと最近には、多くのワークショップがこの調査のためのプロトコール含まれるべき手法の調査と精錬のために組織された。ワークショップ、会合、及び報告書のの完全なリストは全米子ども調査のウェブサイトで見ることができる（2005）。
これらの優先焦点領域に加えて、地域参加と関与が全米子ども調査の成功のキーである。調査設計は厳密には地域ベースではなく、むしろ、調査に含めることが可能な最も代表的な集団を得るための複雑な多平面的サンプリング戦略をもって、全国の多様な場所を含んでいる。子どもセンターからの最大の学ぶべき教訓は、子どもの曝露と健康影響の集中的な調査の中で考慮されるべき無数の記号論理学的複雑さである。地域参加型研究、特にサービスの行き届かない集団での研究における子どもセンターの蓄積する経験は将来の調査に貴重な情報を提供するであろう。 NIEHS/EPA 子ども環境健康疾病予防研究 全米子ども調査を生み出した同じ大統領令がまた、子どもセンターの展開をもたらした。1998年、NIEHSとEPAは、幼児と子どもの曝露をよりよく理解するための共同の取り組みを行い、それらが作用するメカニズムをよりよく理解するためのそのような曝露の健康影響を調査し、そして実施のための証拠を提供するやり方でそのような曝露を低減するための介入戦略を調査する研究プログラムを共同で開発した。 このプログラムは二段階で資金を得た。1998年の第一段階では8つのセンターに資金を出し、さらに4つのセンターは2001年に資金提供された。2003年、新たな審査が実施され7件が資金授与された。そのうち6件は既存のセンターとして更新し、新たに1件が追加された。このプログラムの動機と最初の8センターの概要はもっと詳しく議論されてい（るDearry et al 1999、O'Fallon et al. 2000）。子どもセンターの完全な記述はNIEHSのウェブサイトで見ることができる（NIEHS 2005）。 子どもセンターの目的は2層になっている。 The purpose of the Children's Centers program is 2-fold: first, to create local research environments that promote multidisciplinary interactions among basic, clinical, and behavioral scientists through university/community partnering in order to accelerate translation of basic research findings into clinical prevention or intervention strategies; and second, to support a coordinated nationwide network of scientists and community advocacy groups synergistically sharing their experiences to address relevant questions related to the role of environmental exposures in the health of children in order to enhance community-level capacity to identify and address environmental threats and prevention opportunities. The aims of establishing this national network are to foster communication, innovation, and excellence in children's environmental health; to provide training opportunities for scientists and clinicians for future development of this field of study; and to broaden the national discussions between diverse groups of community advocates and organizers on common interests in protecting and nurturing healthy environments for children. Each center is designed around a central theme focusing on important questions in understanding the role of exposures in one of the following health outcome areas: respiratory disease, childhood learning, and growth and development including developmental disabilities. Exposures to toxicants such as polychlorinated biphenyls (PCBs), mercury, lead, air pollution, allergens, agricultural and urban pesticides, second-hand smoke, and others are part of the Centers Program's research priorities. All centers have multiple projects across scientific disciplines, from basic laboratory-based research and genetics to exposure assessment, epidemiology, and clinical trials. Methods have been developed, field tested, and implemented to detect and define health symptoms and outcomes; new exposure technology has been developed to assess environmental exposures and body burden in a diverse array of biospecimens; and creative approaches to reaching and retaining traditionally "hard to follow" socioeconomic groups have been implemented with community input. -------------------------------- Over the past 5 years and using a variety of methods, scientists from the NIEHS/U.S. EPA Children's Centers Program have made a number of advances that would not have been possible without the establishment of a coordinated network of centers to foster multi- and interdisciplinary research targeted at understanding children's environmental health risks and reducing them. Many of the results of these collaborations and interactions have implications for children's environmental health and the National Children's Study. For example, studies have shown that blood and urine specimens from pregnant women show measurable levels of pesticides, suggesting that the fetus is exposed to these chemicals during early development (Bradman et al. 2003; Whyatt et al. 2003); children in urban and rural environments are exposed to a complex mix of agricultural and household pesticides, environmental tobacco smoke, and polycyclic aromatic hydrocarbons and negative social factors that can affect their early growth and development (Berkowitz et al. 2004; Eskenazi et al. 2004; Perera et al. 2004; Rauh et al. 2004); and exposures to lead in the urban environment can have lifelong effects such as behavioral problems and criminal behavior in early adult life (Ris et al. 2004). Research on air pollution and asthma has broadened our understanding of the inflammatory process in the lung (Walters et al. 2002) such that the effects of air pollution can be seen in school-age children as increased exacerbation of asthma symptoms and increased days absent from school (Gilliland et al. 2003; McConnell et al. 2003). Intervention studies have been conducted to show that the household environment can be cleaned up in a way to significantly reduce allergens from dust mites and cockroaches that should reduce the incidence of asthma symptoms in children (Eggleston et al. 2004). Community-based participatory research. A requirement for every Children's Center is the inclusion of one project that uses community-based participatory research methods. This type of methodology encourages full participation