An Introduction To Risk Assessment, Risk Management by nph82254

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									A Small Dose of ™ Risk Assessment

An Introduction To Risk Assessment,
         Risk Management &
       Precautionary Principle

         DEOHS Summer 511
             July 11, 2005
     Steven G. Gilbert, PhD, DABT
     www.asmalldoseof.org LINK

                            A Small Dose of Risk Assessment – 2/27/04
                             Outline

              Risk in context of society
              Risk Management examples
              Principles of risk assessment
              Lead Risk – CDC 10 to 2 mcg/cl?
              Mercury – cap and trade
              Precautionary Principle
              Seattle and WA State efforts



A Small Dose of Toxicology              A Small Dose of Risk Assessment – 2/27/04
    A Small Dose of Toxicology




         See: www.asmalldoseof.org -- smdose
A Small Dose of Toxicology          A Small Dose of Risk Assessment – 2/27/04
                             NW Public Health


Public Health and
the Precautionary
    Principle
 By Steven G. Gilbert

           See: http://healthlinks.washington.edu/nwcphp/nph/
                                    nwph
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                      Doubt / Uncertainty

"Doubt is our product since it is the best
means of competing with the 'body of fact' that
exists in the mind of the general public.“

1969 an executive at Brown & Williamson
owned by R. J. Reynolds Tobacco Company

(Doubt Is Their Product by David Michaels in
Scientific American, June 15, 2005)

A Small Dose of Toxicology            A Small Dose of Risk Assessment – 2/27/04
         Current Bioethical Issues
      Check the local news paper
      Stem cells (state, national, international)
      Genetically Engineered Organisms
      Knowing your genes
      In vetro fertilization – choosing your child's
       genes and characteristics
      Global warming
      Nanotechnology
      Environmental health
      Chemicals exposures – human health
A Small Dose of Toxicology              A Small Dose of Risk Assessment – 2/27/04
                             Child Health




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                             Decision Making


      Risk Assessment and Risk
      Management in Context of
            Societal Issues



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                 Socially Responsibility


            What is social responsibility?

             What are our responsibilities
                     to society?




A Small Dose of Toxicology         A Small Dose of Risk Assessment – 2/27/04
Socially responsible white guys?




A Small Dose of Toxicology   A Small Dose of Risk Assessment – 2/27/04
                      The First Bioethicist

                                         Aldo Leopold
                                     "A thing is right when it tends to
                                    preserve the integrity, stability, and
                                    beauty of the biotic community. It is
                                     wrong when it tends otherwise." -
                                    Aldo Leopold, 1949, A Sand County
                                                  Almanac




---------- 1887 - 1948 ----------
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                      Limits on Freedom


             “An ethic, ecologically, is
             a limitation on freedom of
             action in the struggle for
                     existence”
                    Aldo Leopold


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                                “The Commons”




The Tragedy of the Commons
By Garrett Hardin, Science, 1968


   A Small Dose of Toxicology              A Small Dose of Risk Assessment – 2/27/04
                             The Tragedy
                            Cattle
                           Farmers
                     Return on Investment
                        Return for me
                      Not the commons
                        Society suffers


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             No Technical Solutions


             “It is our considered
          professional judgment that
             this dilemma has no
             technical solution.”



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              Problems – Solutions?

                            Tick-tack-toe
                            Nuclear disarmament
                            Bioterrorism
                            Fish from the sea
                            Cancer
                            Lead and kids
                            Fetal alcohol syndrome
                            Commons ….


A Small Dose of Toxicology                      A Small Dose of Risk Assessment – 2/27/04
Toxicology Issues / Solutions?

                   Cancer (soot & benzene ….)
                   Radiation exposure
                   Plant and animal toxins
                   Pesticides
                   Drugs
                   Lead and Mercury
                   Fetal alcohol syndrome
                   ….


A Small Dose of Toxicology               A Small Dose of Risk Assessment – 2/27/04
                             Freedom?

        What does toxicology say
          about managing the
              commons?

       Restriction of Freedom?
      Responsibility knowing the
              problem?
A Small Dose of Toxicology              A Small Dose of Risk Assessment – 2/27/04
                  Environmental Health

What is the goal of risk management?

“Conditions that ensure that all living
 things have the best opportunity to
 reach and maintain their full genetic
 potential.”

Steven G. Gilbert, 1999
 A Small Dose of Toxicology       A Small Dose of Risk Assessment – 2/27/04
                             Examples of Risk


   Risk Management Examples

                                Alcohol
                                 Lead
                                Mercury

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                             Ethyl Alcohol

                              H    H

                     H        C    C    OH

                              H    H

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   A Small Dose of Toxicology
FAS Child                       A Small Dose of Risk Assessment – 2/27/04
A Small Dose of Toxicology   A Small Dose of Risk Assessment – 2/27/04
Fetal Alcohol Syndrome (FAS)

1968 - Researchers at the Univ. of Nantes
 Early 1970’s FAS – Univ. of Washington

        4,000-12,000 infants per year in US
        1 to 3 births per 1,000 world wide??

        Most common preventable cause of
            adverse CNS development


A Small Dose of Toxicology         A Small Dose of Risk Assessment – 2/27/04
        Fetal Alcohol Effect (FAE)

                             Milder form of FAS

          7,000-36,000 infants per year in US
                     World wide?

