The Role of Aflatoxin in Human Disease

3 The Role of Aflatoxin in Human Disease R. C. SHANK

1

Department of Nutrition and Food Science, Massachusetts Institute of Technology, Cambridge, Mass. 02139 Since the finding that aflatoxin B is the most potent hepatocarcinogen known, several international studies have been conducted to determine to what extent this toxin is causally related to liver cancer in man. In areas of Uganda and Swaziland where the incidence of liver cancer is high, aflatoxin contamination of food crops is also high. Daily ingestion of aflatoxins in Thailand and Kenya correlated well with liver cancer incidence. Mounting evidence relates aflatoxins to acute poisonings in children, especially Reye's syndrome in Thailand.

Downloaded by AUBURN UNIV on January 10, 2018 | http://pubs.acs.org Publication Date: June 1, 1976 | doi: 10.1021/ba-1976-0149.ch003

1

Much is known about the occurrence and toxicity of the aflatoxins. Aflatoxin B , the most common of the group in natural contamina tion of foodstuffs, is the most potent hepatocarcinogen known for experi mental animals. Obviously the ultimate question is what role if any aflatoxin plays in human disease. 1

Chronic

Toxicity

The first study that associated aflatoxins i n the food supply with the incidence of human liver cancer was done i n Uganda by Alpert and co-workers (1). O f the 480 food samples collected from various areas of Uganda during 1966-1967, almost 4% contained more than 1 ppm total aflatoxins; this is regarded as heavy contamination. More important, there was a geographical distribution to the contamination which when compared with the distribution of liver cancer i n Uganda suggested an association of the toxin and the disease. Keen and Martin (2) measured the extent of aflatoxin contamination in peanuts collected from various areas i n Swaziland and at the same 1

Present address: Department of Community and Environmental Medicine, Col lege of Medicine, University of California, Irvine, Calif. 92664. 51 Rodricks; Mycotoxins and Other Fungal Related Food Problems Advances in Chemistry; American Chemical Society: Washington, DC, 1976.

52

M Y C O T O X I N S

t i m e e s t i m a t e d the g e o g r a p h i c a l d i s t r i b u t i o n of l i v e r c a n c e r cases b a s e d o n c a n c e r r e g i s t r y d a t a f o r 1964 to 1968.

I n areas w h e r e c o n t a m i n a t i o n

of p e a n u t s w a s h i g h , t h e e s t i m a t e d i n c i d e n c e of l i v e r c a n c e r w a s h i g h ; i n a d d i t i o n , i n h a b i t a n t s of t h e h i g h l i v e r c a n c e r areas t e n d e d t o eat m o r e p e a n u t s t h a n those i n other areas, i n c r e a s i n g the l i k e l i h o o d of

greater

exposure to aflatoxin. T h e s e t w o studies d i d n o t s h o w h o w m u c h aflatoxin w a s

consumed.

I n i t i a l reports o n aflatoxin c o n s u m p t i o n c a m e f r o m C a m p b e l l a n d

co

workers (3) w h o examined urine f r o m P h i l i p p i n e c h i l d r e n w h o h a d eaten contaminated peanut butter.

C h e m i c a l analysis p e r f o r m e d

on

peanut


b u t t e r samples f r o m 1967 t o 1969 r e v e a l e d t h a t the l o c a l p r o d u c t h a d a m e d i a n l e v e l of aflatoxins of 500 / x g / k g . C h i l d r e n w h o c o n s u m e d 60 g or m o r e of s u c h p e a n u t b u t t e r e x c r e t e d d e t e c t a b l e levels of t h e aflatoxin m e t a b o l i t e , aflatoxin M i . N o t u n t i l r e c e n t l y w e r e there reports of e p i d e m i o l o g i c

studies

on

levels of aflatoxin c o n s u m e d o n a d a i l y basis a n d t h e simultaneous i n c i d e n c e of h e p a t o c e l l u l a r c a r c i n o m a . O n e s t u d y w a s m a d e i n T h a i l a n d ( 4 , 5, 6,7,

8).

