With the release of the landmark report Toxicity Testing in the 21st Century: A Vision and a Strategy, the U.S. National Academy of Sciences, in 2007, precipitated a major change in the way toxicity testing is conducted. It envisions increased efficiency in toxicity testing and decreased animal usage by transitioning from current expensive and lengthy in vivo testing with qualitative endpoints to in vitro toxicity pathway assays on human cells or cell lines using robotic high-throughput screening with mechanistic quantitative parameters. Risk assessment in the exposed human population would focus on avoiding significant perturbations in these toxicity pathways. Computational systems biology models would be implemented to determine the dose-response models of perturbations of pathway function. Extrapolation of in vitro results to in vivo human blood and tissue concentrations would be based on pharmacokinetic models for the given exposure condition. This practice would enhance human relevance of test results, and would cover several test agents, compared to traditional toxicological testing strategies. As all the tools that are necessary to implement the vision are currently available or in an advanced stage of development, the key prerequisites to achieving this paradigm shift are a commitment to change in the scientific community, which could be facilitated by a broad discussion of the vision, and obtaining necessary resources to enhance current knowledge of pathway perturbations and pathway assays in humans and to implement computational systems biology models. Implementation of these strategies would result in a new toxicity testing paradigm firmly based on human biology.

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This article uses the revealed preference approach to estimate the price for a Disability Adjusted Life Year (DALY) implied by grant decisions by the Global Fund for AIDS, tuberculosis (TB) and malaria (GFATM). A cost-benefit criterion is used that requires the DALY price exceed the cost-effectiveness ratio. The estimated price was $6300 for a DALY saved from any disease, but it was $11 900 from a DALY saved specifically from HIV/AIDS. Estimates of the cost-effectiveness ratios of Antiretroviral Drug Therapies (ARVs) in the literature were examined. At the DALY prices implicit by GFATM decisions, ARVs would be socially worthwhile.

It is now almost accepted practice that distributional weights be incorporated into cost-benefit criteria. While there are still major dissenters on this issue, notably Harberger, the relevant questions now involve the nature of the weights themselves. A number of alternative formulations have been recommended, ranging from "a priori" to "revealed preference" schools. Recognition of these options allows one to select a framework of assumptions in which one may feel comfortable, without being encouraged to return to the traditional position of excluding distributional considerations. Thus, Harberger's influential pur ported defense of the traditional school, which includes some legitimate reservations, should be interpreted as a criticism of certain schools, not the use of weighting per se. By going back to first principles of what distributional weights are trying to achieve, this survey attempts to dispel various widespread misconceptions concerning distributional weights. It argues that redistribution in kind is the major theoretical justification. This provides a perspective from which to judge the type of distributional weighting that is most consistent with some recent advances in the welfare economics literature.

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