Epidemiology of Immunotoxicant Exposure in Children

描述（申请人提供）：对免疫系统发育的毒性作用可能会严重损害人类健康，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。我们已经成功地建立了出生队列，对暴露于海洋污染物的独特捕鱼人群（法罗群岛）进行前瞻性研究，并且我们已经证明，儿童的疫苗反应可以用作与多氯联苯（PCB）暴露相关的免疫毒性模型。这项竞争性更新申请将超过 600 名儿童的同一出生队列的随访时间延长到青春期，以了解针对疫苗和过敏性疾病的持续血清抗体浓度。在最近建立的由 500 名儿童组成的第二个出生队列中，我们将测试 18 个月大时的免疫毒物暴露是否代表随后血清抗体浓度的主要脆弱窗口。此外，我们将探讨过去和累积的暴露水平对疫苗加强免疫反应的影响，如特定抗体浓度以及淋巴细胞群和细胞因子产生的变化所反映的。同样，过敏发生的临床证据，包括针对常见抗原的总 IgE 和特异性 IgE 的血清浓度，将根据产前和产后时间窗口期间的暴露进行评估。除了已经确认的免疫毒性物质 PCB 和甲基汞之外，该研究还将检查血清中总 AhR（二恶英相关）活性以及全氟化合物和丁基锡的可能免疫毒性。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，其中已存有血液样本和已经收集的背景信息（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，以考虑产前发生的暴露以及直至青春期的结果。因此，积累的证据可能对于了解人类发育免疫毒性和免疫毒性药物的风险评估具有重要意义。 公共卫生相关性：由于缺乏系统数据，风险评估中很少考虑免疫毒性。这项系统研究旨在为预防与环境化学物质相关的免疫系统功能障碍提供更强有力的基础。它将检查抗体浓度和细胞对常规儿童免疫接种的反应，以及直到青春期的过敏性疾病的发生情况，这些疾病与产前和出生后不同年龄接触环境化学物质有关。

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.