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Upside-Down and Other Unusual Dose Responses and The Implications for Occupational Exposures

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nothing unique about 'toxic' chemicals. Illustrations: Hormone mimics. Bioremediation ... Can increase or reduce toxicity by supplementing or removing toxic form ... – PowerPoint PPT presentation

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Title: Upside-Down and Other Unusual Dose Responses and The Implications for Occupational Exposures


1
Upside-Down and Other Unusual Dose Responses and
The Implications for Occupational Exposures
  • Robert P. DeMott, Ph.D., DABT
  • ENVIRON International rdemott_at_environcorp.com
  • AIHA Florida Section Conference
  • St. Augustine, Florida 28 September 2006

2
Goal and Approach
  • Provide background on derivation of
    toxicity-based exposure limits
  • Explain dose-response characteristics and
    regulatory simplifications
  • Introduce the growing recognition of
    un-predicted dose-response explanations for the
    complexities of real life.

3
Outline
  • Toxicology and dose-response basics
  • Thresholds and no-effect levels
  • Straight lines good enough of govt work
  • Non-linear low dose characteristics for cancer-
    hormesis
  • Dose-response complexities for individuals and
    chemical combinations

4
Good Chemicals and Hazardous Chemicals
List A Arsenic Lead Trichloroethylene Mercury Warf
arin (D-con rat bait)
List B Oxygen Water Chromium (piccolinate) Vitamin
A Digoxin
5
We Have an Intuitive Grasp of Hazard vs.
Healthful
Which list do you associate with the scenes above?
6
Expected Associations
List B Oxygen Water Chromium (piccolinate)
Vitamin A Digoxin
  • List A
  • Arsenic
  • Lead
  • Trichloroethylene
  • Mercury
  • Warfarin (D-con rat bait)

7
Toxicological Reality
  • List A are all medicines
  • Arsenic Fowlers solution (1809-1950s) and
    other formulations
  • treat asthma, diabetes, malaria, syphilis
  • Lead various historical uses, folk
    remedies continue in use
  • for colic, menstrual disorders
  • TCE
  • general anesthetic orally, as treatment for worms

8
Mercury Historically Significant, and
  • Used to treat
  • Syphilis
  • Various GI upsets, skin conditions
  • historical experimentation lead to Paracelsus
    recognition

There are no substances which are not poisons, it
is the dose that makes the poison
9
A Modern Example Rat Poison or Heart Medication?
Source www.coumadin.com
10
Warfarin
Common trade names Athrombine-K Brumolin
Compound 42 Coumadin Coumafen Coumarin
Coumefene Dethmore Dethnel Eastern States
Duocide Fasco Fascrat Powder Frass-Ratron
Kumader Kumadu Kypfarin Maag Rattentod Cum
Mar-Frin Maveran Panwarfin Prothromadin
Rat-a-way Rat-b-gon Rat-Gard Rat-Kill
Rat-Mix Rat-ola Ratro Rats-No-More Rodafarin
Temus W Warf 42 Warf Compound 42 Warf-12
Warfarat Warfarin Warficide Zoocoumarin
When used as a rodenticide it is formulated as
colorless baits containing 250-1000 mg active
ingredient/kg.
Source IPCS INTERNATIONAL PROGRAMME ON CHEMICAL
SAFETY Health and Safety Guide No. 96 WARFARIN
HEALTH AND SAFETY GUIDE www.inchem.org/documents/h
sg/hsg/hsg096.htm
11
The Dose Differentiates the Poison
  • Probable lethal oral dose -- 50 to 500 mg/kg
  • Total of 1000 mg over 13 days fatal (adult man)
    1.1 mg/kg per day
  • IPCS INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
    Health and Safety Guide No. 96 WARFARIN HEALTH
    AND SAFETY GUIDE
  • Initial therapeutic dosage 0.03-0.07 mg/kg-day
  • About 15X separates therapeutic and lethal doses

12
The Good Chemicals are Toxic too
  • Everything in List B is also associated with
    toxicity

List B Oxygen Water Chromium (picolinate) Vitamin
A Digoxin
13
Some medicinesstarted off aspoisons
  • Atropine stimulant
  • neurological propertiesrecognized from
    poisonings
  • Purified from Deadly Nightshade
  • Digoxin, Digitalis cardiac medications
  • Useful dosages of extract from Foxglove

