Mortality study on a cohort of Italian licensed pesticide users

Mortality study on a cohort of Italian licensed pesticide users

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the Science of the Total Environment ~,~ i ~ t ~ a I ~ m ~ t ~ s e t ~ 0 J k I t m a n l i n ~ tt~ E l ~ r e a B m t ~ t a I t ~ t ~ p *4tb S t ~

The Science of the Total Environment 149 (1994) 183-191

ELSEVIER

Mortality study on a cohort of Italian licensed pesticide userst Pierfederico

T o r c h i o *a, A n n a

P i e t r o C o m b a b, L a u r a

Raffella

S e t t i m i b, S t e f a n o Ferdinando

L e p o r e a, G i o v a n n i Belli b, C o r r a d o

C o r r a o a, M a g n a n i c,

di Orio d

aCenter of Epidemiology. University of L 'Aquila, L 'Aquila, Italy hlstituto Superiore di Sanith, Roma, Italy eUniversity Service of Cancer Epidemiology, USL 8, Torino, Italy dChair of Clinical Epidemiology, University of L 'Aquila, L 'Aquila, Italy

(Received 3 May 1993; accepted 26 May 1993)

Abstract This study describes the mortality experience in a cohort of 23 401 farmers, residing in southern Piedmont, Italy, and licensed to use pesticides. From 1970 to 1986 the cohort included 340 794 person-years and 2683 deaths were observed. A strong attenuation of the death risk was found due to the healthy worker effect (seen as an active role in the application for the license by the members of the cohort) and due to the limited comparability of the cohort with respect to the reference population. The standardized mortality ratios (SMRs) were remarkably < 100 for all causes (SMR = 59; 95% confidence interval = 57-61) and for all tumors (SMR = 60; 95% CI 55-64), but they increased with the increasing duration of the follow-up. A risk increase was observed with respect to melanomas and eye tumors in the entire cohort and lymphoma and tumors of the connective tissue in the subcohort of subjects living in villages with mainly arable land. Key words: Cohort study; Occupational exposure

1. Introduction Even though farmers are usually considered a low risk category for most diseases, various epide* Corresponding author, Centro lnterdipartimentale di Epidemiologia, Via Verdi, 28, 67 100 L'Aquila, Italy. $This work was supported by grants from the Consiglio Nazionale delle Ricerche (CNR) and by the Piedmont Region.

miological studies a m o n g farming communities have reported an excess in the incidence and mortality concerning some cancers [1-13]. It has been assumed that this is related to exposure to biological, physical and chemical agents. In particular, research has been carried out on the role o f some classes o f pesticides in determining such excesses [14-21]. Low relative risks for diseases associated with

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Table 1 Structure and size of the entire cohort and of the three subdivisions in relation to the residence in villages with mainly arable land (cluster 1), in villages of mainly woodland (cluster 2), and in villages of mixed land (cluster 3) Total Size 23 401 Living 20 531 Deceased 2683 Unknown 187 Person-years 340794

Cluster 1

Cluster 2

Cluster 3

12 020 10 626 1309 85 175453

3800 3282 465 53 55212

7581 6623 909 49 110129

cigarette smoking [1,3] and high relative risks for skin, lymphatic, hematopoietic and brain tumors have often been described [1,22]. If the greater incidence of skin tumors is probably due to prolonged exposure to ultraviolet radiation, the excess of the other tumors has been assumed to be related to some insecticides and herbicides [1,22]. The area examined in this article is located in Southern Piedmont, where 20% of the work force is employed in agriculture and the percentage of cultivated land is close to the national average. In this area, in 1970, the consumption of herbicides, based on chlorophenols, was remarkably high: 0.123 kg/ha compared with the national average of 0.060 kg/ha [25]. In 1987, a cohort of farmers was recruited and by analysing the records of the hospital discharges of the region, significantly high standardized incidence ratios for nervous system and skin tumors were observed. Therefore, by dividing the territory into clusters of villages, characterised by homogenous types of predominant cultivations, significant excesses of lymphatic tumors were found in the cluster where there was predominantly arable cultivation [13].

