Assessment of human cancer risk: challenges for alternative approaches.

The ILSI/HESI Workshop on Alternatives to Carcinogenicity Testing aims to develop and apply new methods for assessment of potential carcinogenic risk to humans from various chemicals. The Workshop represents a major cooperative scientific effort. The long-term goals should be to greatly enhance the efficiency and reliability of such testing and to supplant, not just supplement, lifetime rodent bioassays. There are now well-established frameworks for risk assessment and risk management, putting risks into public health context and engaging stakeholders. The Lave-Omenn value-of-information model provides a useful way to assess the social costs and benefits of different strategies for testing large numbers of chemicals.

The new millennium: values, perceptions of risk, and the key roles of science and technology.

Radiation protection and management of radioactive waste streams and products are certain to be important areas of public policy, worker education, and technology development in the new millennium. Overriding values of freedom, sustainability, transparency, and public participation in decision making about technology's benefits and risks will shape the public policy agenda. Early engagement of stakeholders in the identification and assessment of risks and in communications about risk management will be beneficial in most cases. Putting specific environmental problems into broader public health and ecologic context will be helpful to all parties and will improve decisions about how best to utilize precious resources and enhance public confidence in the process and the outcomes.

Prospects for pharmacogenetics and ecogenetics in the new millennium.

Genetics and genomics are certain to have a large impact in drug development and proper pharmaceutical treatment of subgroups of patients with many specific diseases. We should be able to increase the therapeutic margin for many agents. Genetic variation will also be important in refining estimates of risk from all kinds of environmental agents and in choosing more effective and more cost-effective risk reduction strategies. The linkage of information about genetic variation and information about environmental, nutritional, behavioral, metabolic, medical, and healthcare factors will be necessary to interpret the variation in clinical and public health terms. However, there is a great risk that present federal and state efforts to protect confidentiality and privacy of individual genetic information may make such research infeasible. In Michigan, a Governor's Commission has sought to strike an appropriate balance.

Potential clinical and economic effects of homocyst(e)ine lowering.

BACKGROUND: Elevated total homocyst(e)ine levels (>/=11 micromol/L) have been identified as a potential risk factor for coronary heart disease. However, the benefits expected from lowering homocyst(e)ine levels with folic acid and vitamin B(12) supplementation have yet to be demonstrated in clinical trials. SUBJECTS AND METHODS: We constructed a decision analytic model to estimate the clinical benefits and economic costs of 2 homocyst(e)ine-lowering strategies: (1) "treat all"-no screening, daily supplementation with folic acid (400 microg) and vitamin B(12) (cyanocobalamin; 500 microg) for all; (2) "screen and treat"-screening, followed by daily supplementation with folic acid and vitamin B(12) for individuals with elevated homocyst(e)ine levels. Simulated cohorts of 40-year-old men and 50-year-old women in the general population were evaluated. In the base-case analysis, we assumed that lowering elevated levels would reduce excess coronary heart disease risk by 40%; however, this assumption and others were evaluated across a broad range of potential values using sensitivity analysis. Primary outcomes were discounted costs per life-year saved. RESULTS: Although the treat-all strategy was slightly more effective overall, the screen and treat strategy resulted in a much lower cost per life-year saved ($13,600 in men and $27,500 in women) when compared with no intervention. Incremental cost-effectiveness ratios for the treat-all strategy compared with the screen and treat strategy were more than $500,000 per life-year saved in both cohorts. Sensitivity analysis showed that cost-effectiveness ratios for the screen and treat strategy remained less than $50,000 per life-year saved under several unfavorable scenarios, such as when effective homocyst(e)ine lowering was assumed to reduce the relative risk of coronary heart disease-related death by only 11% in men or 23% in women. CONCLUSIONS: Homocyst(e)ine lowering with folic acid and vitamin B(12) supplementation could result in substantial clinical benefits at reasonable costs. If homocyst-(e)ine lowering is considered, a screen and treat strategy is likely to be more cost-effective than universal supplementation. Arch Intern Med. 2000;160:3406-3412.

Risk estimation and value-of-information analysis for three proposed genetic screening programs for chronic beryllium disease prevention.

