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8/11/2019 Preface, Pages Xix-xxi
1/3
P R E F C E
When I was asked to organize a book on neurotoxi-
cology, I was confronted with the problem of what to
include in the text. With much deliberation, I decided
that for a comprehensive coverage of neurotoxicology,
at least three major areas must be addressed: basic
principles of neurotoxicology, current concepts on the
effects and mechanisms of various classes of neurotoxi-
cants, and state-of-the-art approaches and methods in
toxicological research and assessment. This thought
led to the birth of the Trilogy of Neuro toxicology
with which I am so proudly involved.
The volumes Principles of Neurotoxicology and
Handbook of Neurotoxicology
(Marcel Dekker, Inc.)
represent the first two installments of this trilogy. The
current title,
Neurotoxicology: Approaches and Meth-
ods is the final epic of this series. This ambitious proj-
ect was accomplished by the vision of one and the
efforts of many. I cannot thank all the contributors
enough for making this vision a reality.
Neurotox icity has been defined as any adverse effect
on the structure and function of the nervous system.
It becomes obvious that the structural aspects (neuro-
morphology and neuropathology) and the functional
aspects (neurophysiology and neurobehavior) of neural
alterations are critical for the assessment of neurotoxic-
ity. Furthermore, biochemical and molecular events
underlying the toxic effects can provide clues to the
mechanisms of action of the toxicants involved and
may serve as markers for early neurotoxicity detection.
It is hoped that methods developed for neurotoxicology
will aid in accomplishing one or more of the following
objectives: identifying toxic substances, detecting for
toxic effects and lesion development, elucidating the
mechanism of action of toxicity, and providing means
for health risk assessment.
The nervous system is perhaps the most complex
biological system in mammalian species. Therefore the
approaches and methods available for its assessment
are also broad and multiple. The first four sections of
the book are devoted to the four major disciplines in
neuroscience or neurotoxicology: neuroanatomy/neu-
ropathology, neurophysiology, neurobehavioral sci-
ence, and neurobiochemistry. Each of these ap-
proaches provides an index (morphological index,
functional index, biochemical index, etc.) for the as-
sessment of the integrity of the nervous system. Both
qualitative and quantitative methods for such assess-
ments are presented and discussed. It may be surpris-
ing to some readers that quantitative evaluations of
morphological alterations are actually possible and that
biochemical bases for neurobehavioral and neuropath-
ological alterations are also being established. Some
of these approaches are included in this volume.
The first four sections of the book provide the reader
with the opportunity to examine the animal as a whole:
its structures, physiology, chemistry, and function. In-
deed, it would be a grave error to view neurotoxicol-
ogy, or any other medical science, with tunnel vision.
It is my hope that the reader will appreciate the world
of science and the facet of truth that each of the
disciplines (anatomy, physiology, etc.) can offer. We
frequently encounter debates on the relative sensitivity
of each disciplinary approach in the detection of neuro-
toxicity. While it is important to understand the
strengths and limitations of each approach, it is foolish
to argue, as some may, the relative imp ort ance of
each discipline and its contributions to neurotoxicol-
ogy. It is my hope that the reader will come to the
conclusion that each disciplinary approach has much
to offer and a combination of these approaches is
needed for comprehensive assessment of the nervous
system.
It is important and obvious, for authoritative rea-
sons, that each section be organized by experts in that
xix
8/11/2019 Preface, Pages Xix-xxi
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x x Pre fac e
spec ia l iza t ion o f neuro tox ico logy . I am mos t fo r tuna te
and g ra te fu l tha t Drs . Wi l l i am Boyes and Wi l l i am
At c h i s o n (n e u ro p h y s i o l o g y ) , Dr s . De b o ra h C o ry -
S l e c h t a a n d R o b e r t M a c P h a i l ( n e u ro b e h a v i o ra l t o x i c ol -
ogy) , and Dr . Wi l l i am Sl ikker , J r . (neurob iochemis t ry /
molecu lar b io logy) ag reed to serve as sec t ion heads fo r
the i r d i sc ip l ines . I thank them fo r the i r ga l lan t e f fo r t s
in he lp ing me se lec t bo th the chap ter top ics and the
b e s t c o n t r i b u t o r s fo r t h e s e c h a p t e r s .
