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Casarett & Doull’s
Essentials of oxicology
T ird Edition
Editors
Curtis D. Klaassen, PhD
University Distinguished Professor
Division of Gastroenterology
Department of Internal Medicine
University of Kansas Medical Center
Kansas City, Kansas
John B. Watkins III, PhD
Associate Dean and Director
Professor of Pharmacology and oxicology
Medical Sciences Program
Indiana University School of Medicine
Bloomington, Indiana
New York Chicago San Francisco Lisbon London Madrid Mexico City
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Contents
Contributors vii
Pre ace xiii
U N I 1 U N I 4
GENERAL PRINCIPLES OF TARGET ORGAN TOXICITY 163
TOXICOLOGY 1
11. oxic Responses o the Blood
1. History and Scope o oxicology John C. Bloom, Andrew E. Schade,
Michael A. Gallo 1 and John . Brandt 163
2. Principles o oxicology 12. oxic Responses o the Imm ne System
David L. Eaton and Steven G. Gilbert 5 Barbara L.F. Kaplan, Courtney E.W. Sulentic,
Michael P. Holsapple, and Norbert E.
3. Mechanisms o oxicity Kaminski 177
Zoltán Gregus 21
13. oxic Responses o the Liver
4. Risk Assessment Hartmut Jaeschke 195
Elaine M. Faustman and Gilbert S. Omenn 49
14. oxic Responses o the Kidney
Rick G. Schnellmann 209
U N I 2 15. oxic Responses o the Respiratory System
DISPOSITION OF TOXICANTS 61 George D. Leikau 223
5. Absorption, Distrib tion, 16. oxic Responses o the Nervo s System
and Excretion o oxicants Virginia C. Moser, Michael Aschner,
Lois D. Lehman-McKeeman 61 Rudy J. Richardson, and Martin A. Philbert 237
6. Biotrans ormation o Xenobiotics 17. oxic Responses o the Oc lar
Andrew Parkinson, Brian W. Ogilvie, David B. and Vis al System
Buckley, Faraz Kazmi, Maciej Czerwinski, Donald A. Fox and William K. Boyes 255
and Oliver Parkinson 79 18. oxic Responses o the Heart
7. oxicokinetics and Vasc lar System
Danny D. Shen 109 Y. James Kang 271
19. oxic Responses o the Skin
Robert H. Rice and T eodora M. Mauro 291
U N I 3
20. oxic Responses o the Reprod ctive System
NONORGAN-DIRECTED TOXICITY 121 Paul M.D. Foster and L. Earl Gray Jr. 303
8. Chemical Carcinogenesis 21. oxic Responses o the Endocrine System
James E. Klaunig 121 Patricia B. Hoyer and Jodi A. Flaws 319
9. Genetic oxicology
R. Julian Preston and George R. Hof mann 135
10. Developmental oxicology
John M. Rogers 149
v
vi CON EN S
U N I 5 U N I 7
TOXIC AGENTS 333 APPLICATIONS OF TOXICOLOGY 441
22. oxic Ef ects o Pesticides 30. Ecotoxicology
Lucio G. Costa 333 Richard . Di Giulio and Michael C. Newman 441
23. oxic Ef ects o Metals 31. Food oxicology
Erik J. okar, Windy A. Boyd, Jonathan H. Frank N. Kotsonis and George A. Burdock 453
Freedman, and Michael P. Waalkes 347
32. Analytical and Forensic oxicology
24. oxic Ef ects o Solvents and Vapors Bruce A. Goldberger and Diana G. Wilkins 463
James V. Bruckner, S. Satheesh Anand,
33. Clinical oxicology
and D. Alan Warren 361
Louis R. Cantilena Jr. 471
25. oxic Ef ects o Radiation and Radioactive 34. Occ pational oxicology
Materials
Peter S. T orne 481
David G. Hoel 373
26. oxic Ef ects o Plants and Animals
John B. Watkins, III 381 Answers to Chapter Questions 491
Index 495
27. oxic Ef ects o Calories
Martin J. Ronis, Kartik Shankar,
and T omas M. Badger 401
U N I 6
ENVIRONMENTAL TOXICOLOGY 411
28. Nanotoxicology
Gunter Oberdörster, Agnes B. Kane,
Rebecca D. Kapler, and Robert H. Hurt 411
29. Air Poll tion
Daniel L. Costa and erry Gordon 425
Contributors
S. Satheesh Anand, PhD, DAB William K. Boyes, PhD
Senior Research oxicologist Neurotoxicology Branch
Haskell Global Centers or Health and Environmental oxicity Assessment Division
Sciences National Health and Environmental E ects Research
Newark, Delaware Laboratory
Chapter 24 O ce o Research and Development
US Environmental Protection Agency
Michael Aschner, PhD Research riangle Park, North Carolina
Pro essor Chapter 17
Department o Pediatrics
Vanderbilt University Medical Center John . Brandt, MD
Nashville, ennessee Eli Lilly & Co. (retired)
Chapter 16 Indianapolis, Indiana
Chapter 11
T omas M. Badger, PhD
Distinguished Faculty Scholar James V. Br ckner, PhD
