1. Sponsor Organization: NAVAL MEDICAL RESEARCH INSTITUTE DETACHMENT (TOXICOLOGY)

2. Project Title: MOLECULAR APPROACHES TO TOXICITY BY TMPP.

3. Project Focus:

• Project Primary Focus: Exposure Assessment
• Project Secondary Focus:

4. Description:

Molecular approaches have attained a central position in modern experimental andhuman toxicology by providing the means to study basic underlying mechanisms. Molecular methods can be used to identify casual associations that would otherwise beobscure and to make better quantitative estimates of these associations at relevantlevels of exposure. The use of molecular approaches in toxicology should thus result inbetter estimates of risks to human heath. Toxic effects of endocrine disruptors can bedivided into two main classes on the basis of the mechanism of disease causation andreversibility of effects: traditional deterministic toxicity and stochastic toxicity.Deterministic toxicity overwhelms the body's compensatory processes, therebyexceeding the toxicity threshold and leading to pathological effects; the effects arehowever reversible, up to the late stages of the disease process. Toxic effects thatarise from stochastic process have no clear threshold for toxicity, so that exposure tolow doses of an agent over prolonged periods can give rise to serious effects that arenot necessarily related to the level of exposure. Stochastic effects are irreversible orpoorly reversible when low doses are given in the early stages of the disease. Most (ifnot all) molecular effects are stochastic; they occur as a result of a small number ofirreversible changes in the information coded in DNA, resulting in mutagenesis,carcinogenesis and teratogenesis. Risk assessment is ultimately based on aquantitative estimate of the dose of the toxicologically relevant metabolite(s) that isdelivered to target tissues. A new form of dosimetry is increasingly being attempted thatis based on the analysis of the products of chemicals with macromolecules in vivo. Ourstudies include the measurement of DNA adducts from the target tissues by (1)fluorescence spectroscopy, (2) the use of monoclonal and polyclonal antibodies, (3)32P- labeling followed by HPLC separation. Hemoglobin adducts in the exposedanimals will also be carried out, since there is increasing acceptance that hemoglobinadducts are a relevant dosimeter of the exposed population.

5. References:

6. Inventory Category:

• Primary: Measure
• Secondary:

7. Inventory Subcategory:

• Primary: Exposure and Risk Models
• Secondary:

8. Keywords for Experimental System/Species:

• Species:
• Study Type:
  • In Vitro
• Fate and Transport:

9. Keywords for Experimental Endpoints:

• Health Effect:
  • Carcinogenesis
• Hormonal Measures:
• Level Of Study:
• Chemistry Metabolism:
• Life Stage:
• Risk Assessment:

10. Chemical Agents:

• Alkylphenols

11. Performing Institution:

• Naval Medical Research Institute Detachment (Toxicology); 2612 Fifth Street, AreaB, Building 433; Wright-Patterson AFB, Ohio 45433-7903

12. Contact:

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