Epidemiological Studies of Cancer and Pesticide Exposure - ACS

Chapter 13

Epidemiological Studies of Cancer and Pesticide Exposure

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Allan H. Smith and Michael N. Bates Department of Biomedical and Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA 94720 Epidemiological studies concerning human cancer risk and pesticides were reviewed. The most persuasive evidence for a human cancer risk was for the inorganic arsenic pesticides. There was reasonably consistent evidence of an increase in lung cancer risk for professional pesticide applicators, although it was not clear that this could be attributed to pesticides. Several studies have found farmers to be at increased risk for multiple myeloma, non-Hodgkins lymphoma and leukemia, but no clear association with exposure to pesticides has emerged. Some studies, particularly in Sweden, have reported strong associations between exposure to phenoxy herbicides and malignant lymphoma and soft tissue sarcoma. However, these associations have generally not been supported by studies undertaken elsewhere and their biological plausibility is questionable. Few studies have examined the carcinogenic potential of DDT and other organochlorine insecticides. There is a need to do more epidemiological studies, particularly of the most highly exposed group - pesticide applicators. Since the discovery in the Eighteenth Century of scrotal cancer in young chimney sweeps caused by exposure to soot, epidemiological studies have identified a considerable number of human carcinogens. The l i s t includes cigarette smoke, asbestos, benzene, vinyl chloride, nickel, chromium, cadmium, alcohol, ionizing radiation, radon, benzidine and arsenic (1). Many of these discoveries have come from studies of workers in various industries. Epidemiology is an observational science and, therefore, causal inference involves a somewhat different approach to that which is generally used in laboratory-based sciences. Since the epidemiologist cannot usually conduct controlled experiments, 0097-6156/89/0414-O207$06.00/0 ©1989 American Chemical Society Ragsdale and Menzer; Carcinogenicity and Pesticides ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

CARCINOGENICITY AND PESTICIDES


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bias i n the ascertainment of the relationship between exposure and cancer may arise due to errors i n exposure assessment or i n ascertainment of cases or from confounding by other causal factors. For these reasons, epidemiologists use several c r i t e r i a for causal inference i n assessing exposure-disease r e l a t i o n s h i p s . Foremost amongst these are the strength of an observed association (the magnitude of the r e l a t i v e r i s k ) , the l i k e l i h o o d that the association i s spurious, the b i o l o g i c a l p l a u s i b i l i t y of the association and i t s consistency from study to study. The l a t t e r i s a p a r t i c u l a r l y important c r i t e r i o n , since i t i s u n l i k e l y that a spurious association would be found i n several different studies, especially i f they are conducted by different investigators on different populations. The purpose of this paper i s to review epidemiological studies concerning pesticides and human cancer. The review commences with arsenical pesticides since they present the strongest evidence for a group of pesticides causing human cancer. No other pesticide or group of pesticides has been convincingly i d e n t i f i e d as a cause of human cancer. The second strongest association i s that reported between pesticide applicators and lung cancer, although no s p e c i f i c pesticides have been i d e n t i f i e d as causal. Studies i n different parts of the world have reported excess rates of lymphopoietic cancers among farmers and a g r i c u l t u r a l workers. However, our review of these studies suggests that pesticide exposure i s u n l i k e l y to be the cause. The phenoxy herbicides, including 2,4-D and 2,4,5-T (which was i n v a r i a b l y contaminated with 2,3,7,8-tetrachlorodibenzo-pdioxin formed during the manufacturing process), have been postulated as possible causes of increased r i s k s of malignant lymphoma and soft tissue sarcoma among farmers. However, considered c o l l e c t i v e l y , the available studies provide only weak evidence that these herbicides may be carcinogenic to humans. ARSENICAL PESTICIDES It has been well established by a v a r i e t y of epidemiologic studies that inorganic arsenic can cause human cancer. This i s i n spite of the fact that animal studies have not yet shown arsenic to be carcinogenic. Evidence comes from studies of smelter workers, which have demonstrated increased lung cancer r i s k s (2.3). In addition, ingestion of arsenic has been shown to cause cancer of the skin and other s i t e s i n studies of exposure to n a t u r a l l y occurring arsenic i n drinking water i n Taiwan (4.5), and studies of patients who have consumed medicinal arsenic (6.7). Studies involving arsenical pesticides include that of Mabuchi et a l (8) who studied mortality of a cohort of 1393 persons who had worked during the period 1946-77 i n a plant i n Baltimore, Maryland, which manufactured and packaged various p e s t i c i d e s , including inorganic arsenicals. Key results are shown i n Table I . There were 47 cancer deaths with 39.4 expected based on Baltimore City rates (SMR=1.19; 90% confidence i n t e r v a l : 0.92-1.52). Among the cancer deaths, 23 were from lung cancer, 13.7 being expected (SMR=1.68; 90% CI: 1.15-2.38), with

Ragsdale and Menzer; Carcinogenicity and Pesticides ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

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Cancer and Pesticide Exposure

the g r e a t e s t r i s k found f o r workers w i t h 25 o r more y e a r s o f employment (SMR=6.78; 90% C I : 3.54-11.83). These f i n d i n g s demonstrate a s i g n i f i c a n t i n c r e a s e i n l u n g c a n c e r r i s k w e l l beyond t h a t w h i c h c o u l d be a t t r i b u t e d t o c o n f o u n d i n g by smoking Table I .

Cancer F i n d i n g s from Two S t u d i e s I n v o l v i n g Persons Exposed t o A r s e n i c a l P e s t i c i d e s

