in this specific genetic factor alone are likely to affect human susceptibility to the toxic effects of TCDD, other dioxin-like chemicals, and herbicide formulations containing these chemicals. In addition, recent research makes clear that variations in the genetic regulation of the expression or activity of other factors, including proteins that interact with the AhR and the gene products that are regulated by the AhR, are critical in determining susceptibility to the effects of TCDD and the types of toxic effects observed. Studies addressing the identification, distribution, and functional consequences of polymorphisms of the AhR and the other cofactors in human populations should be pursued.

  • A biphasic physiologically based pharmacokinetic (PBPK) model for TCDD is needed.

The committee recognizes the importance of accurate back-extrapolation of serum TCDD concentrations to predict exposure levels at the time of Vietnam service and to categorize veterans accurately into appropriate exposure classifications. As noted in Chapter 3, new human PBPK models have been developed in an effort to incorporate the increasing evidence that TCDD exhibits dose-dependent elimination. The models seriously challenge the paradigm of a one-compartment, first-order elimination model for back-extrapolation of estimates of earlier exposures; however, it remains unclear which type of model should be used for dose reconstruction. Thus, the committee recommends additional validation of the PBPK models and direct comparisons of the resulting exposure classifications when the new models and the standard first-order elimination models are applied to large data sets.

  • Potential emergence of metabolic syndrome should be analyzed.

The committee recognized that, within the study populations reviewed in preparing Update 2006, the values of serum components and specific health outcomes may be interrelated, including hypertriglyceridemia, type 2 diabetes mellitus, hypertension, and ischemic heart disease. The first three of those outcomes are key criteria for the diagnosis of metabolic syndrome, and the fourth is a major consequence of it. Thus, the committee recommends that—in addition to analysis of the association of exposure to the chemicals of interest with individual health outcomes—the incidence of multiple health outcomes that define metabolic syndrome should be analyzed as a group.

  • Possible effects in offspring merit further investigation.

The assessment of any link between exposure of Vietnam veterans to the chemicals of interest and birth defects or developmental disease in their offspring presents distinct challenges. The Department of Veterans Affairs (VA) should review all the possible cognitive and developmental effects in offspring of veterans. Such a review should include the possibility of effects in grandchildren, which are of growing concern to veterans and their families. A recent review of the literature and meta-analysis by Ngo et al. (2006) noted a significant association for

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