Lecture 2Outline of Last LectureI.II. Processes for Toxicity Development (4 Steps)III. Step 1: Delivery of ToxicantIV. Step 2: Reaction of Toxicant with Target MoleculeV. Step 3: Cellular Dysfunction and ToxicitiesVI. Step 4: Repair or DysrepairVII.SummaryOutline of Current Lecture I. Introduction II. DefinitionsIII. Processes (4 Steps of Risk Assessment)IV. Step 1: Hazard IdentificationV. Step 2: Dose-Response AssessmentVI. Step 3: Exposure AssessmentVII. Toxicity TestingCurrent LectureI. Introductiona. Remember: toxin/poison is dependent on the dosei. No chemical either occurring naturally or manufactured is completely free from toxic effectb. Risk Analysis: the overall term for all of Risk Sciencei. Has four elements:1. Risk Assessment (Risk Evaluation)2. Risk Communicationa. When disaster occurs, you need lots of communication between the government agency, the residents of the disaster area, the local government, and possibly the EPA (Environmental Protection Agency)3. Risk Perceptiona. The way in which we see risk and determine its importancePHARM 5509 1st Editioni. Involving humans means that risk analysis can depend on the perception of the risk1. Individual, age, or population difference2. Culturereflection3. Time and information availabilitya. i.e.: rumors after the disaster may cause people’s perception of risk to be changed over time depending on availability of information4. Scientificdiscovery: acceptable or rejecteda. Need toxicologists to do studies to collect correct information in order to let the publicknow the truthi. Daniel Defoe: (over 300 years ago) “The fear of danger is 10,000 times more terrifying than danger itself”—can significantly influence the decision making and the risk management4. Risk Management (Risk Characterization by EPA)ii. National Research Council (NRC) and the Red Book1. Everything is based on the Red Booka. Not just from the NRC but also includes other top sources of research:i. NAS: National Academy of Scienceii. NAE: National Academy of Engineeringiii. IOM: Institute of MedicineII. Definitions NOTE: generally not for memorization but for understanding of terminologya. Risk: the probability of adverse outcome under specified conditionsi. Adverse outcomes: harmful events (including: death, injury, or loss)ii. Specified conditions: exposure to a chemical or physical agent in manufacturinguse, or disposal process1. under specified conditions, you may or may not be exposed to the chemical that can lead to the toxic outcomesb. RiskAssessment: identification and quantification of risk resulting from human exposure to hazardous agents or situationi. EPA definition: scientific evaluation of the probability of harm resulting exposure to toxic substancesc. Risk Management: decision-making process to select the optimal steps for reducing a risk to an acceptable leveli. Any chemical can have an adverse effect and can cause cytotoxicity which makes it necessary to balance the benefits of taking the drug with the adverse effectsii. Factors for consideration:1. Political, social, economic (all three because the industry is critical for thelocal economy), science/engineering (reduce the risk, clean the land and improve air pollution)2. Develop, analyze and compare options,and select the optimal response for safety from a potential hazarda. The goal is to reduce the risk to an acceptable level (try to find theultimate steps to help the situation—optimal response strategies/methodologies)iii. Risk Management Framework: see corresponding flow chart in lecture slides (Slide 7)1. When considering options to clean up the problem: want to reduce the potential risk to exposure to chemicals/toxins2. Evaluation of the final outcome: have you really fixed the problem or are there potentially still some long term toxic outcomes?3. NRC: remember that they published the Red Book4. US Commission on Risk Assessment & Risk Managementa. US Commission (federal government): Presidential & Congressional Commission on Risk Assessment & Risk Managementi. Instead, this is sometimes called the Omenn Commission (previous chairmen was named Gilbert Omenn: professor from the University of Michigan)III. Processes (4 Steps of Risk Assessment)a. Risk Assessment:i. Objectives:1. Balance risks and benefitsa. Drugs and pesticides: drugs and pesticides already have known adverse effects but are things that are being used for beneficial reasons (need to be able to have a balance)2. Set target levels of riska. Food contaminants and water pollutants: for contamination in food and water we need to set the standardi. What is the acceptable daily intake level?ii. What is the tolerable daily impact?3. Set priority for program activities: prioritize the tasks/events for various organizations—different organizations have different priorities/different focusa. Regulatory Agenciesb. Manufacturersc. Environmental/Consumer Organizations4. Estimate residual risks and extend of risk reduction afterstepsare taken to reduce risksa. Remember that it is also important to consider long term effects!ii. Quantification in Risk Assessment:1. Elements, factors, or components:a. Dose-response: critical effectsi. Need to find a dose-response (especially that for critical effects)b. Exposure: quantify the exposurec. Susceptibility variationi. Know different age, gender, ethnicity, etc. of the exposed population in order to determine variability in susceptibility d. Uncertainly characterizationiii. The 4-Step Risk Assessment Process:1. Hazard Identification: what adverse effects are caused by the agent?2. Dose-Response Assessment: what is the relationship between dose and response?a. Important component for the laboratory based toxicological assessmenti. Important because chemicals may be unknown chemicals3. Exposure Assessment: what types, levels, and duration of exposure are experienced or anticipated?a. Important for thinking about the population for the area if anything were to happeni. Particularly when thinking about toxicity in the land/soil (partially the responsibility of the EPA)4. Risk Characterization: what is the extra risk of health problems in the exposed population?a. Can apply to future problems that may be anticipatediv. Risk Assessment/Risk Management Framework1. See corresponding flow chart in lecture slides (Slide 14)a. In order to be able to go through risk assessment, there are research needsb. Once you’ve been able to do a risk assessment, then you can set up agencies and