Human experience with dieldrin in perspective

ECOTOXICOLOGY

AND

ENVIRONMENTAL

Human

SAFETY

Experience

with

H.G. Shell Internationale

Research,

1,203-210(1977)

S.

Maatschappij Received

Dieldrin

VAN

in Perspective

RAALTE

B.V., Postbus March

162, The Hague,

Netherlands

1977

In this paper, the follow-up results of a long-term study of industrial workers are presented. In themselves, these results may be of interest. It is, however, in the context of all the known facts, in its synthesis with other studies that this human experience in pesticide manufacturing assumes its proper significance. Therefore, related animal and other studies are briefly mentioned before the results of our clinical-epidemiological human study. Thus, the latter can be placed in context, and conclusions can be based on all the established facts rather than on the opinions on isolated aspects.

We know that dieldrin and all other properly tested organochlorine pesticides,as well as phenobarbital, cause hepato-carcinomas in mice (l-lo). However, simply counting the tumors in test animals is apparently not sufficient. Today, the early subcellular and biochemical changes should be taken into consideration in the assessmentof the significance for man. The following is a summary of the facts which, together, comprise a five-part synthesis (Table 1) on which the assessmentof the significance for man should be based. (i) The responseof the liver to dieldrin in the mouseis different from such responses in other species(Van Genderen, 1965; Walker and Stevenson, 1969; Deichmann et al., 1970, 1974; Zavon, 1971; Wright et al., 1972).’ (ii) In all speciesexamined, the responseof the liver to dieldrin is indistinguishable from its response to phenobarbital (Stevenson and Walker, 1969; Thorpe, 1974; Thorpe and Walker, 1973; Wright et al., 1972). (iii) It is the experience in human clinical medicinethat primary liver cancers develop primarily in cirrhotic or previously injured livers. The clinical and laboratory manifestations of liver injury and cirrhosis are unequivocal and easy to establish (Edmondson and Peters, 1971; Davies, 1973; Scheuer, 1971; Hutt, 1971). (iv) Another clinical experience in primates is that the presenceof a-fetoprotein in the blood stream accompaniesand sometimesprecedesmanifestations of primary liver carcinoma (Adamson et al., 1974; Alpert et al., 1968, 1974; Payer 1972; Ruoslahti et al., 1974; Kohn and Weaver, 1974). (v) Clemmesen’s(1974) study indicated that, in about 10,000 human epileptics, phenobarbital is not, as it is in the mouse,a carcinogen. (vi) In addition, perhaps as a sixth part of the synthesis, similar evidence is available in the case of DDT. Again, there exists no carcinogenicity in either rats or hamsters ’ Cabral et al. (1977) versus control animals.

reported

Copyright @ 1977 by Academic Press Inc. All rights of reproduction in any form reserved. Printed in Gleat Britain

no differences

in tumor

203

incidence

in hamsters

treated

with

dieldrin

204

H. G. S. VAN RAALTE TABLE 1 FIVE-PART SYNTHESIS FOR INTERPRETATION OF SIGNIFICANCE

1. Response of the liver to dieldrinin different species. 2. Response of the liver to othercompoundsin different species. 3. Experiencefrom clinicalmedicine. 4. Resultsof a continuing study of a long-term high-exposuregroup of factory workers. 5. Epidemiologyof cancerin epilepticstreatedwith phenobarbital. (Truhaut et al., 1974) and, after 5 years, no indication of tumors in monkeys in which recognized carcinogens did produce a positive response (Alpert et al., 1968, 1974;

Anonymous, 1975; Tomatis et al., 1973). In several workers exposed as long as 25 years, there were no tumors, no liver injury, and no cr-fetoprotein (Ortelee, 1958; Laws, 1972; Laws et al., 1967,1973; Hayes et al., 1971; Morgan and Roan, 1974). RESULTS OF A CONTINUING STUDY OF A LONG-TERM HIGH-EXPOSURE GROUP OF FACTORY WORKERS

From the very beginning of its use in 1952 we have had the opportunity of medically supervising workers handling dieldrin. This first occurred in Public Health vectorcontrol programs in yellow fever and malaria eradication campaigns. From 1954 onward we have also been concerned with the health protection of our industrial workers exposed to aldrin and dieldrin and, later, to endrin and telodrin in the manufacturing and formulation plants at Pernis in Holland. Details of this clinicalepidemiological study as of January 1968 and, for some parameters, as of January 1970, have been reported by Jager (1970). Periodic clinical and laboratory examinations, complete in regard to all parameters deemed relevant at the time, were carried out at least twice a year. As new knowledge was developed, the battery of tests was expanded accordingly. Nevertheless, during the earlier years of production, cases of intoxication, some involving convulsions, did occur. In the 13 years from 1954 to 1967 we encountered 32 dieldrin-involved cases of clinical intoxication, 19 of which included convulsions. That so many workers were exposed to the point of having convulsions is, to some extent, an indication of their exposure. The average concentration of dieldrin in the blood at the time of convulsion amounted to 28(1-290 ppb. At a blood level below 200 ppb, no convulsions have ever occurred. On the other hand, blood levels exceeding 400 ppb have been found in apparently perfectly healthy normally functioning workers. NO-EFFECT LEVEL IN MAN In relation to human health, the “no-effect level” of a biological, physical, or chemical agent is understood as the level of administration of this agent which does not cause a change in any parameter of physical or relevant laboratory examination beyond the normal range of inter- and intraindividual fluctuations. In order to determine or establisha no-effect level in humans, two things are required: (i) The determination of the exposure (in this case, by determination of the dieldrin

