1. DOSE-RESPONSE ASSESSMENT
TOPIC 5:
DOSE-RESPONSE ASSESSMENT

2. OVERVIEW Dose and Dose – Response Threshold vs Non-threshold
Safety Factors
Basic Dose Equation
Abbot’s Correction and Poisson Table
DTSC’s PEA Risk Equations

3. DOSE – RESPONSE ASSESSMENT
Dose – response refers to a correlation between a quantified exposure and the percentage of a population that demonstrates a specific effect
Fundamental basis of the quantitative relationship between exposure to an agent and the incidence of an adverse response
The dose – response assessment is the step in the risk assessment in which the dose of an agent is evaluated against a certain endpoint

4. EXTRAPOLATION
Extrapolation = an educated guess based on observable responses and a mathematical model
Mathematical model is used to predict response levels that cannot be directly observed
All dose – response models represent extrapolation
Dose – response assessment must make assumptions
These assumptions must be included in assessment
For example,
Assume that the dose assessment will not underestimate the risk
Assume mechanism for test group and risk group are the same

5. CATEGORIES OF DOSE – RESPONSE MODELS
Chemical Kinetics Model = probability of response is related to the rate of chemical reactions in the body
Model Free Approaches = mathematical construct not based on any biological model of response
Threshold Models = aka. “tolerance distribution model”
“Threshold” is the fundamental basis
Suggests a safe dose for all substances

6. DOSE – RESPONSE RELATIONSHIP
Starts with the determination of the critical effects to be evaluated
EPA has issued toxicity specific guidelines for identifying critical effects such as cancer, developmental toxicity, neurotoxicity, etc.
Critical Adverse Health Effect = the significant adverse biological effect that occurs at the lowest exposure level
Threshold dose – response = reference dose
Non-threshold dose - response = cancer slope factor

7. THRESHOLD DOSE
Reference dose is based on the assumption of a threshold
Threshold = concentration of a substance (or dose) below which there is no harmful effect
Threshold Dose = minimum application of a given substance required to produce an observable effect
NOEL, NOAEL, LOAEL, *LD50, *LC50

8. THRESHOLD DOSE LEVELS NOEL = No Observed Effect Level
Dose in which there is no effect observed
No changes in any response
There is a suggestion that this is a “safe” level
NOAEL = No Observed Adverse Effect Level
Dose in which there may be detected changes
None of the changes are deemed “adverse”
LOAEL = Lowest Observed Adverse Effect Level
Dose in which adverse effects have been detected
Includes data / testing that show a statistical difference between test and control groups

10. THRESHOLD DOSE LEVELS
Generally chose the highest NOEL or NOAEL since this stretches the limit of a dose with no effect
If no NOEL or NOAEL, choose the lowest LOAEL
Used to calculate reference dose of a substance
Safety Factor = aka uncertainty factors; attempts to account for the differences between test group (rats) and the risk group (humans)

11. SAFETY / UNCERTAINTY FACTORS
Generally set at 10 (one order of magnitude)
Not exact but tries to adjust for any uncertainty, such as:
Intra-species variation
Synergism
Alternate route of exposure
Matching control, test and / or risk groups
Latency adjustments
Quality of study

12. USING NOAEL’s
Served as basis for risk assessment calculations for reference doses, reference concentrations, or acceptable daily intake values
Reference dose (RfD) = daily dose with no significant risk over a lifetime
Reference concentration (RfC) = same as RfD for air
Acceptable Daily Intake (ADI) = used by World Health Organization (WHO) for pesticides and food additives to define “the daily intake of a chemical, which during an entire lifetime appears to be without appreciable risk on the basis of all known facts at that time”

13. USING NOAEL’s
Utilized in risk assessments to evaluate a margin of exposure for substances
Ratio of the NOAEL determined in animals and expressed as mg/kg/day, is compared with the level to which a human may be exposed
Low margin of exposure values indicate the human levels of exposure are close to NOAEL in animals
Margin of safety can be calculated and is often used in evaluating pharmaceuticals
Determines effective therapeutic dose compared with a dose causing toxicity