14
18th Century Doc Learns the Dose-Response Lesson
The extract of Foxglove is highly poisonous. This
extract was the poison used in Medieval Times for
the ritual known as Trial By Ordeal! In 1775
Scottish doctor William Withering, who had
written a book on botany, had a very sick
patient. After telling him he was going to die,
the patient went to a local gypsy, who gave him
an herbal remedy.
He immediately got better! Dr. Withering
demanded that the gypsy show him the remedy and
was surprised to discover it to be Foxglove, a
plant he thought was poisonous! Dr. Withering
brought Foxglove to the world of medicine. This
extract became known as Digitalis, one of the
most important heart medicines of today!
The Foxglove Story
Source www.webplastics.com/botoxcoll.htm
15
Critical Concept 1
  • No matter how good or bad the
    associationswith a given chemical
  • The relevant or potentialdose determines the
    risk of undesired outcomes

16
Biology Survives on Chemistry
  • Energy, Communication,Sensory Control depend
    on processing complex chemicals
  • Biochemistry is blind nothing unique about
    toxic chemicals
  • Illustrations
  • Hormone mimics
  • Bioremediation
  • Bioactivation

17
Detoxification Driven by the Liver
  • Tremendous capacity,extensive detoxification
    biochemistry
  • Control byenzymes that respond to chemicals
    presence
  • Foreign chemicals deactivated then packaged for
    excretion

18
Additional Detoxification Organs
  • Kidneys
  • Lungs
  • Skin

Pop Quiz What are the two largest tissues/organs?
19
Critical Concept 2
  • Biological organisms arechemical-utilizing
    machineswith highly evolved protectivefeatures
  • The form, amount, and timing of chemical
    exposures (back to dose again) is critical to the
    balance between detoxification and toxicity

20
Dose-Response Characteristics
  • How changes in dose cause changes in response
    toxicity
  • Need to know because this describesPotency
    Little more Lot worse vs. Lot more
    Little worse
  • Graphical representation common

21
Classic Dose-Response Curve
  • Flat region then response increases with dose

22
Thresholds of Effect
  • Steepness corresponds to Potency
  • Inflection points Threshold Maximal Response

23
Potency Estimation Quiz
  • Chemical Botox
  • Use Injectable skin enhancement

24
Common Chemicals Cant be THAT Toxic, Right?
  • Botox is one of the most popular cosmetic
    mini-treatments today. This procedure
    requires no anesthesia or recovery. Overall, the
    vast majority of patients love this "quick fix"
    and return for a BOTOX boost as soon as the
    wrinkles begin to reappear!

Source www.webplastics.com/botoxcoll.htm
25
Potency Estimation
Botox
The most potent substance known
Botulinum Toxin used as the example of extreme
potency in most texts 50,000,000 times more
toxic than DDT
26
Human Health Toxicity Assessment
  • Need to predict safe exposurelevels
    occupational,environmental
  • Aim for extrapolation to sensitive individuals
  • Type of Response
  • Carcinogen
  • Non-carcinogen/systemic toxic effects
  • Numerical toxicity values
  • Cancer Slope Factor (CSF)
  • Exposure limit / reference dose (RfD)

27
Non-Cancer Value Derivation Using the Threshold
  • Start fromNO-OBSERVABLE-ADVERSE-EFFECTS-LEVEL
    (NOAEL)
  • This conservatively estimated to be below the
    threshold level
  • Adjust downward to account for uncertainties
  • RfD or TLV or PEL NOAEL / UF

28
Toxicity Value Adjustment -- Uncertainty Factors
  • 10 for species X
  • 10 for sensitive individuals X
  • 10 for Less-than-Chronic studies X
  • 10 for LOAEL to NOAEL X
  • 3-10 for Incomplete database
  • Generally total at least 30 1,000 is common

29
Cancer Toxicity Values Using a Straight Line
  • Cancer Slope Factor -- slope of the dose-response
    curve for cancer
  • Assumes the curve doesnt flatten out -- there is
    no threshold.
  • Extend dose-response curve as a straight line all
    the way to zero
  • Certain chemicals are best represented by other
    models

30
Why Cancers Different
  • Early recognition of theoretical basis for cancer
    to be a non -threshold phenomenon
  • Developed from radiation effects on chromosomes
    and one-hit hypothesis
  • Risk not seen as function of detox processing
    capacity being overcome
  • Instead, chance physical interaction between
    chemical and DNA resulting in mutation

31
Theoretically No Threshold
  • Assuming no detox., then no threshold exists
  • Dose-response can no longer be flat below
    threshold
  • Requires extrapolation of dose-response curve
    through low-dose region

32
Straight-Line Extrapolation
  • Requires extrapolation through low-dose region
  • Protective to extrapolate all the way to 0

33
Comparison of Dose Response Assessments
Slope Factor
Carcinogens
Response
Non-Carcinogens
Response
Reference Dose
Dose
34
From Simple to Sublime
  •  Physiology and biochemistry are NOT simple,
    mono-phasic processes
  • Defense/detoxification mechanisms must be
    overcome (saturated)
  • Alternate handling can be stimulated or
    present in certain individuals
  • Multiple responses occurring, interacting

35
Simplification, not Simplistic
  • Scientists not ignorant of dose-response
    complexities
  • Pharmacologists capitalize on multiphasic
    responses
  • Microbiologists understood stimulation at low
    doses
  • Simplifications of dose-response toxicity simply
    sufficient, for a time.