                        Characteristics
                       Growth deficiency
                     Learning dysfunction
                  Nervous systems disabilities

A Small Dose of Toxicology                        A Small Dose of Risk Assessment – 2/27/04
                      Awareness of Lead


      6500 BC. - Lead discovered in Turkey
      500 BC-300 AD.- Roman lead smelting
       produces dangerous emissions (wine)
      100 BC. - Greek physicians give clinical
       description of lead poisoning
      2 BC "Lead makes the mind give way.“
      1920’s - Lead in gasoline, lead in paint


A Small Dose of Toxicology           A Small Dose of Risk Assessment – 2/27/04
                             Lead In Homes




A Small Dose of Toxicology               A Small Dose of Risk Assessment – 2/27/04
                             Lead in Families




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                             Recycling Lead




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       Agency Blood Lead Levels
                                       Acceptable Childhood Blood Lead Levels
                                         60
                                  60
             Blood Lead (ug/dl)



                                  50
                                              40
                                  40
                                                    30
                                  30                      25
                                                                20
                                  20
                                                                        15
                                                                               10
                                  10
                                                                                          2
                                   0
                                       CDC CDC     CDC CDC WHO EPA           CDC CDC
                                       1960 1973   1975 1985 1986 1986       1990 2006?
                                                      Agency and Year


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                 Fetal Effects of MeHg




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           Life-Long Effects of MeHg




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                       The Mercury Cycle




A Small Dose of Toxicology           A Small Dose of Risk Assessment – 2/27/04
                         WA State Advisory

  Limit the amount of canned tuna you
          eat, based on your bodyweight.
 Guidelines are: Women of childbearing age should limit the amount
  of canned tuna they eat to about one can per week (six ounces.) A
  woman who weighs less than 135 pounds should eat less than one
  can of tuna per week. Children under six should eat less than one
 half a can of tuna (three ounces) per week. Specific weekly limits for
  children under six range from one ounce for a twenty pound child,
        to three ounces for a child weighing about sixty pounds.


http://www.doh.wa.gov/fish/FishAdvMercury.htm
  A Small Dose of Toxicology                        A Small Dose of Risk Assessment – 2/27/04
             Precautionary Principle

         "When an activity raises threats of
         harm to the environment or human
         health, precautionary measures
         should be taken even if some cause
         and effect relationships are not fully
         established scientifically."

         - Wingspread Statement on the
         Precautionary Principle, Jan. 1998


A Small Dose of Toxicology             A Small Dose of Risk Assessment – 2/27/04
          Key Words of Toxicology

              Dose / Response

   Hazard X Exposure = Risk

Individual Susceptibility
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              Early Risk Assessment


  “What is food to one man may
   be fierce poison to others.”

  Lucretius (c. 99 B.C.–c. 55 B.C.)



A Small Dose of Toxicology    A Small Dose of Risk Assessment – 2/27/04
                             Perspective


"If someone had evaluated the risk of fire right
   after it was invented, they may well have
   decided to eat their food raw."

Julian Morris of the Institute of Economic
  Affairs in London




A Small Dose of Toxicology                 A Small Dose of Risk Assessment – 2/27/04
                             Perspective


        “One death is a tragedy.
     A million deaths is a statistic.”

Joseph Stalin



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                  Historical Awareness


1775 – Percivall Pott – Occupational –
 cancer of scrotum in chimney sweeps
1895 – Bladder cancer in workers in
 aniline dye industry




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                       Recent Awareness

1938 - Founding of American
 Conference of Governmental Industrial
 Hygienists (ACGIH).
1941 - Chemical Substances
 Committee established to investigate
 and recommend exposure limits for
 chemical substances.
Threshold Limit Values (TLVs) for 148
 chemicals (exposure limits)

A Small Dose of Toxicology          A Small Dose of Risk Assessment – 2/27/04
                                                          Superman
A Small Dose of Toxicology   A Small Dose of Risk Assessment – 2/27/04
                             Risk of What?


    Obvious
         Death, Cancer, Acid burn, Birth defect,
         asthma,
    Subtle
         Decreases in learning and memory (lead),
         Sensitivity of the individual (child)




A Small Dose of Toxicology               A Small Dose of Risk Assessment – 2/27/04
                             Risk Assessment

              Process of estimating
             association between an
            exposure to a chemical or
             physical agent and the
           incidence of some adverse
                   outcome.