A mortality follow-up has been subsequently carried out on the same cohort. 2. Materials and methods

All male subjects from Asti, Alessandria and Cuneo, who were licensed from 1970 to 1974, to buy and use pesticides of Italian toxicological classes I and II (they refer to acute toxicity) were included in the cohort. This period has been chosen because the law regarding the use of pesticides in Italy was only enforced in 1970. In that year the appointed agricultural offices received applications for licenses from all farmers already using pesticides. The licenses were issued over the following five years. Included in this cohort, also, are workers who had been exposed to these products before 1970. Such a cohort consisted initially of 25 945 subjects. The information on age and on the issuing date of the license (that permits the purchase and the use of pesticides) has been obtained from the appointed agricultural offices and recorded on tape. This file has also been checked in order to verify the completeness and the accuracy of the records and 2544 of these subjects were rejected because they were not residing in these provinces at the issuing date of the license or there were doublerecordings in the agricultural offices. The beginning of the follow-up is represented by the issuing of the license; the end point has been fixed 31st December 1986. The assessment of the survival status was carried out on the last known municipality of residence. For the deceased, the cause of death was reported directly from the death certificates, or by means of the record-linkage between the file of the deceased in possession of the license, and the file

Table 2 Standardized mortality ratio (SMR) for all causes, for all tumors and for all cardiovascular diseases, referring to the regional rates (Piedmont) and to the rates of the three provinces under examination (Alessandria, Asti, Cuneo) No. of deceased

All causes All tumors Cardiovascular diseases

2683 770 1080

Regional rates

Provincial rates

Expected

SMR

95% CI

Expected

SMR

95% CI

5050.09 1414.27 2057.23

53 54 52

51-55 51-58 49-56

4560.27 1293.61 1866.92

59 60 58

57-61 55-64 55-61

P. Torchio et al./Sci. Total Environ. 149 (1994) 183-191

of the deceased from the Italian Central Institute of Statistics (ISTAT). The data was analysed using the package OCMAP PC [23]; the person-years were calculated according to age (5-year age groups) and calendar-time (5-year time periods). The mortality experience of the cohort was compared with that expected for the regional and provincial population, by applying specific mortality rates concerning cause, age and calendar time; a Poisson distribution was assumed for the observed number of deaths [24]. The results are presented in terms of standardised mortality ratios (SMRs) with a 95% confidence interval. The SMR values were estimated for the total cohort and for three subcohorts corresponding to groups of villages with the same kind of agricultural practices. The villages in question were identified with a cluster analysis performed on the 560 villages in the three provinces under study, on the basis of the distribution of the proportion of farm land devoted to arable crops and woodland in each village [13]. 3. Results

The overall area under examination seems to have features that can be compared with the na-

185

tional ones. An indication that evidently differentiates the Piedmontese provinces from the rest of Italy is represented by the amount of herbicides used (that in some areas is more than double compared with the national consumption in Italy), in particular, 2-4-D derivatives and MCPA derivatives [25]. Furthermore the cohort represents -40% of the farmers of the area under examination [25]. The mean age of the cohort was 43.1 + 12.8 years. Table 1 describes the structure and the size of the cohort along with the three subcohorts. In the 16 years of follow-up, the cohort has accumulated -341 000 person-years. It can be observed, furthermore, that only 187 subjects (0.8%) were lost to follow-up, mainly because they were unknown in the village of residence. Table 2 reports the SMRs for all causes, for all tumors and for cardiovascular diseases referring to both the regional and provincial rates. A significant and marked mortality defect, more evident when the mortality of the cohort is compared with the regional rates, is observed. Table 3 reports the SMRs for all causes stratified for calendar period and age. A positive trend in the SMR is observed from the first to the last period, that is, as the recruitment moment

Table 3 Standardized mortality ratio (SMR) in relation to calendar period and age of the deceased (entire cohort; provincial reference rates) Age classes

15-49

50-59

60-69

~70

Total

Calendar period

O E SMR O E SMR O E SMR O E SMR O E SMR

ap < 0.05. O, observed; E, expected.

