Koppe Janna G, Bartonova Alena, Bolte Gabriele, Bistrup Marie Louise, Busby Chris, Butter Maureen, Dorfman Paul, Fucic Aleksandra, Gee David, van den Hazel Peter, Howard Vyvyan, Kohlhuber Martina, Leijs Marike, Lundqvist Christofer, Moshammer Hanns, Naginiene Rima, Nicolopoulou-Stamati Polyxeni, Ronchetti Roberto, Salines Georges, Schoeters Greet, ten Tusscher Gavin, Wallis Max K, Zuurbier Moniek
Ecobaby Foundation and Emma Children's Hospital Academic Medical Centre University of Amsterdam, The Netherlands.
Acta Paediatr Suppl. 2006 Oct;95(453):106-13. doi: 10.1080/08035320600886646.
All children are exposed to multiple physical, chemical and biological challenges that can result in adverse health effects before and after birth. In this context, the danger of multiple exposures cannot be assessed from a single-chemical approach as used in classical toxicology.
To open up a 'negotiation space' for the problem of multiple exposure to environmental stressors, defined as any physical, chemical or biological entity that can induce an adverse response. In this context, two further questions obtain: to what extent can synergistic risks be assessed, and how far could potential adverse effects be prevented by enhanced regulation?
A discussion of two general approaches is taken: 1) the investigation of mixtures such as smoking or air pollution without specifying the individual agents, and 2) the investigation of individual substances with a focus on possible interactions in the context of dose to receptor.
Although mixtures of compounds can have effects, it may not be possible to ascribe causation to a single compound. Furthermore, cumulative low-dose insult can, in some circumstances, be more toxic than a single high-dose exposure, e.g. endocrine disruptive effects of a combination of PCBs and dioxins which disrupt the thyroid hormone status; this tends to contradict elements of classical toxicology, . These cumulative insults may further combine with heavy metals and can disrupt the heme synthesis. It is possible that groups of pollutants could be used to test their cumulative capacity to multiple stress-susceptible receptor targets as is done in smoking and air pollution. This methodology could be used for further groups of potential pollutants, for example those associated with cleaning products, or cosmetics. Testing individual substances with a focus on interactions means that not only chemicals but also concurrent diseases should be taken into account. We suggest that the enhanced regulation of potential multiple stressors falls into two discrete categories. The first comprises a more precautionary approach (as demonstrated by the banning of chemicals such as some brominated flame retardants in Europe). The second comprises a more 'permissive' liberal approach involving the initial study of an individual compound, and subsequent interrogation of that compound in combination with another (as demonstrated by lowering the carcinogenicity of aflatoxin by vaccination against hepatitis B).
It is necessary to define and study groups of multiple stressors as in US EPA's Framework for Cumulative Risk Assessment (U.S. EPA 2003). Recent increased knowledge of the greater sensitivity of the unborn baby, the infant and the child, has led to general recognition that a higher degree of precaution is now needed in regulating for multiple stressors on the young. The more liberal permissive approach proceeding from established effects of the individual exposures is becoming less acceptable now that we know that there is much we do not understand about chronic effects of stressors during the early development phases. Conflicts over which approach to take may have to be resolved through engagement and negotiation with a wide community of stakeholders. This "community of interest" may include fundamental research scientists, practicing clinical paediatricians, patient groups, and others concerned with the health and wellbeing of infants and children.
所有儿童在出生前后都会面临多种物理、化学和生物挑战，这些挑战可能会对健康产生不利影响。在这种情况下，无法像传统毒理学那样通过单一化学物质的方法来评估多重暴露的风险。
为环境应激源多重暴露问题开辟一个“协商空间”，环境应激源被定义为任何能够引发不良反应的物理、化学或生物实体。在此背景下，还有另外两个问题：协同风险能在多大程度上得到评估，以及通过加强监管能在多大程度上预防潜在的不利影响？
讨论了两种一般方法：1）对诸如吸烟或空气污染等混合物进行调查，而不具体指明单个成分；2）对单个物质进行调查，重点关注剂量与受体关系背景下可能的相互作用。
尽管化合物混合物可能会产生影响，但可能无法将因果关系归因于单一化合物。此外，在某些情况下，累积低剂量损伤可能比单次高剂量暴露毒性更大，例如多氯联苯和二恶英组合产生的内分泌干扰效应会扰乱甲状腺激素状态；这往往与传统毒理学的某些观点相矛盾。这些累积损伤可能会进一步与重金属结合，从而扰乱血红素合成。有可能像在吸烟和空气污染研究中那样，利用污染物组来测试它们对多个应激敏感受体靶点的累积影响能力。这种方法可用于其他潜在污染物组，例如与清洁产品或化妆品相关的污染物组。重点关注相互作用来测试单个物质意味着不仅要考虑化学物质，还要考虑并发疾病。我们建议对潜在多重应激源的加强监管可分为两个不同类别。第一类包括更具预防性的方法（如欧洲禁止某些溴化阻燃剂等化学品所示）。第二类包括更“宽松”的自由方法，即先对单个化合物进行初步研究，然后再研究该化合物与另一种化合物组合后的情况（如通过接种乙肝疫苗降低黄曲霉毒素的致癌性所示）。
有必要像美国环境保护局的累积风险评估框架（美国环境保护局，2003年）那样定义和研究多重应激源组。最近对未出生婴儿、婴儿和儿童更高敏感性的认识不断增加，已使人们普遍认识到，现在在监管针对年轻人的多重应激源时需要更高程度的预防措施。鉴于我们知道对于应激源在早期发育阶段的慢性影响还有很多不了解的地方，从个体暴露的既定影响出发的更宽松自由方法现在越来越不可接受。关于采用哪种方法的冲突可能必须通过与广泛的利益相关者群体进行参与和协商来解决。这个“利益相关群体”可能包括基础研究科学家、临床儿科医生、患者群体以及其他关注婴儿和儿童健康与福祉的人员。