A Small Dose of Toxicology                A Small Dose of Risk Assessment – 2/27/04
                         Risk Management

                   Policy developed to deal with
                  hazards identified through risk
                            assessment

              Process of evaluating alternative
              regulatory options and selecting
                        among them


A Small Dose of Toxicology                A Small Dose of Risk Assessment – 2/27/04
       Framework for RA and RM

                                 Epidemiology
                                 Toxicology
            Identify hazards     In vitro tests
                                 Structure/Activity Analysis


                                 Potency
            Characterize risks   Exposure
                                 Susceptibility


                                 Information
            Control risks        Regulation
                                 Substitution


A Small Dose of Toxicology                      A Small Dose of Risk Assessment – 2/27/04
Objective of Risk Assessment

           Evaluate the risks
                       Environmental contaminant, drugs,
                        pesticides, industrial chemical
           Evaluate uncertainty of data
           Set target levels of exposure
                       Food, air, water, work place
           Provide information to agencies
                       Regulatory agencies, Manufacturers,
                        Environmental/Consumer Agencies


A Small Dose of Toxicology                             A Small Dose of Risk Assessment – 2/27/04
        Steps in Risk Assessment


    Hazard Identification
    Exposure Assessment
    Dose-Response Assessment
    Risk Characterization



A Small Dose of Toxicology   A Small Dose of Risk Assessment – 2/27/04
                   Hazard Identification


   Review human and animal data
   to determine if a chemical or
   agent has biological effects




A Small Dose of Toxicology          A Small Dose of Risk Assessment – 2/27/04
                   Hazard Identification


 Research
  Structure-Activity Analysis
  Short-term Screening Tests
  Animal Bioassays
  Human Epidemiological Data


A Small Dose of Toxicology          A Small Dose of Risk Assessment – 2/27/04
      Structure-Activity Analysis


  Does structure resemble that of
      a known toxic agent?

                        Computer modeling



A Small Dose of Toxicology             A Small Dose of Risk Assessment – 2/27/04
     Short-term Screening Tests


          Cell Culture, Tissue Culture

           Does the chemical or agent
             adversely effects cells?



A Small Dose of Toxicology     A Small Dose of Risk Assessment – 2/27/04
                        Animal Bioassays

                             Animal Studies

Does the chemical or agent causes effect
                animals?

           What is the potentially for human
                        toxicity?


A Small Dose of Toxicology                    A Small Dose of Risk Assessment – 2/27/04
                       Toxicity Endpoints

                     Carcinogenicity
                     Mutations
                     Altered immune function
                     Teratogenicity
                     Altered reproductive function
                     Neuro-behavioral toxicity
                     Organ-specific effects
                     Ecological effects (wildlife,
                      environmental persistence)

A Small Dose of Toxicology                  A Small Dose of Risk Assessment – 2/27/04
          Pros and Cons - Animals

                 Advantages
                  Monitor progress of
                   toxicity/carcinogenicity
                  Can directly link with exposure
                  Can be used to predict human risks

                  Disadvantages
                   Can be very expensive (>$1 M)
                   Can take many years


A Small Dose of Toxicology                 A Small Dose of Risk Assessment – 2/27/04
            Human Epidemiological


                             Human Studies

  Does the chemical or agent causes
       adverse effect in human
            populations?



A Small Dose of Toxicology                   A Small Dose of Risk Assessment – 2/27/04
          Pros and Cons - Humans
         Advantages
          Yields information in humans
          Yields associations relevant to “real
           world” exposures

         Disadvantages
          Can be very expensive (large N, many
           years)
          Lack control relative to lab
          Many confounding variables


A Small Dose of Toxicology              A Small Dose of Risk Assessment – 2/27/04
                         Human Variability

             Human Subject Variability
•    Lifestyle – risk of exposure to ….
•    Occupation – risk of exposure to ….
•    Breathing & digestion – uptake of chemicals
•    Metabolism & kidney function – elimination
•    Age, gender & disease – susceptibility to
     toxicity



A Small Dose of Toxicology              A Small Dose of Risk Assessment – 2/27/04
               Examples of Variability
• Children spend more time on floor – more
  hand to mouth behavior than adults
• Occupation – exposure to other chemicals
• Rate of breathing higher in children than
  adults
• Lung function and susceptibility are altered
  by smoking or asthma
• Disease effects liver function

 The overall dose-response behavior is subject
   to both intra-individual and inter-individual
                    variability.
A Small Dose of Toxicology         A Small Dose of Risk Assessment – 2/27/04
                             Uncertainty

• Measurements error in experiments
• Extrapolation from animal studies to
  human
• Sample sizes for animal and human
  studies
• Selection of endpoint
• Intra and inter subject variability



A Small Dose of Toxicology                 A Small Dose of Risk Assessment – 2/27/04
               Exposure Assessment

    Route of exposure (skin, oral,
          inhalation)
    Amount of exposure (dose)
    Duration of exposure
    To whom (animals, humans,
          environment)


A Small Dose of Toxicology    A Small Dose of Risk Assessment – 2/27/04
                             Exposure Issues


         •      Home environment
         •      Current events
         •      Workplace
         •      School
         •      Government Decisions (war)
         •      Global and local environment


A Small Dose of Toxicology                A Small Dose of Risk Assessment – 2/27/04
  Dose-Response Assessment



   How much exposure to a chemical
    or agent will cause what effect?




A Small Dose of Toxicology   A Small Dose of Risk Assessment – 2/27/04
                        Chemical Potency
           Response


                                      ED50
                             Threshold (NOAEL




                                        Dose
A Small Dose of Toxicology                      A Small Dose of Risk Assessment – 2/27/04
                 Risk Characterization

        Risk = Hazard X Exposure

   • Hazard (including sensitive populations)
           – May require low dose extrapolation
   • Exposure
           – Route of exposure, amount, duration
                  • dermal, oral, inhalation, injection




A Small Dose of Toxicology                                A Small Dose of Risk Assessment – 2/27/04
                         Risk Management


                              Uncertainty
                              Perception
                              Comparison
                              Education
                              Regulation


A Small Dose of Toxicology                   A Small Dose of Risk Assessment – 2/27/04
                             Uncertainty



           How do you know?
           How good is the data?