14. NOAEL LIMITATIONS Must be one of the experimental dose levels tested
Ignores the rest of the dose – response curve
Experiments that test fewer animals result in larger NOAEL’s and thus larger RfD’s
Does not identify the actual response at the NOAEL and will vary based on experimental design
Other methods, such as benchmark dose, can be used as well

15. NON – THRESHOLD APPROACHES
Cancer potency = refers to dose – response curve for a carcinogen
Any exposure can have a carcinogenic response
Assumes “safe” value for substances if the risk is less than 1 x to 1 X 10-6, usually 1 X 10-6 (one in a million)
Determine cancer potency by calculating upper and lower limits of risk based on values in a Poisson Table

17. REMEMBER…. Pt = Xt / Nt Pt = risk to the test group
Xt = cases in test group
Nt = total in test group
Pc = Xc / Nc
Pc = risk to control group
Xc = cases in control group
Nt = total in control group
Attributable Risk (AR) = Pt – Pc (assumes same mechanism of response for test and control groups)

18. ABBOT’S CORRECTION
Adjusts for different, or independent, mechanisms of response between the test and control groups.
Control – adjusted test group response
P-adjusted = Attributable Risk including Abbot’s Correction
P-adjusted = Pt – Pc / (1 – Pc)
Denominator can be thought of as the total amount of possible risk.
NOTE: if there is 0 risk to the control group, P-adjusted = Pt

19. POISSON TABLE UPPER AND LOWER STATISTICAL LIMITS

20. CALCULATING UPPER AND LOWER RISK FACTORS
Calculate adjusted “P” for upper and lower confidence limits
Once the statistical limits are set, the risk factors for the risk assessment can be calculated.
Risk factor = R = P/ D
R = increase in excess risk per dose increase
Conservative calculation uses the upper limit to determine the risk factor.

21. EXAMPLE #1
Suppose 20 of 200 test rats given a dose 1 mg of chemical X die from cancer, while 10 of 200 control rats die from cancer. Using Abbot’s Correction and the Poisson Table, what are the upper and lower limits of excess risk?
What is the conservative unit risk factor?

22. EXAMPLE #2
Suppose 40 of 200 test rats given a dose 3 mg of chemical X develop tumors, while 10 of 200 control rats develop tumors. Using Abbot’s Correction and the Poisson Table, what are the upper and lower limits of excess risk?
What is the conservative unit risk factor?

23. CALCULATING DOSE D = C/F * I * 70/W * E/L * T D = dose
C = concentration of substance
F = safety factor (usually 10)
I = intake (usually default values)
70 = average weight of a human
W = weight of test animal (rat, etc)
E = average time of exposure in days
L = average lifetime of species
T = time of exposure in humans

24. DOSE EXAMPLE #1
Suppose a suspected carcinogen is found in water at a concentration of 0.2 mg/L. What is the average lifetime daily dose to a human?
For simplicity, assume:
E and L entire lifetime of human
F  No safety factors
T  Lifespan of 79 years x 365 days = 28835
I  default water intake of 2 L/day
W  70 kg for average human (154 lbs)

25. DOSE EXAMPLE #2
Suppose a suspected carcinogen is found in water at a concentration of 0.5mg/L. What is the average lifetime daily dose to a human?
For simplicity, assume:
E and L occur over entire lifetime of human
F = 10
T = Lifespan of 76 years x 365 days = 27,740 days
I = default water intake of 2 L/day
W= 70 kg

26. CALCULATING RfD EXAMPLE #1
Performed testing on chemical X with rats and determined the NOAEL in rats is 1 mg/kg/day.
RfD = NOAEL / F = 1mg/kg/day / 10 = 0.1 mg/kg/day for humans

27. CALCULATING RfD EXAMPLE #2
A neurotoxin has a NOEL of 0.05 gm/day in male rats (weight 0.5kg) What is the RfD for humans?
Assume
F = 10
W = 0.5 kg (weight of male rats)
No latency and lifetime of exposure

28. EXAMPLE #3
Assume the values below and answer the questions on next slide :
C = 1mg/m3
I = daily inhalation of 20 m3/day
T = 78 years x 365 days/yr = 28,470 days
P-adjusted for test animal = 0.1
Test animal lifetime dose = 10kg

