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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 [email protected] 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 [email protected]

AIHA – Florida Section Conference

St. Augustine, Florida 28 September 2006

goal and approach
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.
outline
Outline
  • 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

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…

Which list do you associate with

the scenes above?

expected associations
Expected Associations

List A

Arsenic

Lead

Trichloroethylene

Mercury

Warfarin (D-con rat bait)

List B

Oxygen

Water

Chromium (piccolinate)

Vitamin A

Digoxin

toxicological reality
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
mercury historically significant and
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

warfarin
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/hsg/hsg/hsg096.htm

the dose differentiates the poison
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
the good chemicals are toxic too
The “Good Chemicals” are Toxic too
  • 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 medicinesstarted 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
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

critical concept 1
Critical Concept # 1
  • 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
  • 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
  • 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
  • Kidneys
  • Lungs
  • Skin

Pop Quiz:

What are the two largest tissues/organs?

critical concept 2
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

dose response characteristics
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
classic dose response curve
Classic Dose-Response Curve
  • Flat region then response increases with dose
thresholds of effect
Thresholds of Effect
  • Steepness corresponds to Potency
  • Inflection points –Threshold; Maximal Response
potency estimation quiz
Difficult 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?

“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 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 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)
non cancer value derivation using the threshold
Non-Cancer Value Derivation – Using the Threshold
  • 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
    • 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
  • 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
  • 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
  • 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
  • Requires extrapolation through low-dose region
  • Protective to extrapolate all the way to “0”
slide33
Comparison of Dose

Response Assessments

Slope Factor

Carcinogens

Response

Non-Carcinogens

Response

Reference

Dose

Dose

from simple to sublime
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
simplification not simplistic
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….
observations displace theory
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
hormesis new curve shapes
Hormesis: New Curve Shapes
  • 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

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 …

Response

0.2 mg/kg

2 mg/kg

20 mg/kg

Dose

good outcomes below noel
Good Outcomes Below NOEL

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
  • Long documented phenomenon,
  • Marginalized from application in risk assessment
  • Association with homeopathy
  • Lack of low dose testing
hormesis exists for
Hormesis Exists for:
  • Low-dose radiation
    • Stimulation of repair mechanisms
  • Benzene
  • Ethanol
  • PAHs (combustion products)
  • Drugs
  • Hormones (feedback loops)
reasons for shape shifting
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
examples of modulation
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
hormesis concerns
Hormesis Concerns
  • Incorporating any “allowance” for positive effects at low doses reduces protection
  • What if there are additional unknown negative effects?
slide47
Response

Dose

We could be missing low-dose, highly toxic responses

good u s aren t only shape
Good “U’s” Aren’t Only Shape

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
  • 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

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
  • Concerns about poorlyunderstood health hazard
  • Inconsistent observationsof effects:
    • Mold differences
    • Individual differences
  • Both pertain to dose-response characteristics
possible health effects
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)
toxicology challenges
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
take home messages
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 it’s relevant to exposure limits, we’ll see
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