E X E C U T I V E BOARD Fifty-eighth Session
ORGANISATION MONDIALE DE LA SANTÉ WORLD HEALTH ORGANIZATION
4 M a y 1 9 7 6
INO£XEO E B 5 8 / 5
Provisional agenda item 7
STUDY GROUP M E E T I N G S Report b y the D i r e c t o r - G e n e r a l
INTRODUCTION
In conformity w i t h resolution E B 1 7 . R 1 3 , ^ operative paragraph 4 , the D i r e c t o r - G e n e r a l reports hereunder on two study group m e e t i n g s , for w h i c h the reports h a v e n o w become available in English and French.^
Following a suggestion m a d e b y the E x e c u t i v e Board at its fifty-fifth s e s s i o n , w h e n discussing the D i r e c t o r - G e n e r a l1 s report on expert committee meetings，3 short comments h a v e b e e n a d d e d , w h e n a p p r o p r i a t e , under the relevant s e c t i o n s .
1 . EPIDEMIOLOGICAL M E T H O D S F O R THE A S S E S S M E N T OF THE EFFECTS OF ENVIRONMENTAL A G E N T S ON HUMAN H E A L T H
Report of a W H O Study Group G e n e v a , 7-13 October 197 1•1 Background information
Several Health A s s e m b l y and E x e c u t i v e Board resolutions ( W H A 2 3e6 0 , E B 4 7 . R 3 0 , W H A 2 4 . 4 7 , W H A 2 5 . 5 8 , W H A 2 6 . 5 8 and W H A 2 7 . 4 9 ) h a v e requested the Director-General to p r o m o t e , strengthen a n d coordinate research on the health effects of environmental pollutants and other environ- m e n t a l factors, particularly their combined and long-term e f f e c t s , and to develop protocols
for epidemiological s t u d i e s . This subject w a s also discussed in 1973 b y the A d v i s o r y C o m m i t t e e on M e d i c a l Research a t its fifteenth session and by a W H O Scientific Group on E n v i r o n m e n t a l H e a l t h C r i t e r i a , w h i c h m a d e a n u m b e r of r e c o m m e n d a t i o n s . In response to these requests and r e c o m m e n d a t i o n s , a Study Group on E p i d e m i o l o g i c a l M e t h o d s A p p l i e d to the E s t a b l i s h m e n t of E n v i r o n m e n t a l Health Criteria w a s convened to review the principles of the epidemiological m e t h o d s currently used to evaluate the h e a l t h effects of environmental c o n d i t i o n s , w i t h p a r t i c u l a r reference to chemical and physical a g e n t s , to discuss and m a k e recommendations on the action n e e d e d to improve the quality and comparability of information obtained b y such s t u d i e s , and to recommend topics for further m e t h o d o l o g i c a l research in this f i e l d .
1.2 The report
The Study G r o u p1 s report discusses the principles for epidemiolgical studies on the
effects of environmental agents on h e a l t h , including principles of d e s i g n , choice of populations, a s s e s s m e n t of e x p o s u r e , indices of e f f e c t s , practical considerations in conducting s u r v e y s ,
1 W H O H a n d b o o k of Resolutions and D e c i s i o n s , V o l . I , 1973, p p . 1 4 - 1 5 .
2 For easy r e f e r e n c e , copies of these two reports are annexed to this document (for m e m b e r s of the Executive Board o n l y ) .
3 W H O Official R e c o r d s , N o . 2 2 4 , 1975, p p . 6-15; document E B 5 5 / 4 .
^ D o c u m e n t C E P / 7 6 . 2 .
evaluation of r e s u l t s , and a p p l i c a t i o n of such s t u d i e s . It a l s o points to the need for a m o n o g r a p h on epidemiological m e t h o d s and gives guidelines for its p r e p a r a t i o n .
