Biological Basis of Chemical Carcinogenesis: Insights from Benzene

Benzene is one of the best studied of the known human carcinogens. It causes leukemia in humans and a variety of solid tumors in rats and mice. Decades of research on benzene metabolism, pharmacokinetics, cytotoxicity, genotoxicity, and carcinogenicity in vivo and in vitro are starting to converge on a small set of overlapping hypotheses about the most probable biological mechanisms of benzene toxicity and carcinogenicity. Although there is still room for surprises, it seems likely that the ultimate answer to the mystery of how benzene exerts its multiple effects will consist of elaborations and extensions of one or more of the current hypotheses. This paper reviews benzene health effects and biology, showing how various aspects of metabolism and cytotoxicity fit together with genotoxic and nongenotoxic effects to help explain how benzene may cause cancer. Its goals are: (i) to introduce the qualitative biological background needed for detailed quantitative dose-response modeling of benzene cancer risks; and (ii) to survey a rapidly evolving area of research that shows promise of producing fundamental insights into the mechanisms of toxicity and carcinogenesis for several chemicals--benzene and perhaps phenols, catechols, and other hydroxylated ring hydrocarbons--in the decade ahead.     

Stability in Center Day Care: Relations with Children's Well‐being and Problem Behavior in Day Care1

Mothers and primary professional caregivers of 186 children, aged 6–30 months, participated in this study in which a new measure for daily stability in center day care was developed, describing staffing, grouping, and program features. Relative contributions of infants’ daily experiences of care stability, quality of care, and mother's daily stress to the child's adjustment to day care were analyzed with hierarchical regressions. The child's adjustment was assessed with the Child Behavior Checklist ( Achenbach, 1997 ) and with the Leiden Inventory for the Child's Well‐being in Day Care. Children enrolled in fewer care arrangements showed less internalizing behavior and more well‐being in the day care setting. Children had higher well‐being scores when trusted caregivers were more available. Mother's family management stress was related to more internalizing problem behavior. Interactions between mother's daily stress and stability in care were found to affect the child's adjustment to day care.     

Extending the Stochastic Two-Stage Model of Carcinogenesis to Include Self-Regulation of the Nonmalignant Cell Population

One of the challenges of introducing greater biological realism into stochastic models of cancer induction is to find a way to represent the homeostatic control of the normal cell population over its own size without complicating the analysis too much to obtain useful results. Current two-stage models of carcinogenesis typically ignore homeostatic control. Instead, a deterministic growth path is specified for the population of "normal" cells, while the population of "initiated" cells is assumed to grow randomly according to a birth-death process with random immigrations from the normal population. This paper introduces a simple model of homeostatically controlled cell division for mature tissues, in which the size of the nonmalignant population remains essentially constant over time. Growth of the nonmalignant cell population (normal and initiated cells) is restricted by allowing cells to divide only to fill the "openings" left by cells that die or differentiate, thus maintaining the constant size of the nonmalignant cell population. The fundamental technical insight from this model is that random walks, rather than birth-and-death processes, are the appropriate stochastic processes for describing the kinetics of the initiated cell population. Qualitative and analytic results are presented, drawn from the mathematical theories of random walks and diffusion processes, that describe the probability of spontaneous extinction and the size distribution of surviving initiated populations when the death/differentiation rates of normal and initiated cells are known. The constraint that the nonmalignant population size must remain approximately constant leads to much simpler analytic formulas and approximations, flowing directly from random walk theory, than in previous birth-death models.(ABSTRACT TRUNCATED AT 250 WORDS)     

Some remarks on the paper by Julia Ericksen et al., ‘Fertility patterns and trends among the Old Order Amish’

At the present time there are very few populations, whose members do not practise contraception at all, or only to a very limited extent, and for whom accurate data on nuptiality and fertility exist. Among populations of European residence or origin, there are only a few groups who reject any limitation of families for religious reasons. One of these, the Hutterites, has already been studied; the other, the Old Order Amish, is studied in Ericksen's papers, and my preceding remarks point to the importance of this study.     

Differentiation and complexity in the functionalist corpus: Rethinking the metaphor of system

The following paper examines the cybernetics trajectory of Parsons’ later work and its extension in the work of Luhmann. While the earlier work was focused on social action as a basic unit of sociological analysis, in The Social System Parsons articulates a notion of systems as self-generating and self-regulating. In Luhmann’s Social Systems this trajectory is made more explicit and developed in opposition to the early Parsons. Its metaphorical dimensions are also developed, creating additional levels and layers of abstraction. Those developments are deemed necessary in order to come to terms with the increasingly “complex” nature of modern society; however they are problematic in several respects—including their tautological nature which provides a basis for the unrestrained explanatory power of “system.“     

Miscommunicating Risk,Uncertainty, and Causation: Fine Particulate Air Pollution and Mortality Risk as an Example

A recent paper in this journal (Fann et al., 2012) estimated that “about 80,000 premature mortalities would be avoided by lowering PM_2.5 levels to 5 μg/m³ nationwide” and that 2005 levels of PM_2.5 cause about 130,000 premature mortalities per year among people over age 29, with a 95% confidence interval of 51,000 to 200,000 premature mortalities per year.⁽¹⁾ These conclusions depend entirely on misinterpreting statistical coefficients describing the association between PM_2.5 and mortality rates in selected studies and models as if they were known to be valid causal coefficients. But they are not, and both the expert opinions of EPA researchers and analysis of data suggest that a true value of zero for the PM_2.5 mortality causal coefficient is not excluded by available data. Presenting continuous confidence intervals that exclude the discrete possibility of zero misrepresents what is currently known (and not known) about the hypothesized causal relation between changes in PM_2.5 levels and changes in mortality rates, suggesting greater certainty about projected health benefits than is justified.