1. Risk Assessment Typically decomposed into four steps: –Hazard Identification –Dose-Response Assessment –Exposure Assessment –Risk Characterization

4. Hazard Identification Determine the nature of the hazard: –Exposure pathways of concern, e.g. Ingestion Inhalation Dermal contact Puncture –Toxic endpoints, e.g. Lethal vs. non-lethal Chronic vs. Acute

5. Acute Toxicity Acute toxins result in observed endpoints after few exposures, in short timeframe For lethal endpoints, toxicity is a measure of the amount of exposure required to produce death –Example endpoints: chemical poisoning, radiation sickness

6. Chronic Toxicity Chronic toxins produce observed endpoints only after repeated exposures and/or considerable elapsed time Like acute toxicity, may be lethal or non- lethal Toxicity may be cumulative or not (e.g. mercury vs. carbon monoxide) –Example endpoints: cancer, birth defects

8. Measuring Toxicity Need measures of dose which causes toxic endpoint Measurements for ingested toxins ordinarily normalized for body weight (e.g. mg/kg) Must generalize from populations of experimental subjects For lethal endpoints can use LD 50

9. But LD 50 is limited!

10. e.g.: here A is always more toxic than B

11. but A can be less toxic than C, even with lower LD 50

12. Toxicology vs. Epidemiology Toxicology answers the wrong question well Epidemiology answers the right question poorly

13. Toxicology Controlled laboratory experimental conditions but Surrogate subjects (usually animals) Exaggerated doses

14. Extrapolating High to Low Dose Experimental studies produce minimum detectable responses on order of a percent Desire information on order of 10 -6 It ’ s virtually impossible to perform lab studies with N large enough (e.g. megarat)  We need a mathematical model to perform extrapolation

15. Designing Toxicology Experiments Selection of subject species Control design Multiple dose levels (at high levels to produce observable effect in relatively small number of subjects)

16. Epidemiology Human subjects Realistic doses but Uncontrolled experimental conditions

17. Dose-Response Assessment Relating Dose to (adverse) response “ Response ” typically described as a probability (unitless fraction or percent) Dose-Response Curve –Dose on the abscissa –Response on the ordinate –Intercept with abscissa is “ threshold dose ”

19. Potency Factors (a.k.a. Slope Factors) For chronic chemical toxicity (e.g. cancer), Potency Factor  slope of the low dose DR curve where Chronic Daily Intake (CDI) is measured in units of mg/kg/day

20. Potency Factors (cont ’ d) Re-arranging, Incremental Lifetime Cancer Risk = CDI  PF Potency Factors are available from EPA ’ s Integrated Risk Information System (IRIS): http://www.epa.gov/iris

22. Exposure Assessment Risk has two components: –Toxicity of the substance –Exposure of humans to substance Exposure often forgotten (see, for example, the Scientific American article comparing indoor pollution to outdoor pollution)article

23. Exposure Pathways The route by which a toxin or hazard reaches the human influences its impact Internal factors would include the human contact route (e.g. inhalation, ingestion, &c) External factors would include the physical transport (e.g. distance and travel time in air or water, &c)

24. Exposure Routes and Effects Principle routes for chemicals: –Ingestion –Dermal –Inhalation Other routes for hazard exposure: –Puncture –Eyes –Ears

25. Gastrointestinal Exposures Chemicals gain direct access to mucous membranes in stomach and intestines, allowing transfer of chemical to bloodstream Digestive processes can transform chemicals into others Physical hazard endpoints can apply (e.g. with ingested acids)

26. Dermal Exposure Epidermis consists of former living cells –Removed from blood vessels to some extent –Acts as barrier to loss of fluids and entry of contaminants Some materials are able to pass this barrier –Solvents which can be absorbed into the skin –Pores and hair follicles

27. Inhalation Rapid route of entry to bloodstream Alveoli designed to facilitate transfer of gases (oxygen and carbon dioxide) –Effectively transfer other materials too

28. Distribution of Toxicants Two factors govern transport: –Protein binding - Toxicants can bind to proteins in the blood, thus preventing their access to surrounding cells through capillary walls But access to kidneys (for removal) is also inhibited –Polarity - Polar toxicants obstructed by non-polar membranes Nonpolar toxicants dissolve through readily and can be stored in body fat

29. Metabolism Conversion of materials through reaction For toxicants, tendency is to increase polarization (and therefore reduce bio- uptake) In some cases chemicals can be converted into more toxic materials

30. Pollution Control in the Body Kidneys Liver

31. Kidney Function Blood flowing through kidneys is exposed to porous membrane –the (relatively) small molecules of toxins pass –substantial quantities of water also pass Aqueous solution passes along tubes which selectively retrieve desirable nutrients, water &c Concentrated aqueous toxins expelled as urine

32. Liver Function Metabolize toxicants into more polar structures Some substances removed from blood and transformed into bile, stored in gall bladder Gall bladder sends bile into small intestine to assist with digestion Toxins therefore eliminated with feces (unless resorbed by intestinal walls)

33. Lifetime Exposure where a 70-year lifetime is assumed

35. Risk Characterization Bring Dose-Response together with Exposure assessment to estimate risk

36. Example: Chloroform in Drinking Water Suppose your drinking water has 0.10 mg/L concentration of chloroform (CHCl 3 ) From IRIS, PF = 6.1x10 -3 (mg/kg/day) -1 So incremental lifetime cancer risk is

37. Chloroform Example (cont ’ d) In a city of 500,000 people:

38. General Exposure

39. Example: Occupational Exposure A 60 kg person works 5 days/week, 50 weeks/yr, for 25 years Each workday they breathe 20/3 m 3 of air containing 0.05 mg/m 3 of toxin

40. Example (cont ’ d) If the Potency Factor is 0.02 (mg/kg/day) -1 :

41. Non-carcinogenic Doses Metrics from toxicity experiments include –Lowest Observed Effect Level (LOEL) –Lowest Observed Adverse Effect Level (LOAEL) –No Observed Effect Level (NOEL) –No Observed Adverse Effect Level (NOAEL) Note: NOEL and NOAEL are the highest experimental doses at which no (adverse) effect was seen

42. Reference Dose The Reference Dose (RfD) is taken from the NOAEL: Where Uncertainty Factors are 10 each for differences across population using animal data to estimate human endpoints using only a single species of animal

44. Hazard Quotient Compares exposure to Reference Dose: HQ < 1 should be free of significant risk of toxicity

45. Hazard Index Considers multiple risks (e.g. from multiple chemical toxins) The sum of the Hazard Quotients:

46. Other Factors in Risk Characterization Also consider –Statistical uncertainties –Biological uncertainties –Selection of applicable dose-response and exposure data –Selection of population groups toward which the risk assessment should be targeted

47. Occupational Standards revisited The standards set by OSHA (and ACGIH and NIOSH) are based upon such risk assessment analyses

48. Occupational Standards: TWA The Time-Weighted Average (TWA) assumes an 8-hour day and 40-hour week

49. TWA Example So TWA = 120 ppm / 40 hours = 3 ppm

50. Occupational Standards: STEL Short Term Exposure Level Calculated as a 15-minute TWA Allowed no more than four such exposure periods per day, separated by at least 1 hour

51. Occupational Standards: Ceiling Concentration which must not be exceeded, regardless of duration of exposure.