1 . 2e1 Physical agents a n d b i o l o g i c a l agents
The report highlights the fundamental reason for the greater d i f f i c u l t y in reaching u n e q u i v o c a l conclusions from epidemiological studies involving chemical and physical agents as compared w i t h those involving biological a g e n t s . For the agents of infectious d i s e a s e , there is u s u a l l y a specific relationship between an a g e n t (in combination w i t h other factors) and the disease e n t i t y , w h e r e a s this is n o t always true for chemical and p h y s i c a l a g e n t s . There is o c c a s i o n a l l y a direct c a u s e / e f f e c t relationship b u t m o r e often chemical e n v i r o n m e n t a l agents form p a r t of complex and ill-defined m i x t u r e s that m a y p r o d u c e a v a r i e t y of a d v e r s e effects on h e a l t h w h i c h could also h a v e been produced in m a n y other w a y s .
To approach this p r o b l e m through epidemiological studies a specific environmental chemical ( e . g . an air pollutant such as carbon m o n o x i d e ) m a y be identified; attempts can then be m a d e to m e a s u r e its health effects in a p p r o p r i a t e l y selected populations exposed to it in different
concentrations。 A n o t h e r w a y is to look at the changes in different population groups in terms of incidence of d i s e a s e , such as cardiovascular d i s o r d e r s , and try to identify environmental c h e m i c a l , physical or other factors associated w i t h the changes in i n c i d e n c e . The objective is to identify a possible r e l a t i o n s h i p , p r e f e r a b l y in a q u a n t i t a t i v e m a n n e r , between an agent or agents and specific changes in the health status of the p o p u l a t i o n g r o u p .
1.2.2 A c u t e and chronic effects of agents
In studying the a c u t e effects of a g e n t s that v a r y in concentration or intensity over a short period (days or w e e k s ) , the time-series d e s i g n , i . e . the follow-up of changes in health status and exposure over a given period of time has proved to be m o s t v a l u a b l e . In studying the chronic e f f e c t s , the cross-sectional d e s i g n , ice . the collection of information on the p r e v a l e n c e of a given effect at a given m o m e n t in relation to exposure to a specific p o l l u t a n t , i s m o s t commonly u s e d , a l t h o u g h this type of design involves difficulties because the
r e t r o s p e c t i v e information on health and exposure to e n v i r o n m e n t a l agents is often i n a d e q u a t e . For this r e a s o n , it is a d v i s a b l e , w h e n e v e r p o s s i b l e , to follow the population groups p r o s p e c t i v e l y as is done in cohort or longitudinal s t u d i e s .
1。2,3 Choice of populations and m e a s u r e m e n t of exposure
A difficult problem in epidemiological studies is the c h o i c e of p o p u l a t i o n s . A l t h o u g h the total population of an area m a y b e selected for s t u d y , random samples are m o r e frequently u s e d . T h e use of h i g h - r i s k groups can be p a r t i c u l a r l y u s e f u l in studying the effects of n e w environmental a g e n t s . These h i g h - r i s k groups m a y be populations occupationally e x p o s e d , but they m a y also be sections of the general population at risk b e c a u s e of special environmental or social conditions or dietary h a b i t s .
A difficult part of an epidemiological s t u d y , applied to physical and chemical agents in the e n v i r o n m e n t , is to m e a s u r e the degree of e x p o s u r e . In some s i t u a t i o n s , it m a y be difficult to identify the a g e n t , as is the c a s e , for e x a m p l e , for common u r b a n air pollutants such as oxides of sulfur or suspended p a r t i c u l a t e s , and even m o r e s o , to define the e x p o s u r e . Because of the difficulties in relating environmental m e a s u r e m e n t s to true e x p o s u r e , b i o l o g i c a l indices of e x p o s u r e , such as the concentration of lead in b l o o d , w h e r e a v a i l a b l e , h a v e certain a d v a n t a g e s . For some a g e n t s , such as ionizing r a d i a t i o n , the use of personal m o n i t o r s has been v e r y
s u c c e s s f u l , though limited to occupational or smaller population g r o u p s . The difficulties of using personal m o n i t o r s for large general populations are o b v i o u s .
