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.     

Employment and filial relations: Is there a conflict?

Since children, particularly daughters, are among the most important sources of help and support for older Americans, it has been suggested that women's increasing employment will affect filial relations. Empirical evidence on this issue is inconsistent, in part due to the use of nonprobability samples. Few studies have measured effects for men. We attempt to broaden the scope of this question beyond help to the frail elderly by asking whether employment affects filial relations in general. We examine effects of hours employed on telephone contact, visiting, feelings of closeness, filial attitudes, and assistance to biological parents, for an area probability sample of men and women over 40. There are no effects of employment for men or women on contact, closeness, or assistance. For the vast majority of this population sample, contact and assistance involve few hours per week, and thus do not seem to conflict with employment.     

应用神经元控制器的实时控制装置和实验

针对平衡倒立摆这一非线性控制问题，设计了神经元控制器和控制装置，编制了实时控制程序．控制装置运行良好，成功地平衡了倒立摆．实时控制实验显示，当倒立摆的参数变化时，神经元控制器比一般的控制器具有强得多的自适应能力．     

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.     

One parent or two? The intertwining of American marriage and fertility patterns

Marriage and fertility in the United States have become less firmly entwined as more women bear children without marrying and more couples with children divorce. Today a sizeable number of children are expected to spend a portion of their childhood in one-parent households. Despite the trends in illegitimacy and divorce, the actual effect of out-of-wedlock childbearing on the living arrangements of children has not been fully explicated. Using the National Survey of Family Growth Cycle III, this paper estimates the probability that children aged 0–13 in 1982 are living in two-parent households, controlling for their mothers' marital statuses at their births. We find that marital status at birth is an important predictor of household structure at later ages for both white and black populations; however, the childhood environment is actually quite elastic as women marry, divorce, remarry, and redivorce.