The Multistage Model with a Time-Dependent Dose Pattern: Applications to Carcinogenic Risk Assessment1

A cancer risk assessment methodology based upon the Armitage–Doll multistage model of cancer is applied to animal bioassay data. The method utilizes the exact time-dependent dose pattern used in a bioassay rather than some single measure of dose such as average dose rate or cumulative dose. The methodology can be used to predict risks from arbitrary exposure patterns including, for example, intermittent exposure and short-term exposure occurring at an arbitrary age. The methodology is illustrated by applying it to a National Cancer Institute bioassay of ethylene dibromide in which dose rates were modified several times during the course of the experiment.     

Estimates of the Number of Liver Carcinogens in Bioassays Conducted by the National Toxicology Program

Estimates were made of the numbers of liver carcinogens in 390 long-term bioassays conducted by the National Toxicology Program (NTP). These estimates were obtained from examination of the global pattern of p-values obtained from statistical tests applied to individual bioassays. Representative estimates of the number of liver carcinogens (90% confidence interval in parentheses) obtained in our analysis compared to NTP's determination are as follows: female rats—49 (23, 76), NTP = 30; male rats—88 (59, 116), NTP = 35; female mice—131 (105, 157), NTP = 81; male mice—100 (73, 126), NTP = 61; overall—166 (135, 197), NTP = 108. The estimator from which these estimates were obtained is biased low by an unknown amount. Consequently, this study provides persuasive evidence of the existence of more rodent liver carcinogens than were identified by the NTP.     

Uncertainties in Biologically-Based Modeling of Formaldehyde-Induced Respiratory Cancer Risk: Identification of Key Issues

In a series of articles and a health-risk assessment report, scientists at the CIIT Hamner Institutes developed a model (CIIT model) for estimating respiratory cancer risk due to inhaled formaldehyde within a conceptual framework incorporating extensive mechanistic information and advanced computational methods at the toxicokinetic and toxicodynamic levels. Several regulatory bodies have utilized predictions from this model; on the other hand, upon detailed evaluation the California EPA has decided against doing so. In this article, we study the CIIT model to identify key biological and statistical uncertainties that need careful evaluation if such two-stage clonal expansion models are to be used for extrapolation of cancer risk from animal bioassays to human exposure. Broadly, these issues pertain to the use and interpretation of experimental labeling index and tumor data, the evaluation and biological interpretation of estimated parameters, and uncertainties in model specification, in particular that of initiated cells. We also identify key uncertainties in the scale-up of the CIIT model to humans, focusing on assumptions underlying model parameters for cell replication rates and formaldehyde-induced mutation. We discuss uncertainties in identifying parameter values in the model used to estimate and extrapolate DNA protein cross-link levels. The authors of the CIIT modeling endeavor characterized their human risk estimates as "conservative in the face of modeling uncertainties." The uncertainties discussed in this article indicate that such a claim is premature.     

The Potential Effects of Recall Bias and Selection Bias on the Epidemiological Evidence for the Carcinogenicity of Glyphosate

Glyphosate is a widely used herbicide worldwide. The International Agency for Research on Cancer in 2015 declared that glyphosate is probably carcinogenic to humans, noting a positive association for non-Hodgkin lymphoma (NHL). The principal human data on glyphosate and NHL come from five case–control studies and two cohort studies. The case–control studies are at risk of recall bias resulting from information on exposure to pesticides being collected from cases and controls based on their memories. In addition, two of the case–control studies are additionally at risk of a form of selection bias that can exacerbate the effect of recall bias. Both biases are in the direction of making glyphosate appear carcinogenic. If odds ratios (ORs) are not biased and a pesticide plays no role in causing NHL, the probability that an OR for that pesticide is greater than 1.0 is approximately 0.5. The fractions of ORs for pesticides other than glyphosate that are greater than 1.0 in the case–control studies are 0.90 (n = 92), 0.90 (n = 152), 0.93 (n = 59), 0.76 (n = 140), and 0.53 (n = 54), the first two from studies that are at risk for both types of bias. In the two cohort studies, which are not subject to these biases, the comparable fractions for relative risks for all cancers are 0.51 (n = 70) and 0.48 (n = 158). These results comply closely with what would be expected if evidence for carcinogenicity of glyphosate in these studies results from statistical bias in the case–control studies.     

Partnering with parents to prevent childhood sexual abuse

Although research demonstrates that child‐focused sexual abuse prevention programmes can teach children personal safety knowledge and skills, childhood sexual abuse (CSA) prevention programmes that involve parents have a number of distinct advantages. The more knowledge parents have about CSA, the greater likelihood they can create safer environments for their children and thus prevent the occurrence of sexual exploitation. Research has demonstrated that parents lack crucial information about CSA and can benefit from even brief educational efforts. This paper will identify potential barriers to participation and offer practical suggestions for enhancing both recruitment and retention rates. Recommendations for parent education programmes are offered, including improving parents' confidence and skills in educating their children about CSA, providing them with parent‐friendly materials to use and developing Internet applications. Copyright © 2010 John Wiley & Sons, Ltd.     

Interpretative phenomenological analysis of young people's lived experiences of therapeutic residential care

Concerns of maltreatment and poor outcomes persist in residential care despite numerous government inquiries and recommendations. Young people in residential care continue to be the most vulnerable and marginalized group in the out‐of‐home care population. Young people's voices are also underrepresented in research. Existing studies predominantly focus on service evaluations in which individual voices of young people are overshadowed by adults' perspectives. Other studies examine the perspectives of young people in out‐of‐home care as a homogenous population, limiting understandings of the subjective experiences of young people in residential care. This study focused exclusively on young people's lived experiences in Australian therapeutic residential care, utilizing interpretative phenomenological analysis. The young people in this study revealed experiences of peer victimization, ambiguous loss and uncertainty during transitions. These findings suggest that more work is required in order to provide safe and healing environments and experiences for young people in therapeutic residential care. Each individual voice captured in this study offers valuable insights into how residential care practitioners can strengthen practice to enhance protection, engagement, connection with families and leaving care support.     

The Therapeutic Misconception: A Threat to Valid Parental Consent for Pediatric Neuroimaging Research

Neuroimaging research has brought major advances to child health and well-being. However, because of the vulnerabilities associated with neurological and developmental conditions, the parental need for hope, and the expectation of parents that new medical advances can benefit their child, pediatric neuroimaging research presents significant challenges to the general problem of consent in the context of research involving children. A particular challenge in this domain is created by the presence of therapeutic misconception on the part of parents and other key research stakeholders. This article reviews the concept of therapeutic misconception and its role in pediatric neuroimaging research. It argues that this misconception can compromise consent given by parents for the involvement of their children in research as healthy controls or as persons with neurological and developmental conditions. The article further contends that therapeutic misconception can undermine the research ethics review process for proposed and ongoing neuroimaging studies. Against this backdrop, the article concludes with recommendations for mitigating the effects of therapeutic misconception in pediatric neuroimaging research.