Genetic differences (polymorphisms) among members of a population are thought to influence susceptibility to various environmental exposures. In practice, however, this information is rarely incorporated into quantitative risk assessment and risk management. We describe an analytic framework for predicting the risk reduction and value-of-information (VOI) resulting from specific risk management applications of genetic biomarkers, and we apply the framework to the example of occupational chronic beryllium disease (CBD), an immune-mediated pulmonary granulomatous disease. One described Human Leukocyte Antigen gene variant, HLA-DP beta 1*0201, contains a substitution of glutamate for lysine at position 69 that appears to have high sensitivity (approximately 94%) but low specificity (approximately 70%) with respect to CBD among individuals occupationally exposed to respirable beryllium. The expected postintervention CBD prevalence rates for using the genetic variant (1) as a required job placement screen, (2) as a medical screen for semiannual in place of annual lymphocyte proliferation testing, or (3) as a voluntary job placement screen are 0.08%, 0.8%, and 0.6%, respectively, in a hypothetical cohort with 1% baseline CBD prevalence. VOI analysis is used to examine the reduction in total social cost, calculated as the net value of disease reduction and financial expenditures, expected for proposed CBD intervention programs based on the genetic susceptibility test. For the example cohort, the expected net VOI per beryllium worker for genetically based testing and intervention is $13,000, $1,800, and $5,100, respectively, based on a health valuation of $1.45 million per CBD case avoided. VOI results for alternative CBD evaluations are also presented. Despite large parameter uncertainty, probabilistic analysis predicts generally positive utility for each of the three evaluated programs when avoidance of a CBD case is valued at $1 million or higher. Although the utility of a proposed risk management program may be evaluated solely in terms of risk reduction and financial costs, decisions about genetic testing and program implementation must also consider serious social, legal, and ethical factors.

Caring for the community: the role of partnerships.

While many members of the public are deeply interested in and supportive of the three traditional missions of academic medicine--education, research, and clinical care, they also want to know what academic health centers (AHCs) are doing to improve the overall health of their communities. Much is already being done toward this goal, but improving communities' health in a measurable way requires a far broader agenda. AHCs must bring together the approaches of medicine and public health, and need to partner with many other players. This agenda must proceed despite all the other challenges that AHCs are currently facing. The author reviews illustrative and emerging national, state, and local efforts, public and private, in both medicine and public health, in partnerships with individuals and institutions in the larger community. He also highlights the physician's role in assisting stakeholders' efforts to deal with health threats from the environment, and offers advice about how such efforts should proceed. He closes by emphasizing the importance of community-based research to learn about the health statuses, problems, and resources of particular communities, and presents a set of principles for such community-based research.

Risk assessment for butadiene: introductory and summary comments.

Butadiene and its 2-methyl analog, isoprene, are important chemicals, extensively studied in animals and in worker cohorts. This symposium, building on previous conferences and substantial additional metabolic and epidemiologic data, brought together leading scientists from industry and academia and knowledgeable regulators to address the complex task of assessing likelihood and magnitude of risk to humans and appropriately protective standards for occupational and general environmental exposures. These agents and these discussions are an excellent case study for general challenges in risk assessment and risk management.

Prevention and the reforming U.S. health care system: changing roles and responsibilities for public health.

This review presents historical and cost-effectiveness perspectives of prevention in health care; discusses the nature, extent, and determinants of health system change, particularly the transition to managed care with large integrated health care corporations; and identifies implications for public health agencies and opportunities for prevention within the reforming health system.

A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes.