Reference


Mabuchi e t a l (8) manufacture

25+ y e a r s employed L u c h t r a t h (9) a r s e n i c exposed wine growers

a l l deaths a l l cancer l u n g cancer lung

lung

cancer

cancer

S MR

90% confidence interval

0.97 1.19 1.68

0.86-1.09 0.92-1.52 1.15-2.38

6.78

3.54-11.83

OR 14.7

9.0-24.0

L u c h t r a t h (9) r e p o r t e d a s t u d y o f m o r t a l i t y among German wine-growers a f f e c t e d by c h r o n i c a r s e n i c p o i s o n i n g , e i t h e r t h r o u g h use o f a r s e n i c - c o n t a i n i n g i n s e c t i c i d e s o r from d r i n k i n g Haustrunk, a w i n e - s u b s t i t u t e made from an aqueous i n f u s i o n o f a l r e a d y - p r e s s e d grapes and h a v i n g a h i g h a r s e n i c c o n t e n t . He s t u d i e d post-mortem f i n d i n g s f o r 163 winegrowers who had been d i a g n o s e d as s u f f e r i n g from c h r o n i c a r s e n i c p o i s o n i n g , comparing them w i t h f i n d i n g s f o r another p o s t mortem s e r i e s o f 163 men o f s i m i l a r age. T h i r t y o f the a r s e n i c - p o i s o n e d cases had s k i n c a n c e r compared w i t h none o f the c o n t r o l s . A c t u a l r e l a t i v e r i s k e s t i m a t e s were n o t g i v e n b u t v a r i o u s e s t i m a t e s can be c a l c u l a t e d from d a t a p r e s e n t e d i n the paper. Of the a r s e n i c - p o i s o n e d growers 108 had l u n g c a n c e r compared w i t h o n l y 14 o f the c o n t r o l s . T h i s g i v e s an e s t i m a t e o f the r e l a t i v e r i s k f o r l u n g c a n c e r o f 20.90 (90% C I : 13.12-33.3). T h i s e s t i m a t e i s e x t r a o r d i n a r i l y h i g h and, i n v i e w o f the l i m i t e d d e t a i l s on the p r o c e s s o f s e l e c t i n g b o t h cases and c o n t r o l s , i s open t o the s u s p i c i o n o f s e l e c t i o n b i a s , p a r t i c u l a r l y w i t h the c a s e s . Such a b i a s may be l e s s l i k e l y t o be p r e s e n t i n the m o r t a l i t y d a t a o b t a i n e d from the t r a d e a s s o c i a t i o n , w h i c h was a l s o p r e s e n t e d by L u c h t r a t h . Among 417 deaths o f wine growers, 242 had l u n g carcinomas. U s i n g the same post-mortem comparison group as above l e a d s t o a r e l a t i v e r i s k e s t i m a t e f o r l u n g c a n c e r o f 14.7 ( T a b l e I ) . T h i s e s t i m a t e i s lower than t h a t c a l c u l a t e d b e f o r e , b u t s t i l l g i v e s c l e a r evidence o f markedly i n c r e a s e d l u n g c a n c e r r i s k s , w e l l beyond a n y t h i n g w h i c h might be a t t r i b u t a b l e t o smoking, o r o t h e r s o u r c e s o f b i a s . A l t h o u g h e p i d e m i o l o g i c a l s t u d i e s o f people exposed t o a r s e n i c a l p e s t i c i d e s a r e l i m i t e d i n number, the two r e v i e w e d above p r o v i d e e v i d e n c e o f i n c r e a s e s i n cancer r a t e s a t t r i b u t a b l e



210

t o a r s e n i c . The e v i d e n c e i s c o n v i n c i n g because o f t h e s t r e n g t h o f t h e r e l a t i o n s h i p s ( h i g h r e l a t i v e r i s k e s t i m a t e s ) and because o t h e r s t u d i e s have c o n v i n c i n g l y demonstrated t h a t i n o r g a n i c a r s e n i c i s a human c a r c i n o g e n . Although there i s a l a c k o f e p i d e m i o l o g i c a l s t u d i e s t o j u s t i f y a d e f i n i t i v e statement on t h e matter, organic a r s e n i c a l p e s t i c i d e s are not n e c e s s a r i l y carcinogenic. I f t h e y a r e , i t would be r e a s o n a b l e t o e x p e c t t h a t they w o u l d be be l e s s p o t e n t t h a n i n o r g a n i c a r s e n i c p e s t i c i d e s s i n c e o r g a n i c a r s e n i c a l s a r e g e n e r a l l y e x c r e t e d much more r a p i d l y and t i s s u e c o n c e n t r a t i o n s would, t h e r e f o r e , be lower t h a n f o r i n o r g a n i c a r s e n i c exposure.


PESTICIDE APPLICATORS AND LUNG CANCER C o n s i d e r i n g t h e w i d e s p r e a d c o n c e r n about p o s s i b l e c a n c e r r i s k s from p e s t i c i d e s , t h e r e have been few s t u d i e s o f p r o f e s s i o n a l p e s t i c i d e a p p l i c a t o r s , t h e most h i g h l y exposed group. The most c o n s i s t e n t f i n d i n g s from t h e s t u d i e s w h i c h have been p u b l i s h e d c o n c e r n i n c r e a s e d l u n g c a n c e r r i s k s (Table I I ) . However, t h e r e l a t i v e r i s k e s t i m a t e s were n o t s u f f i c i e n t l y h i g h t o t o t a l l y d i s c o u n t smoking d i f f e r e n c e s as an e x p l a n a t i o n . Table I I .

Lung Cancer S t a n d a r d i z e d M o r t a l i t y R a t i o s (SMRs) from P e s t i c i d e A p p l i c a t o r M o r t a l i t y S t u d i e s

Reference

SMR

90% confidence interval

Wang & MacMahon (10)

a l l deaths a l l cancer lung cancer

0. 84 0. 83 1. 15

0. 76-0. 92 0.,66-1. 04 0.,79-1. 61

MacMahon e t a l (11)


0.,98 1.,11 1..35

0..93-1..03 1..00-1..23 1..14-1..58

B a r t h e l (12)

a l l cancer lung cancer

0.,82 1.,08

0,.55-1..20 0,.62-1..75

R i i h i m a k i e t a l (13)


0,.74 0..82 1..08

0 .61-0,.89 0,.55-1,.20 0 .62-1,.75

B l a i r e t a l (14)

all all lung lung

1,.03 1 .14 1 .35 2 .89

0 .94-1 0 .94-1 1..00-1 1 .44-5

deaths cancer cancer cancer

.12 .37 .80 .21

The f i r s t s t u d y was by Wang and MacMahon (10) and found a s m a l l i n c r e a s e i n l u n g c a n c e r m o r t a l i t y r a t e s among a c o h o r t o f o v e r 16,000 p r o f e s s i o n a l p e s t i c i d e a p p l i c a t o r s . The updated r e p o r t o f t h e same c o h o r t (11) c o n f i r m e d an i n c r e a s e i n l u n g c a n c e r r a t e s (SMR=1.35; 90% C I : 1.14-1.58). The excess r i s k



