Use of a Physiologically Based Pharmacokinetic Model for Rats to Study the Influence of Body Fat Mass and Induction of CYP1A2 on the Pharmacokinetics of TCDD

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly lipophilic chemical that distributes into adipose tissue, especially at low doses. However, at high doses TCDD sequesters in liver because it induces cytochrome P450 1A2 (CYP1A2) that binds TCDD. A physiologically based pharmacokinetic (PBPK) model was developed that included an inducible elimination rate of TCDD in the Sprague-Dawley rat. Objectives of this work were to characterize the influence of induction of CYP1A2 and adipose tissue mass fraction on the terminal elimination half-life (t(1/2)) of TCDD using this PBPK model. When the model assumes a fixed elimination of TCDD, t(1/2) increases with dose, due to hepatic sequestration. Because experimental data indicate that the t(1/2) of TCDD decreases with dose, the model was modified to include an inducible elimination rate. The PBPK model was then used to compare the t(1/2) after an increase of adipose tissue mass fraction from 6.9 to 70%. The model suggests that at low exposures, increasing adipose tissue mass increases the terminal t(1/2). However, at higher exposures, as CYP1A2 is induced, the relationship between adipose tissue mass and t(1/2) reaches a plateau. This demonstrates that an inducible elimination rate is needed in a PBPK model in order to describe the pharmacokinetics of TCDD. At low exposures these models are more sensitive to parameters related to partitioning into adipose tissue

Adjusting a cancer mortality-prediction model for disease status-related eligibility criteria

<p>Abstract</p> <p>Background</p> <p>Volunteering participants in disease studies tend to be healthier than the general population partially due to specific enrollment criteria. Using modeling to accurately predict outcomes of cohort studies enrolling volunteers requires adjusting for the bias introduced in this way. Here we propose a new method to account for the effect of a specific form of healthy volunteer bias resulting from imposing disease status-related eligibility criteria, on disease-specific mortality, by explicitly modeling the length of the time interval between the moment when the subject becomes ineligible for the study, and the outcome.</p> <p>Methods</p> <p>Using survival time data from 1190 newly diagnosed lung cancer patients at MD Anderson Cancer Center, we model the time from clinical lung cancer diagnosis to death using an exponential distribution to approximate the length of this interval for a study where lung cancer death serves as the outcome. Incorporating this interval into our previously developed lung cancer risk model, we adjust for the effect of disease status-related eligibility criteria in predicting the number of lung cancer deaths in the control arm of CARET. The effect of the adjustment using the MD Anderson-derived approximation is compared to that based on SEER data.</p> <p>Results</p> <p>Using the adjustment developed in conjunction with our existing lung cancer model, we are able to accurately predict the number of lung cancer deaths observed in the control arm of CARET.</p> <p>Conclusions</p> <p>The resulting adjustment was accurate in predicting the lower rates of disease observed in the early years while still maintaining reasonable prediction ability in the later years of the trial. This method could be used to adjust for, or predict the duration and relative effect of any possible biases related to disease-specific eligibility criteria in modeling studies of volunteer-based cohorts.</p

Population-Based Precision Cancer Screening: A Symposium on Evidence, Epidemiology, and Next Steps

Precision medicine, an emerging approach for disease treatment that takes into account individual variability in genes, environment, and lifestyle, is under consideration for preventive interventions, including cancer screening. On September 29, 2015, the National Cancer Institute sponsored a symposium entitled “Precision Cancer Screening in the General Population: Evidence, Epidemiology, and Next Steps”. The goal was two-fold: to share current information on the evidence, practices, and challenges surrounding precision screening for breast, cervical, colorectal, lung, and prostate cancers, and to allow for in-depth discussion among experts in relevant fields regarding how epidemiology and other population sciences can be used to generate evidence to inform precision screening strategies. Attendees concluded that the strength of evidence for efficacy and effectiveness of precision strategies varies by cancer site, that no one research strategy or methodology would be able or appropriate to address the many knowledge gaps in precision screening, and that issues surrounding implementation must be researched as well. Additional discussion needs to occur to identify the high priority research areas in precision cancer screening for pertinent organs and to gather the necessary evidence to determine whether further implementation of precision cancer screening strategies in the general population would be feasible and beneficial

Number and Size Distribution of Colorectal Adenomas under the Multistage Clonal Expansion Model of Cancer

