Preface, Pages Xix-xxi

8/11/2019 Preface, Pages Xix-xxi

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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


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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


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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

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Preface, Pages Xix-xxi