Harnessing the latest advances in toxicology for nanotechnology EH&S issues, the fundamentally novel rationale of ENPRA goes beyond traditional toxicity assessment of ENP and seeks to:

• identify the critical ENP physico-chemical characteristics responsible for the observed toxicity;
  
• investigate the cellular and molecular mechanisms underlying the observed association;
  
• develop systems, verifiable with in vivo experiments, which could be used as potential high throughput alternative toxicity tests;
  
• use a Structure-Activity method to facilitate such identification and use this to predict the hazard of new materials;
  
• extrapolate the results from in vitro to in vivo and to other relevant occupational or consumer situations;
  
• incorporate all possible data as weight-of-evidence for a risk assessment of ENP.

 ENPRA will develop and implement a novel, integrated approach for ENP Risk Assessment. This approach is based on the Exposure-Dose-Response Paradigm for ENP (see figure below). This paradigm states that exposure to ENP of different physico-chemical characteristics via inhalation, ingestion or dermal. Our exposure is likely to lead to their distribution, beyond the portal-of-entry organ to other body systems. The cumulative dose in a target organ will eventually lead to an adverse response in a dose-response manner approach will adapt the traditional Risk Assessment approach to ENP and will cover: Hazard Identification; Dose-Response Assessment; Exposure Assessment and Risk Assessment, Management.

Illustrating the Exposure-Dose-Response Paradigm:

The specific objectives of ENPRA in five areas are:

(i) Hazard Identification: Characterize a panel of commercially available ENP carefully chosen to address the relevant hazards, properties and potential mechanisms;

(ii) Dose-response Assessment: Assess the hazards of these ENP by means of in vitro toxicology tests based on:

• five body systems - pulmonary; hepatic; renal; cardio-vascular; and developmental systems;
  
• for five endpoints - oxidative stress; inflammation and immune-responses; genotoxicity; fibrogenecity; and developmental toxicity.

(iii) Verify the in vitro findings with validation tests

(iv) Exposure and Risk Assessment - Use data from this project and other sources to:

• Model exposure and the exposure-dose response relationships by means of mathematical modelling such as PBPK and QSAR-like methods, and extend these deterministic models into probabilistic models
  
• Conduct the risk assessment with uncertainty analysis;

(v) Risk Management: Develop and implement a strategy for dissemination to maximize the anticipated high impact of our findings.