36
Cancer Thresholds Observed in Practice
37
Observations Displace Theory
  •  Many chemicals require biotransformation and
    INTERMEDIATES are carcinogens at low
    concentrations, the abundance of detox capacity
    drives reactions too quickly for intermediates to
    build up
  •  DNA repair mechanisms must be overwhelmed
  •  Epigenetic (non-mutation) basis for cancer now
    well established

38
Hormesis New Curve Shapes
  • Primarily a function of scale or resolution
    looking in the low-dose tail
  • Upside-down Us and Js
  • Demonstrate more than one peak, or shift in
    dose-response direction

39
Higher Dose Lower Effect ?
0.1 mg/kg
0.1 mg/kg
0.2 mg/kg
0.3 mg/kg
Low doses stimulate a response, which is
subsequently reduced
40
Watch the Dose Scale
Response
0.2 mg/kg
2 mg/kg
20 mg/kg
Dose
41
Good Outcomes Below NOEL
Source Jayjock, M.A. Lewis, P.G. (2002)
Implications of Hormesis for Industrial Hygiene.
BELLE Newsletter 10 2
42
Hormesis Rule or Exception
  •  Long documented phenomenon,
  •  Marginalized from application in risk assessment
  •  Association with homeopathy
  •  Lack of low dose testing

43
Hormesis Exists for
  • Low-dose radiation
  • Stimulation of repair mechanisms
  • Benzene
  • Ethanol
  • PAHs (combustion products)
  • Drugs
  • Hormones (feedback loops)

44
Reasons for Shape-Shifting
  •  Chemical modulates its own tox/detox processes
  • Feedback loops with other chemicals/signals
  •  Antagonistic OR Stimulatory
  • Recruitment of a secondary stimulus Call for
    help
  •  Feedback Inhibition -- the response may reach a
    level where it stimulates antagonistic mechanisms

45
Examples of Modulation
  • Stimulation -- Phenobarbital induces P450 3A
    family responsible for multiple drug/chemical
    metabolic processing
  • Inhibition
  • PAH mixtures less potent carcinogens than the
    carcinogenicity of the individual chemicals would
    dictate
  • Inhibition of P450 enzymes by some PAHs slows
    metabolism needed for carcinogen formation from
    others

46
Hormesis Concerns
  • Incorporating any allowance for positive
    effects at low doses reduces protection
  • What if there are additional unknown negative
    effects?

47
Response
Dose
We could be missing low-dose, highly toxic
responses
48
Good Us Arent Only Shape
Source Jayjock, M.A. Lewis, P.G. (2002)
Implications of Hormesis for Industrial Hygiene.
BELLE Newsletter 10 2
49
Beyond Hormesis Other Complex Dose-Responses
  • Metabolism Dependent Effects
  • Stimulation or antagonism of detox processes
  • Some enzyme synthesis is upregulated by presence
    of substrate
  • Example Cytochrome P450 Induction
  • Can increase or reduce toxicity by supplementing
    or removing toxic form

50
Drug Modulating Metabolism
  • Disulfiram changes metabolic profile for
    ethanol
  • Ethanol metabolism classically proceeds via
    acetaldehyde then acetate formation
  • Disulfiram -- Antabuse
  • induces (along with ethanol) cytochrome P450 2E
    family responsible for ethanol metabolism
  • blocks enzyme responsible for conversion to
    acetate
  •  Result is acetaldehyde buildup -- Highly
    unpleasant

51
Hot Topic - Mold
  • Concerns about poorlyunderstood health hazard
  • Inconsistent observationsof effects
  • Mold differences
  • Individual differences
  • Both pertain to dose-response characteristics

52
Possible Health Effects
  • Infection
  • Allergic-type responses
  • Organic dust toxic syndrome
  • Chronic bronchitis
  • Hypersensitivity pneumonitis
  • Asthma, rhinitis and conjunctivitis
  • Toxic responses (i.e., endotoxins, mycotoxins)
  • Irritation (i.e., VOCs)

53
Toxicology Challenges
  • Allergic responses followcomplex dose-response
    characteristics
  • Change over time (sensitization)
  • Affected by other allergens, immune conditions
  • Dose-response curves not even established for
    relevant mold chemicals

54
Journal Article Wall St. Style
55
Take Home Messages
  • The dose ALWAYS matters
  • Dose response simplifications workfor
    protection, but may not explain reality
  • Cancer thresholds are real, and will be addressed
  • Hormesis is real, whether its relevant to
    exposure limits, well see
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