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211

was c o n f i n e d t o p e s t i c i d e a p p l i c a t o r s who had n o t been employed i n t e r m i t e c o n t r o l work (SMR=1.58; 90% C I : 1.29-1.90). The a n i m a l c a r c i n o g e n s c h l o r d a n e and h e p t a c h l o r , w i d e l y employed f o r t e r m i t e c o n t r o l , were t h e r e f o r e thought u n l i k e l y t o be i n v o l v e d . I t was a l s o n o t e d t h a t the excess l u n g c a n c e r cases were l a r g e l y c o n f i n e d t o a p p l i c a t o r s who had been employed l e s s t h a n 5 y e a r s i n such work. T h i s i s e v i d e n c e a g a i n s t a c a u s a l r o l e f o r pesticides. A m o r t a l i t y s t u d y by B a r t h e l o f 1658 German men who had been employed i n a g r i c u l t u r a l work i n v o l v i n g use o f p e s t i c i d e s found 50 l u n g c a n c e r cases when 27.5 were e x p e c t e d (SMR=2.1; 90% CI: 1.6-2.8) ( T a b l e I I ) ( 1 2 ) . A dose-response r e l a t i o n s h i p was demonstrated by y e a r s o f exposure. However i t was n o t p o s s i b l e t o l i n k the i n c r e a s e d l u n g c a n c e r r i s k t o any p a r t i c u l a r p e s t i c i d e o r group o f p e s t i c i d e s . A random sample o f s t u d y s u b j e c t s d i d n o t smoke more t h a n a g e n e r a l p o p u l a t i o n sample. A s t u d y o f F i n n i s h p e s t i c i d e a p p l i c a t o r s by R i i h i m a k i (13) ( T a b l e I I ) f o c u s e d on the phenoxy h e r b i c i d e s 2,4-D and 2,4,5-T. There was no e v i d e n c e o f i n c r e a s e d c a n c e r r i s k s from t h i s r e l a t i v e l y s m a l l s t u d y . Twelve cases o f l u n g c a n c e r were found, w i t h 11.1 e x p e c t e d (SMR=1.08; 90% C I : 0.62-1.75). The f i n a l s t u d y i n t h i s s e c t i o n i n v o l v e d 3827 male l i c e n s e d s t r u c t u r a l p e s t i c i d e a p p l i c a t o r s i n F l o r i d a ( 1 4 ) . The l u n g c a n c e r SMR was 1.35, i n c r e a s i n g t o 2.89 f o r those who had been l i c e n s e d f o r a t l e a s t 20 y e a r s ( T a b l e I I ) . A r e l a t i v e r i s k o f t h i s magnitude i s u n l i k e l y t o be due s o l e l y t o c o n f o u n d i n g by smoking. However, t h e r e was some i n c r e a s e i n deaths from emphysema, p a r t i c u l a r l y i n a p p l i c a t o r s who had been l i c e n s e d f o r 10 y e a r s o r more, i n d i c a t i n g t h a t smoking cannot be e n t i r e l y d i s c o u n t e d as a s o u r c e o f b i a s . A g a i n , i t was n o t p o s s i b l e t o i d e n t i f y s p e c i f i c p e s t i c i d e s w h i c h might have been i n v o l v e d . Taken as a group, the s t u d i e s o f p e s t i c i d e a p p l i c a t o r s provide l i m i t e d , but reasonably c o n s i s t e n t , evidence of i n c r e a s e d l u n g c a n c e r r i s k s , p a r t i c u l a r l y i f the F i n n i s h s t u d y i s r e g a r d e d as a s t u d y o f a s p e c i a l type o f a p p l i c a t i o n ( a g r i c u l t u r a l use o f phenoxy h e r b i c i d e s ) . However, i t i s n o t c e r t a i n t h a t p e s t i c i d e s a r e i m p l i c a t e d and, i f they a r e , the s t u d i e s g i v e no i n d i c a t i o n as t o w h i c h p e s t i c i d e s might be i n v o l v e d . N o n e t h e l e s s , t h e s e f i n d i n g s h i g h l i g h t the need f o r s t u d i e s o f a p p l i c a t o r s w i t h a t l e a s t some i n d i v i d u a l exposure d a t a , however c r u d e . I t i s p o s s i b l e t h a t t h e r e might be c o n s i d e r a b l e i n c r e a s e s i n l u n g cancer r i s k s a t t r i b u t a b l e to p a r t i c u l a r p e s t i c i d e s , but i n a manner t h a t l e a v e s the o v e r a l l r e l a t i v e r i s k s r a t h e r low. INCREASED CANCER RATES IN FARMERS I n c r e a s e d r a t e s o f hemolymphopoietic c a n c e r s among f a r m e r s have been r e p o r t e d i n s t u d i e s from s e v e r a l d i f f e r e n t c o u n t r i e s (1529). T a b l e I I I g i v e s o v e r a l l r e s u l t s f o r s t u d i e s c o n c e r n i n g m u l t i p l e myeloma, non-Hodgkin's lymphoma, and l e u k e m i a . I f the r e p o r t e d e x c e s s e s were a t t r i b u t a b l e t o p e s t i c i d e s , t h e n one would e x p e c t t o f i n d c o n s i d e r a b l e i n c r e a s e d r i s k s among those f a r m e r s and a g r i c u l t u r a l workers most h e a v i l y exposed. Y e t no c l e a r a s s o c i a t i o n s have emerged. I t , t h e r e f o r e , seems u n l i k e l y t h a t



212


Table I I I .

R e l a t i v e R i s k E s t i m a t e s f o r Farming and M u l t i p l e Myeloma (MM), non-Hodkin's Lymphoma (NHL) and Leukemia ( L ) w i t h 95% C o n f i d e n c e I n t e r v a l

RR e s t i m a t e

Confidence Interval

MM NHL L

1. 00 0. 79 1. 14

0.74-1.32 0.53-1.14 0.94-1.36

Oregon & Wash. Oregon Washington

MM L L

1. 79 1. 35 1. 36

1.13-3.00 1.00-1.78 1.13-1.70

B l a i r (28)

Nebraska

L

1. 25

1.05-1.49

B u e s c h i n g (18)

Illinois

NHL L

2. 65 2. 00

< 0.05 < 0.05

C a n t o r (26)

Wisconsin

NHL

1.,22

0.98-1.51

B u r m e i s t e r (20)

Iowa

L

1..24

1.09-1.42

B u r m e i s t e r (15)

Iowa

MM NHL

1,.48 1 .26

< 0.05 < 0.05

G a l l a g h e r (16)

Canada

MM

2 .2

1.2-4.0

C a n t o r (27)

Wisconsin

MM

1 .4

1.0-1.8

D e l z e l l (23)

N. C a r o l i n a

MM

0 .9 1 .0 1• 0 1 .2 0 .8 1 .9

Reference

Location

F a s a l (19)

California

Milham (25)

NHL L

(W) (B) (W) (B) (W) (B)

0.7-1.2 0.9-1.1 0.6-1.5 0.4-3.9 0.7-1.1 1.1-3.1

Schumacher (24)

Utah

NHL

1 .3

0.9-2.3

Pearce (22)

New Z e a l a n d

MM NHL

2 .22 1 .38

1.31-3.75 0.94-2.03

S t e i n e c k (21)

Sweden

MM

1 .2

1.09-1.33

W i k l u n d (29)

Sweden

NHL

0 .97

0.89-1.06

Note:

The D e l z e l l s t u d y gave s e p a r a t e r e s u l t s f o r w h i t e s and b l a c k s ( B ) .


(W)


13.

