Developmental Toxicology

Despite the tragic outcome of thalidomide exposure to pregnant women over 40 years ago, the mechanisms of action by which chemicals adversely affect limb and other types of development remain enigmatic. Using an in vitro model from embryonic chick tissue, EHS researchers identify chemicals that disrupt cartilage differentiation and examine the effects of chemicals on growth, proteoglycan content, apoptosis and gene expression.
Infectious agents can adversely affect the developing human fetus. For example, the pathogen Listeria monoctyogenes is responsible for an estimated 500 deaths in the United States each year of which 25% are stillbirths and spontaneous abortions. Using a primate model, EHS researchers identify the mechanisms by which infectious agents such as listeria result in low birth weight and other adverse pregnancy outcomes.

Toxicological Screening Methods

Valid, reliable, quick and inexpensive methods are needed to screen the hundreds of thousands of chemicals in commerce now and in the future for toxicological effects that could adversely affect human and ecological systems. The genome and the nervous system of the free-living soil nematode C. elegans has been extensively studied. EHS researchers have established a number of toxicological endpoints for C. elegans. A computer tracking system was developed that uses behaviors as an indicator for general toxicology and neurotoxicity. A computer program is also being used to automate other sub-lethal endpoints including growth and reproduction. The imaging system is automated and yields reliable results - two important attributes of screening methods. EHS researchers have also developed a soil bioassay based on C. elegans that was recently adopted by ASTM as a standard method for assessing risks of chemical contamination to soil dwelling organisms. Lastly, C. elegans is being used as a model of nematodes as vehicles for transporting pathogens within and among foods.

Aquatic Toxicology

Conventional and alternative aquatic test species are used by EHS researchers to screen natural waters and sediments for toxicity and to assess the efficacy of drinking water and wastewater treatment systems. The development of novel aquatic test species, such as juvenile mussels or glochidia, and methods is a significant emphasis of current research. Physiological, biochemical and histopathological assays (biomarkers) are used to investigate mechanisms of toxicity in fish and bivalves studied in laboratory, mesocosm and field studies. The effect of pharmaceuticals on aquatic organisms in surface waters is also an area of current emphasis. Goals for the future in this area of research are methods to assess effects of chronic exposure on freshwater organisms and nano-methods for biomarker assays.

Computational Toxicology

Mathematical and statistical methods are used to characterize toxicological data and to extrapolate that information to organisms of special concern such as humans. For example, physiologically based pharmacokinetic (PBPK) models are mathematical expressions used to gain insights into the dosimetry and mode of action for chemicals. PBPK models are used in route-to-route (inhalation to ingestion), between species (e.g., mouse to man), and high-to-low dose extrapolations and risk assessment. PBPK models are useful tools for estimation of internal dose and thereby interpreting information on external exposure and biological response. In PBPK models, the body is divided into compartments with blood flow to each compartment. Chemicals can be introduced into the body by several routes, then metabolized and excreted in breath, feces, and urine. The compartments and flows are described by a system of differential equations that is solved using mathematical modeling software. Current projects in computational toxicology include:

• A biologically based model for the pituitary-thyroid axis to predict chemical induced perturbations in homeostasis.
• Statistical models of epidemiological and laboratory dose-response data for pathogens and selected developmental outcomes.
• A PBPK model for chlorinated acid metabolites of trichloroethylene, a common groundwater contaminant in mice and humans.
• A PBPK model for binary mixtures of chlorinated solvents in the rat.