70-74

75-79

80-84

85-86

Total

74 157.8 47 a 77 156.3 49 a 106 233.4 45 a 39 99 39 a 296 646.3 46 a

100 190.6 52 a 148 298.5 50 a 268 472.3 57 a 216 374.6 58 a 732 1336 55 a

101 137.09 74 a 231 366.1 63 a 324 493 66 a 469 779.8 60 a 1112 1776 63 a

21 37.6 56 a 111 131 85 128 202.2 63 a 283 431.6 66 a 543 802.4 68 a

296 523.1 57 a 554 951.9 58 a 826 1400.9 59 a 1007 1685 60 a 2683 4560.9 59 a

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passes. However, even in the periods that follow, the mortality defect is significant even though it is less marked by comparison with the previous one (SMR = 46 in the first period vs. 68 in the last). It should be noted that there is no age effect present. Table 4 shows the SMRs for some causes of interest; the majority of these are characterised by a mortality defect that often reaches conventional levels of statistical significance. Only two causes present a mortality excess (non-significant): skin melanoma and eye tumor. It can be noted that only four deaths have been observed in the cohort under examination, due to the last cause. Tables 5 - 7 report, for each subcohort, the SMRs for the causes already described. It can be

observed how the eye tumors do not seem to be characterised by a cluster-effect; in fact, the excess (non-significant, however, in that it concerns 2 cases for the 1st cluster and 1 case for the other 2 clusters) concerns the three subcohorts. A further observation pertains to the fact that in the first cluster (characterised by mainly arable land) numerous slight mortality excesses have been observed, even though the level of statistical significance has not been reached in any of the cases. The excesses concern prostate tumors, skin melanomas, other skin tumors, connective tissue tumors, lympho-hematopoietic system tumors, Hodgkin's disease and other lymphoma. Only some of these causes present a mortality excess in the other two

Table 4 Standardized mortality ratio (SMR) for some of the causes (entire cohort; provincial reference rates) Causes

ICD

Deaths

(VlII-rev)

Observed

Expected

140.0-149.9 151.0-151.9 153.0-154.9 155.0 157.0-157.9

18 126 84 15 32

Peritoneum Larynx Lung Prostate Kidney

158.0-158.9 161.0-161.9 162.0-162.9 185.0-185.9 189.0-189.9

Bladder Melanoma of skin Skin, other Eye Brain and nervous system Bone Connective soft tissue Lympho-hematopoietic system

SMR

95% CI

52.34 174.71 144.21 26.95 45.63

34 72 57 56 70

20-54 60-86 45-71 31-92 48-99

4 25 155 66 16

7.76 54.86 342.76 68.93 25.40

52 46 45 96 63

14-132 30-67 38-52 74-122 36-102

188.0-188.9 172.0-172.9 173.0-173.9 190.0-190.9 191.0-192.9

31 9 3 4 15

57.27 7.46 5.01 1.68 28.58

54 121 60 238 53

37-78 55-229 12-175 65-609 29-87

170.0- ! 70.9 171.0-171.9 200.0-207.9

I0 2 58

13.36 2.10 76.01

75 95 76

36-138 11-345 58-99

I1

11.63

95

47-169

Multiple myeloma

201.0-201.9 200.0-200.9 202.0-202.9 203.0-203.9

15 5

16.27 11.85

92 42

52-152 14-99

Leukemia Respiratory diseases Cirrhosis of liver Accidents and suicide

204.0-207.9 460.0-519.9 571.0-571.9 800.0-999.9

27 136 105 278

36.26 292.48 238.38 370.27

75 47 44 75

49-108 39-55 36-53 67-84

Malignant neoplasm of Buccal cavity and pharynx Stomach Large intestine Liver Pancreas

