Toxicology (Summary)

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Toxicology (Summary)

• Exposure Hazard Risk
• All substances can be a poison
• Dose determines the response
• Pathway, duration and frequency of exposure and
  chemical determine dose
• Absorption, distribution, metabolism excretion
• The extent of the effect is dependent upon the
  concentration of the active compound at site of
  action over time
• Bioactivation compounds to reactive metabolites
• Individual variation of the organism will affect
  ADME

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Dose (intake) X Toxicity Risk

• The does makes the poison
• Dose/intake are exposure
• That is
• no matter how dangerous the toxicant
• no risk without exposure

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Risk

• Technical
• of people that will be injured, become ill, or
  die

• Non-Technical
• Upsetting, frightening, or enraging

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Risk Assessment

• A process or method by which we assess the nature
  and magnitude of risk.
• hazardous waste disposal and chemicals
• new and existing technologies
• site facilities
• set priorities
• develop cleanup goals

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• Risk- the likelihood or possibility of
  suffering injury, disease, or death from a hazard
• Hazard-a source of risk, refers to a substance or
  action that can cause harm
• a hazard can not constitute a risk unless
  there is exposure

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• 1983 NRC Report- Risk Assessment in the Federal
  Government Managing the Process
• 1. Hazard identification
• 2. Dose-response assessment
• 3. Exposure assessment
• 4. Risk characterization

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Congressional Commission on Risk Assessment
Risk Assessment and Risk Management in Regulatory
Decision-Making (1997)
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Hazard Identification

• Determining whether a chemical, under plausible
  circumstances, may cause harm to human health or
  the environment

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Types of Information

• 1. Epidemiological studies
• 2. Animal bioassays
• 3. In vitro tests
• 4. SAR analyses

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• Animal Bioassays
• acute studies
• subchronic studies
• chronic studies

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• Acute studies
• single exposure, multiple doses
• observed up to 14 days
• LD50, LC50

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Subchronic Studies

• Repeated exposures, 5 to 90 days
• variable exposure routes
• 3 doses
• NOEL, LOEL vs. NOAEL, LOAEL
• determine MTD

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Chronic Studies

• Several doses- MTD, 1/2 or 1/4 MTD, 0
• majority of lifetime (2 years rodent)
• lower doses, larger N subtle effects
• long time, high cost

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Exposure Assessment

• Estimate or directly measure the quantities of
  chemicals received by individuals, populations,
  or ecosystems
• no risk without exposure
• output is quantitative, used in Risk
  Charterization

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Questions to Answer

• Which chemicals reach target?
• How much exposure?
• In what way?
• For how long?
• Under what circumstances?

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• Biomonitoring- measuring a chemical or its
  byproducts in tissues or fluids as an indicator
  of exposure (exposure vs effect)
• rarely done- expensive, limited tests
• time issues

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Ambient Monitoring

• Monitoring contaminants in media (soil, air,
  water, etc.) to estimate exposure point
  concentrations (EPCs)
• when inadequate, often use modeling

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• Goal of modeling or ambient monitoring
• calculate an intake or dose for organism
• Dose (intake, exposure) x Toxicity Risk

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Intake C x CR x EFD BW x AT

• I is intake or dose
• C is chemical concentration
• CR is contact rate
• EFD is exposure frequency and duration
• BW is body weight
• AT is averaging time

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• These equations are used to calculate doses from
  exposure pathways
• values for inputs are as realistic as research
  allows (Exposure Factors Handbook)
• but many uncertainties exist

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• At GAEPD, evaluate Reasonably Maximally- Exposed
  Individual (RME)
• not a worst case scenario
• may be appropriate to contrast with exposure
  estimates calculated from central tendency
  estimates
• Probability Density Functions (Monte Carlo
  simulations)

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Total Dose (Intake) sum of all doses from
individual pathways

• chronic versus intermittent exposures?
• aggregate

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DOSE-RESPONSE ASSESSMENT

• Intake x Toxicity Risk
• often must extrapolate from animal studies
• two important assumptions
• 1. Thresholds for non-cancer
• 2. No thresholds for cancer

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Dose-Response Relationship
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RESPONSE
0-1 NOAEL 2-3 Linear Range 4 Maximum Response
As the dose increases. so does the
response
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2
0
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DOSE
DOSE DETERMINES THE BIOLOGICAL RESPONSE
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Thresholds exist for most biological effects

• Doses exist below which no adverse effects are
  observable in a population of exposed individuals

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Thresholds do not exist for carcinogens.