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213

the f a i r l y consistent, but small, excess of these cancers among farmers is primarily attributable to pesticides. The most extensively investigated causal hypothesis involves the phenoxy herbicides. However, the studies which address the phenoxy herbicide hypothesis, reviewed i n the next section, do not support the view that exposure to these chemicals i s the explanation of the findings among farmers. One possible explanation of the elevated cancer r i s k s i n Table III i s i n f e c t i o n by zoonotic oncoviruses. However, t h i s hypothesis i s not yet supported by evidence of human s e r o p o s i t i v i t y to such v i r u s e s , although a number of New Zealand studies have provided evidence of an elevated r i s k for nonHodgkins lymphoma and soft tissue sarcoma i n abattoir workers (30-33). The significance of this finding is that such workers are not l i k e l y to have been greatly exposed to pesticides, whereas they w i l l have had ample opportunity for exposure to animal v i r u s e s . MALIGNANT LYMPHOMA AND PHENOXY HERBICIDES The f i r s t study to report an association between malignant lymphoma and phenoxy herbicides was conducted i n Sweden (34) (Table IV). A r e l a t i v e r i s k estimate of 4.8 was obtained for persons who had ever sprayed phenoxy herbicides, mainly 2,4,5-T and 2,4-D. Relative r i s k estimates were 4.3 for those with less than 90 days t o t a l exposure and 7.0 for those with more than 90 days exposure. These were remarkable findings since, with one exception, no occupational exposure had previously been reported to cause such increases i n cancer r i s k after such short exposures. The p a r t i c u l a r exception was a study of asbestosfactory workers i n which r e l a t i v e r i s k s of almost 2 were reported for 3 months of very heavy exposures (35). A r e l a t i v e r i s k of 4.3 from very short-term pesticide exposures would be expected to be associated with an o v e r a l l increase i n cancer r i s k amongst a g r i c u l t u r a l workers. However, Wiklund et a l (29) found a r e l a t i v e r i s k of 0.97 for non-Hodgkins Lymphoma (NHL) and land/animal husbandry (95% CI: 0.89-1.06) for non-Hodgkins Lymphoma (NHL) i n a study of 354,620 Swedish male a g r i c u l t u r a l and forestry workers involving linkage between census and national tumor r e g i s t r y data (Table IV). Also, no increased r i s k s were found i n forestry workers. Moreover, i n a study of 20,245 registered Swedish pesticide applicators (36) the r e l a t i v e r i s k for NHL was found to be 1.16 (95% CI: 0.66-1.86) i n the group which was f i r s t licensed i n 1965/66. No s a t i s f a c t o r y explanation has been put forward to explain the discrepancy between the results of the case-control study and the two cohort studies, and one i s l e f t with questions concerning possible biases i n the case-control study which reported the i n i t i a l association. In contrast to Sweden, a study i n New Zealand reported an o v e r a l l increase i n rates of malignant lymphoma i n farmers (Table III) (22). However, a case-control study revealed no association with phenoxy herbicide use, even though 2,4,5-T and 2,4-D have been used extensively i n New Zealand since the late 1940s (31). The r e l a t i v e r i s k estimates for ever using phenoxy herbicides was



214

1.3 when u s i n g o t h e r c a n c e r c o n t r o l s , and 1.0 when u s i n g g e n e r a l p o p u l a t i o n c o n t r o l s (Table I V ) . T a b l e IV.

S t u d i e s C o n c e r n i n g Non-Hodgkins's Lymphoma and Exposure i n t h e Use o r Manufacture o f Phenoxy H e r b i c i d e s

RR

90 o r 95% confidence interval

4. 8 1.01

2. 9-8.1 0. 6-1.5

1.,3 1.,0

0.,7-2.5 0.,5-2.0

UNITED STATES Hoar e t a l (37) Woods e t a l (38) >15 y e a r s Hoar e t a l (39) >20 d a y s / y e a r

2,.3 1..1 1..7 1,.5 3,.3

1..3-4.3 0..8-1.4 1..0-2.8 0,.9-2.4 0,.5-22.1

PHENOXY HERBICIDE MANUFACTURING Lynge (40) O t t e t a l (41)

1,.3 1,.9

0,.5-2.7 0 .6-4.5

Reference


SWEDEN H a r d e l l e t a l (34) W i k l u n d e t a l (36) NEW ZEALAND Pearce e t a l (22)

A s t u d y i n Kansas (.37) has produced e v i d e n c e s u p p o r t i n g an a s s o c i a t i o n between exposure t o 2,4-D and m a l i g n a n t lymphoma. A r e l a t i v e r i s k o f 2.3 ( 9 5 % C I : 1.3-4.3) was found f o r those who had used phenoxy h e r b i c i d e s ( a l m o s t a l l 2,4-D) ( T a b l e I V ) . However, a r e l a t i v e r i s k o f 6.0 (95% C I : 1.9-19.5) was found f o r those who had used any h e r b i c i d e ( n o t n e c e s s a r i l y 2,4-D) f o r more t h a n 20 days p e r y e a r . T h i s a s s o c i a t i o n was l a r g e l y c o n f i n e d t o e a r l y y e a r s o f h e r b i c i d e use when no independent c o n f i r m a t i o n o f exposure was a v a i l a b l e . There was no a s s o c i a t i o n w i t h number o f y e a r s o f h e r b i c i d e use a f t e r adjustment f o r days o f h e r b i c i d e use p e r y e a r , w h i c h tends t o reduce t h e l i k e l i h o o d of a r e a l a s s o c i a t i o n . A subsequent s t u d y i n Washington S t a t e i n v o l v i n g 576 c a s e s o f NHL r e p o r t e d a r e l a t i v e r i s k o f 1.07 ( 9 5 % C I : 0.8-1.4) a s s o c i a t e d w i t h any p a s t exposure t o phenoxy h e r b i c i d e s (38)· T h i s e s t i m a t e i n c r e a s e d t o 1.7 ( 9 5 % C I : 1.04-2.8) f o r exposure o f more t h a n 15 y e a r s d u r i n g t h e p e r i o d p r i o r t o 15 y e a r s b e f o r e d i a g n o s i s ( T a b l e IV). I n a case c o n t r o l s t u d y o f NHL i n Nebraska, Hoar Zahm e t a l (39) examined t h e a s s o c i a t i o n w i t h exposure t o v a r i o u s p e s t i c i d e s . A s m a l l i n c r e a s e i n NHL (0R-1.5; 95% C I : 0.9-2.4) was a s s o c i a t e d w i t h use o f 2,4-D. The odds r a t i o i n c r e a s e d t o 3.3 ( 9 5 % C I : 0.5-22.1) f o r exposure t o 2,4-D o f more t h a n 20 days per y e a r . S i g n i f i c a n t a s s o c i a t i o n s w i t h use o f c h l o r d a n e , d i a z i n o n , d y f o n a t e and m a l a t h i o n were a l s o found.