Hodgkin's disease Other lymphoma

P. Torchio et al./Sci. Total Environ. 149 (1994) 183-191

187

Table 5 Standardized mortality ratio (SMR) for some of the causes in the sub-divided cohort in relation to the residence in villages with predominantly arable land (cluster I) Causes

ICD

Deaths

(VlIl-rev)

Observed Malignant neoplasm of Buccal cavity and pharynx Stomach Large intestine Liver Pancreas

Expected

SMR

95% CI

140.0-149.9 151.0-151.9 153.0-154.9 155.0 157.0-157.9

8 61 53 10 16

26.00 85.35 70.64 13.28 22.56

31 72 75 75 71

13-61 55-92 56-98 36-138 41-115

Peritoneum Larynx Lung Prostate Kidney

158.0-158.9 161.0-161.9 162.0-162.9 185.0-185.9 189.0-189.9

2 11 81 38 8

3.85 27.19 169.58 33.00 12.59

52 41 48 115 64

6-188 20-72 38 - 59 82-158 27-125

Bladder Melanoma of skin Eye Brain and nervous system

188.0-188.9 172.0-172.9 173.0-173.9 190.0-190.9 191.0-192.9

16 4 3 2 9

27.91 3.75 2.44 0.84 14.39

57 107 123 239 63

33-93 29-273 25-360 29-862 29-119

Bone Connective soft tissue Lympho-hematopoietic system

170.0-170.9 171.0-171.9 200.0-207.9

5 2 38

6.64 1.05 37.68

75 191 I 01

24-176 26-689 71 - 138

6

5.86

102

38-223

Multiple myeloma

201.0-201.9 200.0-200.9 202.0-202.9 203.0-203.9

11 3

8.10 5.80

136 52

68-243 11- 151

Leukemia Respiratory diseases Cirrhosis of liver Accidents and suicide

204.0-207.9 460.0-519.9 571.0-571.9 800.0-999.9

18 58 52 130

17.92 140.99 I 18.74 187.34

100 41 44 70

60-159 31-53 33-57 59-83

Skin, other

Hodgkin's disease Other lymphoma

subcohorts: Hodgkin's disease in the second cluster (characterised mainly by woodland crops) and skin melanomas in the third cluster (characterised by mixed crops). 4. Discussion The cohort is of a cross-sectional type, having been recruited immediately after the enforcement of the law, that made the license compulsory. From 1970-1974 the provincial inspectors granted the applications for licenses that had been submitted in 1970. The duration of previous professional exposure to pesticides had therefore been extremely

variable in the cohort. The dose and type of exposure has remained undefinable. The only element, in this sense, has been represented by a presumable (but not certain) exposure to products of the first and second toxicological classes (that refer to acute toxicity of minor interest in a mortality study). Furthermore, it should not be excluded, that there had been an evident dilution of exposure. Among the components of the cohort not all used pesticides but, since as the authorization was granted after undergoing an examination, the license could be applied for by a member of the family with a higher level of instruction. In a similar study [26], it has been estimated that - 7 % of licensed workers had

188

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Table 6 Standardized mortality ratio (SMR) for some of the causes in the sub-divided cohort in relation to the residence in villages with predominantly woodland areas (cluster 2) Causes

ICD (VIll-rev)

