What to Do at Low Doses: A Bounding Approach for Economic Analysis

To quantify the health benefits of environmental policies, economists generally require estimates of the reduced probability of illness or death. For policies that reduce exposure to carcinogenic substances, these estimates traditionally have been obtained through the linear extrapolation of experimental dose-response data to low-exposure scenarios as described in the U.S. Environmental Protection Agency's Guidelines for Carcinogen Risk Assessment (1986). In response to evolving scientific knowledge, EPA proposed revisions to the guidelines in 1996. Under the proposed revisions, dose-response relationships would not be estimated for carcinogens thought to exhibit nonlinear modes of action. Such a change in cancer-risk assessment methods and outputs will likely have serious consequences for how benefit-cost analyses of policies aimed at reducing cancer risks are conducted. Any tendency for reduced quantification of effects in environmental risk assessments, such as those contemplated in the revisions to EPA's cancer-risk assessment guidelines, impedes the ability of economic analysts to respond to increasing calls for benefit-cost analysis. This article examines the implications for benefit-cost analysis of carcinogenic exposures of the proposed changes to the 1986 Guidelines and proposes an approach for bounding dose-response relationships when no biologically based models are available. In spite of the more limited quantitative information provided in a carcinogen risk assessment under the proposed revisions to the guidelines, we argue that reasonable bounds on dose-response relationships can be estimated for low-level exposures to nonlinear carcinogens. This approach yields estimates of reduced illness for use in a benefit-cost analysis while incorporating evidence of nonlinearities in the dose-response relationship. As an illustration, the bounding approach is applied to the case of chloroform exposure.     

Dose-Response and Risk Assessment of Airborne Hexavalent Chromium and Lung Cancer Mortality

This study evaluates the dose-response relationship for inhalation exposure to hexavalent chromium [Cr(VI)] and lung cancer mortality for workers of a chromate production facility, and provides estimates of the carcinogenic potency. The data were analyzed using relative risk and additive risk dose-response models implemented with both Poisson and Cox regression. Potential confounding by birth cohort and smoking prevalence were also assessed. Lifetime cumulative exposure and highest monthly exposure were the dose metrics evaluated. The estimated lifetime additional risk of lung cancer mortality associated with 45 years of occupational exposure to 1 microg/m3 Cr(VI) (occupational exposure unit risk) was 0.00205 (90%CI: 0.00134, 0.00291) for the relative risk model and 0.00216 (90%CI: 0.00143, 0.00302) for the additive risk model assuming a linear dose response for cumulative exposure with a five-year lag. Extrapolating these findings to a continuous (e.g., environmental) exposure scenario yielded an environmental unit risk of 0.00978 (90%CI: 0.00640, 0.0138) for the relative risk model [e.g., a cancer slope factor of 34 (mg/kg-day)-1] and 0.0125 (90%CI: 0.00833, 0.0175) for the additive risk model. The relative risk model is preferred because it is more consistent with the expected trend for lung cancer risk with age. Based on statistical tests for exposure-related trend, there was no statistically significant increased lung cancer risk below lifetime cumulative occupational exposures of 1.0 mg-yr/m3, and no excess risk for workers whose highest average monthly exposure did not exceed the current Permissible Exposure Limit (52 microg/m3). It is acknowledged that this study had limited power to detect increases at these low exposure levels. These cancer potency estimates are comparable to those developed by U.S. regulatory agencies and should be useful for assessing the potential cancer hazard associated with inhaled Cr(VI).     

Sampling Strategies for Toxic Air Contaminants

Annual concentrations of toxic air contaminants are of primary concern from the perspective of chronic human exposure assessment and risk analysis. Despite recent advances in air quality monitoring technology, resource and technical constraints often impose limitations on the availability of a sufficient number of ambient concentration measurements for performing environmental risk analysis. Therefore, sample size limitations, representativeness of data, and uncertainties in the estimated annual mean concentration must be examined before performing quantitative risk analysis. In this paper, we discuss several factors that need to be considered in designing field-sampling programs for toxic air contaminants and in verifying compliance with environmental regulations. Specifically, we examine the behavior of SO2, TSP, and CO data as surrogates for toxic air contaminants and as examples of point source, area source, and line source-dominated pollutants, respectively, from the standpoint of sampling design. We demonstrate the use of bootstrap resampling method and normal theory in estimating the annual mean concentration and its 95% confidence bounds from limited sampling data, and illustrate the application of operating characteristic (OC) curves to determine optimum sample size and other sampling strategies. We also outline a statistical procedure, based on a one-sided t-test, that utilizes the sampled concentration data for evaluating whether a sampling site is compliance with relevant ambient guideline concentrations for toxic air contaminants.     

Bootstrap Estimation of Benchmark Doses and Confidence Limits with Clustered Quantal Data

The benchmark dose (BMD) is an exposure level that would induce a small risk increase (BMR level) above the background. The BMD approach to deriving a reference dose for risk assessment of noncancer effects is advantageous in that the estimate of BMD is not restricted to experimental doses and utilizes most available dose-response information. To quantify statistical uncertainty of a BMD estimate, we often calculate and report its lower confidence limit (i.e., BMDL), and may even consider it as a more conservative alternative to BMD itself. Computation of BMDL may involve normal confidence limits to BMD in conjunction with the delta method. Therefore, factors, such as small sample size and nonlinearity in model parameters, can affect the performance of the delta method BMDL, and alternative methods are useful. In this article, we propose a bootstrap method to estimate BMDL utilizing a scheme that consists of a resampling of residuals after model fitting and a one-step formula for parameter estimation. We illustrate the method with clustered binary data from developmental toxicity experiments. Our analysis shows that with moderately elevated dose-response data, the distribution of BMD estimator tends to be left-skewed and bootstrap BMDL s are smaller than the delta method BMDL s on average, hence quantifying risk more conservatively. Statistically, the bootstrap BMDL quantifies the uncertainty of the true BMD more honestly than the delta method BMDL as its coverage probability is closer to the nominal level than that of delta method BMDL. We find that BMD and BMDL estimates are generally insensitive to model choices provided that the models fit the data comparably well near the region of BMD. Our analysis also suggests that, in the presence of a significant and moderately strong dose-response relationship, the developmental toxicity experiments under the standard protocol support dose-response assessment at 5% BMR for BMD and 95% confidence level for BMDL.     

