The National Academy of Sciences offers a new framework for addressing global warming issues.

The recent landmark report by the National Academy of Sciences reviewed the science on which the Kyoto Protocol was based. NAS concluded that the policy choices and the mandatory reductions in greenhouse gases by the developed nations were based on incomplete science with significant uncertainties. In view of these uncertainties the NAS report developed a comprehensive strategic 10-year research program to address the basic issue of whether human activity that results in environmental changes is responsible for climate changes. The report provides a new framework for consideration of global warming issues. The UN International Panel on Climate Change (the UN science advisor) in its 1997 report to the Kyoto parties pointed out the confusing difference between scientific usage of the term "climate change" that distinguishes human from natural causes of change and the official usage that combines natural and human causes of changes in climate. The conclusion of the UN panel on human causes is equivocal. The 1999 report of the U.S. Global Science Research Committee also reached an equivocal conclusion on human causes and announced a 10-year research program to be developed in consultation with NAS. The precautionary measures provided in the 1992 UN Framework Convention differ from the ill-defined "precautionary principle" based on fear of uncertainty, and are consistent with the objectives of the NAS proposed research program. These developments together with the third report of the UN Intergovernmental Science Panel on developments in climate science due in 2001 merit consideration by the convention of the parties under the Kyoto Protocol.

A new approach to risk assessment integrating scientific evaluation and economic assessment of costs and benefits.

Traditional quantitative risk assessment based on conservative generic assumptions led to an upper-bound risk value with minimum or no consideration of costs and benefits. There is a growing consensus for a new approach to risk assessment based on a combination of scientific risk assessment and economic cost-benefit analysis. Scientific evaluation would be improved to support the economic cost-benefit analysis. The objective is to demonstrate whether the benefits justify the costs. The move in the new direction is shown by Executive Order 12866 and the Office of Management and Budget implementing document, the proposed regulatory reform legislation in Congress, the draft report of the Risk Assessment and Risk Management Commission, and the Safe Drinking Water Act Amendments of 1996 that enacted the new approach combining scientific and economic assessment of risk. This Commentary discusses these developments with particular reference to contemplated changes in scientific risk assessment to support a parallel economic risk-benefit analysis.

Physical analysis of the region deleted in the tw18 allele of the mouse tcl-4 complementation group.

We have generated a YAC contig of at least 3.3 Mb from the proximal region of In(17)4 of mouse chromosome 17. This region corresponds to DNA lost in the gastrulation mutant tw18, which belongs to the tcl-4 complementation group. Our most proximal and distal probes lie within the deletion-3.3 Mb apart-indicating that we have not cloned the entire region. The deleted region is contained in a genetic interval of less than 1 cM, suggesting that some suppression of recombination must occur.

Executive Order 12866: advantages and disadvantages of the administration's new regulatory plan on risk, benefit, and costs.

The 1993 Executive Order 12866 as implemented by the 1996 OMB document proposes a new paradigm for the evaluation of risks, benefits, and costs. The new regulatory plan would replace the current methodology in two ways. In place of the current methodology for risk assessment based on conservative generic default assumptions that provide an upper-bound risk value that is treated as the "benefit," the new regulatory plan establishes a state of the art guidance for the economic evaluation of risks, benefits, and costs. Second, the new plan requires changes in risk assessment to provide the necessary foundation for the new economic evaluation of risks, benefits, and costs. The advantages and disadvantages of the new regulatory plan are discussed.

Risk assessment: the default conservatism controversy.

EPA cancer risk assessment rests heavily on defaults. Defaults are a reduction of science to generic principles selected as a policy matter on the basis of "conservatism" for use in risk assessment. Conservatism is understood to mean a choice to avoid underestimating risk. The recent report of the National Academy of Sciences (1994) has turned the spotlight on the controversy regarding the use of generic principles as defaults and whether conservatism is the appropriate value criterion for their selection. Defaults had their origin in the early 1970s and the debate has continued regarding the scientific basis for the defaults and whether a conservatism, a value that the NAS said is "beyond science," is appropriate as a basis for the policy choices. This paper briefly examines the CAPRA recommendations to reduce the reliance on defaults, the history of the default conservatism controversy, and EPA's initial draft response to the CAPRA recommendations.

Cloning and characterization of ERF-1, a human member of the Tis11 family of early-response genes.