Pro essor Pro essor o Pharmacology & oxicology
Departments o Pediatrics and Physiology/Biophysics Department o Pharmaceutical & Biomedical
University o Arkansas or Medical Sciences Sciences
Director College o Pharmacy
Arkansas Children’s Nutrition Center University o Georgia
Little Rock, Arkansas Athens, Georgia
Chapter 27 Chapter 24
John C. Bloom, VMD, PhD David B. B ckley, PhD
President Chie Scienti c O cer
Bloom Consulting Services, LLC Xeno ech, LLC
Special Government Employee Lenexa, Kansas
FDA Chapter 6
Adjunct Pro essor o Pathology
George A. B rdock, PhD, DAB , FACN
Schools o Veterinary Medicine
President
University o Pennsylvania and Purdue University
Burdock Group Consultants
Indianapolis, Indiana
Orlando, Florida
Chapter 11
Chapter 31
Windy A. Boyd, PhD
Lo is R. Cantilena Jr., MD, PhD
Biologist
Pro essor, Medicine and Pharmacology
Biomolecular Screening Branch
Department o Medicine
National oxicology Program Division
Uni ormed Services University
National Institute o Environmental Health Sciences, NIH
Bethesda, Maryland
Research riangle Park, North Carolina
Chapter 33
Chapter 23
vii
viii CON RIBu ORS
Daniel L. Costa, PhD Pa l M.D. Foster, PhD
O ce o Research and Development Chie
National Program Director or Air, Climate, and Energy oxicology Branch
Research Program Division o the National oxicology Program
US Environmental Protection Agency National Institute o Environmental Health Sciences
Research riangle Park, North Carolina Research riangle Park, North Carolina
Chapter 29 Chapter 20
L cio G. Costa, PhD Donald A. Fox, PhD
Pro essor Pro essor o Vision Sciences
Department o Environmental and Occupational Biology and Biochemistry, Pharmacology, and Health and
Health Sciences Human Per ormance
School o Public Health University o Houston
University o Washington Houston, exas
Seattle, Washington Chapter 17
Chapter 22
Jonathan H. Freedman, PhD
Maciej Czerwinski, PhD Laboratory o oxicology and Pharmacology
Principal Scientist National Institute o Environmental Health Sciences
Xeno ech, LLC Research riangle Park, North Carolina
Lenexa, Kansas Chapter 23
Chapter 6
Michael A. Gallo, PhD
Richard . Di Gi lio, PhD Environmental and Occupational Health Sciences
Pro essor Institute
Nicholas School o the Environmental Rutgers-T e State University o New Jersey
Duke University UMDNJ-Robert Wood Johnson Medical School
Durham, North Carolina Piscataway, New Jersey
Chapter 30 Chapter 1
David L. Eaton, PhD Steven G. Gilbert, PhD
Pro essor Director
Department o Environmental and Occupational Institute o Neurotoxicology & Neurological Disorders
Health Sciences Seattle, Washington
Associate Vice Provost or Research Chapter 2
University o Washington
Br ce A. Goldberger, PhD
Seattle, Washington
Pro essor and Director o oxicology
Chapter 2
Departments o Pathology and Psychiatry
Elaine M. Fa stman, PhD University o Florida College o Medicine
Pro essor Gainesville, Florida
Institute or Risk Analysis and Risk Communication Chapter 32
Department o Environmental and Occupational
erry Gordon, PhD
Health Sciences
Pro essor
School o Public Health
Department o Environmental Medicine
University o Washington
NYU School o Medicine
Seattle, Washington
uxedo, New York
Chapter 4
Chapter 29
Jodi A. Flaws, PhD
L. Earl Gray Jr., PhD
Pro essor
Reproductive oxicology Branch
Department o Comparative Biosciences
United States Environmental Protection Agency
University o Illinois
Adjunct Pro essor
Urbana, Illinois
North Carolina State University
Chapter 21
Raleigh, North Carolina
Chapter 20
CON RIBu ORS ix
Zoltán Greg s, MD, PhD, DSc, DAB Norbert E. Kaminski, PhD
Pro essor Pro essor
Department o Pharmacology and T erapeutics Department o Pharmacotherapy and oxicology
oxicology Section Director
University o Pecs Center or Integrative oxicology
Medical School Michigan State University
Pecs, Hungary East Lansing, Michigan
Chapter 3 Chapter 12
David G. Hoel, PhD Agnes B. Kane, MD, PhD
Principal Scientist Pro essor
Exponent, Inc Department o Pathology and Laboratory Medicine
Alexandria, Virginia Brown University
Distinguished University Pro essor Providence, Rhode Island
Department o Medicine Chapter 28