OBJECTIVES: To determine the risk of elevated total homocysteine (tHcy) levels for arteriosclerotic vascular disease, estimate the reduction of tHcy by folic acid, and calculate the potential reduction of coronary artery disease (CAD) mortality by increasing folic acid intake. DATA SOURCES: MEDLINE search for meta-analysis of 27 studies relating homocysteine to arteriosclerotic vascular disease and 11 studies of folic acid effects on tHcy levels. STUDY SELECTION AND DATA EXTRACTION: Studies dealing with CAD, cerebrovascular disease, and peripheral arterial vascular disease were selected. Three prospective and six population-based case-control studies were considered of high quality. Five cross-sectional and 13 other case-control studies were also included. Causality of tHcy's role in the pathogenesis of vascular disease was inferred because of consistency across studies by different investigators using different methods in different populations. DATA SYNTHESIS: Elevations in tHcy were considered an independent graded risk factor for arteriosclerotic vascular diseases. The odds ratio (OR) for CAD of a 5-mumol/L tHcy increment is 1.6 (95% confidence interval [CI], 1.4 to 1.7) for men and 1.8 (95% CI, 1.3 to 1.9) for women. A total of 10% of the population's CAD risk appears attributable to tHcy. The OR for cerebrovascular disease (5-mumol/L tHcy increment) is 1.5 (95% CI, 1.3 to 1.9). Peripheral arterial disease also showed a strong association. Increased folic acid intake (approximately 200 micrograms/d) reduces tHcy levels by approximately 4 mumol/L. Assuming that lower tHcy levels decrease CAD mortality, we calculated the effect of (1) increased dietary folate, (2) supplementation by tablets, and (3) grain fortification. Under different assumptions, 13,500 to 50,000 CAD deaths annually could be avoided; fortification of food had the largest impact. CONCLUSIONS: A 5-mumol/L tHcy increment elevates CAD risk by as much as cholesterol increases of 0.5 mmol/L (20 mg/dL). Higher folic acid intake by reducing tHcy levels promises to prevent arteriosclerotic vascular disease. Clinical trials are urgently needed. Concerns about masking cobalamin deficiency by folic acid could be lessened by adding 1 mg of cobalamin to folic acid supplements.

Characteristics of health promotion programs in Federal worksites: findings from the Federal Employee Worksite Project.

PURPOSE: To describe how well-established health promotion programs at selected federal worksites were designed, organized, and implemented and to identify factors related to employee participation. DESIGN: This descriptive study related characteristics of the health promotion program, worksites, and workforce to employee participation and perceptions of program impacts. SETTING: The study was conducted at 10 established federal worksite health promotion programs in various regions of the country. SUBJECTS: A total of 3403 of 5757 federal employees (59%) sampled completed employee surveys. MEASURES: Study data were collected from on-site observations, interviews, focus groups, and employee surveys. RESULTS: Overall, program participation rates were high, and employees reported positive impacts on their health and attitudes toward the agency. Participation in health screening, perceived program convenience, and perceived support by management and others were important determinants of participation and of perceived work-related outcomes. CONCLUSIONS: Although site selection and response rate limit generalizability, the sites evaluated represent a broad cross-section of different types and sizes of agencies. The findings should be relevant in many other settings. Study programs compare favorably with private sector programs. Employees viewed the programs very positively. The most cogent challenge in justifying these, and perhaps other, worksite programs is that most participants already or simultaneously engage in health promotion activities elsewhere "on their own."

Assessing the risk assessment paradigm.

Risk assessment provides an essential framework for organizing, evaluating and characterizing scientific information on the nature and magnitude of hazards from specific chemicals. Such characterization of risk is needed for risk communication and for risk reduction and management. Each element of the risk assessment paradigm--hazard identification, dose-response, exposure analysis and risk characterization--is the target of important efforts to improve methodologies and the biological plausibility and clinical significance of our conclusions.

Research cost analyses to aid in decision making in the conduct of a large prevention trial, CARET. Carotene and Retinol Efficacy Trial.

Because of their larger study populations and longer durations, prevention trials typically are more costly than treatment trials. Thus it is important to analyze costs systematically to aid in making cost-effective decisions during the conduct of prevention trials as well as in the original design. Cost analysis must be tied to sample size estimation because costs depend on such factors as the total number of person-years of follow-up and the number of trial outcomes, which are not basic design parameters but are derived quantities resulting from sample size estimation. We illustrate the use of cost analysis to decide among options for future conduct of an ongoing prevention trial with three issues that have arisen during the Carotene and Retinol Efficacy Trial (CARET): the trade-off between extending the duration of the trial or increasing the number of participants, the effect on costs of delay in accrual, and the cost effectiveness of particular retention activities.