Hazardous waste and health impact: a systematic review of the scientific literature.

Waste is part of the agenda of the European Environment and Health Process and included among the topics of the Sixth Ministerial Conference on Environment and Health. Disposal and management of hazardous waste are worldwide challenges. We performed a systematic review to evaluate the evidence of the health impact of hazardous waste exposure, applying transparent and a priori defined methods. The following five steps, based on pre-defined systematic criteria, were applied. 1. Specify the research question, in terms of "Population-Exposure-Comparators-Outcomes" (PECO). POPULATION: people living near hazardous waste sites; Exposure: exposure to hazardous waste; Comparators: all comparators; Outcomes: all diseases/health disorders. 2. Carry out the literature search, in Medline and EMBASE. 3. Select studies for inclusion: original epidemiological studies, published between 1999 and 2015, on populations residentially exposed to hazardous waste. 4. Assess the quality of selected studies, taking into account study design, exposure and outcome assessment, confounding control. 5. Rate the confidence in the body of evidence for each outcome taking into account the reliability of each study, the strength of the association and concordance of results.Fifty-seven papers of epidemiological investigations on the health status of populations living near hazardous waste sites were selected for the evidence evaluation. The association between 95 health outcomes (diseases and disorders) and residential exposure to hazardous waste sites was evaluated. Health effects of residential hazardous waste exposure, previously partially unrecognized, were highlighted. Sufficient evidence was found of association between exposure to oil industry waste that releases high concentrations of hydrogen sulphide and acute symptoms. The evidence of causal relationship with hazardous waste was defined as limited for: liver, bladder, breast and testis cancers, non-Hodgkin lymphoma, asthma, congenital anomalies overall and anomalies of the neural tube, urogenital, connective and musculoskeletal systems, low birth weight and pre-term birth; evidence was defined as inadequate for the other health outcomes. The results, although not conclusive, provide indications that more effective public health policies on hazardous waste management are urgently needed. International, national and local authorities should oppose and eliminate poor, outdated and illegal practices of waste disposal, including illegal transboundary trade, and increase support regulation and its enforcement.

[The contribution of cancer registries in environmental health studies]. / Il contributo dei Registri tumori negli studi su ambiente e salute.

Cancer incidence is an outcome of interest in studies assessing the health impact of polluted sites, for which an example is represented by SENTIERI Project. Incidence data are characterized by better diagnostic quality and are not influenced by survival factors, furthermore they allow the investigation of high-survival neoplasms (i.e. childhood cancer) and rare malignancies. Furthermore, the study of incidence is more informative than mortality for non-lethal tumours, therefore it represents an advancement in respect to the study of mortality completed in SENTIERI Project. In the last decade in Italy some environmental epidemiology studies used cancer register data, for example the Biancavilla (Sicily) investigation on fluoro-edenite related mesothelioma and the study in an area of Naples Province where hazardous waste was extensively dumped. In this frame, ISS planned some collaborative studies with Siracusa, Mantua and Ferrara cancer Registries, where three major polluted sites are located. Following these pilot studies an ISS-AIRTUM (Italian Association of Cancer Registries) collaborative study has been planned. For a description of SENTIERI, refer to the 2010 supplement of Epidemiology & Prevention, devoted to the Project.

[SENTIERI Project: rationale and objectives]. / Razionale e obiettivi del Progetto SENTIERI.

SENTIERI Project (Mortality study of residents in Italian polluted sites) studied mortality of residents in the sites of national interest for environmental remediation (Italian polluted sites--IPSs). IPSs are in proximity of either active or dismissed industrial areas, near dumping sites of industrial and hazardous waste or incinerators. SENTIERI Project described and evaluated the mortality of the populations residing in IPSs and it specifically focused on causes of death for which environmental exposure is suspected or ascertained to play an etiologic role. The epidemiological evidence of the causal association was classified a priori into one of these three categories: Sufficient (S), Limited (L) and Inadequate (I). The study results will allow the priorities setting in remediation intervention, so as to prevent adverse health effects from environmental exposure. At the time of 2001 Census, about 10%of Italian population resided in the 44 IPSs included in SENTIERI; the mortality analysis was carried out for the years 1995-2002 for 63 causes of death. The study results for the 44 IPSs are here commented and read on the basis the a priori evaluation of the epidemiological evidence in terms of strength of the causal association, and taking into account the limits of a geographic study design and its implied complexities. The procedures and results of the evidence evaluation have been presented in a 2010 Supplement of Epidemiology & Prevention devoted to SENTIERI.

