Modeling for Risk Assessment of Neurotoxic Effects

The regulation of noncancer toxicants, including neurotoxicants, has usually been based upon a reference dose (allowable daily intake). A reference dose is obtained by dividing a no-observed-effect level by uncertainty (safety) factors to account for intraspecies and interspecies sensitivities to a chemical. It is assumed that the risk at the reference dose is negligible, but no attempt generally is made to estimate the risk at the reference dose. A procedure is outlined that provides estimates of risk as a function of dose. The first step is to establish a mathematical relationship between a biological effect and the dose of a chemical. Knowledge of biological mechanisms and/or pharmacokinetics can assist in the choice of plausible mathematical models. The mathematical model provides estimates of average responses as a function of dose. Secondly, estimates of risk require selection of a distribution of individual responses about the average response given by the mathematical model. In the case of a normal or lognormal distribution, only an estimate of the standard deviation is needed. The third step is to define an adverse level for a response so that the probability (risk) of exceeding that level can be estimated as a function of dose. Because a firm response level often cannot be established at which adverse biological effects occur, it may be necessary to at least establish an abnormal response level that only a small proportion of individuals would exceed in an unexposed group. That is, if a normal range of responses can be established, then the probability (risk) of abnormal responses can be estimated. In order to illustrate this process, measures of the neurotransmitter serotonin and its metabolite 5-hydroxyindoleacetic acid in specific areas of the brain of rats and monkeys are analyzed after exposure to the neurotoxicant methylene-dioxymethamphetamine. These risk estimates are compared with risk estimates from the quantal approach in which animals are classified as either abnormal or not depending upon abnormal serotonin levels.     

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.     

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.     

Role of informal sector recycling in waste management in developing countries

Many thousands of people in developing country cities depend on recycling materials from waste for their livelihoods. With the focus of the Millennium Development Goals on poverty reduction, and of waste strategies on improving recycling rates, one of the major challenges in solid waste management in developing countries is how best to work with this informal sector to improve their livelihoods, working conditions and efficiency in recycling.The general characteristics of informal recycling are reviewed, highlighting both positive and negative aspects. Despite the health and social problems associated with informal recycling, it provides significant economic benefits that need to be retained. Experience shows that it can be highly counterproductive to establish new formal waste recycling systems without taking into account informal systems that already exist. The preferred option is to integrate the informal sector into waste management planning, building on their practices and experience, while working to improve efficiency and the living and working conditions of those involved. Issues associated with integrating informal recycling into the formal waste management sector are discussed.     

Teaching Disability Studies in Canada and the USA

Using a 1993 sample (n=107) of persons who teach disability studies courses, a sample (n=27) of disability studies syllabi from the early 1980s, and an extensive bibliography the authors discuss the history and the present condition of disability studies courses in the US and Canada. They discuss the disability paradigm and the methodology used in disability studies courses. The variety and geographical spread of such courses are noted. An extensive comparison of syllabi from the 1980s and the 1990s, including the reading assignments, is carried out.     

On the preservation of copula structure under truncation

The author characterizes the copula associated with the bivariate survival model of Clayton (1978) as the only absolutely continuous copula that is preserved under bivariate truncation.     

Pathways between education and health: a causal modelling approach

Summary.  The association of poor education and poor health has been consistently observed in many studies and in various countries. Thus far, studies examining the mechanisms underlying this association have looked at only a limited set of potential pathways. This study simultaneously examines six distinctive pathways, which have been hypothesized to link education and health and found support from previous studies. A causal analysis of education and health was performed using structural equation models. Data were used from six phases of the National Child Development Study, which is based on following up an initial sample of 17416 children who were born in 1958. The association between education and health appears to be explained by a combination of mechanisms: adolescent health and adult health behaviours for men and women, adult social class among men and parental social class among women. We conclude that improvements in population educational attainment may not automatically lead to improvements in population health, and that health policies for improving health and reducing health inequalities need to target specific causal pathways.     

Reclaiming the spirit: The journeys of gay men and lesbian women toward integration

The goal of this study is to understand and describe the way gay men and lesbian women see and interpret their spiritual journeys. Its intent is to open up the variety of experiences that gay men and lesbians encounter and is, therefore, not based on a single religious tradition or path, such as through crisis or AIDS. The findings included a model which interweaves the coming out process and the spiritual journey for this group of gay men and lesbian women, highlighting the period of questioning, reclaiming, and reintegration that happens for many as they resolve their sense of themselves as sexual and spiritual. Also addressed is the choice of mainstream and non-mainstream spiritual identification. The research discussed in this report was supported in part by the University Research Council, DePaul University.