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      Use of Uncertainty Factors

   Divide Dose by Power of 10
   • Human variability
   • Interspecies extrapolation
   • Children
   • Subchronic to chronic extrapolation
   • Absence of a NOAEL
   • Database uncertainty



A Small Dose of Toxicology     A Small Dose of Risk Assessment – 2/27/04
      Use of Uncertainty Factors
                                    Animal Dose Response Data
                         NOAEL (No Observed Adverse Effect Level)


                                             Divide by 10
                                (Account for inadequate animal data)


                                             Divide by 10
                                  (Animal to Human Extrapolation)


                                             Divide by 10
                             (Human Variability or Individual Sensitivity)


                Reference Dose (RfD) Or Acceptable Daily Intake (ADI)
A Small Dose of Toxicology                                          A Small Dose of Risk Assessment – 2/27/04
                 Reducing Uncertainty


      • Upstanding mechanism of action
      • Physiologically based
        pharmacokinetic models
        (distribution and metabolism)
      • Sample size




A Small Dose of Toxicology       A Small Dose of Risk Assessment – 2/27/04
                             Comparing Risks

                          By probability
                          By expected value
                          By outrage
                          By exposure
                          By experts

A Small Dose of Toxicology                  A Small Dose of Risk Assessment – 2/27/04
Annual Risk Of Death In The U.S.

           HAZARD                    RISK PER MILLION
           All causes                      9,000.0
           Motor vehicle accidents         210.0
           Work accidents                  150.0
           Homicides                       93.0
           Drowning                        37.0
           Poisoning, Solids/liquids       17.0
           Railroads                       0.9
           Civil aviation                  0.8
           Bits and stings                 0.2

            “TO LIVE, IS TO RISK DYING”
A Small Dose of Toxicology                  A Small Dose of Risk Assessment – 2/27/04
                    Characteristics of Risk
     Characteristic                 Level                   Examples

      Knowledge                   Little known              Food additives
                                  Much known                Alcoholic drinks
      Newness                     Old                       Guns
                                  New                       Space travel
      Voluntariness               Not voluntary             Crime
                                  Voluntary                 Rock climbing
      Control                     Not controllable          Natural disasters
                                  Controllable              Smoking
      Dreadedness                 Little dread              Vaccination
                                  Great dread               Nerve gas
      Catastrophic                Not likely                Sunbathing
      potential                   Likely                    War
      Equity                      Distributed               Skiing
                                  Undistributed             Hazardous dump

Adapted from Kraus and Slovic (1988), Risk Anal., 8: 435.
     A Small Dose of Toxicology                              A Small Dose of Risk Assessment – 2/27/04
                                 Risk Perceptions
                                 Unknown
                                                 Lead   w
            w Food coloring               w DNA Research              Knowable
       Saccharin w                        Nuclear Power w
                                                                        Newness
Microwave ovens w                                             Lack of scientific knowledge
                                            w   Asbestos
                                                            Exposure is unknown/unknowable
             w Aspirin                Herbicides
                                                    w
                                     Pesticides w                          Dread
Little Dread                                    Dreaded          Catastrophic potential
           w Anesthetics                                            Involuntariness
                                                                     Personal risk
       w Power Tools                      w Smoking                     Inequity

      Alcohol     w                             w Dynamite
                                 w
                    Motor vehicles
                                                     w Warfare
                                          w Handguns
    A Small Dose of Toxicology    Known                            A Small Dose of Risk Assessment – 2/27/04
         Differences in Risk Perception

                                        Rank by Risk       Rank by non-
                Activity/Agent            Analyst          Risk Analyst

                Motor Vehicles                  1              2
                Smoking                         2              4
                Alcohol                         3              6
                Handguns                        4              3
                Surgery                         5              10
                Motorcycles                     6              5
                X-rays                          7              22
                Pesticides                      8              9
                Electric Power                  9              18
                Swimming                        10             19
                Nuclear Power                   20             1

                 Slovic et
Adapted from of Toxicology al. (1979), Environ., 21: 14.
    A Small Dose                                                    A Small Dose of Risk Assessment – 2/27/04
                             Case Study




                              LEAD


A Small Dose of Toxicology                A Small Dose of Risk Assessment – 2/27/04
                      Ancient Awareness


              "Lead makes the
              mind give way."
                         Greek
                  Dioscerides - 2nd BC
A Small Dose of Toxicology          A Small Dose of Risk Assessment – 2/27/04
       Agency Blood Lead Levels
                                       Acceptable Childhood Blood Lead Levels
                                         60
                                  60
             Blood Lead (ug/dl)



                                  50
                                              40
                                  40
                                                    30
                                  30                      25
                                                                20
                                  20
                                                                        15
                                                                               10
                                  10
                                                                                          2
                                   0
                                       CDC CDC     CDC CDC WHO EPA           CDC CDC
                                       1960 1973   1975 1985 1986 1986       1990 2006?
                                                      Agency and Year


A Small Dose of Toxicology                                                   A Small Dose of Risk Assessment – 2/27/04
              Canfield et al…, 2003
  “Conclusions: Blood lead concentrations,
  even those below 10 mgc/dL, are inversely
 associated with children’s IQ scores at three
and five years of age, and associated declines
in IQ are greater at these concentrations than
   at higher concentrations. These findings
    suggest that more U.S. children may be
adversely affected by environmental lead than
            previously estimated.”

