1. Overview Nanomaterials and Risk Assessment (Example: RA for Inhaled Nanoparticles and Inhaled Benzene) Michael A. Jayjock, PhD CIH The LifeLine Group and LINEA, Inc

2. Examples of Human Health Risk Assessment from Exposure to Two Different Substances Benzene: Component in gasoline, paints and lacquers, paint strippers, cleaning supplies, pesticides, building materials and furnishings, office equipment such as copiers and printers, correction fluids and carbonless copy paper, graphics and craft materials including glues and adhesives, permanent markers, and photographic solutions. http://www.epa.gov/iaq/voc.html http://www.epa.gov/iaq/voc.html Nanoparticles as a result of modern nanotechnology: Ultra- small particles used to impart special properties to materials. Examples, tennis racquets and cosmetics (facial spray), wax spray, leather sealant, etc. 800 product inventory http://www.nanotechproject.org/inventories/consumer/ http://www.nanotechproject.org/inventories/consumer/

3. Human Health Risk Assessment from Chemical Substances is pretty Simple and Straightforward on its Face Risk = f (exposure)(toxic effect/exposure) Risk = Exposure/Exposure Limit Risk > 1 unacceptable  Risk < 1 not unacceptable

4. The Essences of Human Health Risk Assessment from Chemicals Risk = f (exposure)(toxic effect/exposure) Note that the “toxic effect” in the above equation needs to be both identified as to type – a process called hazard identification and its potency for that effect (toxic effect/exposure) needs to be evaluated in a process known as the elucidation of its dose-response.

5. Dose – Response

6. Risk = Exposure/Exposure Limit In order to be compared in this equation, BOTH Exposure (measured or modeled) and Exposure Limits (derived from the dose-response relationship) must have the same units of measure. For example: Exposure Limits expressed as ppm v/v or mg/m 3 inhaled airborne concentration need to be presented as a time weighted average – Over 15 minutes – e.g., ACGIH Short Term Exposure Limit (TLV-STEL) – Over 8 hr Workday – e.g., ACGIH Time Weighted Average (TLV - TWA) – Over 24 hr – e.g., EPA Reference Concentration (RfC) – Over 0 hrs – e.g., Ceiling Limit (TLV-C)

7. ACTUAL Human inhalation Exposures are assessed by either measurement (air monitoring) or estimation (modeling) for these same time periods and then compared to the Exposure Limits. Remember: Risk = Exposure/Exposure Limit Risk > 1 unacceptable  Risk < 1 not unacceptable Exposure = fully half of the Risk Assessment

8. Estimated Exposure and their matching Exposure Limits used in Risk Assessment have different units for the various routes of human exposure considered: Inhalation: Air concentration (mass/volume) over a time period (as above) Mass inhaled per unit time (e.g. mg/day) – using (mass/volume)(inhaled volume per time) Mass inhaled per unit time and body weight (e.g. mg/kg/day) Dermal and Oral: Mass absorbed through the skin per unit time (e.g. mg/day) Mass absorbed through the skin per unit time and body weight (e.g., mg/kg/day Oral: Mass ingested and absorbed per unit time (e.g. mg/day) Mass ingested and absorbed per unit time and body weight (e.g. mg/kg/day)

9. Sometimes there are “portal effects” meaning that the agent will have a specific adverse health effect AT the point of entry into the body. Examples: Upper respiratory irritation from inhalation of acid mist or dermal sensitization from dermal contact. Route specific exposure limits need to take these into account. In the example of dermal sensitization the dose metric is mg/cm 2 of exposed skin since one can become sensitized and get a rash from exposure to this small area.

10. All of these measurements (e.g., ppm v/v, mg/cm 2 ) of exposure are called Exposure Metrics. Exposure Metric = a measureable or estimated property that is assumed to be associated with the identified adverse health effect caused by the agent of interest. It is considered to be the causative agent or at least a property that is highly correlated with the adverse health effect.

11. The Exposure Metric for benzene in today’s science is considered to be understood and pretty straight forward; namely, the weight of benzene that goes into the body per unit time and body weight by the various routes of exposure. Risk Assessment becomes simply means measuring exposure (mg/kg/day) and comparing that exposure to the dose-response curve or the exposure limits expressed in the same units. Exposure Metrics for nanoparticles are not nearly as straightforward or well understood.

12. Hazard Identification for Exposure Metric Hazard Identification for Benzene: Human anemia and leukemia. Hazard Identification for Nanoparticles: So far, pulmonary inflammation with possible fibrogenic and carcinogenic outcomes (portal effect in lung)

13. Possible Exposure Metrics for Nanoparticulate Mass of particles per unit volume inhaled per day: mg/day Surface area of particles inhaled per day : m 2 /day Number of particles inhaled per day: #/day Note: Actual exposure limit(s) will most likely depend on specific reactivity of the chemical type of particle.

14. Remember our simple equation: Risk = Exposure/Exposure Limit Benzene is pretty straightforward – Exposure is mostly from inhalation and dermal – Exposure limits are pretty well established My conclusion: We have quite a way to go to understand the risk of nanoparticles