O f the 2180 samples of foods a n d foodstuffs t h a t w e r e c o l

l e c t e d for a l m o s t t w o years f r o m m a r k e t s , m i l l s , w a r e h o u s e s , d i s t r i b u t o r s , farms, a n d homes throughout T h a i l a n d , 9 %

h a d aflatoxins, a n d p e a n u t s ,

corn, millet, a n d d r i e d c h i l i peppers were contaminated most frequently. T o x i n levels i n foods d e s t i n e d f o r h u m a n c o n s u m p t i o n w e r e as h i g h as 772 / x g / k g i n d r i e d fish, 966 / x g / k g i n d r i e d c h i l i p e p p e r s , 2700 / x g / k g i n c o r n , a n d m o r e t h a n 12,000 / x g / k g i n p e a n u t s . T h e m a r k e t s u r v e y i n d i c a t e d a g e o g r a p h i c a l d i s t r i b u t i o n of aflatoxin c o n t a m i n a t i o n a n d s e r v e d as a basis f o r d e s i g n i n g a p i l o t s t u d y to m e a s u r e s i m u l t a n e o u s l y aflatoxin c o n s u m p t i o n a n d fiver c a n c e r i n c i d e n c e i n t w o different p o p u l a t i o n s . T h r e e v i l l a g e s w e r e selected i n e a c h of t h r e e areas of e x p e c t e d

h i g h , intermediate, a n d l o w toxin consumptions.

In

each

v i l l a g e 16 h o u s e h o l d s w e r e selected r a n d o m l y to serve as t h e d i e t a r y s u r v e y p o p u l a t i o n ; f o o d p r e p a r e d a n d eaten b y these f a m i l i e s w a s a s s a y e d f o r aflatoxins for t h r e e s e p a r a t e t w o - d a y i n t e r v a l s o v e r 12 m o n t h s .

In

central T h a i l a n d w h e r e aflatoxin contamination was shown h i g h b y the m a r k e t s u r v e y , d a i l y t o t a l aflatoxin c o n s u m p t i o n a v e r a g e d 7 3 - 8 1 n g / k g b o d y w e i g h t on a f a m i l y basis; i n western T h a i l a n d where the market s u r v e y i n d i c a t e d m o d e r a t e c o n t a m i n a t i o n , t h e t o t a l aflatoxin c o n s u m p t i o n averaged 4 5 - 7 7 n g / k g b o d y weight per day, a n d i n the southern-most area (expected l o w contamination)

t h e average w a s 5 - 8

n g / k g body

weight per day. A l t h o u g h the m a r k e t s u r v e y i n d i c a t e d t h a t p e a n u t s , c o r n , a n d m i l l e t w e r e h i g h i n t o x i n , these w e r e n o t t h e i m p o r t a n t sources i n t h e T h a i diet.

P e a n u t s i n T h a i l a n d a r e a snack f o o d a n d g a r n i s h , a n d c o r n a n d

m i l l e t a r e o n l y a s m a l l p a r t o f the d i e t .

A l t h o u g h rice i n markets a n d

Rodricks; Mycotoxins and Other Fungal Related Food Problems Advances in Chemistry; American Chemical Society: Washington, DC, 1976.

3.

Aflatoxin

S H A N K

in Human

53

Disease

storage areas w a s r e l a t i v e l y free of aflatoxins, i t w a s a m a j o r source of t o x i n i n the diet. I n d i r e c t e v i d e n c e suggested t h a t l e f t o v e r f o o d s w e r e a n a p p r e c i a b l e source of d i e t a r y aflatoxins. T h e m a r k e t s u r v e y d i d p r e d i c t successfully, h o w e v e r , t h a t foods c o n t a i n i n g g a r l i c , d r i e d c h i l i p e p p e r s , or d r i e d fish, c o m m o n i n g r e d i e n t s i n T h a i foods, w o u l d p r o b a b l y c o n t a i n t h e toxins. D u r i n g the d i e t a r y s u r v e y , t h e i n c i d e n c e of p r i m a r y l i v e r c a n c e r w a s also m e a s u r e d i n w e s t e r n a n d southern-most T h a i l a n d .

I n v e s t i g a t i o n of

a l l h o s p i t a l a n d h o m e deaths w i t h i n a d e f i n e d p o p u l a t i o n o f a p p r o x i m a t e l y 100,000 p e o p l e p e r area c o n t i n u e d f o r 12 m o n t h s .

