EPA's Arsenic Rule: The Benefits of the Standard Do Not Justify the Costs

The U.S. Environmental Protection Agency recently finalized a rule that would reduce the maximum allowable level of arsenic in drinking water by 80 percent. While arsenic is thought to be essential for the human body at low levels, it can cause cancer when consumed at higher concentrations for extended periods of time. This regulatory analysis evaluates the benefits and costs of the EPA's rule. On the basis of currently available information, we find that the EPA's standard cannot be justified on economic grounds. We estimate that the costs of the final rule will exceed the benefits by about $190 million annually. We also find that the rule probably will result in a net loss of life. We find that the rule probably will result in a net loss of life. The direct effect of the rule will be to save about ten lives annually in the future. After taking into account the indirect impacts of the cost of the rule on items like health care expenditures, however, we find that the rule is likely to result in a net loss of about ten lives annually. A question that the rule does not examine carefully is whether other regulatory alternatives could result in positive net benefits. We explore the option of targeting specific water systems and find that this strategy is unlikely to be very helpful. Instead of regulating more stringently now, the agency should wait until more information becomes available over the next few years. Such a strategy would have the advantage of avoiding large capital expenditures until the time that evidence suggests that risks posed by arsenic in drinking water are significant.

Should You Be Allowed to Use Your Cellular Phone While Driving?

Regulation of the use of cellular phones by individuals while driving is now commonplace outside the United States and has been proposed in a number of jurisdictions in the United States. There is growing concern that using cellular phones while driving leads to increases in accidents and fatalities. This paper provides an economic analysis of regulatory options for addressing cellular phone usage by drivers of vehicles. While large uncertainties surrounding both benefits and costs exist, a key conclusion is that banning drivers from using cellular phones is a bad idea. Our best estimate is that the costs of a ban are likely to exceed benefits by about $20 billion annually. Less intrusive regulation, such as requiring the use of a hands-free device that would allow a driver to use both hands for steering also is not likely to be economically justified.

Assessing the Quality of Regulatory Impact Analyses

This study provides the most comprehensive evaluation of the quality of recent economic analyses that agencies conduct before finalizing major regulations. We construct a new dataset that includes analyses of forty-eight major health, safety, and environmental regulations from mid-1996 to mid-1999. This dataset provides detailed information on a variety of issues, including an agency's treatment of benefits, costs, net benefits, discounting, and uncertainty. We use this dataset to assess the quality of recent economic analyses and to determine the extent to which they are consistent with President Clinton's Executive Order 12866 and the benefit-cost guidelines issued by the Office of Management and Budget (OMB). We find that economic analyses prepared by regulatory agencies typically do not provide enough information to make decisions that will maximize the efficiency or effectiveness of a rule. Agencies quantified net benefits for only 29 percent of the rules. Agencies failed to discuss alternatives in 27 percent of the rules and quantified costs and benefits of alternatives in only 31 percent of the rules. Our findings strongly suggest that agencies generally failed to comply with the executive order and adhere to the OMB guidelines. We offer specific suggestions for improving the quality of analysis and the transparency of the regulatory process, including writing clear executive summaries, making analyses available on the Internet, providing more careful consideration of alternatives to a regulation, and estimating net benefits of a regulation when data on costs and benefits are provided.

Assessing Regulatory Impact Analyses: The Failure of Agencies to Comply With Executive Order 12,866

None.Environment, Health and Safety, Regulatory Reform

The PDK1 master kinase is over-expressed in acute myeloid leukemia and promotes PKC-mediated survival of leukemic blasts

PDK1 is a master kinase that activates at least six protein kinase groups including AKT, PKC and S6K and is a potential target in the treatment of a range of malignancies. Here we show overexpression of PDK1 in over 40% of myelomonocytic acute leukemia patients. Overexpression of PDK1 occurred uniformly throughout the leukemic population, including putative leukemia-initiating cells. Clinical outcome analysis revealed PDK1 overexpression was associated with poorer treatment outcome. Primary acute myeloid leukemia blasts over-expressing PDK1 showed improved in vitro survival and ectopic expression of PDK1 promoted the survival of myeloid cell lines. Analysis of PDK1 target kinases revealed that PDK1 overexpression was most closely associated with increased phosphorylation of PKC isoenzymes and inhibition of PKC strongly inhibited the survival advantage of PDK1 over-expressing cells. Membrane localization studies implicated PKCα as a major target for PDK1 in this disease. PDK1 over-expressing blasts showed differential sensitivity to PDK1 inhibition (in the low micromolar range) suggesting oncogene addiction, whilst normal bone marrow progenitors were refractory to PDK1 inhibition at effective inhibitor concentrations. PDK1 inhibition also targeted subpopulations of leukemic blasts with a putative leukemia-initiating cell phenotype. Together these data show that overexpression of PDK1 is common in acute myelomonocytic leukemia and is associated with poorer treatment outcome, probably arising from the cytoprotective function of PDK1. We also show that therapeutic targeting of PDK1 has the potential to be both an effective and selective treatment for these patients, and is also compatible with current treatment regimes