[SENTIERI Project: discussion and conclusions]. / Progetto SENTIERI: discussione e conclusioni.

SENTIERI Project is the first comprehensive study of the health impact of residence in Italian polluted sites (IPSs). The present Chapter examines the main validity aspects of the present mortality investigation and the evaluation of causality of the observed associations; in addition, some recommendations for public health intervention and research priorities in epidemiological studies on environment and health are given. Exposure ascertainment is a key aspect when an ecological study design is adopted in environmental epidemiology, therefore any exposure potentially affecting the population at study should be described in detail. This is here discussed. SENTIERI is an ecological study, based on a priori hypotheses, in which each IPS's types of exposure were described with specific attention to human exposure. Though, when commenting the results, the problem of concurrent air pollution exposure and/or industrial activities implying occupational risk, if present in the IPSs, was taken into account. Socioeconomic status is a determinant of health and disease, therefore in SENTIERI the Standardized Mortality Ratios were computed both crude and adjusted for an ad hoc deprivation index. About 60% versus an expected 40% of IPSs residents are in the two most deprived quintiles of the index. This hints to a possible problem of environmental justice that should be taken into account when planning remediation intervention. The mortality results here presented are a first step in the epidemiological IPSs' characterization, and some developments have been made or planned. Firstly, a mortality analysis was performed combining mortality data in IPSs presenting similar pollution, i.e. asbestos, or industrial hazardous wastes or dumping sites; secondly, the mortality analysis will be extended beyond 2002, namely the year when ICD X started to be in use in Italy. In addition, disease prevalence will be investigated using hospital discharge records; cancer incidence and congenital anomalies incidence will be studied in IPSs in which a Cancer Register or a Congenital Anomalies Register are active. The above described activities will lead to a more valid estimate of the disease burden of IPSs residents, and allow to identify priorities of remediation activities. The method adopted in SENTIERI, specifically the ecological design and the use of mortality data at municipal level, in general does not grant the evaluation of the causal association between environmental exposure and adverse health effects. However, it allows etiological observations that make unacceptable the delay of remediation intervention.

[Mortality results in SENTIERI Project]. / Risultati dell'analisi della mortalità nel Progetto SENTIERI.