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Two s t u d i e s have r e p o r t e d m a l i g n a n t lymphoma m o r t a l i t y f o r the c h e m i c a l m a n u f a c t u r i n g i n d u s t r y ( T a b l e I V ) . Lynge ( 4 0 ) , i n a s t u d y o f c a n c e r i n c i d e n c e i n a c o h o r t o f 4,459 p e r s o n s who had been i n v o l v e d i n phenoxy h e r b i c i d e manufacture i n Denmark, found 7 cases o f m a l i g n a n t lymphoma among males, whereas 5.4 would have been e x p e c t e d (RR=1.30; 95% C I : 0.52-2.69). None o f the 7 cases were r e c o r d e d as h a v i n g p a r t i c i p a t e d i n the manufacture o r p a c k a g i n g o f phenoxy h e r b i c i d e s . O t t e t a l (41) i n a s t u d y o f a c o h o r t o f 2192 workers who had m a n u f a c t u r e d c h l o r o p h e n o l s (and, t h e r e f o r e , had p o t e n t i a l exposure t o c h l o r i n a t e d d i o x i n s ) found 5 deaths due t o m a l i g n a n t lymphoma, when 2.6 would have been e x p e c t e d (SMR=1.92; 95% C I : 0.62-4.49). However, t h e r e was no i n c r e a s i n g t r e n d f o r r i s k a s s o c i a t e d w i t h i n c r e a s i n g o p p o r t u n i t y f o r exposure. Taken o v e r a l l , s t u d i e s t o date have n o t c o n f i r m e d an a s s o c i a t i o n between phenoxy h e r b i c i d e s and m a l i g n a n t lymphoma. I n f a c t , i t seems u n l i k e l y t h a t phenoxy h e r b i c i d e s a r e the e x p l a n a t i o n f o r i n c r e a s e d lymphoma r a t e s among farmers r e p o r t e d i n s e v e r a l s t u d i e s . For example, phenoxy h e r b i c i d e s a r e n o t a s s o c i a t e d w i t h NHL i n New Z e a l a n d , where t h e r e i s an e x c e s s NHL m o r t a l i t y among f a r m e r s , w h i l e the major e v i d e n c e f o r an a s s o c i a t i o n w i t h phenoxy h e r b i c i d e s comes from Sweden where t h e r e i s no o v e r a l l excess o f NHL m o r t a l i t y i n a g r i c u l t u r a l w o r k e r s . As d i s c u s s e d below, the a s s o c i a t i o n a l s o l a c k s b i o l o g i c a l plausibility. SOFT TISSUE SARCOMA AND

PHENOXY HERBICIDES

The h y p o t h e s i s t h a t phenoxy h e r b i c i d e s a r e a cause o f s o f t t i s s u e sarcoma (STS) a l s o commenced i n Sweden. Three c a s e - c o n t r o l s t u d i e s c o n d u c t e d by the same i n v e s t i g a t o r s r e p o r t e d r e l a t i v e r i s k s o f 3.3 t o 5.7 f o r such an a s s o c i a t i o n ( T a b l e V) (42-44). However, as w i t h m a l i g n a n t lymphoma, i t i s d i f f i c u l t t o e x p l a i n such d r a m a t i c r i s k s a s s o c i a t e d w i t h s h o r t term e x p o s u r e s . Moreover, W i k l u n d and Holm (45) found no o v e r a l l r i s k i n c r e a s e from STS among Swedish a g r i c u l t u r e and f o r e s t r y workers (RR=0.9; 95% C I : 0.8-1.0). I n the s t u d y by Lynge, (40) mentioned above, o f workers i n v o l v e d i n the manufacture o f phenoxy h e r b i c i d e s i n Denmark, f i v e male STS cases were found compared t o 1.84 e x p e c t e d (RR=2.72; 95% C I : 0.88-6.34). However, o n l y one o f the p a t i e n t s had worked i n the manufacture and p a c k a g i n g o f phenoxy h e r b i c i d e s , one p r o b a b l y had a h e r e d i t a r y p r e d i s p o s i t i o n t o n e u r o f i b r o s a r c o m a and a n o t h e r appeared t o have been d i a g n o s e d w i t h STS b e f o r e b e g i n n i n g employment a t the p l a n t . Moreover, t h r e e o f the p a t i e n t s had been employed f o r 3 months o r l e s s . S t u d i e s i n New Z e a l a n d , where phenoxy h e r b i c i d e s , p a r t i c u l a r l y 2,4,5-T, have been e x t e n s i v e l y used, have n o t found e v i d e n c e f o r a r e l a t i o n s h i p between use o f t h e s e h e r b i c i d e s and STS ( T a b l e V) (46-47). S t u d i e s i n the U.S. have a l s o n o t found an a s s o c i a t i o n w i t h STS (37-38) . a l t h o u g h one s t u d y d i d f i n d a r e l a t i v e r i s k o f 2.8 a s s o c i a t e d w i t h h a v i n g a S c a n d i n a v i a n surname (95% C I : 0.5-15.6) (38)· I n a d d i t i o n , t h e r e has been no c o n s i s t e n t l i n k w i t h STS i n Vietnam V e t e r a n s , some o f whom were exposed t o the phenoxy


216



T a b l e V.

R e s u l t s o f S t u d i e s C o n c e r n i n g S o f t T i s s u e Sarcoma and Exposure t o Phenoxy H e r b i c i d e s

RR

90 o r 95% confidence interval

5.7 6.8 0.9 3.3

2.9-11.3 2.6-17.3 0.8-1.0 1.4-8.1

NEW ZEALAND Smith e t a l (46) Smith and Pearce (47) Combined s t u d i e s

1.6 0.7 1.1

0.7-3.3 0.3-1.5 0.7-1.8

UNITED STATES Hoar e t a l (37) Woods e t a l (38) Swedish surnames

0.9 0.8 2.8

0.5-1.6 0.5-1.2 0.5-15.6

DENMARK Lynge (40)

2.72

0.88-6.34

Reference SWEDEN H a r d e l l and Eriksson et W i k l u n d and H a r d e l l and

Sandstrom (42) a l (44) Holm (45) E r i k s s o n (43)

AGENT ORANGE, U.S. VIETNAM VETERANS Greenwald e t a l (48) Lawrence e t a l (49) Kang e t a l (51) Kang e t a l (50) M i l i t a r y Region 3 L a t h r o p e t a l (54) Kogan and Clapp (55)

0.53 0.21-1.31 1.15 0.61-2.17 0.83 0.63-1.09 0.85 0.54-1.36 8.64 0.77-111.84 1/1016, Ranch Hand 1/1293, non-Ranch Hand 5.16 2.4-11.1



