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Upside-Down and Other Unusual Dose Responses and The Implications for Occupational Exposures. Robert P. DeMott, Ph.D., DABT ENVIRON International rdemott@environcorp.com AIHA – Florida Section Conference St. Augustine, Florida 28 September 2006. Goal and Approach.

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Upside down and other unusual dose responses and the implications for occupational exposures

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

Robert P. DeMott, Ph.D., DABT

ENVIRON Internationalrdemott@environcorp.com

AIHA – Florida Section Conference

St. Augustine, Florida 28 September 2006


Goal and approach
Goal and Approach Implications for Occupational Exposures

  • 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.


Outline
Outline Implications for Occupational Exposures

  • Toxicology and dose-response basics

  • Thresholds and no-effect levels

  • Straight lines – good enough of gov’t work…

  • Non-linear low dose characteristics for cancer- hormesis

  • Dose-response complexities for individuals and chemical combinations


Good chemicals and hazardous chemicals
“Good Chemicals” and Hazardous Chemicals Implications for Occupational Exposures

List A

Arsenic

Lead

Trichloroethylene

Mercury

Warfarin (D-con rat bait)

List B

Oxygen

Water

Chromium (piccolinate)

Vitamin A

Digoxin


We have an intuitive grasp of hazard vs healthful
We Have an Intuitive Grasp of Hazard vs. Healthful… Implications for Occupational Exposures

Which list do you associate with

the scenes above?


Expected associations
Expected Associations Implications for Occupational Exposures

List A

Arsenic

Lead

Trichloroethylene

Mercury

Warfarin (D-con rat bait)

List B

Oxygen

Water

Chromium (piccolinate)

Vitamin A

Digoxin


Toxicological reality
Toxicological Reality Implications for Occupational Exposures

  • 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


Mercury historically significant and
Mercury – Historically Significant, and … Implications for Occupational Exposures

  • 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


A modern example rat poison or heart medication
A Modern Example: Rat Poison or Heart Medication? Implications for Occupational Exposures

Source: www.coumadin.com


Warfarin
Warfarin Implications for Occupational Exposures

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/hsg/hsg/hsg096.htm


The dose differentiates the poison
The Dose Differentiates the Poison Implications for Occupational Exposures

  • 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


  • The good chemicals are toxic too
    The “Good Chemicals” are Toxic too Implications for Occupational Exposures

    • Everything in List B is also associated with toxicity

    List B

    Oxygen

    Water

    Chromium (picolinate)

    Vitamin A

    Digoxin


    Some medicines started off as poisons
    Some medicines Implications for Occupational Exposuresstarted off aspoisons

    • Atropine – stimulant

      • neurological propertiesrecognized from poisonings

      • Purified from Deadly Nightshade

    • Digoxin, Digitalis – cardiac medications

      • Useful dosages of extract from Foxglove


    18 th century doc learns the dose response lesson
    18 Implications for Occupational Exposuresth 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


    Critical concept 1
    Critical Concept # 1 Implications for Occupational Exposures

    • No matter how “good” or “bad” the associationswith a given chemical:

      The relevant or potentialdose determines the risk of undesired outcomes


    Biology survives on chemistry
    Biology Survives on Chemistry Implications for Occupational Exposures

    • Energy, Communication,Sensory Control – depend on processing complex chemicals

    • Biochemistry is blind –nothing unique about “toxic” chemicals

    • Illustrations:

      • Hormone mimics

      • Bioremediation

      • Bioactivation


    Detoxification driven by the liver
    Detoxification Driven by the Liver Implications for Occupational Exposures

    • Tremendous capacity,extensive detoxification biochemistry

    • Control byenzymes that respond to chemical’s presence

    • Foreign chemicals “deactivated” then packaged for excretion


    Additional detoxification organs
    Additional Detoxification Organs Implications for Occupational Exposures

    • Kidneys

    • Lungs

    • Skin

    Pop Quiz:

    What are the two largest tissues/organs?


    Critical concept 2
    Critical Concept # 2 Implications for Occupational Exposures

    • 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


    Dose response characteristics
    Dose-Response Characteristics Implications for Occupational Exposures

    • 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


    Classic dose response curve
    Classic Dose-Response Curve Implications for Occupational Exposures

    • Flat region then response increases with dose


    Thresholds of effect
    Thresholds of Effect Implications for Occupational Exposures

    • Steepness corresponds to Potency

    • Inflection points –Threshold; Maximal Response


    Potency estimation quiz

    Difficult Implications for Occupational Exposures to Reach Toxicity

    Toxic, but not unusual

    Extra-ordinarily Toxic

    Potency Estimation Quiz

    Chemical – Botox

    Use – Injectable skin enhancement


    Common chemicals can t be that toxic right
    Common Chemicals Can’t be THAT Toxic, Right? Implications for Occupational Exposures

    “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


    Potency estimation

    Difficult Implications for Occupational Exposures to Reach Toxicity

    Toxic, but not unusual

    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


    Human health toxicity assessment
    Human Health Implications for Occupational ExposuresToxicity 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)