As i d e f ro m t h e fo u r m a j o r a r e a s o f n e u ro to x i c o l o g y ,
t h r e e i s s u e s i n n e u ro t o x ic o l o g y h a v e e m e rg e d a n d h a v e
gained increas ing a t ten t ion and impor tance in the pas t
d e c a d e . T h e s e i s s u e s a r e a n i m a l a l t e rn a t i v e m o d e l s in
v i t ro neuro tox ico logy) , tox iconeuro logy (c l in ica l neu-
ro t o x ic o l o g y ) , a n d n e u ro t o x i c i t y r is k a s s e s s m e n t . T h e
l a s t th r e e s e c t io n s o f t h is v o l u m e p ro v i d e c o m p re h e n -
s i ve c o v e ra g e o n t h e s e i s s u e s o f i m p o r t a n c e .
In con t ras t to the in v ivo mode l (who le an imal s tudy) ,
in v i tro
n e u ro t o x i c o l o g y fo c u s e s o n t h e e x p l o ra t i o n o f
neuro tox ico log ica l phenomena v ia ce l l o r t i s sue cu l -
t u r e s . T h e p ro m o t i o n o f in v i tro neuro tox ico logy i s no t
so muc h fo r the po l i ti cs o f an imal r igh ts , bu t be cause
of the unden iab le sc ien t i fi c mer i t s and advan tages o f
t h is a p p ro a c h . A c o m p re h e n s i v e s e c t io n i n th i s v o l u m e
i s d e v o t e d t o t h e v a r i o u s m e t h o d s a n d a p p ro a c h e s v i a
ce l l o r ti s sue cu l tu re fo r the inves t iga t ion o f neuro -
t o x i c o l o g y . I t b e c o m e s a p p a re n t t h a t a s i d e f ro m
n e u ro b e h a v i o ra l t e s t i n g s , m a n y m e t h o d s f ro m n e u ro -
m o rp h o l o g y / n e u ro p a t h o l o g y , n e u ro p h y s i o l o g y , a n d
n e u ro b i o c h e m i s t ry c a n a l s o b e p e r fo rm e d o n t h e in
v i t ro s y s t e m . I a m g re a t l y i n d e b t e d t o P ro fe s s o r A l a n
Gold berg and Pr o fesso r Dan ie l Acos ta fo r the i r wi ll ing -
ness to serve as co -sec t ion heads o f the I n V i t r o N e u r o -
tox ico logy sec t ion . Thei r devo ted ass i s tance in the
p lann ing and o rgan iza t ion o f th i s sec t ion p rov ided the
needed s t reng th and exper t i se fo r th i s impor tan t sub-
jec t . I am cer ta in tha t the exc e l len t co l lec t ion o f in fo r-
mat ion in th i s sec t ion wi l l p rov ide the reader wi th a
c o m p re h e n s i v e v i e w o n a n d s o l i d fo u n d a t i o n fo r in
v i t ro n e u ro t o x i c o l o g y .
A l l m e t h o d s a n d t e c h n i q u e s h a v e t h e i r o wn i n h e re n t
s t r e n g t h s a n d we a k n e s s e s . In v i t ro a p p ro a c h e s a r e n o
e x c e p t i o n . R e a d e r s a n d p ra c t i o n e r s o f th e s e m e t h o d s
are enco urag ed to recogn ize the l imi ta t ions o f the meth -
ods in which they are in te res ted . S tud ies co rre la t ing
d i f fe ren t approaches (e .g . , in v i tro~in v ivo corre la t ion )
wi l l revea l mo re o f the sc ien ti f i c i ssue than s tud ies in
wh i c h e a c h a p p ro a c h i s p e r fo rm e d a l o n e .
S i m i la r l y, a c o r r e l a t i o n b e t we e n e x p e r i m e n t a l m o d -
e l s (bas ic research) and c l in ica l p rac t ice (pa t ien t care)
i s very mu ch ne eded . The f ina l f ron t ie r o f a ll med ica l
rese arc h i s app l icab le hea l th care in cl in ica l s i tua t ions .