Medical University o South Carolina
Y. James Kang, DVM, PhD, FA S
Charleston, South Carolina
Pro essor and Distinguished University Scholar
Chapter 25
Department o Pharmacology and oxicology
George R. Hof mann, PhD University o Louisville School o Medicine
Pro essor Louisville, Kentucky
Department o Biology Chapter 18
College o the Holy Cross
Barbara L.F. Kaplan, PhD
Worcester, Massachusetts
Assistant Pro essor
Chapter 9
Center or Integrative oxicology
Michael P. Holsapple, PhD, A S Department o Pharmacology and oxicology and
Senior Research Leader Neuroscience
Systems oxicology Program
Health and Li e Sciences Global Business Michigan State University
Battelle Memorial Institute East Lansing, Michigan
Columbus, Ohio Chapter 12
Chapter 12
Faraz Kazmi, BS
Patricia B. Hoyer, PhD Senior Scientist
Pro essor Xeno ech, LLC
Department o Physiology Lenexa, Kansas
College o Medicine Chapter 6
T e University o Arizona
Rebecca D. Kapler, PhD
ucson, Arizona
School o Freshwater Sciences
Chapter 21
University o Wisconsin-Milwaukee
Robert H. H rt, PhD Milwaukee, Wisconsin
Pro essor Chapter 28
School o Engineering
James E. Kla nig, PhD, A S, IA P
Director
Pro essor
Institute or Molecular and Nanoscale Innovation
Environmental Health
Brown University
Indiana University
Providence, Rhode Island
Bloomington, Indiana
Chapter 28
Chapter 8
Hartm t Jaeschke, PhD, A S
Frank N. Kotsonis, PhD
Pro essor and Chair
Retired Corporate Vice President
Department o Pharmacology, oxicology & T erapeutics
Worldwide Regulatory Sciences
University o Kansas Medical Center
Monsanto Corporation
Kansas City, Kansas
Skokie, Illinois
Chapter 13
Chapter 31
x CON RIBu ORS
Lois D. Lehman-McKeeman, PhD Gilbert S. Omenn, MD, PhD
Distinguished Research Fellow Pro essor o Internal Medicine, Human Genetics
Discovery oxicology and Public Health
Bristol-Myers Squibb Company Director
Princeton, New Jersey Center or Computational Medicine and Bioin ormatics
Chapter 5 University o Michigan Department o Computational
Medicine and Bioin ormatics
George D. Leika , PhD Ann Arbor, Michigan
Pro essor Chapter 4
Department o Environmental and Occupational Health
Graduate School o Public Health Oliver Parkinson, PhD
University o Pittsburgh XPD Consulting, LLC
Pittsburgh, Pennsylvania Shawnee, Kansas
Chapter 15 Chapter 6
T eodora M. Ma ro, MD Andrew Parkinson, PhD
Pro essor and Vice-Chair CEO
Dermatology Department XPD Consulting, LLC
University o Cali ornia, San Francisco Shawnee, Kansas
Service Chie Chapter 6
Dermatology
Martin A. Philbert, PhD
San Francisco Veterans Medical Center
Pro essor o oxicology and Dean
San Francisco, Cali ornia
School o Public Health
Chapter 19
University o Michigan
Virginia C. Moser, PhD, DAB , FA S Ann Arbor, Michigan
oxicologist Chapter 16
oxicity Assessment Division
R. J lian Preston, MA, PhD
National Health and Environmental E ects Research
Associate Director or Health
Laboratory
National Health and Environmental E ects Research
US Environmental Protection Agency
Laboratory
Research riangle Park, North Carolina
US Environmental Protection Agency
Chapter 16
Research riangle Park, North Carolina
Michael C. Newman, MS, PhD Chapter 9
A. Marshall Acu Jr. Pro essor
Robert H. Rice, PhD
Virginia Institute o Marine Science
Pro essor
College o William & Mary
Department o Environmental oxicology
Gloucester Point, Virginia
University o Cali ornia
Chapter 30
Davis, Cali ornia
G nter Oberdörster, DVM, PhD Chapter 19
Pro essor
R dy J. Richardson, ScD, DAB
Department o Environmental Medicine
oxicology Program
University o Rochester
University o Michigan School o Public Health
School o Medicine & Dentistry
Neurology Department
Rochester, New York
University o Michigan School o Medicine
Chapter 28
Ann Arbor, Michigan
Brian W. Ogilvie, BA Chapter 16
Principal Scientist
Xeno ech, LLC
Lenexa, Kansas
Chapter 6
CON RIBu ORS xi
John M. Rogers, PhD Peter S. T orne, MS, PhD
oxicity Assessment Division Pro essor and Head
National Health and Environmental E ects Research Department o Occupational and Environmental Health
Laboratory College o Public Health
O ce o Research and Development T e University o Iowa
