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.     

A Process for Incorporating Comparative Risk into Environmental Policymaking in Louisiana

The goal of Louisiana's 1990–1991 comparative risk project, also called the Louisiana Environmental Action Plan (LEAP), was to incorporate risk assessment into state environmental planning and policymaking. Scientists, government officials, and citizens were brought together to estimate the relative risk to human health, natural resources, and quality of life posed by 33 selected environmental issues. The issues were then ranked according to their relative estimated risks. It was hoped that this ranking of "comparative risks" would enable state policymakers to target the most important environmental problems and allocate scarce public resources more rationally and efficiently. As a result of the project, the governor issued an Executive Order forming a permanent Public Advisory Committee to continue this type of comparative risk assessment in Louisiana.     

Significance of the Dermal Route of Exposure to Risk Assessment

The skin is a route of exposure that needs to be considered when conducting a risk assessment. It is necessary to identify the potential for dermal penetration by a chemical as well as to determine the overall importance of the dermal route of exposure as compared with inhalation or oral routes of exposure. The physical state of the chemical, vapor or liquid, the concentration, neat or dilute, and the vehicle, lipid or aqueous, is also important. Dermal risk is related to the product of the amounts of penetration and toxicity. Toxicity involves local effects on the skin itself and the potential for systemic effects. Dermal penetration is described in large part by the permeability constant. When permeability constants are not known, partition coefficients can be used to estimate a chemical's potential to permeate the skin. With these concepts in mind, a tiered approach is proposed for dermal risk assessment. A key first step is the determination of a skin-to-air or skin-to-medium partition coefficient to estimate a potential for dermal absorption. Building a physiologically-based pharmacokinetic (PBPK) model is another step in the tiered approach and is useful prior to classical in vivo toxicity tests. A PBPK model can be used to determine a permeability constant for a chemical as well as to show the distribution of the chemical systemically. A detailed understanding of species differences in the structure and function of the skin and how they relate to differences in penetration rates is necessary in order to extrapolate animal data from PBPK models to the human. A study is in progress to examine anatomical differences for four species.     

Therapeutic compliments: setting the stage for successful therapy

Compliments are often viewed primarily as a linear event in which one person expresses approval or admiration of another. Far less attention has been given to the circular nature of compliments and the manner in which they enhance the positions of both the giver and the receiver of the compliment. Therapeutic compliments have proven to be highly effective means of motivating clients, while at the same time increasing therapeutic leverage. This article proposes that compliments should be purposefully given, and that the type of compliment should vary with the stage of therapy and the intended response of the client to the compliment.     

Migration research and immigration policy

The author briefly reviews the impact of migration research on U.S. immigration policy over the period 1964-1992. Consideration is given to legal and illegal migrants and refugees.     

Selectivity,adaptation, or disruption? A comparison of alternative hypotheses on the effects of migration on fertility: the case of Brazil

This study, based on Brazilian data from 1976, compared the fertility of migrants and stayers at both origin and destination areas. Observed patterns of fertility differentials were then analyzed in terms of 4 hypotheses of fertility behavior focused on processes of socialization, adaptation, selectivity, and disruption. In the study sample, 31% of migrants moved from rural to urban areas, 45% of moves were between urban areas, and 20% of moves were between rural areas. Among rural-to-urban migrants, only 1/3 moved from traditional to modern regions. To uncover the main patterns of migrant and stayer fertility differentials in the study population, the major flows of migrants by origin and destination were disaggregated by recency of migration, education, and age. The overall conclusions were as follows: 1) rural-urban migration flows need to be disaggregated into various modern/traditional cross-classifications (e.g., modern-rural, traditional-urban, frontier-urban) and greater emphasis needs to be placed on rural-urban, urban-urban, and rural-rural flows; 2) no robust quantitative measures of migrant-stayer fertility differentials held across migrant groups, implying that migrants differing in terms of age, education, origin, and destination are likely to behave in significantly variable fashion with regard to stayer standards of fertility behavior; 3) migrant groups with overall lower fertility levels, such as the young and better educated, are less likely to experience significant fertility reduction to bridge the origin/destination fertility gap; 4) rural-to-rural migrants do not appear to experience any lasting fertility reduction even when they move to areas with lower overall fertility rates; 5) urban-to-rural migrants tend to bridge a larger fraction of the uphill fertility gap than rural-to-urban migrants; and 6) there was evidence of partial adaptation for most migrant categories once disruption effects disappear and evidence consistent with the socialization hypothesis (no fertility reduction for at least 1 generation) was apparent for migrants originating in the least developed parts of Brazil, the frontier region, and the traditional-rural region.