29. EXAMPLE #3 1. What is the daily dose? (D-day = CIT)
2. What is the lifetime dose? (D- lifetime = CIT)
3. What is the Unit Risk Factor? (R = P-adjusted / D-test animal)
4. What is the lifetime risk to the risk group? (P = R x D- lifetime)

30. DTSC’S PEA HUMAN HEALTH SCREENING RISK EVALUATION
Guidance document provides calculations for human health risk assessments, complete with default values
Exposure Point Concentration (EPC or C) = concentration of the chemical in a particular media (water, air, soil)
Slope Factor (SF) = plausible upper-bound estimate of the probability of a response per unit intake of a chemical over a lifetime; used to estimate the probability of an individual developing cancer as a result of a lifetime of exposure to a carcinogen at a certain dose.
Inhalation Unit Risk = upper-bound excess lifetime cancer risk estimated to result from continuous exposure to a carcinogen at 1ug/m3 in air

31. DTSC’S PEA HUMAN HEALTH SCREENING RISK EVALUATION
Hazard Quotient (HQ)= ratio of a single substance exposure level over a specified time period to a reference dose for that substance derived from a similar exposure period.
Hazard Index (HI) = sum of two or more hazard quotients for multiple substances and/or multiple exposure pathways
Reference Dose or Concentration (RfD or RfC) = estimate of a daily exposure to the human population that is likely to be without appreciable risk of adverse non-cancer effects during a lifetime.

32. LIFETIME AVERAGE DAILY DOSE (LADD) FOR CARCINOGENS IN SOIL
Adds the oral and dermal exposure pathways
adds child and adult exposures

33. LIFETIME AVERAGE DAILY DOSE (LADD) FOR CARCINOGENS IN SOIL
Also adds the child and adult exposures
Air pathway only
Risk is added to the oral and dermal LADD to get LADD total

34. HAZARD INDEX FOR NON-CARCINOGENS IN SOIL
Adds the oral and dermal exposure pathways
Only uses the child values (6 years old) because the Hazard Index for a child will not be exceeded for any other age.
Can calculate adult and add to get total average daily dose (ADD)

35. HAZARD INDEX FOR NON-CARCINOGENS IN SOIL
Air pathway only
Added to the oral and dermal hazard quotients to get total hazard index for a chemical

36. CONVERTING CONCENTRATION IN SOIL TO CONCENTRATION IN AIR

37. EXAMPLE #1 – 1,4 DIOXANE LADD / ADD
Soil is contaminated with 1,4 - dioxane. Maximum soil concentration detected C = 100 mg/kg. What are the child oral, dermal, and inhalation ADD’s and lifetime LADD’s estimates?
EPA IRIS values for 1,4-dioxane are:
RfD oral = 3 x 10-2 mg/kg/day (also used for dermal)
RfC inhal = 3 x 10-2 mg/m3
Cancer slope oral = 1x10-1 mg/kg/day (also used for dermal)
Cancer Inhalation Unit Risk = 5 x 10-6 ug/m3

38. EXAMPLE #2 – STYRENE ADD only
Soil is contaminated with styrene. Maximum soil concentration detected C = 500 mg/kg. What are the child oral, dermal, and inhalation ADD estimates.
EPA IRIS values for Styrene are:
RfD oral = 0.2 mg/kg/day (also used for dermal)
RfC inhal = 1 mg/m3

39. EXAMPLE #3 – BROMOFORM LADD only
Soil is contaminated with bromoform. Maximum soil concentration detected C = 990 mg/kg. What are the lifetime oral, dermal, and inhalation LADD estimates.
EPA IRIS values for Styrene are:
Oral SF = 7.9 x 10-3 mg/kg/day (also used for dermal)
Inhalation SF = 1.1 x10-6 ug/m3

40. NEXT WEEK
Hazard characterization based on Hazard Index and Lifetime Incremental Cancer Risk
Uncertainties Analysis
Acceptable Risks
Site determination

41. REVIEW Dose and Dose – Response Threshold vs Non-threshold
Safety Factors
Basic Dose Equation
Abbot’s Correction and Poisson Table
DTSC’s PEA Risk Equations (for soil)

42. QUESTIONS?