                     Canfield et al. 2003, NEJM, 384
A Small Dose of Toxicology                     A Small Dose of Risk Assessment – 2/27/04
                         Half-life Of Lead


    • 25 DAYS -- BLOOD
    • 40 DAYS -- SOFT TISSUE
    • 20 YEARS -- BONE



A Small Dose of Toxicology              A Small Dose of Risk Assessment – 2/27/04
                         Lead - Absorption

 ORALLY CONSUMED LEAD ABSORBED

    CHILDREN – 30-50% OF LEAD
     ADULTS – 5-10% OF LEAD

      Increased During Pregnancy

A Small Dose of Toxicology             A Small Dose of Risk Assessment – 2/27/04
            Needleman, NEJM, 1979




A Small Dose of Toxicology   A Small Dose of Risk Assessment – 2/27/04
                         Lead Based Paint
1887 - US medical authorities diagnose childhood lead poisoning
1904 - Child lead poisoning linked to lead-based paints
1909 - France, Belgium and Austria ban white-lead interior paint
1914- Pediatric lead-paint poisoning death from eating crib paint
       is described
1921 - National Lead Company admits lead is a poison
1922 - League of Nations bans white-lead interior paint; US
       declines to adopt
1943- Report concludes eating lead paint chips causes physical
       and neurological disorders, behavior, learning and
       intelligence problems in children
1971- Lead-Based Paint Poisoning Prevention Act passed



A Small Dose of Toxicology                      A Small Dose of Risk Assessment – 2/27/04
Lead Industry Advertisements




                             History of Lead Industry Advertisements (LINK)
       h
  http://www.cincinnatichildrens.org/research/project/enviro/hazard/lead/lead-advertising/default.htm
        t
        t
A Small Dose of Toxicology                                                 A Small Dose of Risk Assessment – 2/27/04
                 Lead-associated Reading Deficits
                         in U.S. Children
                 105
                 100
 Reading Score




                 95
                 90
                 85
                 80
                 75
                        <2.5       2.5         5        7.5                  10
                                 Blood lead levels (g/dl)
Lanphear BP, et al. Public Health Reports 2000;115:521-529. (BL’s slide)
    A Small Dose of Toxicology                               A Small Dose of Risk Assessment – 2/27/04
                       IQ and Blood Lead

         Life time overall
         • Increase in 1 mcg/dl = 0.87 IQ drop
         • Covariates - 1 mcg/dl = 0.46 IQ drop

         1 to 10 mcg/dl (bigger drop)
         • Increase in 1 mcg/dl = 1.37 IQ drop
         • Non-linear - 1 mcg/dl = 7.4 IQ drop



                             Canfield R, et al. NEJM 2003;348:1517-1526
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             Societal Consequences




A Small Dose of Toxicology   (Curtsey Bernard Weiss)   A Small Dose of Risk Assessment – 2/27/04
                Cost of Childhood Lead

             Assumptions in calculating costs
             • All lead is harmful and from environment
             • Blood lead of children age 5 – 2.7 ug/dl (CDC)
             • 5-year old boys (1,960,200) and girls (1,869,800)
             • 1 ug/dl of lead = 0.25 IQ point reduction
             • Cost – boys $27.8 and girls $15.6 Billion

             Total Costs $43.4 Billion
           Environmental Pollutants and Disease in American Children: Estimates of
           Morbidity, and Costs for Lead Poisoning, Asthma, Cancer, and Developmental
           Disabilities, by Landrigan, P. et al. EHP, 110, July 2002, 721-728.

A Small Dose of Toxicology                                        A Small Dose of Risk Assessment – 2/27/04
         Current CDC Policy
                                                             Time frame for
Blood lead
                Actions                                      beginning
level µg/dL)b
                                                             intervention
10-14           Provide caregiver lead education.            Within 30 days
                Provide follow-up testing. Refer the child
                for social services if necessary.
15-19           Above actions, plus:                         Within 2 weeks
                If BLLs persist (i.e., 2 venous BLLs in
                this range at least 3 months apart) or
                increase, proceed according to actions
                for BLLs 20-44.
20-44           Above actions, plus:                         Within 1 week
                Provide coordination of care (case
                management).
                Provide clinical evaluation and care. c
                Provide environmental investigation and
                control current
                lead hazards.
45-70           Above actions.                               Within 48 hours
70 or higher    Above actions, plus hospitalize child for    Within 24 hours
                chelation therapy immediately.