United States Environmental Protection Agency Iowa City, Iowa
Research riangle Park, North Carolina Chapter 34
Chapter 10
Erik J. okar, PhD
Martin J. Ronis, BA, MA, PhD Biologist
Pro essor Inorganic oxicology Group
Department o Pharmacology & oxicology Division o the National oxicology Program
College o Medicine National oxicology Program
University o Arkansas or Medical Sciences National Institute o Environmental Health Sciences
Associate Director or Basic Research Research riangle Park, North Carolina
Arkansas Children’s Nutrition Center Chapter 23
Arkansas Children’s Hospital Research Institute
Michael P. Waalkes, PhD
Little Rock, Arkansas
Chie
Chapter 27
National oxicology Group
Andrew E. Schade, MD, PhD Division o the National oxicology Program
Senior Director National oxicology Program
Clinical Diagnostics Laboratory National Institute o Environmental Health Sciences
Diagnostics Research and Development Research riangle Park, North Carolina
Eli Lilly and Co. Chapter 23
Indianapolis, Indiana
D. Alan Warren, MPh, PhD
Chapter 11
Program Director
Rick G. Schnellmann, PhD Environmental Health Science
Pro essor and Chair University o South Carolina Beau ort
Department o Pharmaceutical and Biomedical Sciences Beau ort, South Carolina
Medical University o South Carolina Chapter 24
Charleston, South Carolina
John B. Watkins, III, PhD
Chapter 14
Associate Dean and Director
Kartik Shankar, PhD, DAB Pro essor o Pharmacology and oxicology
Arkansas Children’s Nutrition Center Medical Sciences Program
Department o Pediatrics Indiana University School o Medicine
University o Arkansas or Medical Sciences Bloomington, Indiana
Little Rock, Arkansas Chapter 26
Chapter 27
Diana G. Wilkins, MS, PhD
Danny D. Shen, PhD Director
Pro essor Center or Human oxicology
Departments o Pharmaceuticals and Pharmacy Research Associate Pro essor
School o Pharmacy Department o Pharmacology and oxicology
University o Washington University o Utah
Seattle, Washington Salt Lake City, Utah
Chapter 7 Chapter 32
Co rtney E.W. S lentic, PhD
Associate Pro essor
Department o Pharmacology & oxicology
Boonshof School o Medicine
Wright State University
Dayton, Ohio
Chapter 12
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Preface
T is updated ull-color edition o Essentials of oxicology dis- (6) Environmental oxicology; and (7) Applications o oxi-
tills the major principles and concepts o toxicology that were cology. A summary o key points is included at the beginning
described in detail in the eighth edition o Casarett & Doull’s o each chapter, and a set o review questions is provided at the
oxicology: T e Basic Science of Poisons. We are grate ul to the end o each chapter. We invite readers to send us suggestions
authors who contributed to the eighth edition o Casarett & o ways to improve this text and we appreciate the thought ul
Doull’s oxicology: T e Basic Science of Poisons; their chapters recommendations that we received on the last edition.
in the parent text provided the oundation or the chapters in We would like to acknowledge all individuals who were
this edition o Essentials of oxicology. involved in this project. We particularly give a heart elt and sin-
Essentials of oxicology concisely describes the expansive cere thanks to our amilies or their love, patience, and support
science o toxicology, and includes important concepts rom during the preparation o this book. We especially appreciate
anatomy, physiology, and biochemistry to acilitate the under- Richard J. Batka and Alyssa Shapiro who provided invaluable
standing o the principles and mechanisms o toxicant action assistance on this project. T e capable advice, guidance, and
on speci c organ systems. We trust that this book will assist assistance o the McGraw-Hill sta is grate ully acknowledged.
students in undergraduate and graduate courses in toxicology, Finally, we thank our students or their enthusiasm or learning
as well as students rom other disciplines, to develop a strong and what they have taught us during their time with us.
oundation in the concepts and principles o toxicology.