HUMAN

EXPERIENCE

WITH

DIELDRIN

205

concentration in the blood of the workers; Hunter and Robinson, 1967); (ii) periodic medical examination of the people under study, including all the relevant parameters which, in previous experiments with animals, have been shown to indicate the earliest changes. From studies with animals it appeared that the earliest and reversible effects, not necessarily meaning toxic or adverse effects, occur in the liver. Therefore, a liver profile was included in the periodical examinations. From the total group of more than 800 workers who, in 1968, had been exposed or were being exposed to dieldrin, all those with more than 4 years of exposure, 233 men, were subjected to a further meticulous study on long-term toxic effects. Tables 2 and 3 show the parameters which were examined. TABLE 2 PERIODIC

Physical Hematology

EXAMINATION

I

Including bodyweight, blood pressure, neurology, heart, lungs, liver, spleen, EEG, and chest X ray; and for those older than 45 years an ECG. Hb, BBC, WBC, SB, MCV, and hematocrit, plasma, ChE, SGPT. TABLE 3 PERIODIC

Technicon SMA auto-analyzer

EXAMINATION

II

Calcium2+, inorganic phosphorus, Glucose, BUN, uric acid, cholesterol, bilirubin, SGOT, LDH, alkaline phosphatase, total serum protein, serum albumin.

Serum protein spectrum

A no-effect level in this group of workers was established at a concentration of 200 ppb of dieldrin in the blood. This level corresponds with a total equivalent oral intake of 33 ,ug/kg/day or a total daily intake of more than 2000 &person/day (Hunter and Robinson, 1967). (Current United States average blood level of the general United States population is 0.3 ppb, corresponding with an average equivalent oral intake of 0.05 ,ug/kg/day (Curley, 1974; Selby et al., 1969) or about 3.5 pg/man/day). Biochemical and electron microscopical studies in rats, dogs, mice, and monkeys (Wright et al., 1972) revealed that the earliest easily reversible effect of exposure to dieldrin is the induction of liver microsomal enzyme systems, and this was considered to be the most sensitive parameter. In the course of the next few years, therefore, three parameters of possible enzyme induction were examined in a group of workers with the highest dieldrin blood levels found at that time. During the last few years, the dieldrin levels in the blood of these workers has decreased due to further improvement in industrial hygiene. No signs of enzyme induction occurred in our dieldrin workers when examined with the following tests and compared to a control group (Jager, 1970; Hunter and Robinson, 1967, 1972): (a) concentrations of DDE in the blood; (b) ratio of 6-phydroxycortisol to 17-OH-corticosteroids in the urine; and (c) excretion of D-glucaric acid in the urine.

206

H. G.

S. VAN

RAALTE

The findings in our endrin workers show that the above three tests are capable of demonstrating enzyme induction. Our findings in the dieldrin workers are in agreement with those of Morgan and Roan (1973, 1974). It is well known that, in animals and man, this microsomal stimulation is an effect which occurs, if and when it does, after short exposure or treatment. Since enzyme induction did not occur in the dieldrin workers at the calculated (Hunter and Robinson, TABLE 4 WORKERS WHO LEFT COMPANY EMPLOYMENT AND DIRECT MEDICAL SUPERVISIONS

Meanb

Rangeb 4-16

Exposure Observation Age

4-20 37-72

17

50.5

D Fifty-two workers as of January b All values are in years.

1, 1974.

1967) average daily intakes estimated to be some twenty to several hundred times the current daily intake of the United States general population (Duggan, 1974), during an exposure of 4-16 years, it would probably not occur after a still longer period. So far, the Pernis study, in which a no-effect level for man was established, unequivocally removes any concern about noncancerous toxic effects. In addition, it may also contribute to solving or clarifying the question of dieldrin’s human carcinogenicity. TABLE 5 WORKERS

WITH

MORE

4 YEARS OF EXPOSURE

THAN

AND MORE

THAN

15 YEARS

OF

OBSERVATION

Age (years) Group C3, still exposed C2, still exposed

C 1, left company Total

Exposure (years)

Observation (years)

