Tim Varney, PhD, CIH, RS, CHMM & Bob DeMott, PhD, DABT ENVIRON International, Corp

1. Toxicological Dose, Effect and Non-Monotonic Responses Implications For I.H. Health Risk Assessment Tim Varney, PhD, CIH, RS, CHMM & Bob DeMott, PhD, DABT ENVIRON International, Corp

2. Course Objectives • Establishing key toxicological fundamentals • The concept of dose • Dose response • Influencing variables • Identifying individual/group differences • Advanced dose response concepts • Non-monotonic dose response • Implications for I.H. health risk assessment

3. Exposure ? The concentration of a substance and/or agent in air, water, soil, and/or food associated with ones occupational, home or ambient environment that may or may not result in intake, dose and response.

4. Dose ? The amount/volume of a substance and/or agent taken into the body per unit of time.

5. Effective/Target Dose? The amount/volume of a substance/agent that elicits an observed response and/or that which is associated within specific tissues/organs

6. Dose Response The outcome of intake associated with biological process/defense mechanisms that may have no measurable effect, beneficial effects or effects that may lead to increased morbidity and/or mortality.

7. Exposure does not always=dose It is an agent concentration in air, water, soil, food, etc. It can be acute, chronic, alternating in character Intake must occur before dosing is realized Dose may be a one time or recurring events Dose can be partitioned to whole body, target organ or tissue specific Exposure Versus Dose

8. Dose--------------------Response • Is measurable if concentration and intake of the agent are known • Is a fundamental concept in pharmacology, toxicology and health risk assessment • May originate from exposures to toxicants in air, water, soil, food, etc. • May be derived from animal models, direct measurements and/or exposure assessments • Is often expressed as mg/kg/day • Is central to I.H. health risk assessment

9. Toxicant Interactions That Modify Dose Response • Antagonism: antidotes to bacterial, reptilian or insect toxins/venoms • Potentiation: ethanol and barbiturates • Synergistic: cigarette smoking and coincidental exposures to asbestos and radon decay daughters

10. Factors That Drive Dose-Response & Host Variability • Toxicity • Persistence • Magnitude of the dose • Frequency and duration of intake • Route of exposure • Age • Functional status • Gender • Ethnicity • Other agents in the mix: intrinsic/extrinsic

11. Importance of Functional Status • Respiratory-FEV1, FVC, FEV1/FVC, CO2-02 gas exchange/saturation, mucosiliary clearance • Renal clearance time • Hepatic enzyme activity/levels • Cardiovascular/peripheral circulatory output/efficiency

12. Atypical or Unusual Dose Reactions • Overt Tolerance: may be innate or acquired • Idiosyncratic responses: outside the norm of what is expected or reported • Chemical allergy: “simple” immune response • Type I&II Hypersensitivity: immune system marshals a progressively pronounced response that can become life threatening

13. How Do These Impact Dose-Response Affect/Effect Skin on hands versus skin on head or back Alveolar insult and intake of PM2.5 versus PM10 Intake of Cr III versus Cr VI and latency Relative humidity and intake of formaldehyde Intake of lead at age <5 versus 35 years Lipid versus water solubility

14. Early & Late-Term Dose Responses • Dose response can be immediate: chlorine gas/RADS, bee sting/anaphylaxis, H2S/tissue hypoxia • Dose response can be late: extensive acid burns/renal failure, high levels of NO2/pulmonary edema, Amanita toxin/hepatic necrosis

15. Working With Surrogate I.H. Measures of Exposure/Dose • Job descriptions • Occupational exposure cohorts • Temporal Exposure cohorts • Spatial/geographical exposure cohorts • Ambient toxicant concentrations • Can be subject to marked variation and uncertainty

16. Important ! Exposure and dose will always have temporal and spatial components that can be highly variable and host/cohort specific…understand the exposure setting

17. Or Risk = toxicity x exposure Or Risk = toxicity x intake Risk = Dose

18. What Must be Known Before Dose Can be Determined • Agent & agent characteristics • Exposure concentration • Routes of exposure • Exposure frequency • Exposure duration • Body weight

19. Route of Exposure Is A Critical Dose Factor • Respiratory-DRIVERS? (300-1000 ft2) • Ingestion-DRIVERS? • Dermal-DRIVERS? (12-30 ft2) • Percutaneous-DRIVERS?

20. Computing Average Daily Particle Dose ADD=PM2.5 x INF x EF x ED ÷ BW x EAT Where: PM2.5 = particle concentration INF=inhalation intake factor-resp. rate EF=exposure frequency ED=exposure duration BW=body weight EAT=exposure averaging time

21. Computing Average Daily Vapor/Gas Dose ADD=Cx x INF X EF x ED ÷ BW x EAT Where: Cx=concentration of agent INF=inhalation intake factor EF=exposure frequency ED=exposure duration BW=body weight EAT=exposure averaging time

22. Computing Average DailyDermal Dose ADD=Cx x SSAE x EF x ED ÷ BW x EAT Where: Cx=concentration of agent SSAE=skin surface area exposed EF=exposure frequency ED=exposure duration BW=body weight AT=exposure averaging time

23. Body Burden and Dose Computation/Dose-Response 1.Toxicant burden fluctuates with time and functional status 2. Differential release from body tissue 3. Bone: long-term slow release 4. Adipose tissue: sensitive to change in body weight 5. Blood & Lymph: short lived but subject to releases from bone and adipose tissue 6. Interferes with estimations of dose 7. Complicates dose estimates and dose affect

24. A. D. M. E.---AD ME---ADME • A=adsorption and movement-skin, lungs & digestive tract • D=distribution via blood & lymph • M=metabolism/chemical alteration • E=excretion via lungs, skin, bladder intestines

25. The Myth of The Average 70kg Male And Importance of Left Tail Sensitivity

26. PELs, TLVs, MCLs and Dose • What are PELs, TLVs and MCLs • Are PELs,TLVs and MCLs dose values? • What must be done/known before dose can be accurately determined? • Are PEL,TLV and MCL levels universally protective? • How do occupational PEL/TLV values differ from MCLs

27. Importance of I.H. Exposure Monitoring • Accurate estimations of dose-response hinge on “good” exposure data • Exposure monitoring should be representative of the exposure setting • Exposure monitoring should address both spatial and temporal components • The methods of exposure monitoring should be consonant with practice guidelines

28. Biomedical Monitoring • Choosing the agent and/or metabolite to measure • Choosing the body tissue and/or fluid to sample/collect • Deciding on the time and number of samples • Pre/post shift sampling • Sampling after a weekend, holiday, vacation • Lifestyle choices that confound/modify dose response

29. Gold Standard Measures • Experimental animal models • Epidemiological Clinical trials • Controlled real-time exposure monitoring • Measurement of toxicants and/or their metabolites in tissue, body fluids or waste

30. Working With Markers of Dose Response/Effect • Adverse/potentially adverse/susceptibility • Original agent/toxicant-lead/lead • Metabolites-phenol/benzene • Conjugates-immune components • Adducts-antigen/antibody • Enzymes-SGOT/liver

31. Working With Causal Inference • Biological plausibility • Dose response trends • Temporality of exposure/response-exposure precedes effect • Specificity of the response • Can it be generalized to other exposure settings • Is it supported by a body of peer reviewed literature

32. Children Are Not Small Adults Implications For Dose/Effect • Developing immune & reproductive systems • Rates of intake for food and water greater on a body weight basis than adults • Air intake of infants twice that of adults • Rate and contribution of dermal exposure • Children play closer to sources of contamination • Subject to parental take-home contamination

33. But!What happens When Up Is Down and Down Is Up?

34. Break