T e book is organized into seven units: (1) General Princi-
ples o oxicology; (2) Disposition o oxicants; (3) Nonorgan- Curtis D. Klaassen
directed oxicity; (4) arget Organ oxicity; (5) oxic Agents; John B. Watkins III
xiii
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C H A P T E R
UNIT 1 GENERAL PRINCIPLES OF TOXICOLOGY
1
C H A P T E R
History and Scope
of Toxicology
Michael A. Gallo
HISTORY OF TOXICOLOGY 20 TH CENTURY TOXICOLOGY: THE AWAKENING OF
Antiquity UNDERSTANDING
Middle Ages
AFTER WORLD WAR II
Renaissance
Age of Enlightenment 21 ST CENTURY TOXICOLOGY
KEY P O IN TS
■ oxi ology is the stu y o the verse e e ts o xeno iot- ■ oxi ology pplies s ety ev lu tion n risk ssessment
i s on living systems. to the is ipline.
■ oxi ology ssimil tes knowle ge n te hniques rom
io hemistry, iology, hemistry, geneti s, m them ti s,
me i ine, ph rm ology, physiology, n physi s.
HISTORY OF TOXICOLOGY Antiquity
Mo ern toxi ology goes eyon the stu y o the verse e e ts Knowle ge o nim l venoms n pl nt extr ts or hunting,
o exogenous gents y ssimil ting knowle ge n te hniques w r re, n ss ssin tion presum ly pre te re or e his-
rom most r n hes o io hemistry, iology, hemistry, genet- tory. One o the ol est known writings, the E ers P pyrus ( ir
i s, m them ti s, me i ine, ph rm ology, physiology, n 1500 b.c.), ont ins in orm tion pert ining to m ny re ognize
physi s n pplies s ety ev lu tion n risk ssessment to the poisons, in lu ing hemlo k, onite, opium, n met ls su h s
is ipline. In ll r n hes o toxi ology, s ientists explore the le , opper, n ntimony. T e Book of Job ( ir 1400 b.c.)
me h nisms y whi h hemi ls pro u e verse e e ts in io- spe ks o poison rrows (Jo 6:4) n Hippo r tes ( ir
logi l systems. A tivities in these ro su je ts omplement 400 b.c.) e num er o poisons n lini l toxi ology
toxi ologi rese r h. prin iples pert ining to io v il ility in ther py n
1
2 UNIT 1 Gener l Prin iples o oxi ology
over os ge. T eophr stus (370–286 b.c.), stu ent o Aristotle, Come itter pilot, now t on e run on
in lu e numerous re eren es to poisonous pl nts in De T e shing ro ks thy se si k we ry rk!
Historia Plantarum. Dios ori es, Greek physi i n in the ourt Here’s to my love! O true pothe ry!
o the Rom n emperor Nero, m e the rst ttempt t l ssi y- T y rugs re qui k. T us with kiss I ie.
Romeo and Juliet, t 5, s ene 3
ing poisons s pl nt, nim l, n miner l in his ook De Materia
Medica, whi h ont ins re eren e to some 600 pl nts. Although Ellen og ( ir 1480) w rne o the toxi ity o
One legen tells o Rom n King Mithri tes VI o Pontus, mer ury n le rom gol smithing n Agri ol pu lishe
who w s so e r ul o poisons th t he regul rly ingeste mix- short tre tise on mining ise ses in 1556, the m jor work on
ture o 36 ingre ients s prote tion g inst ss ssin tion. On the su je t, On the Miners’ Sickness and Other Diseases of
the o sion o his imminent pture y enemies, his ttempts Miners (1567), w s pu lishe y P r elsus. T is tre tise
to kill himsel with poison ile e use o his su ess ul nti- resse the etiology o miners’ ise se, long with tre tment
ote on o tion. T is t le le s to use o the wor mithri ti n prevention str tegies. O up tion l toxi ology w s ur-
s n nti ote or prote tive mixture. Be use poisonings in ther v n e y the work o Bern r ino R m zzini when he
politi s e me so extensive, Sull issue the Lex Cornelia pu lishe in 1700 his Discourse on the Diseases of Workers,
( ir 82 b.c.), whi h ppe rs to e the rst l w g inst poison- whi h is usse o up tions r nging rom miners to mi -
ing n l ter e me regul tory st tute ire te t reless wives n in lu ing printers, we vers, n potters. Per iv l
ispensers o rugs. Pott’s (1775) re ognition o the role o soot in s rot l n er
mong himney sweeps w s the rst report o poly rom ti
hy ro r on r inogeni ity. T ese n ings le to improve
Middle Ages me i l pr ti es, p rti ul rly in prevention.