Colorectal cancer (CRC) is believed to arise from mutant stem cells in colonic crypts that undergo a well-characterized progression involving benign adenoma, the precursor to invasive carcinoma. Although a number of (epi)genetic events have been identified as drivers of this process, little is known about the dynamics involved in the stage-wise progression from the first appearance of an adenoma to its ultimate conversion to malignant cancer. By the time adenomas become endoscopically detectable (i.e., are in the range of 1–2 mm in diameter), adenomas are already comprised of hundreds of thousands of cells and may have been in existence for several years if not decades. Thus, a large fraction of adenomas may actually remain undetected during endoscopic screening and, at least in principle, could give rise to cancer before they are detected. It is therefore of importance to establish what fraction of adenomas is detectable, both as a function of when the colon is screened for neoplasia and as a function of the achievable detection limit. To this end, we have derived mathematical expressions for the detectable adenoma number and size distributions based on a recently developed stochastic model of CRC. Our results and illustrations using these expressions suggest (1) that screening efficacy is critically dependent on the detection threshold and implicit knowledge of the relevant stem cell fraction in adenomas, (2) that a large fraction of non-extinct adenomas remains likely undetected assuming plausible detection thresholds and cell division rates, and (3), under a realistic description of adenoma initiation, growth and progression to CRC, the empirical prevalence of adenomas is likely inflated with lesions that are not on the pathway to cancer

The University of Michigan Dioxin Exposure Study: Methods for an Environmental Exposure Study of Polychlorinated Dioxins, Furans, and Biphenyls

Background: The University of Michigan Dioxin Exposure Study (UMDES) was undertaken in response to concerns that the discharge of dioxin-like compounds from the Dow Chemical Company facilities in Midland, Michigan, resulted in contamination of soils in the Tittabawassee River floodplain and areas of the city of Midland, leading to an increase in residents’ body burdens of polychlorinated dibenzodioxins and polychlorinated dibenzofurans. Objectives: The UMDES is a hypothesis-driven study designed to answer important questions about human exposure to dioxins in the environment of Midland, where the Dow Chemical Company has operated for \u3e 100 years, and in neighboring Saginaw, Michigan. In addition, the UMDES includes a referent population from an area of Michigan in which there are no unusual sources of dioxin exposure and from which inferences regarding the general Michigan population can be derived. A central goal of the study is to determine which factors explain variation in serum dioxin levels and to quantify how much variation each factor explains. Conclusions: In this article we describe the study design and methods for a large population-based study of dioxin contamination and its relationship to blood dioxin levels. The study collected questionnaire, blood, dust, and soil samples on 731 people. This study provides a foundation for understanding the exposure pathways by which dioxins in soils, sediments, fish and game, and homegrown produce lead to increased body burdens of these compounds

SAVVY Vaginal Gel (C31G) for Prevention of HIV Infection: A Randomized Controlled Trial in Nigeria

The objective of this trial was to determine the effectiveness of 1.0% C31G (SAVVY) in preventing male-to-female vaginal transmission of HIV infection among women at high risk.This was a Phase 3, double-blind, randomized, placebo-controlled trial. Participants made up to 12 monthly follow-up visits for HIV testing, adverse event reporting, and study product supply. The study was conducted between September 2004 and December 2006 in Lagos and Ibadan, Nigeria, where we enrolled 2153 HIV-negative women at high risk of HIV infection. Participants were randomized 1 ratio 1 to SAVVY or placebo. The effectiveness endpoint was incidence of HIV infection as indicated by detection of HIV antibodies in oral mucosal transudate (rapid test) or blood (ELISA), and confirmed by Western blot or PCR testing. We observed 33 seroconversions (21 in the SAVVY group, 12 in the placebo group). The Kaplan-Meier estimates of the cumulative probability of HIV infection at 12 months were 0.028 in the SAVVY group and 0.015 in the placebo group (2-sided p-value for the log-rank test of treatment effect 0.121). The point estimate of the hazard ratio was 1.7 for SAVVY versus placebo (95% confidence interval 0.9, 3.5). Because of lower-than-expected HIV incidence, we did not observe the required number of HIV infections (66) for adequate power to detect an effect of SAVVY. Follow-up frequencies of adverse events, reproductive tract adverse events, abnormal pelvic examination findings, chlamydial infections and vaginal infections were similar in the study arms. No serious adverse event was attributable to SAVVY use.SAVVY did not reduce the incidence of HIV infection. Although the hazard ratio was higher in the SAVVY than the placebo group, we cannot conclude that there was a harmful treatment effect of SAVVY