SENTIERI Project (Mortality study of residents in Italian polluted sites) studies mortality of residents in 44 sites of national interest for environmental remediation (Italian polluted sites, IPS). The epidemiological evidence of the causal association between causes of death and exposures was a priori classified into one of these three categories: Sufficient (S), Limited (L) and Inadequate (I). In these sites various environmental exposures are present. Asbestos (or asbestiform fibres as in Biancavilla) has been the motivation for defining six sites as IPSs (Balangero, Emarese, Casale Monferrato, Broni, Bari-Fibronit, Biancavilla). In five of these, increases in malignant neoplasm or pleura mortality are detected; in four of them, results are consistent in both genders. In six other sites (Pitelli, Massa Carrara, Aree del Litorale Vesuviano, Tito, "Aree industriali della Val Basento", Priolo), where other sources of environmental pollution in addition to asbestos are reported, mortality from malignant neoplasm of pleura is increased in both genders in Pitelli, Massa Carrara, Priolo, "Litorale vesuviano". In the time span 1995-2002, a total of 416 extra cases of malignant neoplasm of pleura are detected in the twelve asbestos-polluted sites. Asbestos and pleural neoplasm represent an unique case. Unlike mesothelioma, most causes of death analyzed in SENTIERI have multifactorial etiology; furthermore, in most IPSs multiple sources of different pollutants are present, sometimes concurrently with air pollution from urban areas: in these cases, drawing conclusions on the association between environmental exposures and specific health outcomes might be complicated. Notwithstanding these difficulties, in a number of cases an etiological role could be attributed to some environmental exposures. The attribution could be possible on the basis of increases observed in both genders and in different age classes, and the exclusion of a major role of occupational exposures was thus allowed. For example, a role of emissions from refineries and petrochemical plants was hypothesized for the observed increases in mortality from lung cancer and respiratory diseases in Gela and Porto Torres; a role of emissions from metal industries was suggested to explain increased mortality from respiratory diseases in Taranto and in Sulcis-Iglesiente-Guspinese. An etiological role of air pollution in the raise in congenital anomalies and perinatal disorders was suggested in Falconara Marittima, Massa-Carrara, Milazzo and Porto Torres. A causal role of heavy metals, PAH's and halogenated compounds was suspected for mortality from renal failure in Massa Carrara, Piombino, Orbetello, "Basso bacino del fiume Chienti" and Sulcis-Iglesiente-Guspinese. In Trento-Nord, Grado and Marano, and "Basso bacino del fiume Chienti" increases in neurological diseases, for which an etiological role of lead, mercury and organohalogenated solvents is possible, were reported. The increase for non-Hodgkin lymphomas in Brescia was associated with the widespread PCB pollution. Mortality for causes of death with a priori Sufficient or Limited evidence of association with the environmental exposure exceeds the expected figures, with a SMR of 115.8% for men (90% IC 114.4-117.2; 2 439 extra deaths) and 114.4% for women (90% CI 112.4-116.5; 1 069 extra deaths). These excesses are also observed when analysis is extended to all the causes of death (i.e. with no restriction to the ones with a priori Sufficient or Limited evidence): for a total of 403 692 deaths (both men and women), an excess of 9 969 deaths is observed, with an average of about 1 200 extra deaths per year. Most of these excesses are observed in IPSs located in Southern and Central Italy. The procedures and results of the evidence evaluation are presented in a 2010 Supplement of Epidemiology & Prevention devoted to SENTIERI.

[Scientific collaboration between Istituto Superiore di Sanità and Italian Association of Cancer Registries for the study of cancer incidence in Italian polluted sites]. / Collaborazione scientifica ISS-AIRTUM per lo studio dell'incidenza dei tumori nei siti di interesse nazionale per le bonifiche.

The collaborative study between Istituto superiore di sanità and Associazione italiana registri tumori (ISS-AIRTUM) aims at investigating cancer incidence in polluted sites for adults and for children (0-14 years) and adolescents (15-19 years) to comment the study results in the light of a set of a priori hypotheses. On the whole, 141 out of 298 municipalities included in SENTIERI Project are served by a Cancer Register participating to the AIRTUM network. For a description of SENTIERI, refer to the 2010 Supplement of Epidemiology & Prevention devoted to SENTIERI Project. The time window of the study is the period 1996-2005. The number of expected cases in each polluted site will be estimated by applying incidence rates of the national pool of cancer registries and of the pool of the geographic macroarea in which each site is located: Northern, Central, Southern Italy and Islands. Cancer incidence in children and adolescents is one of the main priorities of international public health institutions, because of the need to protect childhood health from involuntary exposure to environmental risk factors. Standardized incidence ratios (SIRs) will be computed using expected figures derived from the national pool of cancer registries.

Cancer mortality and congenital anomalies in a region of Italy with intense environmental pressure due to waste.

OBJECTIVES: Waste management in the Campania region has been characterised, since the 1980s, by widespread uncontrolled and illegal practices of waste dumping, generating concerns over the health implications. The objective of this study was to evaluate possible adverse health effects of such environmental pressure. METHODS: The health effects of waste-related environmental exposures in Campania were assessed in a correlation study on nine causes of death (for the years 1994-2001) and 12 types of congenital anomaly (CA) (1996-2002) in 196 municipalities of the provinces of Naples and Caserta. Poisson regression was used to analyse the association between health outcomes and environmental contamination due to waste, as measured through a composite index, adjusting for deprivation. RESULTS: Statistically significant excess relative risks (ERR, %) in high-index compared with low-index (unexposed) municipalities were found for all-cause mortality (9.2 (95% CI 6.5 to 11.9) in men and 12.4 (9.5 to 15.4) in women and liver cancer (19.3 (1.4 to 40.3) in men and 29.1 (7.6 to 54.8) in women). Increased risks were also found for all cancer mortality (both sexes), stomach and lung cancer (in men). Statistically significant ERRs were found for CAs of the internal urogenital system (82.7 (25.6 to 155.7)) and of the central nervous system (83.5 (24.7 to 169.9)). CONCLUSION: Although the causal nature of the association is uncertain, findings support the hypothesis that waste-related environmental exposures in Campania produce increased risks of mortality and, to a lesser extent, CAs.

