Age-specific absolute and relative organ weight distributions for Fischer 344 rats.

The Fischer 344 (F344) rat has been the standard rat strain used in toxicology studies conducted by the National Cancer Institute (NCI) and the National Toxicology Program (NTP). However, the numerous reports published to date on growth, survival, and tumor incidence have not included an overall compilation of organ weight data. Notably, dose-related organ weight effects are endpoints used by regulatory agencies to develop toxicity reference values (TRVs) for use in human health risk assessments.

The effect of study type on body weight and tumor incidence in B6C3F1 mice fed the NTP-2000 diet.

The B6C3F1 mouse is the standard mouse strain used in National Toxicology Program (NTP) carcinogenesis studies. Over time, increased liver tumorigenesis that was correlated with elevated body weights was noted in males and females. NTP therefore replaced the NIH-07 diet with the NTP-2000 diet and returned to group housing of females as lower body weights were noted in group housed mice.

Absolute and relative organ weight trends in B6C3F1 mice.

Since the early 1970s, the National Cancer Institute (NCI) and National Toxicology Program (NTP) have conducted carcinogenesis and toxicology studies on several hundred chemicals using the B6C3F1 mouse. A number of publications have examined growth, survival, and tumor incidence over time, including the impact of changes in housing and diet. However, no reports have been published to date examining the variation in organ weights over time, especially in light of reported body weight effects associated with housing and diet changes.

Age-specific absolute and relative organ weight distributions for B6C3F1 mice.

The B6C3F1 mouse is the standard mouse strain used in toxicology studies conducted by the National Cancer Institute (NCI) and the National Toxicology Program (NTP). While numerous reports have been published on growth, survival, and tumor incidence, no overall compilation of organ weight data is available. Importantly, organ weight change is an endpoint used by regulatory agencies to develop toxicity reference values (TRVs) for use in human health risk assessments.

Probabilistic dose-response modeling: case study using dichloromethane PBPK model results.

A revised assessment of dichloromethane (DCM) has recently been reported that examines the influence of human genetic polymorphisms on cancer risks using deterministic PBPK and dose-response modeling in the mouse combined with probabilistic PBPK modeling in humans. This assessment utilized Bayesian techniques to optimize kinetic variables in mice and humans with mean values from posterior distributions used in the deterministic modeling in the mouse. To supplement this research, a case study was undertaken to examine the potential impact of probabilistic rather than deterministic PBPK and dose-response modeling in mice on subsequent unit risk factor (URF) determinations.

Variability in physical constant parameter values from standard data sources and the implication of this variability for risk analysis.

Physical property values are used in environmental risk assessments to estimate media and risk-based concentrations. However, considerable variability has recently been reported with such values. To evaluate potential variability in physical parameter values supporting a variety of regulatory programs, eight data sources were chosen for evaluation, and chemicals appearing in at least four sources were selected.

Variability in physical constant parameter values from standard data sources and the implication of this variability for risk analysis.

Physical property values are used in environmental risk assessments to estimate media and risk-based concentrations. Recently, however, considerable variability has been reported with such values. To evaluate potential variability in physical parameter values supporting a variety of regulatory programs, eight data sources were chosen for evaluation, and chemicals appearing in at least four sources were selected.

Revised assessment of cancer risk to dichloromethane: part I Bayesian PBPK and dose-response modeling in mice.

The current USEPA cancer risk assessment for dichloromethane (DCM) is based on deterministic physiologically based pharmacokinetic (PBPK) modeling involving comparative metabolism of DCM by the GST pathway in the lung and liver of humans and mice. Recent advances in PBPK modeling include probabilistic methods and, in particular, Bayesian inference to quantitatively address variability and uncertainty separately. Although Bayesian analysis of human PBPK models has been published, no such efforts have been reported specifically addressing the mouse, apart from results included in the OSHA final rule on DCM.

Revised assessment of cancer risk to dichloromethane II. Application of probabilistic methods to cancer risk determinations.

An updated PBPK model of methylene chloride (DCM, dichloromethane) carcinogenicity in mice was recently published using Bayesian statistical methods (Marino et al., 2006). In this work, this model was applied to humans, as recommended by Sweeney et al.

Physiologically based pharmacokinetic modeling using microsoft excel and visual basic for applications.

Abstract Physiologically based pharmacokinetic (PBPK) models are mathematical descriptions depicting the relationship between external exposure and internal dose. These models have found great utility for interspecies extrapolation. However, specialized computer software packages, which are not widely distributed, have typically been used for model development and utilization.