                                                                  A Small Dose of Risk Assessment – 2/27/04
      Proposed CDC Policy
Blood lead     Actions                                    Time frame for
level                                                     beginning
(µg/dL)                                                   intervention
<2             No action


2-5            Provide caregiver lead education.          Within 30 days
               Provide follow-up testing. Refer the
               child for social services to investigate
               possible sources of lead exposure.
5-10           Above actions, plus:If BLLs persist        Within 2 weeks
               (i.e., 2 venous BLLs in this range at
               least 3 months apart) or increase,
               proceed according to actions for BLLs
               10-20.
10-20          Above actions, plus: Provide               Within 1 week
               coordination of care (case
               management). Provide clinical
               evaluation and care. Provide
               environmental investigation and
               control current lead hazards.
20-70          Above actions.                             Within 24 hours
70 or higher   Above actions, plus hospitalize child      Within 24 hours
               for chelation therapy immediately.             A Small Dose of Risk Assessment – 2/27/04
                             Recycling Lead




A Small Dose of Toxicology                A Small Dose of Risk Assessment – 2/27/04
                             Case Study




                             Mercury


A Small Dose of Toxicology                A Small Dose of Risk Assessment – 2/27/04
                             Hg – Like Water




A Small Dose of Toxicology                 A Small Dose of Risk Assessment – 2/27/04
   Hg – Solid Enough to Sit On




A Small Dose of Toxicology   A Small Dose of Risk Assessment – 2/27/04
    Outbreaks of MeHg Poisoning
                Place          Year    Cases
                Minamata     1953-60        1000
                Nigata       1964-65           646
                Guatemala    1963-65            45
                Ghana          1967            144
                Pakistan       1969            100
                Iraq           1956            100
                Iraq           1960       1,002
                Iraq           1971    40,000
                On-going       2001       ???
A Small Dose of Toxicology             A Small Dose of Risk Assessment – 2/27/04
Iraq Infant - Effects of Mercury




A Small Dose of Toxicology   A Small Dose of Risk Assessment – 2/27/04
 Mercury to Methyl Mercury

         Inorganic - elemental mercury
                             vapor Hg0

                     Biotransformation
       Organic - Methylmercury - CH3Hg+
                     Bioaccumulatio
                     n
A Small Dose of Toxicology               A Small Dose of Risk Assessment – 2/27/04
                             Mercury Release


                50-75% mercury of
                released in the
                environment related
                to human activities


A Small Dose of Toxicology                A Small Dose of Risk Assessment – 2/27/04
                             Atmospheric Hg




A Small Dose of Toxicology                A Small Dose of Risk Assessment – 2/27/04
   Biotransformation of Mercury
   Inorganic                 Discharge
    Mercury
                                            Ambient Water
                   Biomethylation            Sediments

           Methyl-                  Bioaccumulation
           Mercury
                                            Edible Fish

Methyl-Mercury                   Exposure
  In Humans
A Small Dose of Toxicology                    A Small Dose of Risk Assessment – 2/27/04
            Neurobehavioral Effects

   • Blindness - Deafness
   • Cerebral Palsy - Seizures
   • Abnormal reflexes & muscle tone
   • Retarded motor development
   • Visual and Auditory Deficits
   • Delayed motor development
   • Altered DRH performance


A Small Dose of Toxicology    A Small Dose of Risk Assessment – 2/27/04
                   Effects On The Brain


                • Decrease in Brain Size
                • Cell loss
                • Disorganization of cells
                • Cell migration failures




A Small Dose of Toxicology             A Small Dose of Risk Assessment – 2/27/04
       Animal - Risk Assessment


    MONKEY - 25 µg/kg - LOAEL
    RAT - 10 µg/kg - LOAEL
    RAT - 50 µg/kg - replicated



A Small Dose of Toxicology   A Small Dose of Risk Assessment – 2/27/04
       Animal - Risk Assessment


 2.5 µg/kg - NOAEL (animals)
 0.25 µg/kg - Human
 0.025 µg/kg - Sensitive populations

                             (the rule of dividing by 10)




A Small Dose of Toxicology                            A Small Dose of Risk Assessment – 2/27/04
       Human - Risk Assessment


   • 10-20 ppm hair - LOAEL •
  • 40-80 ppb blood - LOAEL •
          • 0.645 µg/kg •
       • 0.06 µg/kg - RfD •


A Small Dose of Toxicology   A Small Dose of Risk Assessment – 2/27/04
    Mercury Fishing Advisories

          In 2000, 41 States have over 2000
           fish consumption advisories
          An increase form 27 in 1993
          Pregnant women, nursing
           mothers, women who intend
           to have children, and children
           under 15


A Small Dose of Toxicology         A Small Dose of Risk Assessment – 2/27/04
                       Recommendations

   • Reduce environmental release
   • Restrict global production and sale
   • Advise women of child bearing age
   • Research mechanisms of action
   • Assess neurodegenerative effects




A Small Dose of Toxicology          A Small Dose of Risk Assessment – 2/27/04
      MeHg Consumption Limits


       US EPA – 0.1 ug/kg-day

       US FDA – 1 ppm (mg/kg)
       in tuna



A Small Dose of Toxicology   A Small Dose of Risk Assessment – 2/27/04
             Mercury A Global Issue

 Mercury distribution
 and exposure is a global
 problem




A Small Dose of Toxicology    A Small Dose of Risk Assessment – 2/27/04
                         Structure of PBDEs

