Factors That Drive Dose-Response

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					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
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
           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.
            Dose ?

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

The amount/volume of a
 substance/agent that elicits an
 observed response and/or that which
 is associated within specific
         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.
Exposure Versus Dose
• Exposure does not        • Intake must occur
    always=dose                before dosing is
•   It is an agent             realized
    concentration in       •   Dose may be a one
    air, water, soil,          time or recurring
    food, etc.                 events
•   It can be acute,       •   Dose can be
    chronic, alternating       partitioned to
    in character               whole body, target
                               organ or tissue
• 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
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
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
Importance of Functional

• Respiratory-FEV1, FVC, FEV1/FVC, CO2-02
  gas exchange/saturation, mucosiliary
• Renal clearance time
• Hepatic enzyme activity/levels
• Cardiovascular/peripheral circulatory
Atypical or Unusual Dose
• Overt Tolerance: may be innate or
•   Idiosyncratic responses: outside the norm
    of what is expected or reported
•   Chemical allergy: “simple” immune
•   Type I&II Hypersensitivity: immune
    system marshals a progressively
    pronounced response that can become life
How Do These Impact Dose-Response

  Skin on hands versus skin on head or back

  Alveolar insult and intake of PM2.5 versus

  Intake of Cr III versus Cr VI and latency

  Relative humidity and intake of

  Intake of lead at age <5 versus 35 years

  Lipid versus water solubility
Early & Late-Term Dose
• 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
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
Important !

Exposure and dose will always
 have temporal and spatial
 components that can be highly
 variable and host/cohort
 specific…understand the
 exposure setting
Risk = toxicity x exposure


 Risk = toxicity x intake

       Risk = Dose
What Must be Known Before
Dose Can be Determined

• Agent & agent characteristics
• Exposure concentration
• Routes of exposure
• Exposure frequency
• Exposure duration
• Body weight
Route of Exposure Is A
Critical Dose Factor
•Respiratory-DRIVERS? (300-1000 ft2)
• Ingestion-DRIVERS?
• Dermal-DRIVERS? (12-30 ft2)
• Percutaneous-DRIVERS?
   Computing Average Daily
       Particle Dose

ADD=PM2.5 x INF x EF x ED ÷ BW x
 PM2.5 = particle concentration
 INF=inhalation intake factor-resp. rate
 EF=exposure frequency
 ED=exposure duration
 BW=body weight
 EAT=exposure averaging time
Computing Average Daily
Vapor/Gas Dose
 ADD=Cx x INF X EF x ED ÷ BW x EAT
  Cx=concentration of agent
  INF=inhalation intake factor
  EF=exposure frequency
  ED=exposure duration
  BW=body weight
  EAT=exposure averaging time
  Computing Average Daily
      Dermal Dose
ADD=Cx x SSAE x EF x ED ÷ BW x EAT
  Cx=concentration of agent
  SSAE=skin surface area exposed
  EF=exposure frequency
  ED=exposure duration
  BW=body weight
  AT=exposure averaging time
Body Burden and Dose
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
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
The Myth of The Average
      70kg Male

  Importance of Left
    Tail Sensitivity
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
• How do occupational PEL/TLV values differ
  from MCLs
Importance of I.H. Exposure
• 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
Biomedical Monitoring
 • Choosing the agent and/or metabolite to
 • Choosing the body tissue and/or fluid to
 • Deciding on the time and number of
 • Pre/post shift sampling
 • Sampling after a weekend, holiday,
 • Lifestyle choices that confound/modify
   dose response
Gold Standard Measures

• Experimental animal models
• Epidemiological Clinical trials
• Controlled real-time exposure
• Measurement of toxicants and/or
  their metabolites in tissue, body
  fluids or waste
Working With Markers of Dose

• Adverse/potentially adverse/susceptibility
• Original agent/toxicant-lead/lead
• Metabolites-phenol/benzene
• Conjugates-immune components
• Adducts-antigen/antibody
• Enzymes-SGOT/liver
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
•   Is it supported by a body of peer reviewed
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
•   Subject to parental take-home contamination
    What happens


Up Is Down and Down Is

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