TOPIC 5:
DOSE-RESPONSE
ASSESSMENT
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
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
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
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
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
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
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
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)
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
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”
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
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
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 10-4 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
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)
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
POISSON TABLE UPPER AND
LOWER STATISTICAL LIMITS
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.
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?
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?
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
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)
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
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
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
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
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)
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
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.
LIFETIME AVERAGE DAILY DOSE
(LADD) FOR CARCINOGENS IN
SOIL
■ Adds the oral and
dermal exposure
pathways
■ adds child and
adult exposures
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
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)
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
CONVERTING CONCENTRATION IN
SOIL TO CONCENTRATION IN AIR
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
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
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
NEXT WEEK
■ Hazard characterization based on Hazard Index and Lifetime
Incremental Cancer Risk
■ Uncertainties Analysis
■ Acceptable Risks
■ Site determination
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)
QUESTIONS?