Deaths Observed

Expected

SMR

95% CI

140.0-149.9 151.0-151.9 153.0-154.9 155.0 157.0-157.9

5 23 15 I 5

8.42 27.84 22.90 4.31 7.27

59 83 66 23 69

19-139 52-124 37-108 I- 129 22-161

Peritoneum Larynx Lung Prostate Kidney

158.0-158.9 161.0-161.9 162.0-162.9 185.0-185.9 189.0-189.9

0 4 32 3 2

1.24 8.82 54.90 10.82 4.09

-45 58 28 49

0-298 12-116 40-82 6-81 6-177

Bladder Melanoma of skin Skin, other Eye Brain and nervous system

188.0-188.9 172.0-172.9 173.0-173.9 190.0-190.9 191.0-192.9

6 I 0 l 1

9.07 1.21 0.80 0.27 4.62

66 83 -371 22

24-144 2-461 0-463 9-2067 1-121

Bone Connective soft tissue Lympho-hematopoietic system

170.0-170.9 171.0-171.9 200.0-207.9

2 0 7

2.15 0.34 12.14

93 -58

11-336 0-1092 23-119

2

1.88

107

13-385

Multiple myeloma

201.0-201.9 200.0-200.9 202.0-202.9 203.0-203.9

2 0

2.6l 1.88

77 --

9-277 0-196

Leukemia Respiratory diseases Cirrhosis of liver Accidents and suicide

204.0-207.9 460.0-519.9 571.0-571.9 800.0-999.9

3 26 17 55

5.77 46.11 38.49 59.92

52 56 44 92

I l - 152 37-83 26-7 l 69-120

Malignant neoplasm of Buccal cavity and pharynx Stomach Large intestine Liver Pancreas

Hodgkin's disease Other lymphoma

not been occupationally exposed to pesticides. O n the other hand, a undefined n u m b e r o f unlicensed agricultural workers had been professionally exposed. We have estimated that with a p r o p o r t i o n of 7% false positives, a true relative risk equal to five would have been reduced to one in the presence of a p r o p o r t i o n o f false negatives o f - 90%. This suggests that although misclassification of exposure has determined a reduction in the power of the study, the presence o f a relationship between the license possession and the mortality risk for certain diseases should emerge. The u n d e r e s t i m a t i o n o f risk could also be attributed to the presence o f a healthy worker effect,

possibly associated with active requiring in the authorisation application. Furthermore, studies on cohorts based on a crosssectional admissibility criterion m a y result in a selective recruitment for the surviving subjects leading to an increase of the healthy worker effect. If the d u r a t i o n of the follow-up is relatively short, as in this study, there is no possibility o f observing the occurrence o f diseases characterized by prolonged periods of induction-latency. Supporting this view, S M R s n o t a b l y inferior to 100 for all causes, all tumors a n d all cardiovascular diseases, have been observed: the S M R s tend to increase as the recruitment m o m e n t passes.

P. Torchio et al. / Sci. Total Environ. 149 (1994) 183-191

189

Table 7 Standardized mortality ratio (SMR) for some of the causes in the sub-divided cohort in relation to the residence in villages with mixed land (cluster 3) Causes

ICD (VIlI-rev)

Deaths Observed

Malignant neoplasm of Buccai cavity and pharynx Stomach Large intestine Liver Pancreas