Members of the Tis11 family of early-response genes are characterized by a high degree of sequence similarity around a putative zinc finger motif. They are induced by a variety of cell agonists and polypeptide mitogens, including 12-O-tetradecanoylphorbol-13-acetate (TPA) and epidermal growth factor (EGF). We describe the cloning and sequencing of a human member of this gene family, EGF-response factor 1 (ERF-1), the homolog of the mouse Tis11b/rat cMG1 genes. The human and rodent genes are similar, with 5' UTR, coding sequence, and 3' UTR highly conserved. The promoter/enhancer region and intron sequences contain multiple putative transcription factor binding motifs characteristic of early-response genes. Amino acid sequence comparison of the seven members of the Tis11 family cloned so far identifies a repeated consensus motif of (x+)YKTELC(x+)x5GxCxYGx(x+)CxFxH involving the potential zinc finger. Toward the carboxyterminal end is a region with a high percentage of prolines (15/73) and, partially overlapping, a serine-rich domain (20/54). These may be important as trans-activation and phosphorylation sites. The 3' untranslated region is unusually long, extending over 1,860 bp. The sequence immediately downstream from the translational stop codon has extensive secondary structure potential. The 3' UTR is 60% AT rich, but contains two GC rich (> 70%) regions. In addition there are multiple reiterations of a destabilization sequence, as well as a single UUAUUUAU motif characteristic of mRNAs specifying proteins involved in the inflammatory response. The mRNA contains a consensus polyadenylation signal.

Some regulatory definitions of risk: interaction of scientific and legal principles.

This paper discusses definitions of risk evolved to accommodate legal principles and scientific development in a time of rapid advances in science. The legal principles that underlie the interrelated definitions of "safe," "significant risk," and "acceptable risk" are examined in light of the major court decisions on benzene and vinyl chloride. The separate origins and development of concepts of de minimis risk and "negligible risk" are examined. The legal definitions are consistent with a judgmental weight-of-the-evidence evaluation of the statutory criteria, the available scientific information, and the risks acceptable in the world in which we live. The legal principles are dynamic, encourage scientific risk assessment based on case-by-case evaluation of the magnitude and character of human risks, and encourage incorporation of new scientific developments in the evaluation to improve the science base for regulatory decisions.

IARC and HHS lists of carcinogens: regulatory use based on misunderstanding of the scope and purpose of the lists.

In the last two decades there has been a tremendous increase in data on carcinogenic activity in experimental animals. While there have been few additions to the list of human carcinogens based on human data, the number of carcinogens based on animal data continues to increase unabated. The International Agency for Research on Cancer (IARC) list of carcinogens grew out of the IARC Monograph Series. The evidence classification system used to prepare the IARC lists in 1980, 1982, and 1988 is based on the sufficiency, i.e., strength, of the evidence of carcinogenic activity in one or more studies, not a full weight-of-the-evidence evaluation of all relevant data. Titles of categories of animal evidence referring to human risk potential were based on a presumption: "for practical purposes . . . as if." No evaluation was made of the predictive relevance of animal data to human risk. The IARC listing did not involve evaluation of potency or mechanism and was intended as a useful input but not as a basis for regulatory or legislative decisions. The Department of Health and Human Services (HHS) lists in the Annual Reports on Carcinogens are selected from the IARC lists and from reports of positive bioassay experiments conducted by the National Toxicology Program (NTP). The reports on the NTP bioassays relate to the strength of the evidence in each experiment and recognize that a "wider analysis" is necessary for determination of human risk. Because of a misunderstanding of the limited scope of the analysis involved, the IARC and HHS lists have recently been used as a basis for legislative and regulatory decisions. Examples of unanticipated use of the lists as triggers for regulatory and legislative decisions will be discussed. Some recommendations to mitigate the consequences of past unanticipated use of the lists and to prevent further misuse are discussed.

Scientific risk assessment and the regulation of human cancer risks: background and new directions.

I consider the importance of scientific risk assessment as optimal basis for socially sound risk management decisions. The health professional has both risk assessment and risk management responsibilities; the functions are conceptually separate and governed by separate criteria: scientific for risk assessment and social for risk management. The history of the development of regulating risk assessment methodology with particular reference to potential carcinogens is discussed. The scientific basis for possible improvements in risk assessment methodology for potential carcinogens is identified and the significance of the potential improvements is considered with special reference to the health professional.