Thomas A. Lewandowski

A computational model for neocortical neuronogenesis predicts ethanol-induced neocortical neuron number deficits.

We have developed a computational model that allows for the evaluation of normal and perturbed neurodevelopmental processes. This mathematical construct is used to test the hypothesis that reduced neuronal production is the critical mechanism behind fetal alcohol syndrome. Model predictions of normal neurodevelopment match independent stereological measures but challenge estimates generated using a previously published model of normal neocortical neuronogenesis. Evaluation of data showing an increased cell cycle length after prenatal exposure to ethanol during neocortical neuronogenesis yields predictions of cellular deficits that can account for the permanent neocortical neuronal loss seen in rodents exposed to ethanol concentrations of public health relevance.

Administrative Censoring in Ecological Analyses of Autism and a Bayesian Solution

Widely cited ecological analyses of autism have reported associations with mercury emissions, with precipitation, and race at the level of counties or school districts. However, state educational agencies often suppress any low numerical autism counts before releasing data—a phenomenon known as “administrative censoring.” Previous analyses did not describe appropriate methods for censored data analysis; common substitution or exclusion methods are known to introduce bias and produce artificially narrow confidence intervals. We apply a Bayesian censored random effects Poisson model to reanalyze associations between 2001 Toxic Release Inventory reported mercury emissions and 2000-2001 autism counts in Texas. Relative risk estimates for autism decreased from 4.44 (95% CI: 4.16, 4.74) per thousand lbs. of air mercury emissions using a naive zero-substitution approach to 1.42 (95% CI: 1.09, 1.78) using the Bayesian approach. Inadequate attention to censoring poses a serious threat to the validity of ecological analyses of autism and other health outcomes.

A comparison of 1H8-and 2H8-toluene toxicokinetics in men

1. To examine the bioequivalence of an isotope-labelled tracer to study toxicant disposition, we conducted 33 controlled human exposures to a mixture of 50 ppm 1H8-toluene and 50 ppm 2H8-toluene for 2 h, and measured concentrations in blood and breath, and metabolite levels in urine for 100 h post-exposure. 2. A physiologically based kinetic (PBK) model found that compared with 1H8-toluene, 2H8-toluene had a 6.4+/-13% (mean+/-SD) lower AUC, a 6.5+/-13% higher systemic clearance (1.46+/-0.27 versus 1.38+/-0.25 l/h-kg), a 17+/-22% larger terminal volume of distribution (66.4+/-14 versus 57.2+/-10 l/kg) and a 9.7+/-26% longer terminal half-life (38+/-12 versus 34+/-10 h) (p < 0.05 for all comparisons). 3. The higher 2H8-toluene clearance may have been due to an increased rate of ring oxidation, consistent with the 17% higher observed fraction of 2H5- versus 1H5-cresol metabolites in urine. 4. The larger terminal volume and half-lives for 2H8-toluene suggested a higher adipose tissue/blood partition coefficient. 5. Observed isotope differences were small compared with interindividual differences in 1H8-toluene kinetics from previous studies. 6. The PBK model allowed us to ascribe observed isotope differences in solvent toxicokinetics to underlying physiologic mechanisms.

Modeling developmental processes in animals: applications in neurodevelopmental toxicology

Biologically based dose-response models can provide a framework for incorporating mechanistic information into our assessments of neurotoxicity considering both kinetic and dynamic processes. We have constructed models for normal midbrain and neocortex development and we have extended these models to evaluate the neurodevelopmental toxicity of ethanol and methyl mercury. Using such modeling approaches, we have been able to test hypothesized modes of action for these neurodevelopmental toxicants. Specifically, we have compared ethanols effects on neocortical neurogenesis and exacerbation of apoptosis during the synaptogenesis period. We have used methylmercury as an example of how one can link toxicokinetic and toxicodynamic models and also as an example of how mechanistic data on gene expression can support model development. In summary, using examples from our research group, this paper illustrates the need for models that evaluate both qualitative and quantitative kinetic and dynamic factors in order to understand the potential impacts of neurodevelopmental toxicants.

Estimation of Background Exposure to Toluene Using a Physiologically-Based Kinetic Model

Estimation of Background Exposure to Toluene Using a Physiologically‐Based Kinetic Model: Crispin H. Pierce, et al. Department of Environmental Health, University of Washington—Estimation of environmental exposure to toxicants has generally been limited to concentration measurements in air, water, and foods. Measurement of background levels of toxicants in biological tissues for this purpose has been limited by analytical detection. After developing a sensitive headspace GC‐MS method, we conducted 33 controlled human exposures of 50 ppm 1Hg8‐toluene and 50 ppm 2H8‐toluene for 2 h, and measured concentrations in blood and breath for 100 h post‐exposure. Blood and breath samples from a separate cohort of 9 men exposed to 2H8‐toluene only were also measured for background 1H ‐toluene levels. A physiologically‐based kinetic (PBK) model, previously constructed and validated in an analysis of the 2H8‐toluene data, was used to predict the level of ambient 1H8‐toluene exposure that produced the observed breath levels. The model‐derived estimate of mean background 1H8‐toluene exposure was 47 ± 44 ppb (mean ± s.d.), which is consistent with indoor air measurements from this and previous studies of 3‐27 ppb and outdoor measurements of 2‐43 ppb. According to the PBK model, background exposure was expected to produce an average blood concentration of 5.9 nmol/l, which was within a measured range of 3‐16 nmol/l, and a corresponding alveolar air concentration of 310 nmol/m3, within a range of 138‐764 nmol/m3. This work extends the use of physiologic modeling to back‐predict environmental dose, and found that significant differences in inter‐individual 1H8‐toluene background exposures exist.