T e writings o M imoni es (Moses en M imon, a .d. 1135–
1204) in lu e tre tise on the tre tment o poisonings rom
inse ts, sn kes, n m ogs ( reatise on Poisons and T eir Age of Enlightenment
Antidotes, 1198). M imoni es es ri e the su je t o io v il- Experiment l toxi ology omp nie the growth o org ni
ility, noting th t milk, utter, n re m oul el y intestin l hemistry n evelope r pi ly uring the nineteenth en-
sorption. In the e rly Ren iss n e n un er the guise o tury. M gen ie (1783–1885), Or l (1787–1853), n Bern r
elivering proven er to the si k n the poor, C therine e (1813–1878) l i the groun work or ph rm ology, experi-
Me i i teste toxi on o tions, re ully noting the r pi ity o ment l ther peuti s, n o up tion l toxi ology.
the toxi response (onset o tion), the e e tiveness o the om- Or l , Sp nish physi i n in the Fren h ourt, use utopsy
poun (poten y), the egree o response o the p rts o the o y m teri l n hemi l n lysis system ti lly s leg l proo o
(spe i ity n site o tion), n the ompl ints o the vi tim poisoning. His intro u tion o this et ile type o n lysis
( lini l signs n symptoms). survives s the un erpinning o orensi toxi ology. Or l
pu lishe m jor work evote expressly to the toxi ity o
n tur l gents in 1815. M gen ie, physi i n n experimen-
Renaissance t l physiologist, stu ie the me h nisms o tion o emetine
n stry hnine. His rese r h etermine the sorption n
All su st n es re poisons; there is none th t is not poison. T e right
istri ution o these ompoun s in the o y. One o
ose i erenti tes poison rom reme y.
Paracelsus M gen ie’s more mous stu ents, Cl u e Bern r , ontri -
ute the l ssi tre tise, An Introduction to the Study of
Philippus Aureolus T eophr stus Bom stus von Hohenheim- Experimental Medicine.
P r elsus (1493–1541) w s pivot l, st n ing etween the phi- Germ n s ientists Osw l S hmie e erg (1838–1921) n
losophy n m gi o l ssi ntiquity n the philosophy n Louis Lewin (1850–1929) m e m ny ontri utions to the s i-
s ien e wille to us y gures o the seventeenth n eighteenth en e o toxi ology. S hmei e erg tr ine pproxim tely
enturies. P r elsus, physi i n- l hemist, ormul te m ny 120 stu ents who l ter popul te the most import nt l or to-
revolution ry views th t rem in integr l to the stru ture o ries o ph rm ology n toxi ology throughout the worl .
toxi ology, ph rm ology, n ther peuti s to y. He o use Lewin pu lishe mu h o the e rly work on the toxi ity o n r-
on the prim ry toxi gent s hemi l entity, n hel th t oti s, meth nol, gly erol, rolein, n hloro orm.
(1) experiment tion is essenti l in the ex min tion o responses
to hemi ls, (2) one shoul m ke istin tion etween the
ther peuti n toxi properties o hemi ls, (3) these proper- 20 TH CENTURY TOXICOLOGY: THE
ties re sometimes ut not lw ys in istinguish le ex ept y AWAKENING OF UNDERSTANDING
ose, n (4) one n s ert in egree o spe i ity o hemi-
ls n their ther peuti or toxi e e ts. T ese prin iples le oxi ology h s r wn its strength n iversity rom its pro-
P r elsus to rti ul te the ose–response rel tion s ulw rk livity to orrowing rom lmost ll the si s ien es to test its
o toxi ology. hypotheses. T is t, ouple with the he lth n o up tion l
CHAPTER 1 History n S ope o oxi ology 3
regul tions th t h ve riven toxi ology rese r h sin e 1900, h s were oun e . Cellul r n mole ul r toxi ology evelope s
m e this is ipline ex eption l in the history o s ien e. su is ipline, n risk ssessment e me m jor pro u t o
With the vent o nestheti s n isin e t nts in the l te toxi ologi investig tions.