1.2.4 Selection of indices of effect
The report discusses the problem of selecting a p p r o p r i a t e indices of e f f e c t . In addition to m o r t a l i t y or m o r b i d i t y , there are indices based on clinical o b s e r v a t i o n s , on answers to q u e s t i o n n a i r e s concerning s y m p t o m s , or on records of day-to-day changes in the general condition of the persons u n d e r s t u d y . It is p r e f e r a b l e to u s e indices that can be o b j e c t i v e l y m e a s u r e d - for e x a m p l e , changes in lung function or changes in enzyme a c t i v i t y . A l t h o u g h difficult to a p p l y in field w o r k , tests of a b i l i t y to perform fine tasks a n d other p s y c h o p h y s i o l o g i c a l or b e h a v i o u r a l tests m a y be required to ascertain n e u r o l o g i c a l effects of exposure to c h e m i c a l s . The selection of a p p r o p r i a t e indices that p e r m i t the early detection of health impairment is one of the m a j o r fields w h e r e further research is n e c e s s a r y .
1.2.5 Other considerations
M a n y epidemiological studies h a v e not been completed satisfactorily b e c a u s e p r a c t i c a l considerations h a v e been n e g l e c t e d . It is essential to train field workers in m e t h o d s of m e a s u r e m e n t before the m a i n study starts and efforts should be m a d e to avoid a n y bias that m a y
be introduced either b y the persons examined or b y the i n v e s t i g a t o r . Possible ethical problems should b e examined before the study is i n i t i a t e d .
1.2.6 Evaluation of results
T h e final step of an epidemiological study is evaluation of the r e s u l t s , including statistical analysis• E x p e r t advice and guidance is n e c e s s a r y and close collaboration w i t h the statisticians should b e established from the b e g i n n i n g . In interpreting the r e s u l t s , it is important to n o t e that statistical significance a l o n e cannot b e regarded as a criterion for the existence of a health effect; the m a g n i t u d e and the health relevance of the b i o l o g i c a l changes observed m u s t also b e c o n s i d e r e d . A b o v e a l l , it m u s t be recognized that correlation does n o t n e c e s s a r i l y imply c a u s a t i o n .
The practical application of results of epidemiological studies has obviously to b e borne in m i n d . A n important application is the establishment of environmental health criteria and dose-response r e l a t i o n s h i p s . A l t h o u g h in m a n y cases epidemiological studies m a y n o t be sufficiently sensitive to determine q u a n t i t a t i v e exposure/response relationships at low dose l e v e l s , they a r e n e v e r t h e l e s s considered to be the m o s t important basis for the e s t a b l i s h m e n t of environmental h e a l t h s t a n d a r d s . A n o t h e r important application of epidemiological studies is to v a l i d a t e criteria and dose-response relationships obtained in other w a y s , e . g . from experimental studies^ E p i d e m i o l o g i c a l investigations are also used as a m e a n s for evaluating the efficacy of control m e a s u r e s .
1.2.7 M o n o g r a p h on epidemiological m e t h o d s
A l t h o u g h there are numerous reports scattered throughout the literature dealing w i t h epidemiological m e t h o d s as applied to physical and chemical a g e n t s , there is n o single publication that sets out the appropriate m e t h o d o l o g y for such s t u d i e s . The Study Group discussed the preparation and publication of a m o n o g r a p h on the conduct of epidemiological studies in this field and recommended that it should deal w i t h the following aspects : types of environmental agents and their m e a s u r e m e n t ; types of health effects and their m e a s u r e m e n t ; planning and analysis of epidemiological s t u d i e s , including statistical methods and assessment of the h e a l t h significance of results; and the organization and conduct of e p i d e m i o l o g i c a l s t u d i e s . M o s t i m p o r t a n t , the m o n o g r a p h w o u l d include examples of epidemiological studies actually carried o u t , w i t h a critical analysis of the specific features of such s t u d i e se