Expected

SMR

95% CI

140.0-149.9 151.0-151.9 153.0-154.9 155.0 157.0-157.9

5 42 14 4 I1

17.93 61.52 50.67 9.36 15.81

28 68 28 43 70

9-65 49-92 15-46 12-109 35-125

Peritoneum Larynx Lung Prostate Kidney

158.0-158.9 161.0-161.9 162.0-162.9 185.0-185.9 189.0-189.9

2 10 42 25 6

2.67 18.85 I 18.28 25.11 8.71

75 53 36 100 69

9-271 25-98 26-48 64-147 25-150

Bladder Melanoma of skin Skin, other Eye Brain and nervous system

188.0-188.9 172.0-172.9 173.0-173.9 190.0-190.9 191.0-192.9

9 4 0 1 5

20.29 2.50 1.78 0.57 9.57

44 160 -174 52

20-84 44-410 0-208 4-971 17-122

Bone Connective soft tissue Lympho-hematopoietic system

170.0-170.9 171.0-171.9 200.0-207.9

3 0 13

4.57 0.71 26.18

66 -50

14-192 0-519 26-85

3

3.89

77

16-225

Leukemia

201.0-201.9 200.0-200.9 202.0-202.9 204.0-207.9

2 6

5.56 12.56

36 48

4-130 18-104

Multiple myeloma Respiratory diseases Cirrhosis of liver Accidents and suicide

203.0-203.9 460.0-519.9 571.0-571.9 800.0-999.9

2 51 36 92

4.17 113.30 81.16 123.01

48 45 44 75

6-173 34-59 31-61 60-92

Hodgkins' disease Other lymphoma

The most important limit of the cohort under study is the inadequate comparability between the cohort itself and the reference: farmers represent the near totality of the licensed population, versus - 2 0 % of the comparison population, and all the studies on farmers agree in referring to a strong mortality defect in the latter [22,27]; thus it can be concluded that the defects observed in this study are to be attributed to the differet life styles that characterize farmers and non-farmers. The highest SMRs observed, when the mortality of the cohort is compared with that relative to the provincial population (characterized by a higher proportion of farm workers with respect to the

regional population), seem to confirm the hypothesis put forward. Two studies, recently published, on cohorts of licensed subjects, have indicated SMRs similar to those reported in this study. In particular, a study carried out on a cohort of licensed workers in Emilia Region [28] reported SMR = 56 for all causes and SMR = 61 for all tumors; the study carried out on a cohort in Latium Region [26] reported SMR = 54 for all causes, SMR = 50 for cardiovascular diseases and SMR = 72 for all tumors. A further observation concerns the analogy with other studies that have indicated high mortality defects for tumors, mostly associated with cigarette

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smoking (tumors of the mouth and the pharynx, of the larynx, of the lungs and of the bladder); the defect has been attributed to a lower amount of smokers among the rural inhabitants [3,20,29]. In the cohort under study, the observed mortality defect has suggested a critical revision of our previous study carried out on the same cohort [13]. At that time, the estimate of the person-years of the licensed workers was based on the survival rates of the general population. Since our licensed workers are characterized by a mortality rate of - 60% of the general population, the standardized incidence ratios of the previous work were certainly overestimated. In this study the limits, even though potentially capable of generating biased estimates of the relative risks, generally determine an underestimation of the relative risks. If this is true, in a general situation characterized by high mortality defects, the mortality excesses of skin melanoma and of eye tumors, even though nonsignificant, would assume a remarkable importance. The excess of eye tumors, reported in this study, has been based on 4 observed instead of 1.68 expected. The reported deaths have been distributed as follows: two eye-ball tumors (ICD: 190.0) and two eye not-specified tumors (ICD: 190.9). Tumor of the eye is a rare disease and its geographical distribution shows a higher incidence in rural areas [271. The occurrence of eye melanoma, that represents the most frequent form in adult individuals, has been related to exposure to solar radiation and to indicators of a higher sensitivity [30,31]. However, such an aetiological role needs further confirmations [32]. In two studies of proportional mortality, subsequently carried out in the United States, a mortality excess for eye tumors among farmers has been pointed out [9,33]. Other situations where the observed deaths coincide or are just over the expected deaths have been observed, particularly, in the subcohort residing in villages with predominantly arable land. These situations concern soft tissue tumors (SMR = 191; 2 observed cases), lympho-hematopoietic system neoplasm (SMR = 101; 38 observed cases), Hodgkin's disease (SMR = 102; 6 observed cases) and other lymphomas (SMR = 136; 11 observed cases). Although the excesses are weak and refer to just a

few observed cases, it should be noted that a cluster effect occurs for such diseases: the fact that these excesses are concentrated in the cluster with predominantly arable land and where the amount of herbicide used is higher, may not prove to be accidental and would confirm reported associations between herbicides exposure and risk of lymphoma [3-15] and soft-tissue tumor [16-19]. In conclusion we believe that the SMRs presented in this study were underestimated; thus, the weak and non-significant mortality excesses for some causes and in some areas should be interpreted as 'sentinel health events' rather than a valid estimate of the risk associated with the specified expositions. Moreover, we believe that SMR is an inadequate association measure whenever an agricultural, cross-sectional cohort is followed for a short period; we cannot exclude that other approaches (i.e. mortality odds ratio analysis) [34,35] might be adequate in this context. 5. References

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