title: Exposure to multiple environmental agents and their effect.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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?
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Ecobaby Foundation and Emma Children's Hospital Academic Medical Centre University of Amsterdam, The Netherlands. Janna.Koppe@inter.nl.net
authors.forename: Janna G
authors.initials: JG
authors.lastname: Koppe
authors.forename: Alena
authors.initials: A
authors.lastname: Bartonova
authors.forename: Gabriele
authors.initials: G
authors.lastname: Bolte
authors.forename: Marie Louise
authors.initials: ML
authors.lastname: Bistrup
authors.forename: Chris
authors.initials: C
authors.lastname: Busby
authors.forename: Maureen
authors.initials: M
authors.lastname: Butter
authors.forename: Paul
authors.initials: P
authors.lastname: Dorfman
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Fucic
authors.forename: David
authors.initials: D
authors.lastname: Gee
authors.forename: Peter
authors.initials: P
authors.lastname: van den Hazel
authors.forename: Vyvyan
authors.initials: V
authors.lastname: Howard
authors.forename: Martina
authors.initials: M
authors.lastname: Kohlhuber
authors.forename: Marike
authors.initials: M
authors.lastname: Leijs
authors.forename: Christofer
authors.initials: C
authors.lastname: Lundqvist
authors.forename: Hanns
authors.initials: H
authors.lastname: Moshammer
authors.forename: Rima
authors.initials: R
authors.lastname: Naginiene
authors.forename: Polyxeni
authors.initials: P
authors.lastname: Nicolopoulou-Stamati
authors.forename: Roberto
authors.initials: R
authors.lastname: Ronchetti
authors.forename: Georges
authors.initials: G
authors.lastname: Salines
authors.forename: Greet
authors.initials: G
authors.lastname: Schoeters
authors.forename: Gavin
authors.initials: G
authors.lastname: ten Tusscher
authors.forename: Max K
authors.initials: MK
authors.lastname: Wallis
authors.forename: Moniek
authors.initials: M
authors.lastname: Zuurbier
mesh_terms: D000397:Air Pollution; D001942:Breast Feeding; D002648:Child; D002669:Child Welfare; D003718:Denmark; D004781:Environmental Exposure; D005260:Female; D005333:Fetus / Q000187:drug effects; D006801:Humans; D018811:Maternal Exposure; D009426:Netherlands; D011247:Pregnancy; D018570:Risk Assessment; D018154:Slovakia