1。3 The r e c o m m e n d a t i o n s
The S t u d y G r o u p1 s r e c o m m e n d a t i o n s , f o r m u l a t e d on the b a s i s of the d i s c u s s i o n d e s c r i b e d a b o v e , can b e s u m m a r i z e d as follows :
(a) W H O should p r e p a r e a m o n o g r a p h on e p i d e m i o l o g i c a l m e t h o d s in e n v i r o n m e n t a l h e a l t h effects studies;
(b) s p e c i a l i z e d training should be p r o v i d e d in e p i d e m i o l o g y ;
(c) e p i d e m i o l o g i c a l and s t a t i s t i c a l m e t h o d s should b e i n c o r p o r a t e d in a l l stages of m e d i c a l e d u c a t i o n ;
(d) W H O c o l l a b o r a t i n g centres on e p i d e m i o l o g i c a l m e t h o d s should be d e s i g n a t e d ; (e) b i o l o g i c a l indices of e x p o s u r e s h o u l d b e d e v e l o p e d ;
(f) m e t h o d s for m e a s u r i n g h e a l t h effects should b e developed;
(g) e x p o s u r e to e n v i r o n m e n t a l a g e n t s in the h o m e , e s p e c i a l l y c h e m i c a l c o n s u m e r p r o d u c t s , should be evaluated;
(h) m o r e e f f e c t i v e u s e should b e m a d e of a v a i l a b l e data on the h e a l t h status of large p o p u l a t i o n s and c o o r d i n a t i o n of a l l a v a i l a b l e i n f o r m a t i o n , at b o t h n a t i o n a l and
i n t e r n a t i o n a l l e v e l .
C o m m e n t : T h e r e c o m m e n d a t i o n s of the S t u d y Group a r e of d i r e c t r e l e v a n c e to the W H O
p r o g r a m m e in e n v i r o n m e n t a l h e a l t h a n d e p i d e m i o l o g y , and the S e c r e t a r i a t has a l r e a d y found t h e m e x t r e m e l y u s e f u l and p r a c t i c a l . The r e p o r t itself is a clear s t a t e m e n t of the b a s i c p r i n c i p l e s for e p i d e m i o l o g i c a l studies as a p p l i e d to c h e m i c a l and p h y s i c a l agents a n d can be used also as a b a s i c g u i d e for the design and c o n d u c t of such s t u d i e s . 1.4 I m p l i c a t i o n s for the O r g a n i z a t i o n!s p r o g r a m m e
The report provides g u i d a n c e for future W H O a c t i v i t i e s intended to h a r m o n i z e epidemio- logical m e t h o d s as a p p l i e d to the study of e n v i r o n m e n t a l p o l l u t a n t s and o t h e r h a z a r d s , and to i m p r o v e the q u a l i t y and c o m p a r a b i l i t y of the results of such s t u d i e s . It w i l l e n a b l e the S e c r e t a r i a t to initiate the drafting of a m o n o g r a p h i m m e d i a t e l y , in collaboratiori w i t h n a t i o n a l experts and research i n s t i t u t i o n s .
A similar p r o j e c t is a l r e a d y u n d e r w a y for the e x p e r i m e n t a l t o x i c o l o g i c a l e v a l u a t i o n of c h e m i c a l s .
2 . C E R E B R O S P I N A L M E N I N G I T I S CONTROL R e p o r t of a W H O Study Group G e n e v a , 2 7 - 3 1 O c t o b e r 1975^
2.1 B a c k g r o u n d
T h e p u b l i c h e a l t h importance of c e r e b r o s p i n a l m e n i n g i t i s , in p a r t i c u l a r in A f r i c a n countriesj and the n e e d for the d e v e l o p m e n t of a v a c c i n e a g a i n s t this d i s e a s e in v i e w of the i n c r e a s i n g s u l f o n a m i d e r e s i s t a n c e in m e n i n g o c o c c i , w e r e r e c o g n i z e d b y the S c i e n t i f i c Groups on R e s e a r c h in I m m u n o l o g y that m e t in 1962,^ the M e e t i n g on N e i s s e r i a R e s e a r c h in 1964,^ and the A d v i s o r y C o m m i t t e e on M e d i c a l R e s e a r c h in 1969。^" On the basis of their recommendations
1 W H O T e c h n i c a l Report S e r i e s , N o . 5 8 8 , 1 9 7 6 . 2 W H O T e c h n i c a l Report S e r i e s , N o . 2 8 6 , 1 9 6 4 . о
D o c u m e n t W Ho / b d / mEn / i. 6 5 .
