aldrin and Neoplasms

In 1987, the US Environmental Protection Agency (EPA) classified aldrin and dieldrin as category B2 carcinogens, i.e. probable human carcinogens, based largely on the increase in liver tumors in mice fed either organochlorine insecticide. At that date, the relevant epidemiology was deemed inadequate to influence the cancer risk assessment. More time has now elapsed since early exposures of manufacturing workers to aldrin/dieldrin; therefore, updated epidemiological data possess more power to detect exposure-related differences in cancer risk and mortality. Also, recent experimental studies provide a plausible mode of action to explain the mouse specificity of dieldrin-induced hepatocarcinogenesis and call into question the relevance of this activity to human cancer risk. This monograph places this new information within the historic and current perspectives of human cancer risk assessment, including EPA's 1996 Proposed Guidelines for Carcinogen Risk Assessment. Updated epidemiological studies of manufacturing workers in which lifetime exposures to aldrin/dieldrin have been quantified do not indicate increased mortality or cancer risk. In fact, at the middle range of exposures, there is evidence of a decrease in both mortality from all causes and cancer. Recent experimental studies indicate that dieldrin-induced hepatocarcinogenesis in mice occurs through a nongenotoxic mode of action, in which the slow oxidative metabolism of dieldrin is accompanied by an increased production of reactive oxygen species, depletion of hepatic antioxidant defenses (particularly alpha-tocopherol), and peroxidation of liver lipids. Dieldrin-induced oxidative stress or its sequelae apparently result in modulation of gene expression that favors expansion of initiated mouse, but not rat, liver cells; thus, dieldrin acts as a nongenotoxic promoter/accelerator of background liver tumorigenesis in the mouse. Within the framework of EPA's Proposed Guidelines for Carcinogen Risk Assessment, it is proposed that the most appropriate cancer risk descriptor for aldrin/dieldrin, relating to the mouse liver tumor response, is 'not likely a human carcinogen', a descriptor consistent with the example of phenobarbital cited by EPA.

Topics: Aldrin; Animals; Carcinogens; Cell Transformation, Neoplastic; Dieldrin; DNA, Neoplasm; Humans; Insecticides; Neoplasms; Risk Factors

Topics: Aldrin; Animals; Dieldrin; Environmental Monitoring; Epidemiological Monitoring; Humans; Industry; Liver; Neoplasms; Occupational Diseases; Occupational Exposure

Topics: Aged; Aldrin; Animals; Arsenic; Capsules; Carcinogens; Dieldrin; Dioxins; Humans; Legislation, Drug; Male; Mice; Neoplasms; Neurons; Occupational Diseases; Pesticides; Rats; United States; Vinyl Chloride

Topics: Aldrin; Animals; Carcinogens; DDT; Dieldrin; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Induction; Food Contamination; Government Agencies; Liver Neoplasms; Lung Neoplasms; Neoplasms; Pesticide Residues; Pesticides; Photolysis; United States; United States Food and Drug Administration