    Non cancer value derivation using the threshold
    Non-Cancer Value Derivation – Using the Threshold Implications for Occupational Exposures

    • Start from:NO-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


    Toxicity value adjustment uncertainty factors
    Toxicity Value Adjustment -- Uncertainty Factors Implications for Occupational Exposures

    • 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


  • Cancer toxicity values using a straight line
    Cancer Toxicity Values – Using a Straight Line Implications for Occupational Exposures

    • Cancer Slope Factor -- slope of the dose-response curve for cancer

    • Assumes the curve doesn’t 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


    Why cancer s different
    Why Cancer’s Different Implications for Occupational Exposures

    • 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


    Theoretically no threshold
    Theoretically – No Threshold Implications for Occupational Exposures

    • 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


    Straight line extrapolation
    Straight-Line Extrapolation Implications for Occupational Exposures

    • Requires extrapolation through low-dose region

    • Protective to extrapolate all the way to “0”


    Upside down and other unusual dose responses and the implications for occupational exposures

    Comparison of Dose Implications for Occupational Exposures

    Response Assessments

    Slope Factor

    Carcinogens

    Response

    Non-Carcinogens

    Response

    Reference

    Dose

    Dose


    From simple to sublime
    From Simple to Sublime… Implications for Occupational Exposures

    • 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


    Simplification not simplistic
    Simplification, not Simplistic Implications for Occupational Exposures

    • 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….


    Cancer thresholds observed in practice
    Cancer Thresholds Observed in Practice Implications for Occupational Exposures


    Observations displace theory
    Observations Displace Theory Implications for Occupational Exposures

    • 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


    Hormesis new curve shapes
    Hormesis: New Curve Shapes Implications for Occupational Exposures

    • Primarily a function of scale or resolution – looking in the low-dose tail

    • Upside-down U’s and J’s

    • Demonstrate more than one peak, or shift in dose-response direction


    Higher dose lower effect

    Response Implications for Occupational Exposures

    Dose

    Higher Dose = Lower Effect ?

    0.1 mg/kg

    0.2 mg/kg

    0.1 mg/kg

    0.3 mg/kg

    Low doses stimulate a response, which is subsequently reduced


    Watch the dose scale
    Watch the Dose Scale … Implications for Occupational Exposures

    Response

    0.2 mg/kg

    2 mg/kg

    20 mg/kg

    Dose


    Good outcomes below noel
    Good Outcomes Below NOEL Implications for Occupational Exposures

    Source: Jayjock, M.A. & Lewis, P.G. (2002) Implications of Hormesis for Industrial Hygiene. BELLE Newsletter 10: 2


    Hormesis rule or exception
    Hormesis: Rule or Exception Implications for Occupational Exposures

    • Long documented phenomenon,

    • Marginalized from application in risk assessment

    • Association with homeopathy

    • Lack of low dose testing


    Hormesis exists for
    Hormesis Exists for: Implications for Occupational Exposures

    • Low-dose radiation

      • Stimulation of repair mechanisms

    • Benzene

    • Ethanol

    • PAHs (combustion products)

    • Drugs

    • Hormones (feedback loops)


    Reasons for shape shifting
    Reasons for Shape-Shifting Implications for Occupational Exposures

    • 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


    Examples of modulation
    Examples of Modulation Implications for Occupational Exposures

    • 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


    Hormesis concerns
    Hormesis Concerns Implications for Occupational Exposures

    • Incorporating any “allowance” for positive effects at low doses reduces protection

    • What if there are additional unknown negative effects?


    Upside down and other unusual dose responses and the implications for occupational exposures

    Response Implications for Occupational Exposures

    Dose

    We could be missing low-dose, highly toxic responses


    Good u s aren t only shape
    Good “U’s” Aren’t Only Shape Implications for Occupational Exposures

    Source: Jayjock, M.A. & Lewis, P.G. (2002) Implications of Hormesis for Industrial Hygiene. BELLE Newsletter 10: 2


    Beyond hormesis other complex dose responses
    Beyond Hormesis – Other Complex Dose-Responses Implications for Occupational Exposures

    • 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


    Drug modulating metabolism
    Drug Modulating Metabolism Implications for Occupational Exposures

    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


    Hot topic mold
    Hot Topic - Mold Implications for Occupational Exposures

    • Concerns about poorlyunderstood health hazard

    • Inconsistent observationsof effects:

      • Mold differences

      • Individual differences

    • Both pertain to dose-response characteristics


    Possible health effects
    Possible Health Effects Implications for Occupational Exposures

    • 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)


  • Toxicology challenges
    Toxicology Challenges Implications for Occupational Exposures

    • 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


    Journal article wall st style
    Journal Article – Wall St. Style Implications for Occupational Exposures


    Take home messages
    Take Home Messages Implications for Occupational Exposures

    • 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 it’s relevant to exposure limits, we’ll see


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