Epidemiology of Immunotoxicant Exposure in Children

描述（由申请人提供）：对免疫系统发育的毒性作用可能严重损害人体健康，但在环境化学品的风险评估中很少考虑免疫毒性。一个主要问题是缺乏系统的流行病学证据。我们已经成功地在接触海洋污染物的独特捕鱼人群——法罗群岛——中建立了前瞻性研究的出生队列，并且我们已经证明，儿童的疫苗反应可以作为与多氯联苯接触有关的免疫毒性模型。这一竞争性更新的应用扩大了对同一出生队列的600名儿童的随访，以持续血清中抗疫苗抗体的浓度和有关过敏性疾病的浓度，直至青春期。在最近建立的500名儿童的第二个出生队列中，我们将测试18个月时的免疫毒物暴露是否代表了随后血清抗体浓度的主要脆弱性窗口。此外，我们将探讨过去和累积暴露水平对疫苗增强剂反应的影响，这反映在特定抗体浓度和淋巴细胞群和细胞因子产生的变化中。同样，过敏发展的临床证据，包括针对常见抗原的总和特异性IgEs的血清浓度，将根据产前和产后时间窗的暴露进行评估。除了已经确认的免疫毒物多氯联苯和甲基汞外，该研究还将审查血清中AhR（与二恶英相关）总活性以及全氟化合物和丁胺素可能的免疫毒性。破伤风和白喉类毒素的疫苗抗体检测将扩大到包括肺炎球菌多糖抗原。由于这项研究依赖于两个现有的出生队列，这些队列拥有已收集的血液样本和背景信息（部分由其他来源资助），因此拟议的研究将涵盖14年的时间跨度，以考虑产前暴露以及直到青春期的结果。因此，累积的证据可能对了解人类发育性免疫毒性和免疫毒性药物的风险评估具有重要意义。

DESCRIPTION (provided by applicant): Toxic effects on immune system development may seriously impair human health, but immunotoxicity is rarely considered in risk assessment of environmental chemicals. A main problem is the absence of systematic epidemiological evidence. We have successfully established birth cohorts for prospective studies in a unique fishing population exposed to marine contaminants - the Faroe Islands - and we have demonstrated that vaccine responses in children can be applied as a model of immunotoxicity associated with polychlorinated biphenyl (PCB) exposure. This competitive renewal application extends the follow-up of the same birth cohort of >600 children for sustained serum concentrations of antibodies against vaccines and in regard to allergic disease up to adolescence. In a second birth cohort of 500 children recently established, we will test whether the immunotoxicant exposure at age 18 months represents a main window of vulnerability in regard to the subsequent serum antibody concentrations. Further, we will explore the impact of past and cumulated exposure levels on responses to a vaccine booster, as reflected by specific antibody concentrations and by changes in lymphocyte populations and cytokine production. Likewise, clinical evidence of allergy development, including serum concentrations of total and specific IgEs against common antigens, will be evaluated in regard to exposures during prenatal and postnatal time windows. In addition to already confirmed immunotoxicants PCBs and methylmercury, the study will examine the possible immunotoxicity of the total AhR (dioxin-related) activity in serum and of perfluorinated compounds and butyltins. Vaccine antibody assays for tetanus and diphtheria toxoids will be expanded to include Pneumococcus polysaccharide antigens. Because this study relies on two existing birth cohorts with banked blood samples and background information already collected - in part financed by other sources - the proposed research will cover a time span of 14 years to allow consideration of exposures incurred prenatally and outcomes followed until adolescence. The cumulated evidence will therefore likely be of substantial importance for the understanding of developmental immunotoxicity in humans and for risk assessment of immunotoxic agents. PUBLIC HEALTH RELEVANCE: Due to the lack of systematic data, immunotoxicity is rarely taken into account in risk assessment. This systematic study aims at providing a stronger basis for prevention of immune system dysfunctions related to environmental chemicals. It will examine antibody concentrations and cellular responses to routine childhood immunizations as well as the occurrence of allergic disease up to adolescence in regard to exposures to environmental chemicals prenatally and at different ages after birth.