A study of exposure, health effects and mortality of workers engaged in the manufacture and formulation of the insecticides aldrin and dieldrin

In this thesis an epidemiological study is reported on possible long-term health effects of exposures to the organochlorine insecticides aldrin and dieldrin which were manufactured and formulated in an insecticides plant in Pernis, The Netherlands, between 1954–1990. The insecticides workers have been under continuous occupational health surveillance since the beginning of their employment. As a follow-up of previous studies, the present study provides an evaluation of exposures and possible long-term health effects as recorded during the entire period of manufacture from the start up of the insecticides plant in 1954 until complete termination of manufacture in 1990. Section 1 is a general introduction, describing the background and scope of the study. The production, use and regulatory aspects of aldrin and dieldrin, in a historic perspective, are described. Section 2 describes the toxicity of aldrin and dieldrin and the possible human health effects. The results of studies in experimental animals, including carcinogenicity studies are summarised. Health effects of aldrin and dieldrin as reported in case studies, and in clinical and epidemiological studies are discussed. The environmental health aspects of aldrin and dieldrin are reviewed, in particular in relation to the traces of dieldrin which have been detected in the past in environmental compartments, including in human food and human tissues. Safe handling, health surveillance and medical treatment advice in case of over-exposure to aldrin or dieldrin is provided, on the basis of the long experience with these insecticides. The toxicology and potential human health effects of endrin and telodrin, other organochlorine insecticides produced and formulated in the same plant as aldrin and dieldrin, are summarised. Throughout the study, the toxicology and potential health effects of aldrin and dieldrin are considered together, as aldrin is rapidly epoxydised to dieldrin, both in animals and humans. Section 3 provides a detailed description of the plant processes and of jobs and tasks of the workers in the various sections of the plant. A description is provided of how exposures to aldrin and dieldrin could occur, in particular during the period 1954–1970, and of the measures taken over the years to reduce exposures. The retrospective occupational hygiene study resulted in the identification of 570 workers eligible for mortality follow-up, defined as all workers, including the contractors, who were employed in the insecticides plant for a period of 1 year or more before 1st January, 1970. Each of the 570 subjects was assigned to one out of four defined job types and to one out of three exposure groups. Section 4 reports on the results of measurements of the concentration of dieldrin in the blood of plant workers as carried out from 1963 onwards. On the basis of the results of a dose-excretion study, previously carried out in human volunteers, it was possible to calculate the personal average daily aldrin/dieldrin dose, expressed as the oral dieldrin intake, and the total aldrin/dieldrin dose of most members of the cohort employed during or after 1963. The data from the retrospective occupational hygiene study were used to estimate the personal average daily intake and total intake of subjects employed in the plant before 1963 and of subjects who had no dieldrin blood measurements in the period 1963–1970. On the basis of the estimated total individual aldrin/dieldrin intake three new exposure groups were formed to undo the misclassification of some of the members of the cohort in the originally constructed exposure groups. Section 5 reports the results of the mortality study. The vital status of the members of the cohort was established on 1st January, 1987. At the end of the observation period, 445 out of the 570 workers were alive. There were 76 deaths. Thirty-four subjects emigrated to foreign countries and were taken into account in the analysis until the date of emigration. Fifteen (2.1%) subjects were lost to follow-up. The calculation of the power of the study indicated a high power to detect an increased risk for all cause mortality and total cancer mortality. The power of the study to detect specific cancer risks was lower, but is greatly enhanced by the availability of the individual aldrin/dieldrin dose of each cohort member. Causes of death were obtained from the Dutch Central Bureau of Statistics and standardised mortality ratios (SMRs) were calculated by a person-time analysis on the basis of the observed deaths in the cohort and expected death rates in the general population. The overall mortality among the pesticides workers was lower than expected (SMR = 77.1). The mortality from all cancers was similar to the expected number (SMR = 103.6). No statistically significant excess mortality was observed for any of the site-specific cancers examined in the exposed groups. The analysis of dose-response relationships revealed no specific trends for any of the observed site-specific cancers. The conclusion of the study is that no increased risk was demonstrated for any major category of diseases, including for cancer and for specific cancer sites, which could be attributed to exposures to aldrin and dieldrin. Section 6 reports on the results of various liver function tests which were evaluated in a group of 100 insecticides plant workers who were exposed to aldrin and dieldrin for more than one year. As part of the periodic health examinations of these workers in 1982, the activity of the serum alkaline phosphatase, ALAT, ASAT, LDH and GGT were compared with a large control group not occupationally exposed to aldrin and dieldrin. In addition, the urinary concentration of d-glucaric acid was assessed as an indirect index of hepatic microsomal enzyme induction. The average daily intake and the total intake of dieldrin (and aldrin), as oral equivalents, of each individual subject were calculated from the dieldrin concentration in blood. The conclusion of the study is that long-term occupational exposures to aldrin and dieldrin in a group of long-term and high exposed insecticides workers did not produce detectable liver function damage or hepatic enzyme induction. Section 7 reports the results of the analysis of specific disease codes as recorded in medical computer systems since 1979 up to 1990. The study was carried out to evaluate the incidence of neoplasms, diseases of the central and peripheral nervous system, diseases of the blood and blood-forming organs, diseases of the liver, and mental disorders among the insecticides plant workers in comparison with the rest of the Pernis site workers as controls. The results show that the incidence of malignant neoplasms in the period 1979–1990 was the same as in the controls (relative risk = 1). The relative risk for liver diseases was statistically significantly increased among the insecticides workers. But the individual medical history of the subjects concerned did not give any indication for a chemical, work-related, cause. The occurrence in only one age group supports the conclusion that there is no work-related cause. The overall conclusion is that the analysis of the disease incidence as recorded among the insecticides workers in the period 1979–1990 does not indicate any specific disease patterns which can be related to exposures to insecticides, including aldrin/ dieldrin. Section 8 provides an overall discussion of the study results reported in the previous chapters, and of the results of experimental animal and human epidemiological studies, in relation to the reported exposure levels in the present study and in the scientific literature. It is concluded, that the insecticides plant workers had aldrin/ dieldrin exposures which were up to about 200 times higher than members of the general population in the same period of time. The high and long-term exposed insecticides workers had an average daily aldrin/dieldrin intake and an estimated average dieldrin blood level at steady state, which was in the same order of magnitude as those in the low, respectively medium dose groups of mice showing a dose-related, statistically significant increase of liver tumours, including malignant liver tumours. From an evaluation of published epidemiological studies among populations exposed to DDT, phenobarbital and heptachlor/chlordane, it is concluded that these compounds, that have shown to produce the same type of liver cancer as aldrin/diel-drin in mice, do present little, if any, specific carcinogenic hazard to humans. Results from a quantitative risk assessment on the basis of the combination of the human data and experimental animal data do not suggest that aldrin and dieldrin are carcinogenic for humans even at relatively high occupational exposure levels. The overall conclusion is that there is no evidence that aldrin and dieldrin are carcinogenic to humans. There is no evidence that aldrin and dieldrin even at high and long-term occupational exposures cause detectable liver function damage or hepatic enzyme induction, the latter considered to be an early reversible effect of aldrin and dieldrin exposure on the liver of rodents, including strains of mouse showing a high incidence of liver tumours in carcinogenicity experiments with aldrin or dieldrin. On the basis of the evidence reported in this study it is suggested that risk assessment, and occupational health and environmental standards for aldrin and dieldrin should be based on noncarcinogenic effects in humans and in experimental animals rather than on the carcinogenic effects in mice.