Peritoneal mesothelioma mortality in Italy: Spatial analysis and search for asbestos exposure sources.

BACKGROUND: This study is part of a national plan of epidemiological surveillance of malignant mesothelioma (MM) mortality in Italy. The paper shows the results of malignant peritoneal mesothelioma (MPeM) mortality study in Italian Regions and municipalities. METHODS: National Bureau of Statistics data for MPeM municipal mortality (ICD-10, Code C45.1) were analyzed in the time-window 2003-2014: mortality standardized rates (reference Italian population, census 2011), temporal trends of the annual national rates, Standardized Mortality Ratios and a municipal clustering analysis were performed. RESULTS: 747 deaths for MPeM were recorded (0.10/100,000): 464 in men (0.14/100,000) and in 283 women (0.07/100,000). No significant MPeM mortality temporal trend was found. Seventeen municipalities showed excesses of mortality for MPeM in at least one gender and/or overall population. Four clusters in male population, and one in women were identified. CONCLUSIONS: The study identifies some areas where remediation activities and/or health care actions may be warranted.

Mesothelioma associated with environmental exposures.

BACKGROUND: The main sources of environmental, non-occupational exposure to asbestos or asbestiform fibres are: a) industrial plants in which asbestos was used in the production process; b) asbestos "in place" (mainly in buildings); c) contaminated soils. The association of these exposures with increasing risk of mesothelioma has been documented since 1960 in many places. OBJECTIVES AND METHODS: The present paper is aimed at describing the main results of studies performed in the locations with soils naturally contaminated with asbestos or asbestiform fibres. Environmental exposure data and asbestos-related health outcomes, mainly mesothelioma, are analyzed through a review of the literature. RESULTS: The sites with asbestos or other mesotheliomatogenous fibres in soils are characterized by low concentration levels of airborne fibres. Furthermore, exposure levels may increase when specific activities are carried out (mainly related to building construction), involving mechanical disturbance of fibre-containing materials. The type of fibres found are mainly amphiboles (tremolite). The population at risk of exposure is the general population, which can be exposed from birth. In these sites, the sex ratio of mesothelioma cases is close to 1.0 and the average age of cases ranges from 50 to 60 years. CONCLUSIONS: Both "natural"and industrial environmental asbestos or asbestiform fibre exposures increase potential risk for mesothelioma. Strategies of environmental reclamation and risk communication should be implemented in these areas.

A cohort study on vinyl chloride manufacturers in Italy: study design and preliminary results.

A cohort mortality study of 5000 vinyl chloride manufacturers is ongoing in 9 Italian plants. They represent the entire workforce of those ever employed in the production of the monomer and its polymerization. The objectives of the study are to investigate the mortality of the exposed population and to clear up the carcinogenic spectrum of vinyl chloride. This article gives the results for 3 out of 9 plants, Rosignano, Ferrara and Ravenna, which represent about 25% of the total cohort. The expected deaths have been calculated using the mortality rates of the Italian population. For the deceased persons information from the death certificates were used in the analysis of mortality; additional clinical and pathological data were collected (best pathological evidence, b.p.e.). In Ferrara a statistically significant excess for all malignant tumors and lung cancer was detected. In Rosignano and Ravenna the number of observed deaths were small and therefore no comments can be made on cancer mortality. The cohort study is ongoing in the 6 remaining cohorts and the future analysis will consider duration and level of exposure and latency.

Nitrate and nitrite exposure in Italian populations with different gastric cancer rates.