1850s, toxi ology s it is urrently un erstoo eg n. T e prev- Currently, m ny ozens o pro ession l, government l, n
lent use o “p tent” me i ines le to sever l in i ents o poi- other s ienti org niz tions with thous n s o mem ers n
sonings rom these me i ments, whi h, when ouple with over 120 journ ls re e i te to toxi ology n rel te is i-
the response to Upton Sin l ir’s exposé o the me tp king plines. In ition, the Intern tion l Congress o oxi ology is
in ustry in T e Jungle, ulmin te in the p ss ge o the Wiley ompose o toxi ology so ieties rom Europe, South Ameri ,
Bill in 1906, the rst o m ny U.S. pure oo n rug l ws. Asi , A ri , n Austr li , whi h rings together the ro est
During the 1890s n e rly 1900s, the is overy o r io - represent tion o toxi ologists.
tivity n the vit mins, or “vit l mines,” le to the use o the
rst l rge-s le io ss ys (multiple nim l stu ies) to eter-
mine whether these “new” hemi ls were ene i l or h rm- 21 ST CENTURY TOXICOLOGY
ul to l or tory nim ls. T e sequen ing o the hum n genome n th t o sever l other
One o the rst journ ls expressly e i te to experiment l org nisms h s m rke ly e te ll iologi l s ien es, in lu -
toxi ology, Archiv für oxikologie, eg n pu li tion in Europe ing toxi ology. Geneti lly mo i ying org nisms is now om-
in 1930. T t s me ye r the N tion l Institutes o He lth (NIH) monpl e n those possessing orthologs o hum n genes (e.g.,
w s est lishe in the Unite St tes. As response to the tr gi ze r sh [Danio rerio], roun worms [Caenorhabditis elegans],
onsequen es o ute ki ney ilure er t king sul nil mi e n ruit ys [Drosophila melanogaster]) re wi ely use in
in gly ol solutions, the Copel n ill w s p sse in 1938. T is toxi ology. Deeper un erst n ing o epigeneti s h s provi e
w s the se on m jor ill involving the orm tion o the U.S. novel ppro hes to stu ying the et l origin o ult ise ses
Foo n Drug A ministr tion (FDA). T e rst m jor U.S. in lu ing n ers, i etes, n neuro egener tive ise ses
pesti i e t w s signe into l w in 1947. T e signi n e o n isor ers.
the initi l Fe er l Inse ti i e, Fungi i e, n Ro enti i e A t oxi ology h s n interesting n v rie history. Perh ps s
w s th t or the rst time in U.S. history su st n e th t w s s ien e th t h s grown n prospere y orrowing rom m ny
neither rug nor oo h to e shown to e s e n e - is iplines, it h s su ere rom the sen e o single go l, ut
ious or pprov l. its iversi tion h s llowe or the interspersion o i e s n
on epts rom higher e u tion, in ustry, n government.
T is h s resulte in n ex iting, innov tive, n iversi e el
AFTER WORLD WAR II th t is serving s ien e n the ommunity t l rge. Few is i-
plines n point to oth si s ien es n ire t ppli tions
You too n e toxi ologist in two e sy lessons, e h o ten ye rs.
t the s me time. oxi ology—the stu y o the verse e e ts
Arnold Lehman ( ir 1955)
o xeno ioti s—m y e unique in this reg r .
T e mi -1950s witnesse the strengthening o the U.S. FDA’s
ommitment to toxi ology. T e U.S. Congress p sse n the
presi ent o the Unite St tes signe the itives men ments BIBLIOGRAPHY
to the Foo , Drug, n Cosmeti A t. T e Del ney l use Bry n CP: T e Papyrus Ebers. Lon on: Geo rey B les, 1930.