N

Mean

Range

Mean

Range

Mean

40 73 53

47.7 46.2 50.5 47.1

36-64 36-64 3 7-70 36-72

16.9

15-19 4-16 4-16 4-19

16.9 17.4 17 17.1

166

Range 15-19 4-20 4-20 4-20

The Pernis population studied numbered 1000 men. Not all of them, of course, had as prolonged or severe an exposure to be meaningful for use in carcinogenicity evaluation (Tables 4,5, and 6). Therefore, smaller groups with meaningful exposures were taken. From a statistical point of view, the numbers are admittedly small. The question may be raised as to whether it would have been at all possible to detect a carcinogenic effect in the Pernis group if it did occur. Some people maintain that the detection of a chemical carcinogen in a small population, such as in a chemical plant, is unlikely. The reasonsgiven include the small

number of people involved, the long latent period, often averaging several decades, and the advanced age at onset.

HUMAN

EXPERIENCE

WITH

207

DIELDRIN

Theoretically, in regard to the identification of an environmental carcinogen in the general population, the above statement seems to be true. In real life, however, the facts show that almost all compounds known to be carcinogenic to man have been detected in small populations. This has been accomplished by an observant physician, more often than not, in industry. TABLE 6 WORKERS WITH MORE THAN 10 YEARS

OF EXPOSURE OBSERVATION

Age (years) Group C3, still exposed C2, still exposed

C 1, left company Total

N

Range

40

47.4

1.5 14

46

36-64 39-51 39-70 36-72

51 49

THAN

Exposure (years)

Mean

69

AND MORE

Mean 16.9 11.2 13.2 14.9

15 YEARS

OF

Observation (years)

Range

Mean 16.9 17.7 17.9 17.2

15-19 lo-16 10.1-19 lo-19

Range 1.5-19 15-19 15-19 15-19

Tables 7 and 8 display a number of these known human carcinogens along with the sizes of the groups in which they were identified, the earliest latency periods, and the ages of onset (Van Raalte, 1975). It is interesting to compare these to the sizes, observation periods, and ages in our group. Among these latter 166 men, 51 were older than 50 years. One cancer death was a gastric carcinoma in a man with only 5 years of comparatively mild exposure. TABLE 7 KNOWN

Compound RadonC.S.

P.A.H. in soot P.A.H. in cutting oils Arsenic Chromates

HUMAN

(OCCUPATIONAL)

Physician surgeon Paracelsus Harting Pirchan Martland Pott Thony Paris Hutchinson Pfeil Gross

One other case, a lymphosarcoma,

CARCINOGENS

Sizeof group

I Latency (years)

Age at onset (years)

200 262 406

800 Londonpractice 495

1

Girls

2 4

8 46

7

32

Rural practice Londonpractice One smallplant

occurred in a man with 7 years of very mild

exposure (blood level only borderline higher than that of controls). Both incidences

occurred before 1964. There have been no new cases in the last 11 years. Instead of an increase in the incidence of carcinoma during the following years, when both the exposure time and the latency period were longer, no new cases have occurred. Instead of encountering the tumors in the workers more heavily exposed for the longest period, the two tumors occurred in people less heavily exposed for a relatively short period with

208

H. G.

S. VAN

RAALTE

an equally short latency period. At the same time, there was no undue mortality from other causes that might mask a higher cancer incidence (one coronary and one traffic accident in 20 years among 170 workers). TABLE 8 KNOWN

Compound Aromatic amines Asbestos Benzene B.C.M.E. VCM

HUMAN

Physician surgeon Rehn Leuenberger Hueper Gloyne Selikoff Vigliani Mallory Fishbein Oettel and Thiess M.C.A.

(OCCUPATIONAL)

CARCINOGENS

Size of group

II Latency (years)

Age at onset (years)

1

8:: 100 933 Milan shops 100

18

1 8

35

10

7 8 11

32 31 37

In conclusion, the results show that, at Pernis, there occurred no excess tumors and, what is much more important, no premonitory toxic changes which, if unchecked, might have conceivably led to the development of a carcinoma. REFERENCES ADAMSON, R. H., CORREA, P., AND DALGARD, D. W. (1974). Induction of tumors in non-human primates with various chemical carcinogens. In Proceedings, Societyfor Toxicology, Thirteenth Annual Meeting, Washington, D.C., March 10-14. ALPERT, M. E., URIEL, J., AND DENECHAUD, B. (1968). Alpha fetoglobulm in the diagnosis of human hepatoma. N. Engl. J. Med. 278,984-986. ALPERT, M. E., URIEL, J., AND DENBCHAUD, B. (1974). Forum Rir Wissenschaft, Wirtschaft, und Politik and International Academy of Environmental Safety.Working Session, Vienna, December 2-3. Anonymous (1975). Citing Dr. Leonard R. Axelrod: “DDT is probably not a human carcinogen.” Pestic.

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(1971). The Effect of Long Continued Kettering Laboratory, Cincinnati, Ohio.

M. R.

Ingestion

of Dieldrin

on Rhesus Monkeys

(a Six Year