        PolyBrominated Diphenyl Ether
                                    O




                             Brx             Br
                                             y
                    X & Y are number of Bromine atoms
                    Common Penta, Octa, and Deca



A Small Dose of Toxicology                       A Small Dose of Risk Assessment – 2/27/04
          PBDEs in House Dust (ppb)




From EWG - Toxic Fire Retardants Contaminate American Homes - http://www.ewg.org/reports/inthedust/summary.php

A Small Dose of Toxicology                                                       A Small Dose of Risk Assessment – 2/27/04
           PBDEs in Breast Milk (ppb)




From EWG - Toxic Fire Retardants in Breast Milk from American Mothers - http://www.ewg.org/reports/mothersmilk/es.php

A Small Dose of Toxicology                                                         A Small Dose of Risk Assessment – 2/27/04
                   Developmental Data
   2863 above 1 Million pounds
         12 or 0.4%
         good data                 21.4% some
                                   data




 78.2% no data
                               www.preventingharm.org
A Small Dose of Toxicology          A Small Dose of Risk Assessment – 2/27/04
                     The Consequences

        Nearly 12 million children (17%)
         under age 18 in the US suffer
         from one or more developmental
         disabilities
        Learning disabilities – 5-10% of
         kids in public school
        ADHD – 3-6% of all school kids,
         maybe higher

A Small Dose of Toxicology        A Small Dose of Risk Assessment – 2/27/04
   Genomic and Ecological Bioethics


                             The challenge
           To develop an individual and
           societal ethical framework for
         decision making that supports the
        long term maintenance of a globally
                sustainable ecology



A Small Dose of Toxicology               A Small Dose of Risk Assessment – 2/27/04
                  Knowledgeable Bioethics



                             The challenge
         “the knowledge of how to
        use knowledge for the social
                  good”


A Small Dose of Toxicology               A Small Dose of Risk Assessment – 2/27/04
                  Sir Austin Bradford Hill


"All scientific work is incomplete - whether it
  be observational or experimental. All
  scientific work is liable to be upset or
  modified by advancing knowledge. That
  does not confer upon us a freedom to
  ignore the knowledge we already have or
  postpone the action that it appears to
  demand at a given time. "

  Sir Austin Bradford Hill (1965)
A Small Dose of Toxicology           A Small Dose of Risk Assessment – 2/27/04
                  Determining Causation

    1.     Strength of association
    2.     Consistency of findings
    3.     Biological gradient
    4.     Temporal sequence
    5.     Biologic or theoretical plausibility
    6.     Coherence with established knowledge
    7.     Specificity of association

     Sir Austin Bradford Hill (1965)

A Small Dose of Toxicology             A Small Dose of Risk Assessment – 2/27/04
             Precautionary Principle

  “When an activity raises threats of harm to
      human health or the environment,
precautionary measures should be take even if
 some cause and effect relationships are not
        fully established scientifically.”

                     Wingspread Conference, 1998.




A Small Dose of Toxicology                   A Small Dose of Risk Assessment – 2/27/04
        Safety & Efficacy vs Harm

 FDA regulations of Drugs (1938)
 FDA regulations of Dietary
  Supplements (Dietary Supplement
       Health and Education Act of 1994
       (DSHEA))
 Ephedra present an unreasonable risk
  of illness or injury (Dec, 2003)

A Small Dose of Toxicology       A Small Dose of Risk Assessment – 2/27/04
                    Central components
• Taking preventive action in the face of
  uncertainty
• Shifting the burden of proof/responsibility
  to the proponents of an activity
• Exploring a wide range of alternatives to
  possibly harmful actions
• Increasing public participation in decision
  making (environmental justice)

                     Wingspread Conference, 1998.

A Small Dose of Toxicology                   A Small Dose of Risk Assessment – 2/27/04
                     Purpose/Objectives

 Improve decision making
 Promote integrated assessments
 Promote transparency
 Promote sharing of information
 Examine alternatives
 Examine uncertainties
 Encourage discussion among
  stake holders
A Small Dose of Toxicology          A Small Dose of Risk Assessment – 2/27/04
                             Seattle Initiative
      City Comprehensive Plans
      • Every citizen of Seattle has an
        equal right to a healthy and safe
        environment.
      • Seattle sees the Precautionary
        Principle approach as its policy
        framework to develop laws for a
        healthier and more just Seattle.
           Seattle PP working group
A Small Dose of Toxicology                   A Small Dose of Risk Assessment – 2/27/04
                             Result of Effort

• Seattle Precautionary Principle
  White Paper (www.asmalldoseof.org)
• Inclusion of PP in Comp Plan
  Environment Element
(http://www.seattle.gov/dpd/Planning/Seattle's_Compr
    ehensive_Plan/DPD_001178.asp) Link




A Small Dose of Toxicology                  A Small Dose of Risk Assessment – 2/27/04
                      WSPHA Resolution

      “Protecting Public Health by
      Adopting the Precautionary
      Principle as an Approach to
      Decision Making”
      Resolution Submitted to Washington
      State Public Health Association


A Small Dose of Toxicology         A Small Dose of Risk Assessment – 2/27/04
                     Citizen Toxicologist
          Socially Responsible Toxicologist

The citizen toxicologist is a thoughtful
  advocate for human and environmental
  health, who strives to share their
  scientific knowledge with the public,
  speaking to public interests rather than
  private or special interests.