The increas ing in te res t in and a t ten t ion to b r idg ing
e x p e r i m e n t a l n e u ro t o x i c o l o g y a n d t o x i c o n e u ro l o g y
therefo re become log ica l . Such b r idg ing led to the de-
ve lop me nt o f c l in ica l neuro to x ico log y . A spe c ia l sec-
t ion in th i s vo lume i s devo ted to th i s impor tan t a rea
o f n e u ro to x i c o l o g y . I a m t h a n k fu l t o Dr . N e i l R o s e n -
b e rg a n d Dr . R o b e r t F e l d m a n fo r t h e i r e n t h u s i a s t i c
s u p p o r t a n d a s s i s t a n c e i n t h e d e v e l o p m e n t a n d o rg a n i -
za t ion o f thi s sec t ion , in which the ba s ic p r inc ip les
and c l in ica l approaches in c l in ica l neuro tox ico logy are
t h o ro u g h l y p re s e n t e d a n d d i s c u s s e d . I a m s u re t h a t t h is
i n fo rm a t i o n w i ll b e e x t r e m e l y i m p o r t a n t a n d u s e fu l t o
c l in ica l p rac t i t ioners in tox iconeuro logy as wel l as to
bas ic researc hers in neuro tox ico logy . I t i s a l so my hope
tha t the reader wi l l be s t imula ted and mot iva ted to p lay
a par t in the fu tu re de velo pm ent o f th i s v ita l a rea o f
n e u ro t o x i c o l o g y . E x t r a p o l a t i o n o f e x p e r i m e n t a l d a t a
to c lin ica l p rac t ice a nd the t rans fer o f bas ic researc h
knowledge to hea l th care app l ica t ions a re the u l t imate
goals and respons ib i l i t i es o f a l l med ica l (bo th bas ic and
clinical) scient is ts .
T h e c o n t ro l a n d p re v e n t i o n o f to x i c e p i s o d e s c a n b e
b e s t a c c o m p l i s h e d v i a e a r l y d e t e c t i o n a n d p re d i c t i o n
of tox ic even ts . Th is conc ep t l eads to one o f the mo s t
impo r tan t and rap id ly deve lop ing f ie lds in neuro tox ico l -
o g y: n e u ro t o x i c i t y r i s k a s s e s s m e n t . On e m a y v i e w r i s k
a s s e s s m e n t a s a p p l i e d t o x i c o l o g y i n wh i c h i n fo rm a -
t io n g e n e ra t e d f ro m b o t h b a s i c a n d c l in i c al r e s e a rc h e s
i s u s e d t o d e v e l o p m e t h o d s fo r e a r l y d e t e c t i o n a n d
pred ic t ion o f tox ic i ty . De sp i te the e f fo r t dev o ted to
t h i s a r e a o f s c i e n c e , n e u ro t o x i c i t y r i s k a s s e s s m e n t i s
s t i l l in i t s in fancy . In the Neuro tox ic i ty Risk Assess -
men t sec t ion o f th i s vo lume, D r . H ugh T i l son , the sec-
t i on h e a d , h a s p u t t o g e t h e r c h a p t e r s s u rv e y i n g t h e c u r-
r e n t c o n c e p t s a n d a p p ro a c h e s i n t h i s i m p o r t a n t a r e a
o f n e u ro to x i c o l o g y . T h e c o n c e p t s o f q u a n t it a t i v e r i s k
a s s e s s m e n t , t h e d e v e l o p m e n t o f b i o m a rk e r s fo r n e u ro -
tox ic r i sks , and the is sues o f r isk asses sm en t w i th de-
v e l o p m e n t a l n e u ro t o x i c i t y a r e a l l c o v e re d a n d p re -
sen ted by ac t ive researchers in th i s f i e ld . I t i s my hope
tha t readers wi l l be s t imula ted by the c r i t i ca l impor-
t a n c e o f t h is a r e a o f n e u ro t o x i c o l o g y . A l l t h e m e t h o d o l -
o g ie s t h a t we p re s e n t i n t h is v o l u m e c a n b e c o m e u s e fu l
t o o ls fo r e a r l y d e t e c t i o n o r p r e d i c t i o n o f n e u ro t o x i c i t y .