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h e r b i c i d e m i x t u r e Agent Orange (Table V) (48-52). E l e v a t e d r a t e s have been r e p o r t e d f o r M a s s a c h u s e t t s V e t e r a n s (53.) and i n a s t u d y i n v o l v i n g West V i r g i n i a V e t e r a n s (which i n v o l v e d o n l y 3 exposed c a s e s ) ( 5 2 ) . However, e l e v a t e d r i s k s were not found i n the l a r g e r s t u d i e s (48. 49. 51. 54). I n a d d i t i o n , the s e r v i c e m e n who s e r v e d i n O p e r a t i o n Ranch Hand had much h i g h e r exposures t o Agent Orange t h a n most V e t e r a n s , b u t so f a r no excess o f STS has been found i n t h i s group (Table V) (54). One c a s e - c o n t r o l s t u d y i n I t a l y has r e p o r t e d an i n c r e a s e d r i s k o f STS f o r women who worked i n r i c e f i e l d s ( 5 5 ) . W h i l e i t has been s u g g e s t e d t h a t t h i s s t u d y p r o v i d e s e v i d e n c e i m p l i c a t i n g phenoxy h e r b i c i d e s , a t b e s t the e v i d e n c e i s v e r y weak, s i n c e the a s s o c i a t i o n was based on 3 women who worked i n the r i c e f i e l d s d u r i n g the 1950s. There i s no s u g g e s t i o n t h a t they had any d i r e c t c o n t a c t w i t h phenoxy h e r b i c i d e s , a l t h o u g h i t was p o s t u l a t e d t h a t they may have had i n d i r e c t exposure i n the r i c e p a d d i e s from p r e v i o u s l y - a p p l i e d h e r b i c i d e s . When the STS s t u d i e s are c o n s i d e r e d t o g e t h e r , the e v i d e n c e i m p l i c a t i n g phenoxy h e r b i c i d e exposure i s weak. The s t u d i e s w h i c h p r o v i d e the s t r o n g e s t e v i d e n c e are from Sweden, and the absence o f an o v e r a l l r i s k i n c r e a s e i n a g r i c u l t u r e and f o r e s t r y i n t h a t c o u n t r y has not been s a t i s f a c t o r i l y e x p l a i n e d . BIOLOGICAL PLAUSIBILITY OF PHENOXY HERBICIDES CAUSING CANCER The i n i t i a l h y p o t h e s i s t h a t phenoxy h e r b i c i d e s were a cause o f human c a n c e r was prompted by the f a c t t h a t 2,4,5-T was c o n t a m i n a t e d w i t h 2,3,7,8-TCDD, a p o t e n t a n i m a l c a r c i n o g e n . However, the e p i d e m i o l o g i c e v i d e n c e does not s u p p o r t t h i s hypothesis. B e f o r e about 1970 2,4,5-T was c o n t a m i n a t e d w i t h about 1 ppm o f 2,3,7,8-TCDD ( 4 7 ) ( 5 6 ) . Studies i n d i c a t e that a 2,4,5-T s p r a y e r g e n e r a l l y absorbs l e s s t h a n 0.2 mg/kg/workday o f 2,4,5-T ( 5 7 ) . Assuming a d i r e c t l y p r o p o r t i o n a t e amount o f 2,3,7,8-TCDD contaminant i s c o n c u r r e n t l y absorbed, t h e n 0.2 ng/kg/day o f TCDD would be absorbed a t a 2,4,5-T c o n t a m i n a t i o n l e v e l o f 1 ppm. Making the f u r t h e r a s s u m p t i o n t h a t the human c a n c e r p o t e n c y o f TCDD i s s i m i l a r i n man t o a n i m a l s , i t can be shown t h a t i t i s u n l i k e l y t h a t i n c r e a s e s i n human c a n c e r r i s k would be e p i d e m i o l o g i c a l l y d e t e c t e d ( 5 8 ) . I t i s a l s o n o t e w o r t h y t h a t 2,3,7,8-TCDD has a v e r y l o n g h a l f l i f e i n humans, and e l e v a t e d l e v e l s have been r e p o r t e d many y e a r s a f t e r exposure i n the b l o o d o f Ranch Hand s e r v i c e m e n and w o r k e r s who had been i n v o l v e d i n t r i c h l o r o p h e n o l manufacture ( 5 9 ) . However, s t u d i e s i n Sweden i n v o l v i n g cases o f s o f t t i s s u e sarcoma and m a l i g n a n t lymphoma have not found i n c r e a s e d l e v e l s o f 2,3,7,8-TCDD i n f a t ( 6 0 ) . T h i s p r o v i d e s e v i d e n c e a g a i n s t the i m p l i c a t i o n o f 2,4,5-T, s i n c e s i g n i f i c a n t exposure t o t h i s h e r b i c i d e s h o u l d l e a d t o l o n g term i n c r e a s e s i n l e v e l s o f 2,3,7,8-TCDD i n a d i p o s e t i s s u e . I t i s p o s s i b l e t h a t the phenoxy h e r b i c i d e s themselves may cause c a n c e r . However, t h i s h y p o t h e s i s l a c k s b i o l o g i c a l p l a u s i b i l i t y s i n c e the uncontaminated phenoxy h e r b i c i d e s are not a n i m a l c a r c i n o g e n s , nor are they g e n o t o x i c . The example o f a r s e n i c shows t h a t one s h o u l d not a u t o m a t i c a l l y c o n c l u d e t h a t non-animal c a r c i n o g e n s would not cause c a n c e r i n humans.


218

CARCINOGENICITY AND PESTICIDES However, the human c a r c i n o g e n i c i t y f i n d i n g s f o r a r s e n i c a r e c o n v i n c i n g , i n p a r t because exposures were h i g h and over a l o n g p e r i o d , p r o d u c i n g o t h e r t o x i c e f f e c t s as w e l l as c a n c e r . By c o n t r a s t , t h o s e s t u d i e s w h i c h have produced i n c r e a s e d c a n c e r r i s k s w i t h phenoxy h e r b i c i d e exposure have i n v o l v e d s h o r t low i n t e n s i t y e x p o s u r e s . T h i s tends t o reduce the b i o l o g i c a l p l a u s i b i l i t y o f such f i n d i n g s .


ORGANOCHLORINE PESTICIDES I t i s w e l l e s t a b l i s h e d t h a t o r g a n o c h l o r i n e p e s t i c i d e s , such as DDT, d i e l d r i n , a l d r i n , h e p t a c h l o r and c h l o r d a n e , can cause tumors i n r o d e n t s , p a r t i c u l a r l y l i v e r c a n c e r i n mice. A number o f i n v e s t i g a t i o n s have sought t o determine whether t h e s e p e s t i c i d e s a r e c a r c i n o g e n i c t o humans. C o n s i d e r i n g i t s r e l a t i v e l y long h i s t o r y of widespread use, i t i s remarkable t h a t e p i d e m i o l o g i c a l s t u d i e s of cancer r i s k focused on DDT exposure a r e a l m o s t n o n - e x i s t e n t . D i t r a g l i a e t a l (61) s t u d i e d m o r t a l i t y i n workers from f o u r o r g a n o c h l o r i n e p e s t i c i d e m a n u f a c t u r i n g p l a n t s , one o f w h i c h had s o l e l y manufactured DDT s i n c e 1947. C o h o r t s were d e f i n e d as a l l workers who had been employed f o r a t l e a s t s i x months p r i o r t o 1965 and v i t a l s t a t u s was a s c e r t a i n e d up t o 1976. F o r the DDT p l a n t a t o t a l o f 6 c a n c e r deaths were found l e a d i n g t o the c a l c u l a t i o n o f an SMR o f 0.68 (95% C I : 0.25-2.47) f o r a l l c a n c e r s combined. The u t i l i t y o f t h i s s t u d y i s l i m i t e d because o f the s m a l l number o f w o r k e r s involved. Ortelee (62) s t u d i e d a t o t a l o f 40 men employed i n the manufacture o r f o r m u l a t i o n o f DDT f o r up t o 8 y e a r s and c o n c l u d e d t h a t , w i t h the e x c e p t i o n o f some minor s k i n and eye i r r i t a t i o n s , no i l l n e s s was a s s o c i a t e d w i t h exposure t o DDT i n t h i s group o f workers. Laws e t a l (63.) s t u d i e d a group o f 35 men who had been employed i n the p r o d u c t i o n o f DDT f o r more t h a n f i v e y e a r s . The a u t h o r s c o n c l u d e d t h a t t h e y had found no i l l e f f e c t s , i n c l u d i n g c a n c e r , a t t r i b u t a b l e t o exposure t o DDT. N e i t h e r o f the l a t t e r two s t u d i e s has e i t h e r s u f f i c i e n t s u b j e c t s o r s u f f i c i e n t time o f f o l l o w - u p f o r any c o n c l u s i o n s t o be drawn r e g a r d i n g the human c a n c e r r i s k o f DDT. I n a r e t r o s p e c t i v e c o h o r t s t u d y o f 1403 male p e s t i c i d e w o r k e r s employed i n the manufacture o f c h l o r d a n e and h e p t a c h l o r between 1946 and 1976, Wang and MacMahon (64) found no s t a t i s t i c a l l y s i g n i f i c a n t excess of cancer m o r t a l i t y e i t h e r o v e r a l l (SMR=82; 95% C I : 54-120) o r a t any p a r t i c u l a r c a n c e r site. However, the SMR f o r l u n g c a n c e r was 1.34 (95% C I : 73228), b u t t h e r e was no p a t t e r n i n r e l a t i o n t o e i t h e r exposure l e v e l o r l a t e n c y w h i c h would suggest a c a u s a l r o l e f o r h e p t a c h l o r or chlordane. D i t r a g l i a e t a l (61) a l s o s t u d i e d m o r t a l i t y e x p e r i e n c e i n workers from the two p l a n t s i n v o l v e d i n the s t u d y by Wang and MacMahon as w e l l as two a d d i t i o n a l p l a n t s , one o f w h i c h had m a n u f a c t u r e d a l d r i n , d i e l d r i n and e n d r i n . The o t h e r , d i s c u s s e d above, had m a n u f a c t u r e d o n l y DDT. M o r t a l i t y from a l l m a l i g n a n t neoplasms was l e s s t h a n e x p e c t e d , w i t h SMR's from 0.73 t o 0.91 f o r the t h r e e p l a n t s w h i c h had n o t manufactured DDT. Although