Exposure to nitrate and nitrite from dietary sources was estimated by questionnaire and measurement of salivary levels of the ions in residents of four regions of Italy with longstanding, contrasting, gastric cancer mortality rates. Whether using salivary levels or dietary questionnaire estimations no association was found between nitrate and nitrite exposure and gastric cancer mortality rates. For salivary nitrate and nitrite, the intra-provincial variation was greater than any inter-province difference. However, for dietary nitrate and nitrite intakes, there were significant differences between the regional groups (but not related to gastric cancer risk). Despite the limitations of the methods used, there was a weak positive association between salivary concentrations of nitrate and questionnaire assessment. Dietary factors are likely to play key roles at different stages of the gastric carcinogenic process. Nitrate may play a part but is unlikely to be a rate-limiting factor in all individuals or populations.

A copper(I) oxygenation precursor in the entatic state: two isomers of a copper(I) compound of a rigid tetradentate ligand

Oxygenation of [CuI(L1)(NC-CH3)]+ (L1 = dimethyl 2,4-bis(2-pyridinyl)-3,7-diazabicyclo-[3.3.1]-nonane-9-on-1,5-dicarboxylate) leads to a relatively stable mu-peroxo-dicopper(II) product. The stability of this type of oxygenation product has been shown before to be the result of the square pyramidal geometry of L1; preorganization by a dinucleating ligand has been shown to increase the stability of the mu-peroxo-dicopper(II) compound. The structural data presented here indicate that destabilization of the copper(I) precursor is another important factor. There are two isomers of [CuI(L1)(NCCH3)]+; one is yellow, and the other is red. X-ray crystallography indicates that one pyridinyl donor is not coordinated in the yellow compound and that the red compound is 5-coordinate. In the light of the X-ray structure of the metal-free ligand and that of the corresponding copper(II) compound, it emerges that the ligand cavity is well suited for copper(II), whereas the copper(I) compounds are highly strained. This is supported by 1H NMR spectra of the copper(I) species where a fast dynamic process leads to line broadening and by electrochemical data, which indicate that the copper(II) products are exceptionally stable. Also presented are structural (copper(II)), electrochemical, and spectroscopic data (1H NMR, copper(I)) of the derivative [Cu(L2)(X)]n+ with a methyl substituent at the alpha-carbon atom of the two coordinated pyridinyl groups (L2 = dimethyl 2,4-bis(2-pyridinyl-6-methyl)-3,7-diazabicyclo-[3.3.1]-nonane-9-on-1,5-dicarboxylate). There are two structural forms of [CuII(L2)(X)]n+ (X = NCCH3, Cl), which depend on the steric demand of the fifth donor X. For both, van der Waals repulsion leads to a destabilization of the copper(II) products, and this is also evident from an increase in the reduction potential (-110 mV vs. -477 mV, Ag/AgNO3).

Nasal cancer in leather workers: an occupational disease.

Nasal cancer has a number of causative agents; exposures to most of the established nasal carcinogens occur in the workplace. An increased risk of nasal cancer has been ascertained in shoe-making and shoe-repairing, but the results for leather goods manufacture and leather tanning don't provide adequate evidence of carcinogenicity. Findings from two epidemiological studies carried out in Italy (a case/control study and a case/series report) add further information on this issue. The case/control study was performed in the provinces of Siena (Tuscany), Verona and Vicenza (Venetia) including 96 cases and 378 controls. A significant increased risk (Odds Ratio: 6.8; 90% C.I. = 1.9-25) of sinonasal cancer was found for the employ in the whole leather industry; Odds Ratio of 8.3 (C.I. = 1.9-36) and 5.0 (C.I. = 0.92-28) were associated with shoe-making and leather tanning. The case/series report is based on 110 patients accepted in some Italian hospitals during last three years (1990-1993): 26 cases had worked in the leather industry; adenocarcinoma is the most frequent type observed. Chromium salts and natural tannins are indicated as possible aetiological agents.

Effects of low-dose radiation - a correlation study.

The effects of low-dose radiation have been a matter of controversy over the years, and the epidemiologic results have been conflicting. A couple of recent studies have indicated a possible impact on lung cancer mortality from exposure to indoor levels of radon and radon daughters. In this study, selected mortality rates, ie, lung cancer, pancreatic cancer, breast cancer (females only), leukemia, and multiple myeloma were correlated for the counties of Sweden with estimates of average background radiation exposure in these areas. Significant correlations were obtained for lung cancer (males, r = 0.46; females r = 0.55) and pancreatic cancer (males, r = 0.59; females, r = 0.40) , and there was a borderline correlation (r = 0.36; p = 0.04) for leukemia in males. In all, there were positive correlations for eight out of the nine computations made. Since background radiation correlates with urbanization and therefore with smoking, air pollution, etc, the correlations might be spurious due to confounding; on the other hand confounding is a reciprocal phenomenon which suggests that background radiation should to be taken into consideration when widespread risk factors like smoking, coffee drinking, general air pollution, etc, are studied.