L i v e r viscer-


o t o m y specimens w e r e c o l l e c t e d w h e n e v r p o s s i b l e f o r h i s t o p a t h o l o g i c a l e x a m i n a t i o n a n d v e r i f i c a t i o n of diagnosis. T h e i n c i d e n c e of p r i m a r y l i v e r c a n c e r i n w e s t e r n T h a i l a n d w a s six n e w cases p e r y e a r p e r 100,000 p e o p l e , u n a d j u s t e d for sex a n d age. I n southern-most T h a i l a n d t h e i n c i d e n c e w a s 2 / 1 0 0 , 0 0 0 / y e a r ; thus w h e r e aflatoxin c o n s u m p t i o n w a s h i g h , i n c i d e n c e of fiver cancer w a s also h i g h . N o t e h o w e v e r t h a t t h e r e is p r e s u m a b l y a l a g b e t w e e n aflatoxin c o n s u m p t i o n a n d t u m o r expression, a n d t h e r e f o r e i t m u s t b e a s s u m e d that aflatoxin intakes m e a s u r e d i n the T h a i l a n d s u r v e y w e r e i n d i c a t i v e of those of t h e l i v e r c a n c e r cases at t h e t i m e t h e i r t u m o r s w e r e b e i n g i n d u c e d . A l t h o u g h t h e a m o u n t of aflatoxin c o n s u m e d seem m i n u t e , the p o t e n c y of aflatoxin B i m u s t b e r e m e m b e r e d .

may

Continu

ous exposure of aflatoxin B i to rats at a 1 / x g / k g d i e t l e v e l results i n a significant i n c i d e n c e of l i v e r t u m o r s . T h e h i g h e s t d a i l y a f l a t o x i n B i i n t a k e m e a s u r e d i n T h a i l a n d w a s 55 n g / k g b o d y w e i g h t ( 6 ) , c o m p a r a b l e to a c a r c i n o g e n i c dose for the rat. F u r t h e r s u p p o r t t h a t c a u s a l l y relates d i e t a r y aflatoxins to h u m a n fiver cancer are the results f r o m a n extensive a n d c a r e f u l e p i d e m i o l o g i c a l s t u d y c a r r i e d out i n K e n y a f r o m 1967 to 1970 b y P e e r s a n d L i n s e l l

(9).

T h e s t u d y w a s c o n d u c t e d i n t h e M u r a n g ' a d i s t r i c t ( p o p u l a t i o n 334,068, 16 years of age a n d o l d e r ) o n the eastern slopes of the A b e r d a r e M o u n tains w i t h three g e o g r a p h i c a l l y d i s t i n c t areas of h i g h , i n t e r m e d i a t e , a n d l o w e l e v a t i o n . T h e a m o u n t s of aflatoxins c o n t a m i n a t i n g t h e f o o d s u p p l i e s a n d the d i e t a r y loads of aflatoxins i n these areas v a r i e d i n v e r s e l y w i t h altitude.

T h e i n c i d e n c e of l i v e r c a n c e r w a s d e t e r m i n e d t h r o u g h t h e

c a n c e r r e g i s t r y i n the same g e n e r a l p o p u l a t i o n s i n w h i c h aflatoxin i n g e s t i o n w a s m e a s u r e d . T h e d a t a w e r e p l o t t e d as i n c i d e n c e vs. l o g dose to y i e l d a regression l i n e w i t h a c o r r e l a t i o n coefficient o f 0.87 degrees of f r e e d o m ) .

(for

four

T h e d a t a o b t a i n e d f r o m T h a i l a n d a r e i n excellent

a g r e e m e n t w i t h the K e n y a n regression l i n e . N o t e that t h e 10,885 females o v e r t h e age of 16 i n t h e h i g h e l e v a t i o n a r e a h a d n o cases of l i v e r cancer w i t h i n t h e 1 2 - m o n t h s t u d y p e r i o d e v e n t h o u g h t h e m e a n aflatoxin c o n s u m p t i o n w a s 3.46 n g / k g b o d y w e i g h t ; h o w e v e r this does n o t m e a n t h a t this l e v e l of aflatoxin c o n s u m p t i o n is n o t


54

MYCOTOXINS

carcinogenic.

