Research Interests of the NCSU Center for Chemical Toxicology Research and Pharmacokinetics (CCTRP)
Percutaneous absorption of topically applied drugs and chemicals:
The CCTRP has had some 20 years experience in modeling the percutaneous absorption of drugs and chemicals across skin using in vitro and in vivo techniques. This work earned the Center the 1991 Ebert Prize from the American Pharmaceutical Association. Our unique expertise is focused on the development within our Center of the isolated perfused porcine skin flap model which has been used to accurately predict absorption in humans. We also conduct studies using in vitro porcine and human skin diffusion cells as well as in vivo pig studies and extensive QSAR models of dermal absorption. We recently conducted in vivo pig studies for Cellegy Pharmaceuticals in support of a new transdermal testosterone formulation which now is in Phase III human trials.
Mult-Walled Carbon Nanotubes Localized Within Human Epidermal Keratinocytes
Presently, there are minimal data available on the interaction between manufactured nanoparticles and biological tissues. The basic requirement for any risk assessment includes information on hazard (e.g. toxicity) and exposure (e.g. absorption). The CCTRP research interest will assess the nature of interaction between manufactured nanoparticles and the skin; including dermal absorption, cutaneous toxicity as well as the ability to distribute to the skin after systemic exposure. Current nanomaterial studies are supported by an EPA STAR grant and the National Academy of Sciences KECK Future Initiatives grant.
Dermal absorption and cutaneous toxicology of chemical mixtures:
We have instituted a research program some seven years ago designed to determine a rational basis for assessing chemical absorption from topically applied mixtures. Our approach, termed Mechanistically Defined Chemical Mixtures (MDCM) essentially is an attempt to classify components of a mixture on the basis of their ability to modulate the absorption of specific toxic chemicals of interest. This work has been funded from competitive extramural grants from NIEHS (pesticides), NIOSH (machine cutting fluids), EPA (contaminants), ATSDR (contaminants), as well as the U.S. Air Force (jet fuels) and Army Gulf War Illness initiatives (permethrin, pyridostigmine, DEET). As expected, mixture components do significantly affect absorption and invalidate the use of a single chemical exposure to predict absorption of that chemical in a mixture. Studies have also been conducted to develop non-invasive markers of irritation (e.g. cytokine release) which correlate to chemical- induced modulation of absorption. Finally, novel statistical approaches have been developed to assess these multi-component interactions (e.g. Compass plots with significance intervals) and to develop a simple but robust modeling approach which could be used to extrapolate these findings to in vivo human exposure.
Transdermal Drug Delivery:
Our Center has spent considerable efforts on investigating electrically-assisted transdermal drug delivery (iontophoresis, electroporation). These studies, funded by human pharmaceutical and drug delivery companies have resulted in 4 patents and numerous drugs presently in Phase II and III clinical trials. We have conclusively demonstrated the feasibility of transdermal peptide delivery and have published some of the only manuscripts assessing the toxicology of these novel drug delivery strategies.
Toxicology of military chemical vesicants:
The U.S. Army has continually funded researchers in our Center since the early 1980s to determine the mechanism of cutaneous vesication secondary to sulfur mustard and Lewisite topical exposure. These studies have demonstrated that a primary target of chemical vesicants are the molecules which compose the epidermal basement membrane. This has directly led to a different therapeutic approach to the treatment of chemical-induced vesicants.
Chemical Industry toxicology studies:
Under the auspices of the former Chemical Manufacturers Association’s chemical panels, we have studied the dermal absorption of alkyl phenols and decontamination strategies for topical phenol exposure.
Tissue residues and pharmacokinetics:
The CCTRP is a founding component of the Food Animal Residue Avoidance databank (FARAD) program which includes a global database of comparative pharmacokinetic data used to predict the tissue depletion of drugs and chemicals in food producing animals. We have patented a unique algorithm to extrapolate contaminant and extra-label drug used withdrawal times from available approved drug registrations coupled with pharmacokinetic data. This program has also supported studies to apply population pharmacokinetic techniques (mixed-effects modeling) to this arena. Its risk management component includes a national hotline (1-888-USFARAD) and website, which received permanent congressional authorization in 1999 and a federal line-item budget this year. Finally, this program has expanded internationally with Canada, China, France and the United Kingdom joining our consortium with the aim of producing a global compendium of drugs used in food production. This program is also in partnership with the Commonwealth Agriculture Bureau International (CABI) efforts to develop global information resources. The faculty of the CCTRP in this arena are also responsible for teaching all of the pharmacokinetic lectures and courses in the NCSU College of Veterinary Medicine professional and graduate programs.