Mortality study of workers employed by the Italian National Institute of Health, 1960-1989.

A cohort mortality study was conducted to evaluate the cancer risk of workers employed by the National Institute of Health in Rome, Italy. Cancer mortality was evaluated for research staff. A deficit of overall cancer mortality was found for the men, but not for the women. Elevated (albeit statistically nonsignificant) standardized mortality ratios were found for cancer of the pancreas (men 155, women 236), cancer of the brain (men 159), lympho- and reticulosarcomas (men 233, women 512), and lymphatic and hematopoietic tumors (women 623). In addition the women had a statistically significantly elevated risk of breast cancer (288). Although most of these results, with the exception of breast cancer among the women, were not statistically significant, due to the limited study size, they point to the existence of excess risks for some tumors. The possibility that these increases are related to exposures occurring in the laboratory setting deserves further consideration.

A case-referent study on nasal cancer and exposure to wood dust in the province of Siena, Italy.

The aim of the present study was to assess the risk of nasal cancer associated with exposure to dust in the wood and furniture industry in the province of Siena, Italy. Four to seven percent of the active male population is employed in this sector. A case-referent approach was used. The cases included male subjects seen at the Ear, Nose and Throat Clinic and the Radiotherapy Unit of Siena and diagnosed as having cancer of the nasal cavities or paranasal sinuses between 1963 and 1981. The referents were male patients admitted to the Medical Clinic of Siena for all causes except nasal neoplasia; they were matched 5:1 to the cancer patients for age and time of admission. Information was gathered (by postal questionnaires) on the occupational histories of all 36 of the cancer patients and 164 of the 180 referents. The odds ratio associated with exposure to wood dust was 5.4 (1.7-17.2) for all carcinomas, and 87.7 (19.8-407.3) for mucinous adenocarcinoma. The woods used by the exposed cancer patients were mainly oak, chestnut, poplar, and fir. The median duration of exposure was 40 years; no exposed cancer patient reported the presence of exhaust systems in their work environment.

Mortality among pyrite miners with low-level exposure to radon daughters.

Mortality among pyrite miners with low-level exposure to radon daughters. Scand J Work Environ Health 14 (1988) 280-285. A cohort mortality study was conducted with regard to a pyrite mine located in central Italy. Exposure to radon ranged from 0.12 to 0.36 working levels (WL) in the work areas; most measurements were around 0.2 WL. The concentration of free silica in the dust was less than 2%. The cohort was determined from company files and included 1,899 subjects. Mortality was studied for the years 1965-1983. The loss to follow-up was less than 2%. The standardized mortality ratio for all causes and all neoplasms was 97 and 107, respectively. That for lung cancer and for nonmalignant respiratory diseases was 131 (95% confidence interval 97-175) and 173 (95% confidence interval 135-231), respectively. It was estimated that the extra cases of lung cancer attributable to radon daughters numbered 13 per 10(6) person-years and working level month in the whole cohort and 21.3 per 10(6) person-years in the subcohort with 10-25 years of exposure.

A collaborative study of cancer incidence and mortality among vinyl chloride workers.

A large European multicentric cohort study has been coordinated by the International Agency for Research on Cancer with the objectives of investigating the dose-response relationship between liver cancer and exposure to vinyl chloride and assessing cancer risk for sites other than the liver. A nearly threefold increase in liver cancer was detected on the basis of 24 observed deaths and 8.4 expected (standardized mortality ratio 286, 95% confidence interval 186-425). The excess from liver cancer was clearly related to time since first exposure, duration of employment, and estimated ranked and quantitative exposures. Other cancer sites investigated on the basis of a priori hypotheses were either not in excess (lung) or apparently unrelated to the exposure variables (brain and lymphoma).

Mortality study on a cohort of Italian licensed pesticide users.

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.