of the community in the design, implementation, evaluation, and translation of the research. Research ideas may begin with the concerns of the community. Community partners, scientists, and clinicians share knowledge of exposure, health effects, and prevention strategies. Many studies train and employ community members as study coordinators, interviewers, or environmental technicians. Community participation ensures the relevance of the research questions and appropriateness of the research strategies. Research results are disseminated back to the community on an ongoing basis through community advisory boards, newsletters, health fairs, and other educational activities. Table 2. Cohorts and study designs. Most of the centers have established cohorts of children in which to study the dynamic relationship between exposures to environmental agents and health outcomes. In general, two distinct age groups are targeted: birth cohorts where pregnant women were enrolled and their offspring become study participants, and cohorts of school-age children enrolled either in school settings or in a medical care environment. The birth cohort studies seek to understand exposures during fetal development and health risks related to respiratory illness progression and neurodevelopmental effects, including motor, sensory, and cognitive deficits. Because asthma cannot be definitively diagnosed until ages 3-4, prospective follow-up of a group of young children provides for new opportunities as they age. The school-age cohort studies focus on asthma, and children are recruited through school classrooms, neighborhood health clinics, and other medical care settings. One large cohort study of school children in Los Angeles, California, that was started 10 years ago continues to follow the children and compare genetic factors from recently collected specimens with historical air pollution and medical data. Case-only or case-control designs are used in two other studies of children that focus on understanding the possible environmental causes of autism, a relatively rare disorder. Intervention/prevention studies include cohorts of children with disease or unique exposures that can be found in urban and rural settings. These studies are unique with regard to community participation, recruitment and retention, and dissemination of study results; Table 2 lists the types of studies and centers. ------------------------------------------------------ Government/Children's Centers partnerships. The NIEHS and U.S. EPA, as federal funding partners, continue to align their priorities and working relationships to manage and support this $140 million program. The agencies' commitment to overcoming differences in their regulatory and research mandates is reflected in the broad success of the Centers Program's impact on public policy and influence in several fields of public health. The federal partners share responsibility in both supporting the national network of researchers and sponsoring annual center meetings. Bringing center scientists and community members together on a consistent basis has been instrumental in the success of these programs. This created a stronger working relationship across the Children's Centers than would have been fostered with individual programs working alone. At the inception of the program, many meetings were held to discuss definitions of health outcomes and ways to measure them, methodologies for exposure assessment, questionnaire items, and follow-up strategies with special attention to retention of study participants, cultural sensitivities, and engagement of community. Information was shared and protocols were designed for individual studies that strove for commonality. The goal was not to have standardized methods employed, but rather to see where collaborations could be built and methodologies shared. The NIEHS/U.S. EPA Children's Centers Program is now in its seventh year. The program has generated important scientific results and expanded our knowledge of exposures to young children and how they affect their health status. There is a wealth of knowledge about issues that pertain to conducting future studies in this field, especially the National Children's Study. This mini-monograph is an attempt to describe in detail the lessons learned from these important groundbreaking studies. Major Lessons Considered Important for Planning the National Children's Study Several major lessons from the Children's Centers are important for consideration in planning the National Children's Study. These and a number of others are discussed in detail in the articles in this mini-monograph (Dietrich et al. 2005; Eggleston et al. 2005; Eskenazi et al. 2005; Fenske et al. 2005; Gilliland et al. 2005; Israel et al. 2005). First, long-term studies that follow participants into adolescence and early adulthood are considered essential to assess the full range of developmental consequences of exposure to environmental chemicals. It is also important to identify a population with a wide range of exposure concentrations for those key pollutants hypothesized a priori to be of interest in order to evaluate the relationships