A Small Dose of Toxicology            A Small Dose of Risk Assessment – 2/27/04
 Socially Responsible Actions

                             • Testifying
                             • Writing review papers
                             • K-12 class room
                               teaching
                             • Adding expertise to
                               community groups
                             • Education
                             • Mentoring
                             • Speakers Bureau
A Small Dose of Toxicology                       A Small Dose of Risk Assessment – 2/27/04
  SOT - ELSI Specialty Section

           • Forum in which to discuss the
             ethical implications of results
             from our science as well as
             the resulting legal and social
             implications.
           • 2005 SOT meeting – workshop
             on Conflict of Interest

http://www.toxicology.org/memberservices/specsection/specsection.html

A Small Dose of Toxicology                        A Small Dose of Risk Assessment – 2/27/04
     Knowledge - Responsibility

• Children have a right to a safe, fair
  and healthy environment
• Ethical Responsibility to share
  and use of knowledge
• Duty to promote health and well
  being of children
• Thoughtful public health advocate
A Small Dose of Toxicology   A Small Dose of Risk Assessment – 2/27/04
          The Potential of Children




A Small Dose of Toxicology   A Small Dose of Risk Assessment – 2/27/04
      Additional Information
 The Science and Environmental Health Network
  (SEHN) (www.sehn.org)
 Late lessons from early warnings: the
  precautionary principle 1896-2000 – European
  Environment Agency (free)
 Garrett Hardin - The Tragedy of the Commons
  (Science, 1968)
 Ethics and Environmental Health – Mini
  Monograph - Environmental Health Perspectives
  (November 2003)
 Ethical, legal, and social issues: our children's
  future. Steven G. Gilbert. Neurotoxicology, in
  press, 2005

                                       A Small Dose of Risk Assessment – 2/27/04
A Small Dose of ™ Risk Assessment




A Small Dose of Toxicology   A Small Dose of Risk Assessment – 2/27/04
               Additional Information

        Web Sites
                 World Health Organization - The
                  International Programme on Chemical
                  Safety (IPCS) – Risk Assessment –
                  http://www.who.int/pcs/ra_main.html
                 U.S. Environmental Protection Agencies -
                  National Center for Environmental
                  Assessment (NCEA) – Access:
                  http://cfpub.epa.gov/ncea/



A Small Dose of Toxicology                     A Small Dose of Risk Assessment – 2/27/04
             Authorship Information


   This presentation is supplement to
      “A Small Dose of Toxicology”

               For Additional Information Contact
                 Steven G. Gilbert, PhD, DABT
               E-mail: smdose@asmalldoseof.org
                  Web: www.asmalldoseof.org


A Small Dose of Toxicology                A Small Dose of Risk Assessment – 2/27/04
             Precautionary Principle

         "When an activity raises threats of
         harm to the environment or human
         health, precautionary measures
         should be taken even if some cause
         and effect relationships are not fully
         established scientifically."

         - Wingspread Statement on the
         Precautionary Principle, Jan. 1998


A Small Dose of Toxicology             A Small Dose of Risk Assessment – 2/27/04
                         Scientific Process
   Variability
  Uncertainty




A Small Dose of Toxicology              A Small Dose of Risk Assessment – 2/27/04
                   Types of Uncertainty


                             • Statistical
                             • Model
                             • Fundamental


A Small Dose of Toxicology              A Small Dose of Risk Assessment – 2/27/04
                Statistical Uncertainty


              • Easiest to examine & reduce
              • Not knowing the exact value
                of a variable (inter and intra
                subject variance)
              • Sample size




A Small Dose of Toxicology              A Small Dose of Risk Assessment – 2/27/04
  Model or System Uncertainty


              • Not fully understanding the
                relations between variables
                (mechanism of action)
              • Which variables are most
                important (high dose vs low
                dose)



A Small Dose of Toxicology            A Small Dose of Risk Assessment – 2/27/04
          Fundamental Uncertainty


              • Not knowing the right
                questions to ask
              • Most sensitive end point
              • “we don’t know what we
                don’t know”




A Small Dose of Toxicology            A Small Dose of Risk Assessment – 2/27/04
                  Sir Austin Bradford Hill


"All scientific work is incomplete - whether it
  be observational or experimental. All
  scientific work is liable to be upset or
  modified by advancing knowledge. That
  does not confer upon us a freedom to
  ignore the knowledge we already have or
  postpone the action that it appears to
  demand at a given time. "

  Sir Austin Bradford Hill (1965)
A Small Dose of Toxicology           A Small Dose of Risk Assessment – 2/27/04
                  Determining Causation

    1.     Strength of association
    2.     Consistency of findings
    3.     Biological gradient
    4.     Temporal sequence
    5.     Biologic or theoretical plausibility
    6.     Coherence with established knowledge
    7.     Specificity of association

     Sir Austin Bradford Hill (1965)

A Small Dose of Toxicology             A Small Dose of Risk Assessment – 2/27/04

								
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