Susceptibility-exposure paradigm

A. Development of a Susceptibility Exposure Paradigm to Access the Effects of Prenatal Exposure to PAHs on CNS Development... 

Over the years, work fi-om our laboratory focused on the refinement of a susceptibility exposure paradigm to better assess the effects of prenatal exposure to environmental toxicants on certain aspects of CNS development (Hood et al, 2000 Ramesh et al, 2001a, b Wormley et al, 2004). Because CNS events have windows of susceptibility during development, it was reasoned that there should be a time frame when the lowest dose and shortest duration of exposure to an environmental contaminant would be... 

FIGURE 17.3. A Modified Barker Hypothesis the susceptibility exposure paradigm used as a model to assess the effects of prenatal exposure to polycyclic aromatic hydrocarhons. Adapted with permission Ifom Neurotoxicology and Brown et al. (2007). 

The toxicity to the nervous system depends on the delivered dose and exposiue duration. In the case of pregnant women, pharmacokinetic processes (absorption, distribution, metabolism, and excretion) govern PAH disposition within the mother and the nervous system of children. Moreover, unique physiological features, such as the presence of a placental barrier and the gradual development of the blood-brain barrier influence PAH disposition and thus modulate developmental neurotoxicity. Because CNS effects are dependent upon windows of susceptibility when the lowest dose and shortest duration of exposure to environmental PAHs will have the greatest negative impact on brain development, a susceptibility exposure paradigm has proven to be the most reliable model in which to study developmental insult. The intent of this chapter was to review... 

A second rare, but potentially fatal, condition associated with acute inhalational anesthetic exposure is malignant hypothermia. This is an autosomal dominant disease in which there is excessive sarcoplasmic release of intracellular Ca " " in skeletal muscles during exposure to inhalational anesthetics. This produces a hypermetabolic state that is manifested as increased muscle rigidity and contracture, tachycardia and metabolic acidosis. Extreme hyperthermia is also present. There are currently a number of worldwide registries for tracking this disease and an ex vivo testing paradigm exists to determine a potentially susceptible persons phenotype. 

As described in a highly referenced document (NRC, 1983), important components of this process include hazard identification, assessment of exposure and dose-response relationships, and characterization of the risk. Uncertainty factors are built into the risk assessment process to account for variations in individual susceptibility, extrapolation of data from studies in laboratory animals to humans (i.e. interspecies variation in toxicokinetics), and extrapolation from high-dose to low-dose exposures. In the case of the association between exposure to chemicals and drugs and autoimmunity or autoimmune diseases, much of the information needed to evaluate risk in the context of the traditional United States National Research Council paradigm is not available. The following represents a discussion of issues in chemical-induced autoimmunity relevant to the use of existing data and data needs in risk assessment. 

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