between the distributions of multiple exposures and observed effects. It is necessary to allow for population differences in literacy, language, and culture when establishing study procedures for recruitment and retention and in determining the type of information collected and the methods of collection. Assessment tools need to balance measures both broad and narrow in scope. Questionnaires, neurodevelopmental instruments, and the like employed in these studies should include a core set to evaluate the entire cohort and additional segments for selected populations that may be unique based on their exposure or other attributes. --------------------------------- Exposure assessment should include a combination of environmental and personal measurements as well as data derived from questionnaires and from observational and ecologic data. The exposure assessment effort should take advantage of modeling approaches to provide estimates for the entire cohort. Targeted exposure studies in a selected subsample of study subjects may be useful for improving exposure assessment. The depth of assessments that can be realistically implemented will be restricted in populations that are widely dispersed geographically, have limited transportation, or lack trained personnel in the community. Procedures for monitoring the quality and accuracy of data collection must be established and maintained not only for the collection and analysis of biologic or environmental specimens, but also for the assessment of questionnaire, developmental testing, and other health outcome data. Data safety and monitoring procedures must be in place. Active and meaningful participation of the community is essential for determining the relevant research questions, enrolling and retaining the cohort in an intensive investigation over the long term, and contributing to translation of scientific principles and research results for communities and the public at large. This requires establishing trust and respecting differences in culture and knowledge of the community. Sufficient time and resources are necessary to develop community partnerships. The ethical issues in a longitudinal birth cohort study are likely to become increasingly more complex in the changing medical and legal environment and must be carefully considered in designing research protocols and following the cohort. It is necessary to develop clear plans of referral when children with disease, developmental difficulties, or adverse social situations emerge. Communication of risk to participants and the community and translation of research findings into interventions and policies are of utmost importance and should be part of the research plan and cost consideration. Funding for a longitudinal birth cohort study must be adequate for the start-up period, continuous without gaps, and long term. Costs have often been underestimated because tracking and maintaining study participants is labor intensive. The unique characteristics at each developmental stage from birth through adulthood must be considered. Every age presents special challenges in both outcome and exposure assessment. Finally, the health and development of children are multifactorially determined. The greatest challenge is anticipating the data and specimens that will allow the questions of the future to be answered. This requires state-of-the-art tools for data collection and tracking participants, environmental and biologic specimen repositories, and anticipation of future human subject requirements in consent procedures. The unique challenges faced by the Children's Centers in studying diverse populations will be especially helpful for the National Children's Study, which is intended to be a nationwide study representative of the many populations across the United States. Although the Children's Centers have reported important findings from their individual studies, it is only by examining the collective experiences of the Children's Centers in these lessons learned articles that we gain a better perspective of the potential challenges to be met in the many National Children's Study sites. -------------------------------------- References Berkowitz GS, Wetmur JG, Birman-Deych E, Obel J, Lapinski RH, Godhold JH, et al. 2004. In utero pesticide exposure, maternal paraoxonase activity, and head circumference. Environ Health Perspect 112:388-391. Bradman A, McKone T, Barr DB, Harnly ME, Eskenazi B. 2003. Cumulative organophosphate pesticide exposure and risk assessment among pregnant women living in an agricultural community: a case study from the CHAMACOS cohort. Environ Health Perspect 111:1779-1782. Children's Health Act of 2000. 