“ D o c u m e n t A C M R l l / 6 9e 1 0 .
c o l l a b o r a t i v e laboratory studies w e r e sponsored b y W H O and several e x p e r i m e n t a l lots of vaccinei w e r e e v e n t u a l l y prepared and tested in the f i e l d . Of t h e s e , w h o l e - c e l l v a c c i n e proved to be
too reactogenic and w a s a b a n d o n e d . P o l y s a c c h a r i d e v a c c i n e a g a i n s t Group A m e n i n g o c o c c i , on the c o n t r a r y , proved to be innocuous and w a s shown to be e f f e c t i v e in field trials in A f r i c a . The need for standardization of this v a c c i n e then a r o s e in order to ensure that v a c c i n e of good q u a l i t y w o u l d be used in p u b l i c health p r a c t i c e .
The Study Group w a s convened in October 1975 to discuss the c o n t r o l of c e r e b r o s p i n a l m e n i n g i t i s in general a n d , in p a r t i c u l a r , the p r e p a r a t i o n , p o t e n c y testing and u s e of v a c c i n e s .
It w a s also called upon to p r o p o s e requirements for p o l y s a c c h a r i d e Group A and G r o u p С v a c c i n e s for c o n s i d e r a t i o n b y the E x p e r t C o m m i t t e e on B i o l o g i c a l S t a n d a r d i z a t i o n (2-8 D e c e m b e r 1 9 7 5 ) . 2.2 The report
T h e report of the Study G r o u p concentrates on m a j o r aspects a n d p r o b l e m s of c e r e b r o s p i n a l m e n i n g i t i s control。
Discussions took place on diagnostic p r o c e d u r e s , i d e n t i f i c a t i o n , g r o u p i n g and typing of m e n i n g o c o c c i , as w e l l as on a p p r o p r i a t e b a c t e r i o l o g i c a l m e t h o d s .
Immunity and vaccines are discussed in some d e t a i l . A d e s c r i p t i o n of v a r i o u s s e r o l o g i c a l tests is given and their relative v a l u e d i s c u s s e d . T h e m e t h o d s of p r e p a r a t i o n a n d p o t e n c y testing of p o l y s a c c h a r i d e Group A and Group С v a c c i n e s a r e p r e s e n t e d , as w e l l as the evidence of the effectiveness of this type of v a c c i n e that has a c c u m u l a t e d from 8 c o n t r o l l e d field trials carried out in A f r i c a , the A m e r i c a s , and E u r o p e .
The Group concludes that there is d e f i n i t e e v i d e n c e of the e f f e c t i v e n e s s of p o l y s a c c h a r i d e vaccines a g a i n s t serogroup A and С m e n i n g o c o c c i . A l t h o u g h these v a c c i n e s h a v e limitations in that they do n o t protect young children a n d individuals infected b y other serogroups and they a r e still e x p e n s i v e , they can n e v e r t h e l e s s b e u s e d e f f e c t i v e l y in the p r e v e n t i o n of cerebro- spinal m e n i n g i t i s due to serogroups A and C .
The Group also discusses other m e t h o d s of control of c e r e b r o s p i n a l m e n i n g i t i s , n a m e l y the m e r i t s and risks of chemo- and a n t i b i o t h e r a p y and p r o p h y l a x i s , a n d the b e s t w a y s of u s i n g
a n t i m i c r o b i a l agents in p r a c t i c e . 2.3 The recommendations
A m o n g the m o s t important of the Study G r o u p1 s r e c o m m e n d a t i o n s a r e the following:
(a) The proposed text for the Requirements for p o l y s a c c h a r i d e Groups A a n d С v a c c i n e s in order to ensure their q u a l i t y and innocuity should b e a d o p t e d . (The R e q u i r e m e n t s w e r e p r e s e n t e d to and adopted b y the E x p e r t C o m m i t t e e on B i o l o g i c a l S t a n d a r d i z a t i o n at its m e e t i n g in December 1975.1)
(b) Further laboratory a n d field studies should b e c o n d u c t e d for the p r e p a r a t i o n of m o r e potent vaccines against n o t only Group A and С m e n i n g o c o c c i , but a l s o other m a j o r sero- g r o u p s , as w e l l as for stabilization of the a n t i g e n . C o m b i n e d v a c c i n e s should be
developed in w h i c h the m e n i n g o c o c c a l v a c c i n e s w o u l d b e a s s o c i a t e d w i t h other c o m m o n l y used immunizing agents in order to simplify and reduce the cost of immunizations in p u b l i c h e a l t h p r a c t i c e .