Pesticides, which are associated with endocrine dysfunction, immunological dysregulation, and cancer, are widespread sources of drinking water contamination. The state of Paraná has a population of 11 million, is the second largest grain producer in Brazil and is a leading consumer of pesticides. In this study, we analyzed the extent of drinking water contamination from 11 proven, probable, or potentially carcinogenic pesticides (alachlor, aldrin-dieldrin, atrazine, chlordane, DDT-DDD-DDE, diuron, glyphosate-AMPA, lindane-γ-HCH, mancozeb-ETU, molinate, and trifluralin) in 127 grain-producing municipalities in the state of Paraná. Extensive contamination of drinking water was found, including legacy pesticides such as aldrin-dieldrin (mean 0.047 ppb), DDT-DDD-DDE (mean: 0.07), chlordane (mean: 0.181), and lindane-HCH (mean: 2.17). Most of the municipalities were significantly above the maximum limits for each one of the currently allowed pesticides (67% for alachlor, 9.44% for atrazine, 96.85% for diuron, 100% for glyphosate-AMPA, 80.31% for mancozeb-ETU, 91.33% for molinate, and 12.6% for trifluralin). Ninety-seven percent of municipalities presented a sum of all pesticides at levels significantly above (189.84 ppb) the European Union preconized limits (<0.5 ppb). Using the mean pesticide concentration in water (ppb), the exposed population for each municipality, and the benchmark cancer risk for pesticides, we estimated the minimum number of cancer cases attributable to pesticide-contaminated drinking water during the period (total of 542 cases). More than 80% were attributed to mancozeb-ETU and diuron. Glyphosate-AMPA and diuron-attributable cases strongly correlated with the total cancer cases in the same period (R = 0.8117 and 0.8138, respectively) as well as with breast cancer cases (R = 0.7695 and 0.7551, respectively). Water contamination was significantly correlated with the sum of the estimated cancer cases for all 11 pesticides detected in each city (R = 0.58 and p < 0.0001). These findings reveal extensive contamination of drinking water in the state of Paraná and suggest that contamination may increase the risk of cancer in this region.

Topics: Aldrin; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Atrazine; Brazil; Chlordan; DDT; Dichlorodiphenyl Dichloroethylene; Dieldrin; Diuron; Drinking Water; Hexachlorocyclohexane; Neoplasms; Pesticides; Trifluralin

The dose-response analyses of cancer and noncancer health effects of aldrin and dieldrin were evaluated using current methodology, including benchmark dose analysis and the current U.S. Environmental Protection Agency (U.S. EPA) guidance on body weight scaling and uncertainty factors. A literature review was performed to determine the most appropriate adverse effect endpoints. Using current methodology and information, the estimated reference dose values were 0.0001 and 0.00008 mg/kg-day for aldrin and dieldrin, respectively. The estimated cancer slope factors for aldrin and dieldrin were 3.4 and 7.0 (mg/kg-day)(-1), respectively (i.e., about 5- and 2.3-fold lower risk than the 1987 U.S. EPA assessments). Because aldrin and dieldrin are no longer used as pesticides in the United States, they are presumed to be a low priority for additional review by the U.S. EPA. However, because they are persistent and still detected in environmental samples, quantitative risk assessments based on the best available methods are required. Recent epidemiologic studies do not demonstrate a causal association between aldrin and dieldrin and human cancer risk. The proposed reevaluations suggest that these two compounds pose a lower human health risk than currently reported by the U.S. EPA.

Topics: Aldrin; Dieldrin; Dose-Response Relationship, Drug; Humans; Insecticides; Neoplasms

Dieldrin and aldrin, pesticides widely used until the 1970s, have been under suspicion of being carcinogenic. In this study, overall and cause-specific mortality was assessed in a cohort of 570 employees occupationally exposed to the pesticides dieldrin and aldrin to investigate the long-term health effects, in particular carcinogenic effects.. All of the employees worked in the production plants between January 1954 and January 1970 and were followed for cause-specific mortality until 30 April 2006. Based on dieldrin levels in blood samples taken from 343 workers during the exposure period, the total intake of dieldrin was estimated for each individual subjects in the cohort. The estimated total intake ranged from 11 to 7,755 mg of dieldrin, with an average of 737 mg.. Two hundred and twenty-six workers had died before 30 April 2006 compared with an expected number of 327.3, giving a standardized mortality ratio (SMR) of 69.0 (95% confidence interval (CI): 60.3-78.7). Overall cancer mortality was also significantly lower than expected (SMR: 76.4, 95% CI: 60.8-94.9). Also, none of the specific cancer sites showed a significant excess mortality and no association between exposure level and cancer mortality was found.. The results from this study support findings from other epidemiological and recent animal studies concluding that dieldrin and aldrin are not likely human carcinogens.