Summary of the Workshop on Issues in Risk Assessment: Quantitative Methods for Developmental Toxicology

This report summarizes the proceedings of a conference on quantitative methods for assessing the risks of developmental toxicants. The conference was planned by a subcommittee of the National Research Council's Committee on Risk Assessment Methodology ⁴ in conjunction with staff from several federal agencies, including the U.S. Environmental Protection Agency, U.S. Food and Drug Administration, U.S. Consumer Products Safety Commission, and Health and Welfare Canada. Issues discussed at the workshop included computerized techniques for hazard identification, use of human and animal data for defining risks in a clinical setting, relationships between end points in developmental toxicity testing, reference dose calculations for developmental toxicology, analysis of quantitative dose-response data, mechanisms of developmental toxicity, physiologically based pharmacokinetic models, and structure-activity relationships. Although a formal consensus was not sought, many participants favored the evolution of quantitative techniques for developmental toxicology risk assessment, including the replacement of lowest observed adverse effect levels (LOAELs) and no observed adverse effect levels (NOAELs) with the benchmark dose methodology.     

Principal curves revisited

A principal curve (Hastie and Stuetzle, 1989) is a smooth curve passing through the middle of a distribution or data cloud, and is a generalization of linear principal components. We give an alternative definition of a principal curve, based on a mixture model. Estimation is carried out through an EM algorithm. Some comparisons are made to the Hastie-Stuetzle definition.     

Resampling-based Classification Using Depth for Functional Curves

The depths, which have been used to detect outliers or to extract a representative subset, can be applied to classification. We propose a resampling-based classification method based on the fact that resampling techniques yield a consistent estimator of the distribution of a statistic. The performance of this method was evaluated with eight contaminated models in terms of Correct Classification Rates (CCRs), and the results were compared with other known methods. The proposed method consistently showed higher average CCRs and 4% higher CCR at the maximum compared to other methods. In addition, this method was applied to Berkeley data. The average CCRs were between 0.79 and 0.85.     

On sequential closed testing dose groups with a control

Methods for a sequential test of a dose-response effect in pre-clinical studies are investigated. The objective of the test procedure is to compare several dose groups with a zero-dose control. The sequential testing is conducted within a closed family of one-sided tests. The procedures investigated are based on a monotonicity assumption. These closed procedures strongly control the familywise error rate while providing information about the shape of the dose-responce relationship. Performance of sequential testing procedures are compared via a Monte Carlo simulation study. We illustrae the procedures by application to a real data set.     

An Automatic Test for the Umbrella Alternatives

The paper proposes a new test for detecting the umbrella pattern under a general non‐parametric scheme. The alternative asserts that the umbrella ordering holds while the hypothesis is its complement. The main focus is put on controlling the power function of the test outside the alternative. As a result, the asymptotic error of the first kind of the constructed solution is smaller than or equal to the fixed significance level α on the whole set where the umbrella ordering does not hold. Also, under finite sample sizes, this error is controlled to a satisfactory extent. A simulation study shows, among other things, that the new test improves upon the solution widely recommended in the literature of the subject. A routine, written in R, is attached as the Supporting Information file.     

Issues in Estimating New Keynesian Phillips Curves in the Presence of Unknown Structural Change

Many articles which have estimated models with forward looking expectations have reported that the magnitude of the coefficients of the expectations term is very large when compared with the effects coming from past dynamics. This has sometimes been regarded as implausible and led to the feeling that the expectations coefficient is biased upwards. A relatively general argument that has been advanced is that the bias could be due to structural changes in the means of the variables entering the structural equation. An alternative explanation is that the bias comes from weak instruments. In this article, we investigate the issue of upward bias in the estimated coefficients of the expectations variable based on a model where we can see what causes the breaks and how to control for them. We conclude that weak instruments are the most likely cause of any bias and note that structural change can affect the quality of instruments. We also look at some empirical work in Castle et al. (2014 Castle, J. L., Doornik, J. A., Hendry, D. F., Nymoen, R. (2014). Misspecification testing: non-invariance of expectations models of inflation. Econometric Reviews 33:5–6, 553–574, doi:10.1080/07474938.2013.825137[Taylor &; Francis Online], [Web of Science ®] , [Google Scholar]) on the new Kaynesian Phillips curve (NYPC) in the Euro Area and U.S. assessing whether the smaller coefficient on expectations that Castle et al. (2014 Castle, J. L., Doornik, J. A., Hendry, D. F., Nymoen, R. (2014). Misspecification testing: non-invariance of expectations models of inflation. Econometric Reviews 33:5–6, 553–574, doi:10.1080/07474938.2013.825137[Taylor &; Francis Online], [Web of Science ®] , [Google Scholar]) highlight is due to structural change. Our conclusion is that it is not. Instead it comes from their addition of variables to the NKPC. After allowing for the fact that there are weak instruments in the estimated re-specified model, it would seem that the forward coefficient estimate is actually quite high rather than low.