Ultracold Bosonic Atoms in Disordered Optical Superlattices

The influence of disorder on ultracold atomic Bose gases in quasiperiodic optical lattices is discussed in the framework of the one-dimensional Bose-Hubbard model. It is shown that simple periodic modulations of the well depths generate a rich phase diagram consisting of superfluid, Mott insulator, Bose-glass and Anderson localized phases. The detailed evolution of mean occupation numbers and number fluctuations as function of modulation amplitude and interaction strength is discussed. Finally, the signatures of the different phases, especially of the Bose-glass phase, in matter-wave interference experiments are investigated.Comment: 4 pages, 4 figures, using REVTEX

Combination of a mitogen‐activated protein kinase inhibitor with the tyrosine kinase inhibitor pacritinib combats cell adhesion‐based residual disease and prevents re‐expansion of FLT3 ‐ITD acute myeloid leukaemia

Minimal residual disease (MRD) in acute myeloid leukaemia (AML) poses a major challenge due to drug insensitivity and high risk of relapse. Intensification of chemotherapy and stem cell transplantation are often pivoted on MRD status. Relapse rates are high even with the integration of first‐generation FMS‐like tyrosine kinase 3 (FLT3) inhibitors in pre‐ and post‐transplant regimes and as maintenance in FLT3 ‐mutated AML. Pre‐clinical progress is hampered by the lack of suitable modelling of residual disease and post‐therapy relapse. In the present study, we investigated the nature of pro‐survival signalling in primary residual tyrosine kinase inhibitor (TKI)‐treated AML cells adherent to stroma and further determined their drug sensitivity in order to inform rational future therapy combinations. Using a primary human leukaemia‐human stroma model to mimic the cell–cell interactions occurring in patients, the ability of several TKIs in clinical use, to abrogate stroma‐driven leukaemic signalling was determined, and a synergistic combination with a mitogen‐activated protein kinase (MEK) inhibitor identified for potential therapeutic application in the MRD setting. The findings reveal a common mechanism of stroma‐mediated resistance that may be independent of mutational status but can be targeted through rational drug design, to eradicate MRD and reduce treatment‐related toxicity

Cord blood-derived quiescent CD34+ cells are more transcriptionally matched to AML blasts than cytokine-induced normal human hematopoietic CD34+ cells

Acute myeloid leukemia (AML) is characterized by developmental arrest, which is thought to arise from transcriptional dysregulation of myeloid development programs. Hematopoietic stem and progenitor cells (HSPCs) isolated from human blood are frequently used as a normal comparator in AML studies. Previous studies have reported changes in the transcriptional program of genes involved in proliferation, differentiation, apoptosis, and homing when HSPCs were expanded ex vivo. The intrinsic functional differences between quiescent and dividing CD34+ HSPCs prompted us to determine whether fresh or cytokine-induced cord blood-derived CD34+ HSPCs are a more appropriate normal control compared to AML blasts. Based on principal component analysis and gene expression profiling we demonstrate that CD34+ HSPCs that do not undergo ex vivo expansion are transcriptionally similar to minimally differentiated AML blasts. This was confirmed by comparing the cell cycle status of the AML blasts and the HSPCs. We suggest that freshly isolated CD34+ HSPCs that do not undergo ex vivo expansion would serve as a better control to identify novel transcriptional targets in the AML blast population

A randomized assessment of adding the kinase inhibitor lestaurtinib to first-line chemotherapy for FLT3-mutated AML

The clinical benefit of adding FMS-like tyrosine kinase-3 (FLT3)-directed small molecule therapy to standard first-line treatment of acute myeloid leukemia (AML) has not yet been established. As part of the UK AML15 and AML17 trials, patients with previously untreated AML and confirmed FLT3-activating mutations, mostly younger than 60 years, were randomly assigned either to receive oral lestaurtinib (CEP701) or not after each of 4 cycles of induction and consolidation chemotherapy. Lestaurtinib was commenced 2 days after completing chemotherapy and administered in cycles of up to 28 days. The trials ran consecutively. Primary endpoints were overall survival in AML15 and relapse-free survival in AML17; outcome data were meta-analyzed. Five hundred patients were randomly assigned between lestaurtinib and control: 74% had FLT3-internal tandem duplication mutations, 23% FLT3–tyrosine kinase domain point mutations, and 2% both types. No significant differences were seen in either 5-year overall survival (lestaurtinib 46% vs control 45%; hazard ratio, 0.90; 95% CI 0.70-1.15; P = .3) or 5-year relapse-free survival (40% vs 36%; hazard ratio, 0.88; 95% CI 0.69-1.12; P = .3). Exploratory subgroup analysis suggested survival benefit with lestaurtinib in patients receiving concomitant azole antifungal prophylaxis and gemtuzumab ozogamicin with the first course of chemotherapy. Correlative studies included analysis of in vivo FLT3 inhibition by plasma inhibitory activity assay and indicated improved overall survival and significantly reduced rates of relapse in lestaurtinib-treated patients who achieved sustained greater than 85% FLT3 inhibition. In conclusion, combining lestaurtinib with intensive chemotherapy proved feasible in younger patients with newly diagnosed FLT3-mutated AML, but yielded no overall clinical benefit. The improved clinical outcomes seen in patients achieving sustained FLT3 inhibition encourage continued evaluation of FLT3-directed therapy alongside front-line AML treatment. The UK AML15 and AML17 trials are registered at www.isrctn.com/ISRCTN17161961 and www.isrctn.com/ISRCTN55675535 respectively