Topics: Aldrin; Dieldrin; Follow-Up Studies; Humans; Insecticides; Male; Neoplasms; Netherlands; Occupational Diseases; Occupational Exposure

Organochlorine (OC) insecticides have been regulated as possible human carcinogens primarily on the basis of animal studies. However, the epidemiologic evidence is inconsistent. We investigated the relationship between cancer incidence and OC insecticide use among pesticide applicators enrolled in the Agricultural Health Study, a prospective cohort study of 57,311 licensed applicators in Iowa and North Carolina enrolled between 1993 and 1997. Information on ever use of 7 OC insecticides (aldrin, chlordane, DDT, dieldrin, heptachlor, lindane, toxaphene) was collected from a self-administered questionnaire at enrollment. Lifetime exposure-days to OC insecticides were calculated using additional data from a take-home questionnaire completed by 25,291 participants (44% of total). We found no clear evidence of an association between use of OC insecticides and incident cancers (N = 1,150) ascertained through December, 2002. When we focused on individual insecticides and structurally similar groups (aldrin and dieldrin; chlordane and heptachlor), significantly increased relative risks of some cancers were observed for use of some chemicals (rectal cancer and chlordane, lung cancer and dieldrin, non-Hodgkin lymphoma (NHL) and lindane, melanoma and toxaphene, leukemia and chlordane/heptachlor). Some significant decreased relative risks were also observed (colon cancer and aldrin; overall cancer and heptachlor). In conclusion, we did not observe any clear relationship between cancer risk and the use of OC insecticides. Our chemical-specific findings are based on small numbers and multiple comparisons, and should be interpreted with caution; however, some observed associations (lindane and NHL, chlordane/heptachlor and leukemia) are supported by previous evidence.

Topics: Adult; Aged; Agricultural Workers' Diseases; Aldrin; Chlordan; Dieldrin; Environmental Pollution; Female; Heptachlor; Humans; Hydrocarbons, Chlorinated; Incidence; Insecticides; Iowa; Male; Middle Aged; Neoplasms; North Carolina; Occupational Exposure; Prospective Studies; Surveys and Questionnaires

This study was conducted to investigate the possible long-term health effects, in particular carcinogenic effects, of occupational exposure to the organochlorine insecticides dieldrin and aldrin. We updated an earlier cohort mortality study of 570 employees involved in the production of these insecticides. All of the employees had worked in the production plants between 1 January 1954 and 1 January 1970 and were followed for cause-specific mortality until 1 January 2001. Based on dieldrin levels in blood samples taken during the exposure period, available for 343 workers, individual estimates of the total intake of dieldrin were estimated for all individual subjects in the cohort. The estimated total intake ranged from 11 to 7755 mg of dieldrin, with an average of 737 mg. One hundred and seventy-one workers had died before 1 January 2001, compared with an expected number of 226.6, giving a standardized mortality ratio (SMR) of 75.6 [95% confidence interval (CI): 64.6-87.7]. This deficit in total mortality was mainly attributable to a deficit in cardiovascular disease mortality, but cancer mortality was also lower than expected. The observed number of deaths from rectal cancer was significantly higher than expected (SMR = 300.0; 95% CI: 109.5-649.3), but was most pronounced in the low-intake subgroup and appears to be unrelated to exposure to dieldrin and aldrin. This study reinforces the earlier findings that occupational exposure of workers to significant amounts of dieldrin and aldrin has not led to a higher cancer mortality than would be found in an unexposed population.

