class: center, middle, inverse, title-slide # Human Health Risk Assessment ## : A tutorial ### Arindam Basu ### 2021-09-19 --- --- # Human Health Risk Assessment <div id="htmlwidget-97265ece2899003bffd3" style="width:504px;height:504px;" class="DiagrammeR html-widget"></div> <script type="application/json" data-for="htmlwidget-97265ece2899003bffd3">{"x":{"diagram":"\n graph TD\n A[Hazard Identification]-->B[Exposure Assessment]\n A[Hazard Identification]-->C[Dose Response Assessment]\n B[Exposure Assessment]-->D[Risk Characterisation]\n C[Dose Response Relationship]-->D[Risk Characterisation]\n \n "},"evals":[],"jsHooks":[]}</script> --- # Step 1: Hazard Identification - Animal Experiments - Epidemiological Studies - Toxicokinetics and Toxicodynamics --- # Hazard Identification: Animal Experiments - Identify animals such as mammals similar to Humans - Expose the animals to the Toxins - Study the health outcomes --- # Hazard Identification: Advantages of animal experimental data - Direct observation - Animals can be close models of human diseases - Details of dosage can be studied - Mechanisms of action of the toxins can be studied --- # Hazard Identificaiton: Problems with experimental data - An animal cannot always be a reliable model - Human illnesses and health outcomes cannot be replicated - The dosage may not be relevant for humans --- # Hazard Identification: Epidemiological data - Observational epidemiological studies - Case control studies - Cohort studies - Ecological studies --- # Advantages of Epidemiological data - Direct relevance to humans - Can study those health effects that cannot be reproduced in animals - Relevant dose response assessments can be possible --- # Limitations of epidemiological data for hazard identification - Exposure assessment and determination of outcomes can be biased - The association between exposure and outcomes may not be causal - There are human to human variation in the effects - If a toxin exerts effect over many years (Arsenic, Asbestos): - Difficult to obtain exact estimates --- # Toxicokinetics and toxicodynamics based hazard identification - Using computer simulations - Physiology based toxicokinetic modelling (PBTK) - Based on understanding of physiology of the toxins - Warning: computer simulation may not be reliable --- # What data will you use for ascertaining hazard identification? - Animal experiments - Epidemiological studies - Toxicokinetic and toxicodynamic modelling - All three if available --- # Classification of Hazards - Whether the toxin can cause cancer of not - Does not cause cancer - Possible carcinogen - Probable carcinogen - Definite carcinogen --- # Step 2: Exposure Assessment - Direct measurement of the toxin in the environment - Environmental media: air, water, soil specimen, food - Directly obtain samples from the environmental media - Use tools to measure the toxins in the media collected - Use modelling to decide the amount of toxins humans are exposed --- # What to consider for exposure assessment? - Concentration of the toxin the environnmental media - How much of the media is consumed by humans in a day - The weight of the person - If the toxin exerts long term action over years, then: - 365 days/ year X number of years (usually at 70 years) --- # Formula for exposure assessment .middle[ $$ Exposure\ in\ mg/day = Concentration * Ingestion\ Rate/day / Body\ Weight $$ ] --- # Example of an Exposure Assessment Exercise Imagine we are investigating Arsenic toxicity in Town T found in the drinking water supplies. We conducted a measurement of inorganic Arsenic (InAs) in 500 samples of drinking water from T's water supplies. We found that average InAs concentration was 50 `\(\mu\)`g `\(/\)` L. We assumed each adult resident in T consumes about 2 litres of water everyday for drinking. We assume that drinking is the ONLY mode of exposure to InAs. We also assume that adults in T have an average 60 kg bodyweight What is the average exposure? --- # Calculation of Exposure - Average InAs concentration in drinking water: 50 `\(\mu\)`gm per litre - Average amount of water consumed: 2 litres per day - Therefore, total amount of InAs consumed per day: 50 times 2 = 100 `\(\mu\)`g per day - Adult's body weight: 60 kg - Therefore, **average exposure** = InAs consumed per day `\(/\)` Body Weight - This is: 100 `\(/\)` 60 = 1.6666667 `\(\mu\)`g/Kg/day - This is also equal to: 1666.6666667 mg/Kg/day --- # Step 3: Dose Response Assessment <div id="htmlwidget-fcc00e4b7ed94cb68d45" style="width:504px;height:504px;" class="DiagrammeR html-widget"></div> <script type="application/json" data-for="htmlwidget-fcc00e4b7ed94cb68d45">{"x":{"diagram":"\n graph TD\n A[Hazard Identification]-->B[Exposure Assessment]\n A[Hazard Identification]-->C[Dose Response Assessment]\n B[Exposure Assessment]-->D[Risk Assessment]\n C[Dose Response Relationship]-->D[Risk Assessment]\n \n "},"evals":[],"jsHooks":[]}</script> --- # What is dose response assessment - How much dose at cell levels will produce how much effect? - Expressed in units of mg/Kg/day for toxins that are solid, e.g. metals - Expressed in units of ml/Kg/day for gaseous or liquid toxins - Depends on whether the toxin can cause Cancer or Does not cause cancer --- # What factors to consider: - If the toxin is NOT cancerous, then: - Obtain No observed adverse effect level from animal studies - Obtain Lowest Observed adverse effect level from animal or human studies - If the toxin is known to cause cancer, then: - Obtain the SLOPE PARAMETER --- # Formula for Dose Response Effect - Calculate the Slope factor OR NOAEL OR LOAEL - Divide by Uncertainty factors (UF) - UF: in units of 10X - Consider uncertainty between animals to humans, and humans to humans - Derive reference dose leve - `\(Reference\ Dose (Rfd) = NOAEL / UF\)` - For gas/liquid: - `\(Reference\ Concentration (Rfc) = Slope\ Factor/UF\)` --- # Example of Rfd Inorganic Arsenic (InAs) causes skin diseases in humans and animals. Suppose in guinea pigs, we find that exposure to the dose of 3 mg/kg/day leads to skin diseases. Assume uncertainty factor for guinea pigs to humans is 100, and uncertainty factors for humans is 100. What is the Rfd for InAs? --- # Calculation of Rfd for InAs caused skin diseases - Dose for guinea pigs for skin diseease: 3 mg/Kg/day - Uncertainty factor (UF1) for guinea pigs to humans: 100 - Uncertainty factor (UF2) for humans to humans: 100 - `\(Rfd = Dose\ for\ guinea\ pigs / UF1 * UF2\)` - Rfd = `\(3 / 100 * 100 = 0.0003\)` mg/Kg/day --- # Internet sources for obtaining Dose Response Data - IRIS system - [https://iris.epa.gov/AtoZ/?list_type=alpha](https://iris.epa.gov/AtoZ/?list_type=alpha) - Lists almost all known toxins for which assessments are done - TERA system (comprehensive) - [https://tera.org/sseus/iternew/searchres.php?backfrchem=BACK](https://tera.org/sseus/iternew/searchres.php?backfrchem=BACK) --- # Step 4: Risk Characterisation - This is the final step - Combine Data from Exposure assessment and Dose Response Assessment - Derive Hazard Quotient (**HQ**) and Hazard Index (**HI**) - Formula for Hazard Quotient - `\(Hazard\ Quotient = Exposure\ Value / Rfd\)` - if `\(HQ>1\)`, then the toxin is hazardous for the health effect - if `\(HQ<1\)`, then the toxin can be monitored, no evidence for health effect --- # Risk Characterisation: Hazard Quotient and Hazard Index - Hazard Quotient for an individual toxin - Usually, we are exposed to many toxins through many pathways - Add the hazard quotients for each toxin for all sites - The sum of all hazard quotients is **Hazard Index** - If the Hazard Index is `\(>1\)`, then the toxin must be addressed --- # Risk Charaterisation: example Suppose we have conducted a risk assessment for InAs in Town T. We have assessed the exposure, and we found that people are exposed to 1667 mg/Kg/day of InAs. We also looked up dose response relationship in IRIS database, and we found that the Rfd was 0.0003 mg/kg/day of InAs What is the Hazard Quotient for residents in this case in Town T? --- # Worked out example of Risk Characterisation - Exposure: 1667 mg/Kg/day - Rfd: 0.0003 mg/Kg/day - HQ: `\(1667/0.0003 > 1\)` - InAs in this location of Town T **must be addressed!** --- # Summary - Human Health Risk Assessment has four steps - Hazard Identification - Exposure Assessment - Dose Response Assessment - Risk Characterisation ---