1. Human and Animal Testing: What’s Appropriate

2. HUMAN AND ANIMAL TESTING; WHAT’S APPROPRIATE? JOHN DOULL
As toxicologists we share responsibility for providing answers to the public for safety questions; Is it safe? & Will it hurt me?
To provide answers, we need the “right” information:
Right chemical, right exposure scenario, right subject.
Chemical/agent identity: (wrong salt, racemate); purity (mixture); surrogate with similar physical, chemical and/or biological properties etc.
Tool: SAR

3. HUMAN AND ANIMAL TESTING; WHAT’S APPROPRIATE? JOHN DOULL
Exposure: wrong dose/duration, wrong route etc.
Tools: interpolation, kinetics/Haber, extrapolation.
Subject or target: Population/individual; susceptibility (sex, age, race, disease, environment etc.).
Tool: surrogate species, WOE.

4. General Acute Toxicity Repeated Dose Toxicity
TYPICAL COSTS OF DESCRIPTIVE TOXICITY TESTS Casarett & Doull, Chapter 2, 6th Ed.
TEST
COST, $
General Acute Toxicity
Acute toxicity (rat, two routes)
6,500
Acute dermal toxicity (rabbit)
3,500
Acute inhalation toxicity (rat)
10,000
Acute dermal irritation (rabbit)
2,000
Acute eye irritation (rabbit)
1,500
Skin sensitization (guinea pig)
5,000
Repeated Dose Toxicity
14-day exposure (rat)
45,000
90-day exposure (rat)
110,000
1-year (diet; rat)
250,000
1-year (oral gavage; rat)
300,000
2-year (diet; rat)
685,000
2-year (oral gavage; rat)
860,000

5. Genetic Toxicology Tests
TYPICAL COSTS OF DESCRIPTIVE TOXICITY TESTS Casarett & Doull, Chapter 2, 6th Ed.
TEST
COST, $
Genetic Toxicology Tests
Bacterial reverse mutation (Ames test)
7,000
Mammalian cell forward mutation
25,000
In vitro cytogenetics (CHO cells)
20,000
In vivo micronucleus (mouse)
11,000
In vivo chromosome aberration (rat)
22,500
Dominant lethal (mouse)
85,000
Drosophila sex-linked recessive lethal
55,000
Mammalian bone marrow cytogenetics (in vivo; rat)
Reproduction
Segment I (rat)
90,000
Segment II (rat)
63,000
Segment II (rabbit)
72,000
Segment III (rat)
160,000

6. HOW RELIABLE ARE ANIMAL TESTS?
Quantitative: species vary in their susceptibility: PPAR
Qualitative: some species have unique ability: Alpha-2-glob
Protocols with inadequate power: Vioxx
Protocols inadequate: headache, depression, anxiety
Alternatives
Alan Goldberg, CAAT at John’s Hopkins, Celebrating 25 years in 2006, Hits?

7. PROPOSED TIMEFRAME FOR FULL REPLACEMENT OF ANIMAL TESTS
Human Health Effects
Foreseeable Time Involved for Full Replacement
Acute toxicity
> 2014
Skin irritation
Skin corrosion
< 2004
Eye irritation
> 2010
Skin Sensitization
> 2019
Skin absorption/penetration
> 2006
Subacute/subchronic toxicity
> > 2014 (not forseeable)
Genotoxicity/mutagenicity
> 2016
UV-induced effects
> > 2019 (not forseeable)
Toxicokinetics and biotransformation
Carcinogenicity
Reproductive toxicity
SCCNFP, Annual European Meeting Toxicology Forum, Brussels,