(c) L a b o r a t o r y services and facilities for the s u r v e i l l a n c e of m e n i n g o c o c c a l infection should be s t r e n g t h e n e d , since they are important for the p r o p e r u s e of v a c c i n e s as w e l l as a n t i m i c r o b i a l a g e n t s .
1 W H O Technical Report S e r i e s , N o 5 9 4 , 1976 (in p r e s s ) .
(d) C o o p e r a t i v e i n t e r n a t i o n a l studies should b e carried out for the improvement of b a c t e r i o l o g i c a l and s e r o l o g i c a l t e c h n i q u e s .
C o m m e n t : In a d d i t i o n to m a k i n g recommendations on the m a j o r aspects and problems of c e r e b r o s p i n a l m e n i n g i t i s c o n t r o l , the Study Group r e c o m m e n d e d requirements for a c h e m i c a l v a c c i n e w i t h a k n o w n c h e m i c a l structure。 This is p r o b a b l y the first time that a chemical v a c c i n e has b e e n found e f f e c t i v e in protecting a g a i n s t c e r e b r o s p i n a l m e n i n g i t i s of the h o m o l o g u e group in A f r i c a , the A m e r i c a s and E u r o p e . These products require an entirely n e w a p p r o a c h to q u a l i t y control w h i c h cannot b e limited to b i o l o g i c a l or chemical tests a l o n e a n d should a l s o include immunochemical a s s a y . W i t h the s u b s e q u e n t adoption of the p r o p o s e d r e q u i r e m e n t s , W H O has m a d e a step forward in the recognition of a n e w class of v a c c i n e s that b e l o n g to the f u t u r e .
2.4 I m p l i c a t i o n s for the O r g a n i z a t i o n1 s p r o g r a m m e
The r e c o m m e n d a t i o n s of the Group a r e directly related to the W H O programmes for promotion of r e s e a r c h in this field and to c o l l a b o r a t i o n w i t h countries in the control of cerebrospinal m e n i n g i t i s .
The r e c o m m e n d a t i o n s are n o t only i m p o r t a n t for the p l a n n i n g of research activities in the field of m e n i n g o c o c c a l v a c c i n e s , including related b a c t e r i o l o g i c a l and serological s t u d i e s , but w i l l a l s o h a v e an impact on a related field of r e s e a r c h , n a m e l y the development of v a c c i n e s a g a i n s t gonorrhoea (which w a s a l s o b r i e f l y discussed b y the G r o u p ) .
A n u m b e r of s p e c i f i c a l l y p r o p o s e d international c o o p e r a t i v e laboratory studies w i l l be c a r r i e d out b y W H O c o l l a b o r a t i n g c e n t r e s . It is expected that in a t least one region it w i l l b e p o s s i b l e to p r o m o t e c o l l a b o r a t i o n b e t w e e n several laboratories interested in cerebrospinal
m e n i n i g i t i s r e s e a r c h .
A s for the p r a c t i c a l a p p l i c a t i o n in terms of v a c c i n e , the Study G r o u p1 s report is expected to s t i m u l a t e various laboratories to s t u d y a n d p r o d u c e this type of v a c c i n e . This w i l l
u n d o u b t e d l y result in due c o u r s e in b e t t e r quality a n d cheaper v a c c i n e s that can be used m o r e e x t e n s i v e l y in the c o n t r o l of this d i s e a s e .
•к /V
