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.     

A Tabu Search Heuristic for the Location of Multi-Type Protection Devices on Electrical Supply Tree Networks

The problem of determining the number of multi-type protection devices and their locations on electrical supply tree networks with subtree dependency is investigated. The aim is to reduce the amount of inconvenience caused to customers that are affected by any given fault on the networks. An appropriate implementation of tabu search is proposed. We exploit a variable neighborhood and a soft aspiration level, and we embed a data structure and reduction tests into the search to speed up the process. Computational tests are performed on randomly generated electrical tree networks varying in size and branch complexity with encouraging results.     

A theory of prudential values and a rule utilitarian theory of morality

Ethics can be divided into a theory of prudential values and a theory of morality in a narrower sense. My paper proposes a utilitarian — a rule-utilitarian — theory of morality. But it deviates from most of the utilitarian tradition by rejecting the hedonistic and subjectivistic accounts of prudential values favored by many utilitarian writers. While economists tend to define people's utility levels in terms of their actual preferences, ethics must define them in terms of their informed preferences. To prefer A over B does not mean to have a stronger desire for A than for B. Rather, it means to regard one's access to A as being more important than one's access to B. Even though different people often have quite different preferences, their basic desires seem to be much the same. We must choose our moral rules, and our society's moral code as a whole, by their social utility. An important factor in determining their social utility are their expectation effects. Unlike the rule — utilitarian more code, the act — utilitarian moral code would be unable to give proper weight to these expectation effects. It would also unduly restrict our individual freedom. Finally, I shall argue against Kant that morality is primarily a servant of many other human values rather than itself the highest value of human life.     

Characteristics of smokeless tobacco use among high school football players as related to type of smokeless tobacco and period of use.

The present study was conducted to assess differences in the behavioral and demographic characteristics of snuff (dip) users as compared to users of chewing tobacco. High School football players (1116) were surveyed concerning their use and perceptions of smokeless tobacco. Adolescent athletes who tried smokeless tobacco were more likely to be white, to use cigarettes, alcohol, and cigars and to have family users than those who never tried. Initial use was highest before the age of fourteen years and was influenced by friends, curiosity and family. Dippers tended to initiate use because of friends, while chewers started because of family users. Users of both dip and chew started primarily because of curiosity. Users of both were more likely to consume greater amounts to alcohol and cigarettes and to smoke cigars and pipes. It appears that the longer smokeless tobacco is consumed, the more likely both dip and chew will be used. Users of smokeless tobacco for more than two years tended to consume more of the product each week, used it for more hours/day, initiated use at an earlier age, and used it more often at school and work than those using it for less than two years. Use of cigars/pipes, consumption of alcohol, and quantity of cigarette consumption increased significantly with longer duration of smokeless tobacco use. Intervention and prevention programs would be helped by understanding differences between users of various smokeless tobacco products and differences related to the duration of use. In addition, further analyses of smokeless tobacco users should study chewers, dippers, and users of both separately.     

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.     

Rural/Urban Residence,Migration, HIV/AIDS,and Safe Sex Practices among Men in Zimbabwe*

Abstract The AIDS epidemic was initially thought to be primarily an urban phenomenon. However, migration between rural and urban areas has resulted in the spread of the virus to all segments of the population. Prevention efforts continue to focus on the ABCs of AIDS, namely, abstinence among young adults, being faithful within a monogamous relationship, and/or using condoms at each sexual encounter. We examine the effects of residence, migration status, and selected social and demographic variables on the use of these three practices among men in Zimbabwe, a nation experiencing one of the highest HIV/AIDS prevalence rates in the world. Both residence and migration status were found to be significantly related to safe sex practices. Knowledge of a source with easy access to condoms was the strongest predictor of this behavior. Knowledge of prevention methods and experience with persons with AIDS also exerted significant effects, although not always in the manner hypothesized. Possible reasons for the findings and implications for policy are discussed.