A t that exposure the o b s e r v e d i n c i d e n c e of l i v e r

cancer

w a s zero p e r 10,000 p e o p l e i n o n e y e a r a n d s h o u l d n o t b e c o n s i d e r e d as t h e safe o r no-effect l e v e l . Acute

Toxicity

Aflatoxins w e r e d i s c o v e r e d b e c a u s e of t h e i r a c u t e t o x i c i t y ; i t is r e a s o n a b l e to assume t h a t i f these toxins are sufficiently p r e v a l e n t i n t h e h u m a n d i e t to b e c a u s a l l y r e l a t e d to h u m a n l i v e r cancer, there exists a p o t e n t i a l for exposure to l a r g e r a m o u n t s for shorter p e r i o d s r e s u l t i n g i n


a n a c u t e response.

T h r e e reports h a v e associated aflatoxins w i t h acute

poisoning i n man—specifically, rural children. I n 1967 L i n g a n d c o - w o r k e r s

(10)

r e p o r t e d o n a n i n t o x i c a t i o n of

26 persons w i t h t h r e e deaths i n t w o T a i w a n f a r m i n g v i l l a g e s . T h e v i c t i m s suffered e d e m a of t h e l o w e r e x t r e m i t i e s , a b d o m i n a l p a i n , v o m i t i n g , a n d p a l p a b l e l i v e r b u t n o fever. I n t h r e e f a m i l i e s of t e n households, households

c o n s u m e d m o l d y r i c e f o r p e r i o d s u p to three w e e k s

five and

e x p e r i e n c e d t h e i n t o x i c a t i o n . M e m b e r s of the same f a m i l i e s l i v i n g i n t h e same c o m p o u n d s b u t i n different houses c o n s u m e d other r i c e a n d w e r e unaffected.

O n e or t w o samples o f r i c e w e r e t a k e n f r o m e a c h of the

affected f a m i l i e s a n d assayed f o r aflatoxin B i ; i n o n l y t w o s a m p l e s , b o t h f r o m the same f a m i l y , w a s the t o x i n f o u n d at a p p r o x i m a t e l y 200 / * g / k g . N e i t h e r sex n o r age g o v e r n e d the illness, b u t a l l three deaths w e r e c h i l d r e n a g e d f o u r , five, a n d six years. O n e c h i l d d i e d 6V2 hrs after t h e onset of illness, another 3y

2

days after, a n d t h e t h i r d s e v e r a l days after.

A n o t h e r r e p o r t (11)

of s u s p e c t e d aflatoxin p o i s o n i n g i n v o l v e d a 15-

y e a r o l d A f r i c a n ( U g a n d a ) b o y w i t h a h i s t o r y of f o u r days of a b d o m i n a l p a i n a n d s w e l l i n g . U p o n a d m i s s i o n to t h e h o s p i t a l h e h a d e d e m a of b o t h legs, a p a l p a b l e t e n d e r l i v e r , a n d n o fever, s y m p t o m s closely r e s e m b l i n g t h e T a i w a n cases.

H e w a s treated f o r h e a r t f a i l u r e , b u t h i s c o n d i t i o n

w o r s e n e d , a n d h e d i e d t w o d a y s after a d m i s s i o n . T h e a u t o p s y r e v e a l e d p u l m o n a r y e d e m a , a flabby h e a r t , a n d diffuse necrosis of the l i v e r ; there w a s congestion a n d e d e m a of t h e l u n g , i n t e r s t i t i a l e d e m a of the heart, a n d c e n t r i l o b u l a r necrosis a n d m i l d f a t t y changes i n t h e s i b l i n g s w e r e also i l l at the same t i m e b u t r e c o v e r e d .

fiver.

Two

T h e children's diet

c o n s i s t e d p r i n c i p a l l y of cassava, b e a n s , fish, a n d m e a t .

A n a l y s i s of the

cassava s a m p l e d i n t h e h o m e r e v e a l e d m o l d i n f e s t a t i o n a n d a n aflatoxin c o n c e n t r a t i o n of 1.7 m g / k g ; p r e s u m a b l y this l e v e l , b a s e d o n

monkey

d a t a ( 1 2 ) , c o u l d b e f a t a l i f t h e b o y ate cassava f o r a f e w w e e k s . T h e m o s t i n c r i m i n a t i n g e v i d e n c e comes f r o m T h a i l a n d

(13,

14).

