Steady-State Solutions to PBPK Models and Their Applications to Risk Assessment I: Route-to-Route Extrapolation of Volatile Chemicals

Although analysis of in vivo pharmacokinetic data necessitates use of time-dependent physiologically-based pharmacokinetic (PBPK) models, risk assessment applications are often driven primarily by steady-state and/or integrated (e.g., AUC) dosimetry. To that end, we present an analysis of steady-state solutions to a PBPK model for a generic volatile chemical metabolized in the liver. We derive an equivalent model that is much simpler and contains many fewer parameters than the full PBPK model. The state of the system can be specified by two state variables-the rate of metabolism and the rate of clearance by exhalation. For a given oral dose rate or inhalation exposure concentration, the system state only depends on the blood-air partition coefficient, metabolic constants, and the rates of blood flow to the liver and of alveolar ventilation. At exposures where metabolism is close to linear, only the effective first-order metabolic rate is needed. Furthermore, in this case, the relationship between cumulative exposure and average internal dose (e.g., AUCs) remains the same for time-varying exposures. We apply our analysis to oral-inhalation route extrapolation, showing that for any dose metric, route equivalence only depends on the parameters that determine the system state. Even if the appropriate dose metric is unknown, bounds can be placed on the route-to-route equivalence with very limited data. We illustrate this analysis by showing that it reproduces exactly the PBPK-model-based route-to-route extrapolation in EPA's 2000 risk assessment for vinyl chloride. Overall, we find that in many cases, steady-state solutions exactly reproduce or closely approximate the solutions using the full PBPK model, while being substantially more transparent. Subsequent work will examine the utility of steady-state solutions for analyzing cross-species extrapolation and intraspecies variability.     

Becoming married, depression, and alcohol problems among young adults

This paper examines three questions regarding the relationship between marriage and mental health, specifically depression and alcohol problems. First, does marriage lead to improved mental health compared to never marrying? Second, do any mental health benefits of marriage primarily accrue to men? Third, what qualitative aspects of marriage are related to psychological disorder? We explore these questions in a longitudinal sample of young adults sampled at age 21 and again at age 24. We find no indication that marriage reduces depression. Married people do report fewer alcohol problems than the never-married but this could be due to the selection of less problematic drinkers into marriage. We also fail to find that men receive disproportionate mental health benefits from marriage. Finally, we find that marital conflict is associated with problem drinking for men and depression for women. The results indicate the importance of considering stage in the life cycle and gender-sensitive indicators of psychological disorder in studies of marriage and mental health.     

The use of the weighted likelihood in the natural exponential families with quadratic variance

The authors propose a weighted likelihood concept for the estimation of parameters in natural exponential families with quadratic variance. They apply the results to both simulated and real data.     

Frustrated Fertility: Infertility and Psychological Distress Among Women

Using a random sample of 580 Midwestern women, we test the hypothesis that women who have experienced infertility report higher psychological distress. Approximately one third of our sample reports having experienced infertility sometime in their lives, although the majority of the infertile now have biological children. Drawing hypotheses from identity and stress theories, we examine whether roles or resources condition the effects of infertility or whether its effects are limited to childless women. Infertility combined with involuntary childlessness (including biological and social) is associated with significantly greater distress. For women in this category, the risk of distress is substantial.     

Automatic Block-Length Selection for the Dependent Bootstrap

We review the different block bootstrap methods for time series, and present them in a unified framework. We then revisit a recent result of Lahiri [Lahiri, S. N. (1999b). Theoretical comparisons of block bootstrap methods, Ann. Statist. 27:386-404] comparing the different methods and give a corrected bound on their asymptotic relative efficiency; we also introduce a new notion of finite-sample “attainable” relative efficiency. Finally, based on the notion of spectral estimation via the flat-top lag-windows of Politis and Romano [Politis, D. N., Romano, J. P. (1995). Bias-corrected nonparametric spectral estimation. J. Time Series Anal. 16:67-103], we propose practically useful estimators of the optimal block size for the aforementioned block bootstrap methods. Our estimators are characterized by the fastest possible rate of convergence which is adaptive on the strength of the correlation of the time series as measured by the correlogram.     

Ethnic Identity Development Among Adolescents in Foster Care

Because past research indicates that stronger ethnic identity is related to better outcomes in areas such as academic achievement and mental health, it is important to provide youth in foster care with opportunities to develop their ethnic identity. Using data from in-person interviews with 188 youth aged 14–17 in foster care (88.7% response rate), this paper explores two areas related to ethnic identity: (1) youth perceptions about their own ethnic identity, and (2) attitudes about ethnic identity development specific to the experience of being in foster care. Results suggest that black youth and Hispanic/Latino youth have a stronger sense of ethnic identity than white youth. Most youth are interested in learning more about their ethnic background. Understanding how youth in foster care identify ethnically and understanding their beliefs related to ethnic identity may lead to the enhancement of services provided to youth across child welfare, education, and mental health systems.

Correlates of partner abuse in male same-sex relationships

We investigated correlates of partner abuse in male same-sex relationships in a randomly selected community sample (N = 186). We included factors associated with abuse in heterosexual relationships, as well as factors of relevance to gay relationships. We assessed perpetration and receipt of partner abuse to examine whether variables were associated independently with abuse perpetration and/or receipt. Correlates of same-sex partner abuse were largely parallel to established correlates of heterosexual abuse. Income, education, and attachment orientation were associated with bidirectional partner abuse, and family violence and substance use were uniquely associated with victimization. Further, there were factors unique to same-sex partner abuse; HIV status and public outness were associated with bidirectional partner abuse, and internalized homophobia was uniquely associated with abuse perpetration.