Consequence Assessment - Dose Response and Risk Characterization

Deterministic effects

severity is a function of dose, severity increases with dose, threshold, first type of damage

Stochastic effects

probability is a function of dose, severity independent of dose, no threshold, binary

Threshold effect

toxic threshold below which adverse effects don’t occur

Non-threshold effect

effects that can potentially result from the action of a single molecule of a contaminant or radioactive emission

Pharmacokinetic model

evaluation of the kinetics of therapeutic substances within the field of pharmacology

LD50

mean lethal dose, single dose of contaminant that results in death of 50% of test species under a specified set of conditions

Cohort study

contaminant exposure is known and we look for the health effects (atomic bomb survivors)

Case control study

health effect known need to find exposure (male breast cancer at Camp Lejeune)

Tolerance distribution model

deterministic or stochastic effect modeling where a threshold level of exposure is required to induce the effect and the threshold varies in a statistical manner in the exposed population

Mechanistic model

based on theoretical conceptualization of underlying biolgoical processes (usually carcinogenic)

Maximum tolerated dose (MTD)

highest dose of a contaminant given over a specified period of time that does not result in increased overt toxicity

Give advantages and disadvantages of epidemiological studies and animal studies for evaluating the potential effects of human exposure to contaminants

Epidemiological = actual understanding of human effects, ethical complications, casualty determinations subjective, usually just give us hypotheses, uncertainties in dose, limited numbers

Animal studies = “more” ethical, not necessarily an easy correlation to make, well-controlled, precise doses, easy repetition

Explain the difference between a threshold and non-threshold dose-response relationship

threshold = dose below which adverse effects not expected or dose at which most sensitive member of population exhibits effect

non = effects from action of single molecule of contaminant or radioactive emission, conservative assumptions made at low doses for stochastic effects bc of uncertainty at low doses

Using epidemiological or animal data, generate a cumulative dose-response curve

Describe the role of epidemiological studies, animal studies, and structure-activity relationships in the development of dose-response relationships

Explain the difficulty in quantifying health effects in humans using animal data and give the two extrapolations that are required

• animal to human extrapolation

• high to low dose rate

Briefly describe the basic assumption(s) behind the single-hit and multi-hit (mechanistic) dose-effect models

single hit - single initiating event has potential to cause a stochastic effect, probability of cancer at low doses rises linearly

multi hit - toxic response occurs as result of alpha hits over fixed period of time, hit probability is constant and does not change with age

List three tolerance distribution models

• body weight extrapolation (n = 0 → m = 1)

• surface area extrapolation (n = 1/3 → m = 2/3)

• metabolic rate extrapolation (n = ¼ → m = 3/4)

Explain the rationales (mass)^(3/4), (mass)^(2/3), and (mass)^1 animal to human dose extrapolation

Show that a (mass)^(3/4) dose extrapolation is more conservative than a mass^1 extrapolation

Given appropriate information, convert animal dose to human dose using both scaling methods

Given dose response data for deterministic effects, be able to identify NOAEL and LOAEL

NOAEL = no observed adverse effects level

LOAEL = lowest observed adverse effects level

Given dose response data for stochastic effects, use the one hit model to estimate the slope in the low dose region of the dose-response curve

Margin of safety

threshold dose/actual dose; ratio of dose expected to produce specified effect to estimated dose received

Fractional response

incidence/number in population

Reference dose

conservative measure of dose that is expected to be without appreciable effects over lifetime of exposure to most sensitive member of a population

Reference concentration

conservative measure of concentration that is expected to be without appreciable effects over lifetime of exposure to most sensitive member of a population

Hazard quotient

quantitative measure of threshold effects, HQ = D_dot/RfD or HQ = C/RfC

Hazard index

HQs for individual contaminants and/or multiple exposure pathways summed, <1 indicates no effects likely to be observed, > 1 more complex

Uncertainty factors

factors that contribute to uncertainty propagation

Slope/potency factor

incrementally increased risk of cancer incidence from exposure to a substance per unit dose

Radiation risk factor

risk posed by given radionuclide based on radionuclide, age at exposure, gender, and cancer type

Explain the fundamental difference between the margin of safety and fractional response approaches to quantifying human health effects

Explain how Reference Doses and Reference Concentrations are obtained

Perform quantitative characterization of deterministic effects using the reference dose and the reference concentration

Perform quantitative characterization of stochastic effects due to chemical and radiological contaminants using risk factors

Obtain health effect parameters from the Integrated Risk Information System