• Any level of exposure to the chemical corresponds
  to some non-zero increase of inducing genotoxic
  effects.

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Non-cancer evaluation

• Reference Dose- an estimate (with uncertainty
  spanning perhaps an order of magnitude) of a
  daily or continuous exposure for human
  populations, including sensitive subgroups, that
  is likely to be without appreciable risks of
  deleterious effects occurring in a lifetime.

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RfD NOAEL or LOAELUFs x MFs

• NOAEL OR LOAEL for critical effect

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UF 1 to 10 to account for

• Variation in humans
• extrapolation from animals to humans
• subchronic instead of chronic
• LOAEL instead of NOAEL

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Assumptions

• Population threshold exists
• RfD estimate represents subthreshold doses
• preventing critical effect protects against all
  effects

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CANCER EVALUATION

• EPAs guidelines published in 1986
• weight of evidence- all human and animal

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86 Scheme

• Group A- known human carcinogen sufficient human
  data
• Group B- probable human carcinogen
• B1- limited human, sufficient animal data
• B2- inadequate human, sufficient animal data

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• Group C- possible human equivocable animal data
• Group D- not classifiable inadequate or no data
• Group E- evidence of noncarcinogenicity

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Current practice

• Data (usually animal) fit with model to
  extrapolate into low dose range
• EPA uses Linearized Multistage Model

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LMS

• Accommodates nonlinearity at high doses
• Constrains results to linear form at low doses
• Based on current understanding of cancer as
  multistage process

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LMS

• Output in form of slope factor
• Represents steepness of dose-response curve
  (larger number more potent)
• Slope factor represents upper bound (95th
  percentile) caner risk per unit dose

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Risk Characterization

• Where all components of assessment are brought
  together in a quantitative evaluation and
  transparent qualitative discussion

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• Integrate information from Haz ID, Dose-Response,
  and Exp Assess
• discuss overall quality, degree of confidence in
  estimates and conclusions (uncertainty)
• describe risk to individuals and populations
  (extent, severity, probable harm)

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• Calculating risk (numeric) and hazard indices
• Non-cancer- hazard quotient, hazard index
• HQ intake/ RfD
• Both intake and RfD have units of mg/kg-day

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• HQ lt 1.0 no detrimental effects
• HQ gt 1.0 potential for effects to occur
• HI is sum of HQs
• Summing based on assumption of additivity of
  effects

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Cancer risk

• Calculate theoretical lifetime
• Cancer risk from estimated exposure or intake
• Excess or additional risk
• Upper-bound on risk

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Risk Intake x SF

• Intake units of mg/kg-day
• SF units of 1/(mg/kg-day)
• Risk is unitless (probability)
• Sum cancer risk for all chemicals

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Risk Char Discussion

• Confidence in key site-related chemical identity
  and conc. relative to background
• Describe types of cancer and health effects,
  distinguish between known effects in humans
  versus animal derived or predicted

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• Confidence in quantitative tox info used to
  estimate risk, and qualitative info on chemicals
  not included in assessment
• Confide in exposure estimates for key pathways
  and inputs
• Magnitude of cancer risks and non-cancer HIs

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• Major factors driving risk (chem., pways, and
  pway combinations)
• Major factors reducing certainties and the
  significance of uncertainties (ex. adding risk
  over chemicals and pways)
• Exposed population characteristics

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Risk Hazard Outrage(the non-technical side)

• Voluntary vs. Involuntary
• Natural vs. Industrial
• Familiar vs. Exotic
• Dreaded or Not

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WEB RESOURCES

• www.epa.gov/ncea/raf/cancer.htm
• Draft revised guidelines for carcinogenic risk
  assessment (1999)
• www.epa.gov/iris/
• Methylmercury
• Polychorinated biphenyls