B i o l o g i c a l m a rk e r (b i o m a rk e r ) r e s e a rc h h a s b e c o m e
o n e o f t h e m o s t i m p o r t a n t r e s e a rc h a r e a s i n c a n c e r
r e s e a rc h . S u c h m a rk e r s a r e u s e d a s e a r l y wa rn i n g
s i gn s o r c o n f i rm a t io n a l i n d i c e s o f c a n c e r d e v e l o p m e n t .
B i o m a rk e r r e s e a rc h fo r n e u ro t o x i c i t y h a s a l s o d e v e l -
o p e d d u r i n g t h e p a s t d e c a d e . E n c o u ra g i n g f i n d i n g s
h a v e b e e n o b t a i n e d a n d a r e p r e s e n t e d i n s o m e o f t h e
chap ters in th i s sec t ion . Fu tu re advances in th i s a rea
wi ll i n c lu d e t h e d e v e l o p m e n t o f p e r i p h e ra l m a rk e r s
fo r cen t ra l (cen t ra l nervous sys tem) ef fec t s (e .g . , a
marker in the per iphera l b lood o r t i s sue to re f lec t
c h a n g e s i n t he C N S ) a n d t h e c o r r e l a t i o n o f a n i m a l
8/11/2019 Preface, Pages Xix-xxi
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reface xxi
markers (biomarkers found in animal models) with clin-
ical applications. Biomarker research and risk assess-
ment development are new kids on the block for
neurotoxicology. I hope that the reader will find this
section exciting and stimulating.
The objective of this volume is to present the general
principles and concepts of the various approaches to
the assessment of neurotoxicity. It is my hope that
through the information provided in this volume, read-
ers will be in a better position to select the approaches
and methods for their individual needs. Readers may
also become aware of the many state-of-the-art meth-
ods available to them as investigators of neurotoxi-
cology.
This volume is not intended to serve as a technical
manual. For the convenience of the readers, some con-
tributors (particularly those contributing to the Neuro-
morphology/Neuropathology section) were encour-
aged to include step-by-step procedures for some of
the techniques described in their chapters. The precise
procedures and technical performance of many of the
methods are difficult to describe. Many methods are
subject to individual laboratory variations and modifi-
cations. Readers interested in those methods are en-
couraged to consult the references provided in each
chapter as well as to observe the performance of such
techniques in laboratories that have experience with
them. For technical mastery, there is no substitute for
repeated practice.
Readers must also be reminded that all methods
and techniques have their advantages (strengths) and
limitations (weaknesses). No single approach or
method can provide all of the answers. A combination
of methods and correlated approaches is needed to
probe and to explore the complexity of the nervous
system and the secrets of its diseases. This volume
certainly provides many state-of-the-art options for
these combinations and correlations. It is my hope that
with the aid of this volume readers will make these
choices wisely.
I am grateful to all of my distinguished colleagues
for their enthusiastic assistance with and support of
this project. The number of distinguished contributors
involved in this project is overwhelming indeed. (The
list of contributors in this series of the trilogy reads
like an international Who's Who in Neurotoxicology.)
This strong endorsement by my colleagues of this proj-
ect is especially comforting because it reflects the im-
portance and need for these volumes to the community
of neurotoxicology. Without the genuine support and
assistance from my fellow scientists, this project could
never have been accomplished.
While we are at the twilight of the 20th century,
we may look back and be proud of all the exciting
developments in neurotoxicology. The trilogy that I
have put together serves as a summation and document
of most, if not all, the major developments and accom-
plishments in neurotoxicology in the past decades. It
also provides an overview of our present standing on
many issues in neurotoxicology. As we look ahead
to the new century, we can sense the exciting and
formidable challenges that we will be facing. It is my
hope that this trilogy in neurotoxicology will serve as
the stepping stone for some and the inspiration for
many to carry this torch forth and bring neurotoxicol-
ogy to a new era of excellence.
LouIs W. CHANG