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SMR's for some i n d i v i d u a l cancer s i t e s exceeded 1, the observed numbers of cancers were small. Austin et a l (65) performed a case-control study using 80 hepatocellular cancer patients and 146 matched h o s p i t a l controls. Relative r i s k s for exposures to herbicides and other pesticides were 1.0 and 2.1 (95% CI: 0.6-6.9), respectively. In conclusion, epidemiological evidence has not indicated an association of organochlorine pesticides with increases i n human cancer incidence rates. However, i n regard to DDT at l e a s t , there i s no adequate epidemiological evidence on which to base a judgement of human carcinogenicity. Any conclusion regarding the other organochlorine pesticides must be tempered by the low numbers of exposed subjects (and consequent low power to detect moderate increases i n r e l a t i v e r i s k ) i n the studies which have been performed so f a r . [Note added i n proof: A recently published study reported results of a prospective follow-up study of 1,708 adult residents of Charleston, S. Carolina (6j£) . Study subjects were not selected on the basis of any p a r t i c u l a r occupational exposure. Blood samples were taken i n 1974-75 and analysed for DDT and DDE. V i t a l status of the cohort was ascertained i n 1984-85. No elevation of r i s k for o v e r a l l cancer mortality was found, although there was a non-significant increasing trend for respiratory cancer deaths with increasing blood DDT l e v e l ] . AMITROLE Amitrole, a t r i a z o l e herbicide and plant growth regulator, has been shown i n t o x i c o l o g i c a l studies to be carcinogenic to both rats and mice, but not hamsters (66.). Axelson and Sundell (67) found an SMR for cancer of 3.6 (4 observed, 1.11 expected; 90% CI: 1.2-8.2) for exposure to amitrole with a latent period of at least 5 years i n a cohort of Swedish railway workers. In a further study which extended the follow-up period by 6 years Axelson et a l (68) obtained an SMR of 1.5 for amitrole exposure (5 observed, 3.34 expected; 90% CI: 0.6-3.1). The observed tumors were of a range of types, with two being lung cancers. The authors also noted excess cancers for those exposed to both phenoxy herbicides and amitrole and suggested that the phenoxy herbicides may be responsible for the observed cancers. CONCLUSION With the exception of the inorganic arsenicals, epidemiological studies have not consistently demonstrated increased cancer r i s k s with the use of p e s t i c i d e s , although findings of increased lung cancer r i s k s amongst applicators warrant further study and further investigatation of phenoxy herbicides i s needed. The epidemiological studies to date are reassuring for the general population, which i s exposed to much lower levels of pesticides than the occupational groups studied. However, studies of pesticide users are very l i m i t e d and p r i o r i t y should be given to studies among professional pesticide applicators, the most highly exposed group, including prospective cancer incidence surveillance.


220


LITERATURE CITED 1. 2. 3. 4. 5. 6.


7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31.

Doll, R.; Peto, R. J . Natl. Cancer Inst. 1981, 66, 1192-308. Axelson, O.; Dahlgren, E.; Jansson, C. D.; Rehnlund, S. O. Br. J . Ind. Med. 1978, 35, 8-15. Enterline, P. E . ; March, G. M. Am. J . Epidemiol. 1982, 116. 895-911. Tseng, W-P. Environ. Health Persp. 1977, 19, 109-19. Tseng, W. P.; Chu, H. M.; How, S. W.; Fong, J . M.; Lin, C. S.; Yeh, S. JNCI 1968, 40, 453-63. Cusick, J.; Evans, S.; Gillman, M.; Price, Evans D. A. Br. J . Cancer 1982, 45, 904-11. Sommers,S. C.; McManus, R. G. Cancer 1953, 6, 347-59. Mabuchi, K . ; Lilienfeld, A. M.; Snell, L. M. Prev. Med. 1980, 9, 51-77. Luchtrath H. J . Cancer Res. Clin. Oncol. 1983, 105, 173-82. Wang, H. H . ; MacMahon, B. J . Occup. Med. 1979, 21, 741-44. MacMahon, B . ; Monson, R. R.; Wang, H. H.; Zhang, T. JOM 1988, 30, 429-32. Barthel, E. J . Toxicol. Environ. Health 1981, 8, 1027-40. Riihimaki, V . ; Asp, S.; Pukkala, E.; Hernberg, S. Chemosphere 1983, 12, 779-84. Blair, Α.; Grauman, D. J.; Lubin, J . H.; Fraumeni, J . F. JNCI 1983, 71, 31-7. Burmeister, L. F.; Everett, G. D.; Lier, S. F.; Isaacson, P. Am. J . Epidemiol. 1983, 118, 72-7. Gallagher, R. P.; Spinelli, J . J . ; Elwood, J . M.; Skippen, D. H. Br. J . Cancer 1983, 48, 853-7. Priester, W.A.; Mason, T. J . JNCI 1974, 53, 45-9. Buesching, D. P.; Wollstadt, L. JNCI 1984, 72, 503. Fasal, E . ; Jackson, E. W.; Klauber, M. R. Am. J . Epidemiol. 1968, 87, 267-74. Burmeister, L. F.; Lier, S. F.; Isaccson, P. Am. J . Epidemiol. 1982, 115, 720-8. Steineck, G.; Wiklund, K. Inter. J . Epi. 1986, 15, 321-5. Pearce, N. E . ; Smith, A. H.; Fisher, D. O. Am. J . Epidemiol. 1985, 121, 225-37. Delzell, E.; Grufferman, S. Am. J . Epidemiol. 1985, 121. 391-402. Schumacher, M. C. J . Occup. Med. 1985, 27, 580-4. Milham, S. Am. J . Epidemiol. 1971, 94. 307-10. Cantor, K. P. Int. J . Cancer 1982, 29, 239-47. Cantor, K. P.; Blair, A. JNCI 1984, 72, 251-55. Blair, Α.; Thomas, T. L. Am. J . Epidemiol. 1979, 110, 26473. Wiklund, K . ; Lindefors, B-M. ; Holm, L-E. Br. J . Ind. Med. 1988, 45, 19-24. Smith, A. H . ; Pearce, N. E.; Fisher, D. O.; Giles, H. J.; Teague, C. A; Howard, J . K. JNCI 1984, 73, 1111-17. Pearce, N. E . ; Smith, A. H . ; Howard, J . K.; Sheppard, R. Α.; Giles, H. J.; Teague, C. A. Br. J . Ind. Med. 1986, 43, 7583.