Topics: Aldrin; Cohort Studies; Dieldrin; Humans; Insecticides; Male; Neoplasms; Netherlands; Occupational Diseases; Occupational Exposure; Registries; Retrospective Studies

The paper applies classical statistical principles to yield new tools for risk assessment and makes new use of epidemiological data for human risk assessment. An extensive clinical and epidemiological study of workers engaged in the manufacturing and formulation of aldrin and dieldrin provides occupational hygiene and biological monitoring data on individual exposures over the years of employment and provides unusually accurate measures of individual lifetime average daily doses. In the cancer dose-response modeling, each worker is treated as a separate experimental unit with his own unique dose. Maximum likelihood estimates of added cancer risk are calculated for multistage, multistage-Weibull, and proportional hazards models. Distributional characterizations of added cancer risk are based on bootstrap and relative likelihood techniques. The cancer mortality data on these male workers suggest that low-dose exposures to aldrin and dieldrin do not significantly increase human cancer risk and may even decrease the human hazard rate for all types of cancer combined at low doses (e.g., 1 microgram/kg/day). The apparent hormetic effect in the best fitting dose-response models for this data set is statistically significant. The decrease in cancer risk at low doses of aldrin and dieldrin is in sharp contrast to the U.S. Environmental Protection Agency's upper bound on cancer potency based on mouse liver tumors. The EPA's upper bound implies that lifetime average daily doses of 0.0000625 and 0.00625 microgram/kg body weight/day would correspond to increased cancer risks of 0.000001 and 0.0001, respectively. However, the best estimate from the Pernis epidemiological data is that there is no increase in cancer risk in these workers at these doses or even at doses as large as 2 micrograms/kg/day.

Topics: Aldrin; Animals; Dieldrin; Dose-Response Relationship, Drug; Humans; Insecticides; Likelihood Functions; Liver Neoplasms, Experimental; Male; Mice; Models, Biological; Neoplasms; Netherlands; Occupational Diseases; Occupational Exposure; Proportional Hazards Models; Risk Assessment

To investigate the occurrence of long term health effects in humans exposed to aldrin and dieldrin, with an update of an earlier retrospective cohort mortality study.. A group of 570 workers employed between 1 January 1954 and 1 January 1970 either in a production or formulation plant were followed up for mortality until 1 January 1993. There were extensive industrial hygiene data available and biological monitoring data of aldrin and dieldrin for most of the workers. From these data individual estimates were made of the total intake of dieldrin. A total number of 2539.37 person-years at risk was added to the original study.. 118 deaths were observed compared with 156 expected. No increase in mortality from liver cancer was found. However, there was an excess in mortality from rectal cancer. This excess was inversely related to the dose gradient. An analysis by job title did not show any excess cancer in any particular job.. The study does not support a carcinogenic effect of dieldrin and aldrin in humans.

Topics: Adult; Aldrin; Chemical Industry; Dieldrin; Dose-Response Relationship, Drug; Follow-Up Studies; Humans; Insecticides; Male; Neoplasms; Netherlands; Occupational Diseases; Occupational Exposure; Retrospective Studies

Vital status and cause of death were assessed for 232 of a group of 233 workers engaged in the manufacturing and formulation of aldrin, dieldrin, endrin and (for a limited period) Telodrin. This group is part of the total exposed population of more than 1000 workers and was selected for follow up on account of the high exposures in the initial years of manufacturing and formulation and of the long exposure (mean 11 years) and observation (mean 24 years) periods. Total observed mortality was 25 versus 38 expected on the basis of the death statistics of the male Dutch population. Of the 9 cancer deaths, 3 were caused by lung cancer, while the remaining 6 were each of a different nature. Although in this group exposures have been high and exposure, as well as observation periods, were long enough for meaningful evaluation, this study revealed no indication of a specific carcinogenic activity of aldrin, dieldrin or endrin in manufacturing plant workers exposed to these products.

Topics: Aged; Aldrin; Carcinogens; Dieldrin; Endrin; Humans; Longitudinal Studies; Male; Middle Aged; Neoplasms; Netherlands; Occupational Diseases

Topics: Adipose Tissue; Aldrin; Animals; Chlordan; DDT; Dieldrin; Dogs; Drug Synergism; Endrin; Environmental Exposure; Estrus; Female; Fertility; Food Deprivation; Humans; Hydrocarbons, Halogenated; Lactation; Liver Diseases; Male; Mice; Neoplasms; Pesticides; Pregnancy; Rats; Reproduction