Transcript Document

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
 Provide background on derivation of toxicitybased exposure limits
 Explain dose-response characteristics and
regulatory simplifications
 Introduce the growing recognition of “unpredicted” dose-response explanations for the
complexities of real life.
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
List A
List B
Arsenic
Oxygen
Lead
Water
Trichloroethylene
Chromium (piccolinate)
Mercury
Vitamin A
Warfarin (D-con rat bait)
Digoxin
We Have an Intuitive Grasp of
Hazard vs. Healthful…
Which list do you associate with
the scenes above?
Expected Associations
List A
List B
Arsenic
Oxygen
Lead
Water
Trichloroethylene
Chromium (piccolinate)
Mercury
Vitamin A
Warfarin (D-con rat bait)
Digoxin
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 …
 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?
Source: www.coumadin.com
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; MarFrin; Maveran; Panwarfin; Prothromadin; Rat-away; Rat-b-gon; Rat-Gard; Rat-Kill; Rat-Mix; Ratola; 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
 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
 Everything in List B
is also associated
with toxicity
List B
Oxygen
Water
Chromium (picolinate)
Vitamin A
Digoxin
Some medicines
started off as
poisons
 Atropine – stimulant
- neurological properties
recognized from poisonings
- Purified from Deadly Nightshade
 Digoxin, Digitalis – cardiac medications
- Useful dosages of extract from Foxglove
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.
The Foxglove Story
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!
Source: www.webplastics.com/botoxcoll.htm
Critical Concept # 1
 No matter how “good” or
“bad” the associations
with a given chemical:
The relevant or potential
dose determines the risk
of undesired outcomes
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
 Tremendous capacity,
extensive
detoxification
biochemistry
 Control by
enzymes that respond
to chemical’s presence
 Foreign chemicals “deactivated” then
packaged for excretion
Additional Detoxification
Organs
 Kidneys
 Lungs
 Skin
Pop Quiz:
What are the two largest
tissues/organs?
Critical Concept # 2
 Biological organisms are
chemical-utilizing machines
with highly evolved protective
features
The form, amount, and timing of chemical
exposures (back to dose again) is critical to
the balance between detoxification and toxicity
Dose-Response Characteristics
 How changes in dose cause changes in
response – toxicity
 Need to know because this describes
Potency :
Little more = Lot worse
vs.
Lot more = Little worse
 Graphical representation common
Classic Dose-Response Curve
 Flat region then response increases with dose
Thresholds of Effect
 Steepness corresponds to Potency
 Inflection points – Threshold; Maximal Response
Potency Estimation Quiz
Chemical – Botox
Use
– Injectable skin enhancement
Difficult
to Reach
Toxicity
Toxic, but
not
Extra-
unusual
Toxic
ordinarily
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
Botox
Difficult
to Reach
Toxicity
Toxic, but
not
unusual
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
• Need to predict safe exposure
levels – 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
 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
- 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 Slope Factor -- slope of the doseresponse 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
 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
 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
 Requires
extrapolation
through lowdose region
 Protective to
extrapolate all
the way to “0”
Comparison of Dose
Response Assessments
Slope Factor
Carcinogens
Non-Carcinogens
Reference
Dose
Dose
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
 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
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
 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
0
0.1 .
mg/kg1
m
g
/
k
g
Dose
0.2
mg/kg
0.3
mg/kg
Low doses stimulate a response, which is subsequently
reduced
Watch the Dose Scale …
Response
0.2
mg/kg
Dose
2
mg/kg
20
mg/kg
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
 Long documented phenomenon,
 Marginalized from application in risk
assessment
 Association with homeopathy
 Lack of low dose testing
Hormesis Exists for:
 Low-dose radiation
- Stimulation of repair mechanisms
 Benzene
 Ethanol
 PAHs (combustion products)
 Drugs
 Hormones (feedback loops)
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
 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
 Incorporating any “allowance” for positive
effects at low doses reduces protection
 What if there are additional unknown negative
effects?
Response
Dose
We could be missing low-dose, highly toxic responses
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
 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
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
 Concerns about poorly
understood health hazard
 Inconsistent observations
of effects:
- Mold differences
- Individual differences
 Both pertain to dose-response
characteristics
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
 Allergic responses follow
complex 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
Take Home Messages
 The dose ALWAYS matters
 Dose response simplifications work
for 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