2000. Public Law 106-310. Clinton WJ. 1997. Executive Order 13045. Protection of Children from Environmental Health Risks and Safety Risks. Fed Reg 62:19883-19888. Dearry A, Collman GW, Saint C, Fields N, Redd S. 1999. Introduction: building a network of research in children's environmental health. Environ Health Perspect 107(suppl 3):391-392. Dietrich KN, Eskenazi B, Schantz S, Yolton K, Rauh VA, Johnson CB, et al. 2005. Principles and practices of neurodevelopmental assessment in children: lessons learned from the Centers for Children's Environmental Health and Disease Prevention Research. Environ Health Perspect 113: 1437-1446. Eggleston PA, Butz A, Rand C, Callahan K, Curtin-Brosnan J, Merriman B, et al. 2004. Home environmental treatment improves asthma in inner city children [Abstract]. J Allergy Clin Immunol 113:S179. Eggleston PA, Diette G, Lipsett M, Lewis T, Tager I, McConnell R, et al. 2005. Lessons learned for the study of childhood asthma from the Centers for Children's Environmental Health and Disease Prevention Research. Environ Health Perspect 113:1430-1436. Eskenazi B, Harley K, Bradman A, Weltzien E, Jewell N, Barr D, et al. 2004. Association of in utero organophosphate pesticide exposure and fetal growth and length of gestation in an agricultural population. Environ Health Perspect 112: 1116-1124; doi:10.1289/ehp.6789 [Online 11 March 2004]. Eskenazi B, Gladstone EA, Berkowitz GS, Drew CH, Faustman EM, Holland NT, et al. 2005. Methodologic and logistic issues in conducting longitudinal birth cohort studies: lessons learned from the Centers for Children's Environmental Health and Disease Prevention Research. Environ Health Perspect 113:1419-1429. Fenske RA, Bradman A, Whyatt RM, Wolff MS, Barr DB. 2005. Lessons learned for the assessment of children's pesticide exposure: critical sampling and analytical issues for future studies. Environ Health Perspect 113:1455-1462. Gilliland FD, Berhane K, Islam T, Wenten M, Rappaport E, Avol E. 2003. Environmental tocbacco smoke and absenteeism related to respiratory illness in school children. Am J Epidemiol 157:861-869. Gilliland F, Avol E, Kinney P, Jerrett M, Dvonch T, Lurmann F, et al. 2005. Air pollution exposure assessment for epidemiologic studies of pregnant women and children: lessons learned from the Centers for Children's Environmental Health and Disease Prevention Research. Environ Health Perspect 113:1447-1454. Israel BA, Parker EA, Rowe Z, Salvatore A, Minkler M, Lopez J, et al. 2005. Community-based participatory research: lessons learned from the Centers for Children's Environmental Health and Disease Prevention Research. Environ Health Perspect 113:1463-1471. McConnell R, Berhane K, Gilliland F, Molitor J, Thomas D, Lurman F, et al. 2003. Prospective study of air pollution and bronchitic symptoms in children with asthma. Am J Respir Crit Care Med 168:790-797. National Children's Study. 2005. Homepage. Available: http://www.nationalchildrensstudy.gov/ [accessed 8 August 2005). National Children's Study Interagency Coordinating Committee. 2003. The National Children's Study of environmental effects on child health and development. Environ Health Perspect 111:642-646. NIEHS. 2005. Centers for Children's Environmental Health and Disease Prevention Research. Research Triangle Park, NC:National Institute of Environmental Health Sciences. Available: http://www.niehs.nih.gov/translat/children/children.htm [accessed 28 February 2005]. O'Fallon LR, Collman GW, Dearry A. 2000. The National Institute of Environmental Health Sciences' research program on children's environmental health. J Expo Anal Environ Epidemiol 10(6 pt 2): 630-637. Perera FP, Rauh V, Whyatt RM, Tsai WY, Bernet JT, Tu YH, et al. 2004. Molecular evidence of an interaction between prenatal environmental exposures and birth outcomes in a multiethnic population. Environ Health Perspect 112:626-630. Rauh VA, Whyatt RM, Garfinkel R, Andrews H, Hoepner L, Reyes A, et al. 2004. Developmental effects of exposure to environmental tobacco smoke and material hardship among inner-city children. Neurotoxicol Teratol 26: 373-385. Ris MD, Dietrich KN, Succop PA, Berger OG, Bornschein RL. 2004. Early exposure to lead and neuropsychological outcome in adolescence. J Int Neuropsychol Soc 10:261-270. Rockett JC, Kavlock RJ, Lambright CR, Parks LG, Schmid JE, Wilson VS, et al. 2002. DNA arrays to monitor gene expression in rat blood and uterus following 17β-estradiol exposure: biomonitoring environmental effects using surrogate tissues. Toxicol Sci 69:49-59. Sharbaugh C, Viet SM, Frazier A, Mcmaster SB. 2003. Comparable measures of cognitive function in human infants and laboratory animals to identify environmental health risks to children. Environ Health Perspect 111:1630-1639. U.S. EPA. 2004a. Demonstration of Low Cost, Low Burden, Exposure Monitoring Strategies for use in Longitudinal Cohort Studies. EPA/600/R-04/109. Research Triangle Park, NC:U.S. Environmental Protection Agency. Available: http://www.epa.gov/heasdweb/children/children.htm/ [accessed 28 February 2005]. U.S. EPA. 2004b. Biomarkers Database. Research Triangle Park, NC:U.S. Environmental Protection Agency, 26 July. Available: http://cfpub.epa.gov/ncea/ [accessed 28 February 2005]. Walters DM, Breysse PN, Schofield B, Wills-Karp M. 2002. Complement factor 3 mediates particulate matter-induced airway hyperresponsiveness. Am J Respir Cell Mol Biol 27:413-418. Whyatt RM, Barr DB, Camann DE, Kinney PL, Barr JR, Andrews HF, et al. 2003. Contemporary-use pesticides in personal air samples during pregnancy and blood samples at delivery among urban minority mothers and newborns. Environ Health Perspect 111:749-756. |