R e y e ' s s y n d r o m e w h i c h occurs i n e p i d e m i c p r o p o r t i o n s i n n o r t h e a s t e r n T h a i l a n d (15) vomiting,

is a c h i l d r e n ' s disease c h a r a c t e r i z e d b y a short p r o d r o m e ,

hypoglycemia,

convulsions,

hyperammoniemia,

coma,


and

3.

S H A N K

usually

Aflatoxin

death.

in Human

55

Disease

Histopathologic

examination

reveals

severe

cerebral

e d e m a a n d extensive f a t t y a c c u m u l a t i o n i n hepatocytes, r e n a l t u b u l a r e p i t h e l i u m , a n d m y o c a r d i a l fibers. A l t h o u g h attempts to associate a v i r u s w i t h the T h a i cases h a v e n o t b e e n successful etiology (13).

(16),

a case d i d o c c u r w h i c h suggested

a mycotoxin

A t h r e e - y e a r - o l d T h a i b o y h a d b e e n i l l f o r 12 h r s w i t h

fever, v o m i t i n g , c o m a , a n d c o n v u l s i o n s . where examination showed

H e was admitted to a hospital

severe h y p o g l y c e m i a — 2 4

mg/100

ml.

hours l a t e r the c h i l d d i e d , a n d t h e diagnosis of Reye's s y n d r o m e confirmed b y autopsy a n d histopathology.

Six was

A v i s i t to t h e boy's v i l l a g e


h o m e r e v e a l e d t h a t for t w o days p r i o r to the onset of i l l n e s s , t h e c h i l d h a d eaten o n l y l e f t o v e r c o o k e d r i c e s t o r e d w i t h o u t r e f r i g e r a t i o n . T h e r i c e w a s m o l d y b u t o r g a n o l e p t i c a l l y a p p e a l i n g ; i t assayed at m o r e t h a n 10 m g total aflatoxins/kg. S i n c e the r o d e n t does n o t r e s p o n d to aflatoxin i n a n y w a y s i m i l a r to Reye's s y n d r o m e , acute aflatôxicosis w a s r e - e x a m i n e d i n t h e m o n k e y a n d w a s s t r i k i n g l y s i m i l a r to the h u m a n disease

macaque

(13).

Tissue

analysis f r o m m o n k e y s i n this test d e m o n s t r a t e d r e c o v e r a b l e aflatoxin B i f r o m b r a i n , l i v e r , k i d n e y , h e a r t , b i l e , a n d b l o o d u p to six days after s i n g l e o r a l a d m i n i s t r a t i o n of t h e t o x i n ( 1 7 ) .

This

finding

prompted

analyses o n a u t o p s y s p e c i m e n s f r o m T h a i Reye's s y n d r o m e cases

similar (14).

A f l a t o x i n Βχ was f o u n d i n one o r m o r e specimens f r o m 22 of t h e 23 cases s t u d i e d ; i n t w o instances t h e h u m a n tissue levels w e r e c o m p a r a b l e w i t h those i n the m o n k e y s g i v e n n e a r l y a n L D Becroft and Webster

(18)

5 0

dose of aflatoxin.

f o u n d aflatoxin i n t w o cases of

s y n d r o m e i n N e w Z e a l a n d , a n d D v o r a c k o v a (19) cases i n C z e c h o s l o v a k i a .

However,

we

Reye's

f o u n d t h e t o x i n i n six

examined autopsy

specimens

f r o m five cases i n the U n i t e d States a n d h a v e n o t d e t e c t e d aflatoxin B i or a n y of its c h l o r o f o r m - s o l u b l e m e t a b o l i t e s .

Doris Collins (20)

recog

n i z e d i n t r a n u c l e a r i n c l u s i o n s i n p a n c r e a t i c a c i n a r cells i n f o u r N e w Y o r k and

M a s s a c h u s e t t s cases of Reye's s y n d r o m e a n d notes t h e i r s i m i l a r i t y

to s u c h i n c l u s i o n s seen i n m a c a q u e s a c u t e l y p o i s o n e d w i t h aflatoxin B i (13).