(1958) o these men ments st te ro ly th t ny hemi l C rson R: Silent Spring. Boston, MA: Houghton Mif in, 1962.
oun to e r inogeni in l or tory nim ls or hum ns Gunther R : T e Greek Herbal of Dioscorides. New York: Ox or
oul not e e to the U.S. oo supply. Del ney e me University Press, 1934.
ttle ry or m ny groups n resulte in the in lusion t new Guthrie DA: A History of Medicine. Phil elphi , PA: Lippin ott,
level o iost tisti i ns n m them ti l mo elers in the el 1946.
o toxi ology. Shortly er the Del ney men ment, the rst H ys HW: Society of oxicology History, 1961–1986. W shington, DC:
Ameri n journ l e i te to toxi ology, oxicology and So iety o oxi ology, 1986.
Applied Pharmacology, w s l un he . T e oun ing o the Munter S (e .): reatise on Poisons and T eir Antidotes. Vol. II of the
Medical Writings of Moses Maimonides. Phil elphi , PA: Lippin ott,
So iety o oxi ology ollowe shortly erw r .
1966.
T e 1960s st rte with the tr gi th li omi e in i ent, in P gel W: Paracelsus: An Introduction to Philosophical Medicine in the
whi h sever l thous n hil ren were orn with serious irth Era of the Renaissance. New York: K rger, 1958.
e e ts, n the pu li tion o R hel C rson’s Silent Spring T ompson CJS: Poisons and Poisoners: With Historical Accounts of
(1962). Attempts to un erst n the e e ts o hemi ls on the Some Famous Mysteries in Ancient and Modern imes. Lon on:
em ryo n etus n on the environment s whole g ine Sh ylor, 1931.
momentum. New legisl tion w s p sse , n new journ ls http://www.toxipe i .org/ ispl y/toxipe i /History+ o + oxi ology
4 UNIT 1 Gener l Prin iples o oxi ology
Q UES TIO N S
1. Whi h one o the ollowing st tements reg r ing toxi ol- 4. T e rt o toxi ology requires ye rs o experien e to
ogy is true? quire, even though the knowle ge se o ts m y e
a. Mo ern toxi ology is on erne with the stu y o the le rne more qui kly. Whi h mo ern toxi ologist is re -
verse e e ts o hemi ls on n ient orms o li e. ite with s ying th t “you n e toxi ologist in two e sy
b. Mo ern toxi ology stu ies em r e prin iples rom lesions, e h o 10 ye rs?”
su h is iplines s io hemistry, ot ny, hemistry, a. Cl u e Bern r .
physiology, n physi s. b. R hel C rson.
c. Mo ern toxi ology h s its roots in the knowle ge o c. Upton Sin l ir.
pl nt n nim l poisons, whi h pre tes re or e d. Arnol Lehm n.
history n h s een use to promote pe e. e. Osw l S hmie e erg.
d. Mo ern toxi ology stu ies the me h nisms y whi h
inorg ni hemi ls pro u e v nt geous s well s 5. Whi h o the ollowing st tements is orre t?
eleterious e e ts. a. Cl u e Bern r w s proli s ientist who tr ine
e. Mo ern toxi ology is on erne with the stu y o over 120 stu ents n pu lishe numerous ontri u-
hemi ls in m mm li n spe ies. tions to the s ienti liter ture.
b. Louis Lewin tr ine un er Osw l S hmie e erg
2. Knowle ge o the toxi ology o poisonous gents w s n pu lishe mu h o the e rly work on the toxi ity
pu lishe e rliest in the: o n r oti s, meth nol, n hloro orm.
a. E ers p pyrus. c. An Introduction to the Study of Experimental Medicine
b. De Historia Plantarum. w s written y the Sp nish physi i n Or l .
c. De Materia Medica. d. M gen ie use utopsy m teri l n hemi l n ly-
d. Lex Cornelia. sis system ti lly s leg l proo o poisoning.
e. reatise on Poisons and T eir Antidotes. e. Per iv l Potts w s instrument l in emonstr ting the
hemi l omplexity o sn ke venoms.
3. P r elsus, physi i n- l hemist, ormul te m ny revo-
lution ry views th t rem in integr l to the stru ture o
toxi ology, ph rm ology, n ther peuti s to y. He
o use on the prim ry toxi gent s hemi l entity
n rti ul te the ose–response rel tion. Whi h one o
the ollowing st tements is not ttri ut le to P r elsus?
a. N tur l poisons re qui k in their onset o tions.
b. Experiment tion is essenti l in the ex min tion o
responses to hemi ls.
c. One shoul m ke istin tion etween the ther -
peuti n toxi properties o hemi ls.
d. T ese properties re sometimes ut not lw ys in is-
tinguish le ex ept y ose.
e. One n s ert in egree o spe i ity o hemi ls
n their ther peuti or toxi e e ts.