13. SMITH & BATES 32. 33. 34. 35. 36. 37. 38.


39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54.

55.

56. 57. 58.


221

Pearce, N. E.; Sheppard, R. A.; Howard, J . K.; Fraser, J.; Lilley, B. M. Am. J . Epidemiol. 1986, 124, 402-9. Pearce, N. E.; Sheppard, R. Α.; Smith, A. H.; Teague, C. A. Int. J . Cancer 1987, 39, 155-61. Hardell, L . ; Eriksson, M.; Lenner, P.; Lundgren, E. Br. J . Cancer 1981, 43, 169-76. Seidman, H.; Selikoff, I. J.; Hammond, E. C.; Ann. NY. Acad. Sci. 1979, 330, 61-90. Wiklund, K.; Dich, J.; Holm, L-E. Br. J . Cancer 1987, 56, 505-8. Hoar, S. K.; Blair, Α.; Holmes, F. F.; Boysen, C. D.; Robel, R. J.; Hoover, R.; Fraumeni, J . F. JAMA 1986, 256, 1141-7. Woods, J . S.; Polissar, L.; Severson, R. K.; Heuser, L. S.; Kulander, B. G. JNCI 1987, 78, 899-910. Hoar, Zahm S.; Wiesenberger, D. D.; Babbitt, P. Α.; Saal, R. C.; Cantor, K. P.; Blair, A. Presented at the Society for Epidemiological Research. 1988. Lynge, E. Br. J . Cancer 1985, 52, 259-70. Ott, M. G.; Olson, R. Α.; Cook, R. R.; Bond, G. G. J. Occup. Med. 1987, 29, 422-9. Hardell, L . ; Sandstrom, A. Br. J . Cancer 1979, 39, 711-17. Hardell, L.; Eriksson, M. Cancer 1988, 62. Eriksson, M; Hardell, L . ; Berg, N. O.; Moller, T.; Axelson, O. Br. J . Ind. Med. 1981, 38, 27-33. Wiklund, K.; Holm, L. E. JNCI 1986, 76, 229-34. Smith, A. H.; Fisher, D. O.; Pearce, H.; Teague, C. A. Community Health Stud 1982, 6, 114-19. Smith AH, Pearce NE. Chemosphere 1986, 15 1795-8. Greenwald, P.; Kovasznay, B.; Collins, D. N.; Therriault, G. JNCI 1984, 73, 1107-9. Lawrence, C. E.; Reilly, Α. Α.; Quickenton, P.; Greenwald, P.; Page, W. F.; Kuntz, A. J . AJPH 1985, 75, 277-9. Kang, H.; Enziger, F.; Breslin, P.; Feil, M.; Lee, Y.; Shepard, B. JNCI 1987, 79, 693-9. Kang, Η. K.; Weatherbee, L.; Breslin, P. P.; Lee, Y.; Shepard, Β. M. J . Occup. Med. 1986, 28, 1215-8. West Virginia Health Department. In West Virginia Vietnamera Veterans Mortality Study. 1986. Kogan, M. D.; Clapp, R. W. Int. J . Epidemiol. 1988, 17, 39. Lathrop, G. D.; Machado, S. G.; Karrison, T. G.; Grubbs, W. D.; Thomas, W. F.; Wolfe, W. H.; Michalek, J . E.; Miner, J . C.; Peterson, M. R.; Ogershok, R. W. Science Applications International Corporation, 1987. Vineis, P.; Terracini, B.; Ciccone, G.; Cignetti, Α.; Colombo, E.; Donna, Α.; Maffi, L.; Pisa, R.; Ricci, P.; Zanini, E.; Comba, P. Scand. J . Work Environ. Health 1986, 13, 9-17. Norstrom, Α.; Rappe, C.; Lindahl, R; Buser, H. R. Scand. J . Work Environ. Health 1979, 5, 375-378. Leng, M. L . ; Lavy, T. L.; Ramsey, J . C.; Braun, W. H. American Chemical Society 1982, p 133-156. Human Health Aspects of Environmental Exposure to Polychlorinated Dibenzo-p-dioxins and Polychlorinated Dibenzofurans. Universities Associated for Research and Education in Pathology, Inc., Bethesda, MD, 1988.


222 59. 60. 61. 62. 63. 64. 65. 66.


67. 68. 69.

CARCINOGENICITY AND PESTICIDES Centers for Disease Control. JAMA 1988, 259, 3533-5. Nygren, M. Academic Thesis, University of Umea, Sweden, 1988. Ditraglia, D.; Brown, D. P.; Namekata, T.; Iverson, N. Scand. J . Work Environ. Health 1981, 7, Suppl. 4, 140-46. Ortelee, M. F. ΑΜΑ Arch. Ind. Health 1958, 18, 433-40. Laws, E. R.; Curley, Α.; Biros, F. J.; Arch. Environ. Health 1967, 15, 766-75. Wang, H, MacMahon, B. J . Occup. Med. 1979, 21, 745-48. Austin, H.; Delzell, E.; Grufferman, S.; Levine, R.; Morrison, A. S.; Stolley, P. D.; Cole, P. JOM 1987, 29, 665-9. International Agency for Research on Cancer. Vol. 41, France, 1986. Axelson, O.; Sundell, L. Work Environ. Health 1974, 11, 218. Axelson, O.; Sundell, L . ; Andersson, K.; Edling, C.; Hogstedt, C.; Kling, H. Scand. J . Work Environ. Health 1980, 6, 73-9. Austin, H.; Keil, J . E.; Cole, P. Amer. J . Pub. Health 1989, 79, 43-46.

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Epidemiological Studies of Cancer and Pesticide Exposure - ACS

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