T h e s e d a t a d o n o t e s t a b l i s h aflatoxins as the c a u s a t i v e agents i n

Reye's s y n d r o m e , b u t t h e y s t r o n g l y suggest t h a t these m y c o t o x i n s s h o u l d b e c o n s i d e r e d as at least one f a c t o r i n the genesis of the disease. T h e r e m a y b e a n association b e t w e e n

Reye's s y n d r o m e a n d l i v e r

c a n c e r i n T h a i l a n d . Reye's s y n d r o m e occurs most f r e q u e n t l y i n northeast T h a i l a n d , a n d , a l t h o u g h t h e l i v e r c a n c e r rate has n o t b e e n

measured

d i r e c t l y i n t h a t a r e a , a r e v i e w of h o s p i t a l records c o v e r i n g a l l p r o v i n c e s of T h a i l a n d i n d i c a t e d t h a t t h e northeast h a d the greatest n u m b e r

of

r e p o r t e d cases of l i v e r c a n c e r p e r c a p i t a . H o w e v e r , i n m a n y instances these cases w e r e n o t p r o v e d b y h i s t o p a t h o l o g y ( 7 ) , a n d l i v e r p a r a s i t i s m , e s p e c i a l l y o p i s t h o r c i a s i s , w a s also f r e q u e n t l y r e p o r t e d i n t h i s a r e a .


It

56

MYCOTOXINS

m a y b e that R e y e s s y n d r o m e i n T h a i l a n d , as a m a n i f e s t a t i o n of a c u t e aflatoxicosis, identifies a p o p u l a t i o n at i n c r e a s e d r i s k f o r l i v e r

cancer;

i n d e e d not o n l y greater exposure is suggested, b u t s u r v i v o r s o f t h e a c u t e disease m a y h a v e a n e s p e c i a l l y h i g h r i s k f o r l i v e r c a n c e r . T h i s p o s s i b l e association s h o u l d b e tested e p i d e m i o l o g i c a l l y . T o c o m p l e t e this s u r v e y of e v i d e n c e i m p l i c a t i n g aflatoxins i n h u m a n disease, i t is necessary to c o n s i d e r I n d i a n c h i l d h o o d c i r r h o s i s . T h i s is a disease m a r k e d b y i n f i l t r a t i o n of hepatocytes w i t h n e u t r a l f a t l e a d i n g to d e g e n e r a t i o n , fibrosis, a n d h e p a t o m e g a l y . to j a u n d i c e , ascites, a n d h e p a t i c c o m a .

I n a d v a n c e d stages i t p r o c e e d s

P r e s u m p t i v e tests i n d i c a t e d afla


t o x i n Βχ i n peanuts a n d p e a n u t p r o d u c t s eaten b y c h i l d r e n w i t h t h i s disease a n d i n a f e w samples of h u m a n m i l k a n d u r i n e f r o m m o t h e r s of patients (21).

K w a s h i o r k o r cases t h a t w e r e f e d p r o t e i n s u p p l e m e n t s

( d e r i v e d f r o m peanuts c o n t a m i n a t e d w i t h aflatoxins, 3 0 0 / x g / k g s u p p l e ment)

d e v e l o p e d c e n t r a l a n d p e r i p o r t a l fat a c c u m u l a t i o n , fibrosis, a n d

cirrhosis of the l i v e r (22).

M o r e e p i d e m i o l o g i c a l s t u d i e s a r e n e e d e d to

assess the r o l e of aflatoxins i n I n d i a n c h i l d h o o d c i r r h o s i s . Summary C o n s i d e r a b l e i n d i r e c t e v i d e n c e suggests t h a t t h e aflatoxins p l a y a r o l e i n the e t i o l o g y of p r i m a r y c a n c e r of the l i v e r i n h u m a n p o p u l a t i o n s of A f r i c a a n d Southeast A s i a w h e r e m o l d d a m a g e t o f o o d s a n d foodstuffs is frequent. F u r t h e r e p i d e m i o l o g i c a l studies m a y s u p p o r t this suggestion b y i n c r e a s i n g statistical significance of the d a t a , b u t t h e y are u n l i k e l y to p r o v i d e a m o r e d i r e c t association t h a n has a l r e a d y b e e n e s t a b l i s h e d . D i e t s c o n t a m i n a t e d w i t h aflatoxin are l i k e l y to c o n t a i n other m y c o toxins a n d f o o d - b o r n e toxicants, b u t n o s u c h agents are k n o w n w h i c h a p p r o a c h , e v e n r e m o t e l y , the c a r c i n o g e n i c p o t e n c y o f aflatoxin (as d e m o n s t r a t e d i n t h e r a t a n d t r o u t ) . F o r this r e a s o n p r i m a r y focus o n afla t o x i n Βχ seems justified b u t does n o t e x c l u d e t h e p o s s i b i l i t y t h a t other factors s u c h as d i e t a r y ones also m a y c o n t r i b u t e to t h i s disease. I n a d d i t i o n to the c h r o n i c effects of aflatoxin c o n s u m p t i o n , c i r c u m s t a n t i a l e v i d e n c e suggests t h a t this m o l d m e t a b o l i t e m a y b e a f a c t o r i n t h e etiology of R e y e s s y n d r o m e at least as i t o c c u r s i n T h a i l a n d .

An

e p i d e m i o l o g i c a l s t u d y s h o u l d b e c a r r i e d out t o e v a l u a t e m o r e f u l l y the r o l e of aflatoxins i n Reye's s y n d r o m e . Literature

Cited

1. Alpert, M. E., Hurt, M . S. R., Wogan, G. N., Davidson, C. S., Cancer Res. (1971) 28, 253. 2. Keen, P., Martin, P., Trop. Geogr. Med. (1971) 23, 35. 3. Campbell, T. C., Caedo, J. P., Jr., Bulatao-Jayme, J., Salamat, L . , Engel, R. W., Nature (1970) 227, 403.



3.

SHANK

Aflatoxin

in Human

Disease

57

4. Shank, R. C., Wogan, G. N., Gibson, J. B., Food Cosmet. Toxicol. (1972) 10, 51. 5. Shank, R. C., Wogan, G. N., Gibson, J. B., Nondasuta, Α., Food Cosmet. Toxicol (1972) 10, 61. 6. Shank, R. C., Gordon, J. E., Wogan, G. N., Nondasuta, Α., Subhamani, B., Food Cosmet. Toxicol. (1972) 10, 71. 7. Shank, R. C., Bhamarapravati, N . , Gordon, J. E., Wogan, G. N . , Food Cosmet. Toxicol. (1972) 10, 171. 8. Shank, R. C., Siddhichai, P., Subhamani, B., Bhamarapravati, N., Gordon, J. E., Wogan, G. N., Food Cosmet. Toxicol. (1972) 10, 181. 9. Peers, F. G., Linsell, C. Α., Brit. J. Cancer (1973) 27, 473. 10. Ling, K.-H., Wang, J.-J., Wu, R., Tung, T.-C., Lin, C.-K., Lin, S.-S., Lin, T.-M., J. Formosan Med. Ass. (1967) 66, 517. 11. Serck-Hanssen, Α., Arch. Environ. Health (1970) 20, 729. 12. Alpert, E., Serck-Hanssen, Α., Rajagopolan, B., Arch. Environ. Health (1970) 20, 723. 13. Bourgeois, C. H., Shank, R. C., Grossman, R. Α., Johnsen, D. O., Wooding, W. L., Chandavimol, P., Lab. Invest. (1971) 24, 206. 14. Shank, R. C., Bourgeois, C. H., Keschamras, N., Chandavimol, P., Food Cosmet. Toxicol. (1971) 9, 501. 15. Bourgeois, C., Olson, L., Comer, D., Evans, H., Keschamras, N., Cotton, R., Grossman, R., Smith, T., Amer. J. Clin. Pathol. (1971) 56, 558. 16. Olson, L., Bourgeois, C. H., Cotton, R., Harikul, S., Grossman, R , Smith, T., Pediatrics (1971) 47, 707. 17. Shank, R. C., Johnsen, D. O., Tanticharoenyos, P., Wooding, W. L., Bourgeois, C. H., Toxicol Appl. Pharmacol. (1971) 20, 227. 18. Becroft, D. M . O., Webster, D. R., Brit. Med. J. (1972) 4, 117. 19. Dvorackova, Ivana, private communication. 20. Collins, D. N., Lab. Invest. (1974) 30, 333. 21. Robinson, P., Clin. Pediatrics (1967) 6, 57. 22. Amla, I., Kamala, C. S., Gopalakrishna, G. S., Jayaraj, A. P., Sreenivasamurthy, V., Parpia, H . A. B., Amer. J. Clin. Nutr. (1971) 24, 609. R E C E I V E D November 8,

1974.


The Role of Aflatoxin in Human Disease

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