Chemosphere 43 )2001) 951±966

Dioxin exposure and public health in Chapaevsk,

B. Revich a,*, E. Aksel b, T. Ushakova b, I. Ivanova c, N. Zhuchenko c, N. Klyuev d, B. Brodsky d, Y. Sotskov e

a Center for Demography and Human Ecology of Institute for Forecasting, Russian Academy of Sciences, Nakhimov's prosp. 47, Moscow 117418, Russian Federation b Cancer Scienti®c Research Center, Russian Academy of Medicine Sciences, Kashirskoe Drive 24, Moscow 115478, Russian Federation c Moscow Medical Academy, Rossolima str., 11a, Moscow, Russian Federation d Severtsov Institute of Ecology and Evolution, Russian Academy of Sciences, Leninsky prospekt, 33, Moscow 117071, Russian Federation e State Committee of Environmental Protection, Barrikadnaya 2/6, Moscow 123812, Russian Federation

Abstract

One of the largest environmental polluters in Chapaevsk ) Region, Russia) is the Middle chemical plant. From 1967 to 1987, it produced hexachlorocyclohexane )lindane) and its derivatives. Currently, it produces crop protection chemicals )liquid chlorine acids, methyl chloroform, vinyl chloride, and some other chemicals). Dioxins were detected in air 0:116 pg=m3), in soil )8,9±298 ng/kg), in the town's drinking water )28,4±74,1 pg/liter), and in the cow's milk )the content of 2,3,7,8 ± TCDD was 17,32 pg TEQ/g fat). The mean content of dioxins in seven pooled samples of human milk )40 individual trials) was 42,26 pg TEQ/g fat, in four female workers' blood samples ± 412,4 pg TEQ/g fat, in six residents'blood samples )those who lived 1±3 km from the chemical plant) ± 75,2 pg TEQ/g fat, in four residents' blood samples )5±8 km from the plant) ± 24,5 pg TEQ/g fat. To assess cancer risk and reproductive health status, ocial medical statistical information was used. In general, the male cancer mortality observed rate in Chapaevsk is higher than expected. The SMR is higher for lung cancer 3.1)C.I. 2.6±3.8), urinary organs 2.6)C.I. 1.7±3.6). Chapaevsk women have a higher risk overall due to breast cancer 2.1)C.I. 1.6±2.7) and cervix cancer 1.8)C.I. 1.0±3.1). The incidence rates were higher for lung cancer in males and for female breast cancer in all age groups compared to Russia and Samara Region in 1998. Signi®cant disruptions in reproductive function were detected. The mean frequency of spontaneous abortions in the last seven years was statistically higher 24.4% in Chapaevsk )compared to other of the towns region). The average rate of premature labor was 45.7 per 1000 women in Chapaevsk that is signi®cantly higher than in most Samara Region towns. The frequency of newborns with low birth weight was 7.4%. In Russia and in most of the Samara Region towns, this rate is lower )6.2±5.1%) but not statistically di€erent. For the determination of congenital morphogenetic conditions )CMGC), 369 children born between 1990 and 1995 were examined. The average number of CMGC per child was signi®cantly higher, 4.5 for boys and 4.4 for girls. The ®rst results indicated serious disruptions associated with high dioxin levels in human milk and blood in Chapaevsk. We suggest that Chapaevsk is an incredibly interesting site for further environmental-epidemiological research to assess the impact of dioxins on human health. Ó 2001 Published by Elsevier Science Ltd.

Keywords: Dioxins; Blood; Human milk; Breast cancer; Lung cancer; Spontaneous abortions; Newborns with low birth weight; Congenital morphogenetic e€ects; Congenital morphogenetic conditions; Congenital malformations; Sex ratio; Environmental health; Russia

* Corresponding author. Tel.: +7-095-332-4313; fax: +7-095-718-9771. E-mail address: [email protected] )B. Revich).

0045-6535/01/$ - see front matter Ó 2001 Published by Elsevier Science Ltd. PII: S 0 045-6535)00)00456-2 952 B. Revich et al. / Chemosphere 43 62001) 951±966

1. Introduction 3. to estimate incidence and mortality rates, and specif- ically describe reproductive health in the population Published studies of dioxin exposure and its impact according to ocial statistical data; on human health are few in number and limited to 4. to assess the impact on genetic characteristics; certain geographical regions. The majority of studies 5. to assess male sexual maturation and abnormalities in have been concentrated in Italy )after the incident in the male reproductive system based on case-control Seveso), the US, Vietnam )as a result of using Agent studies. Orange), Germany )occupational studies) and other An article by Revazova et al. )2000) about the cyto- countries. There are two towns in Russia where similar genic e€ects of dioxins in residents of Chapaevsk has studies are being conducted ± Ufa )Bashkiria) and been published in this issue of Chemosphere. Chapaevsk )Samara Region). Chapaevsk is located 43 km to the southwest of Sa- mara, on the Chapaevka River, which ¯ows into the Volga River. The population of the town is 83,000. One 2. Methods of study of the largest environmental polluters in Chapaevsk is the Middle Volga chemical plant. Prior to 1949, the 2.1. Sampling human milk Plant produced chemical blister agents: mustard gas and lewisite. From 1967 to 1987, it produced hexachlorocy- Sampling of human milk was carried out in Decem- clohexane )lindane) and its derivatives. Currently, it ber 1997±June 1998 according to the World Health produces crop protection chemicals )liquid chlorine, Organization )WHO) criteria. Forty samples of human acids, methyl chloroform, vinyl chloride, and some other milk were pooled into seven samples. The average age of chemicals). Previously it was considered that hexachlo- mothers was 22.0 years. All surveyed mothers classi®ed rane production was responsible for dioxin contamina- their diet as mixed. Ninety percent of women eat ®sh tion in the city's environment. Tests seemed to con®rm once a week or rarely, 80% of women eat meat more it. But after the production was stopped in 1987, a than two times a week, and dairy products every day. All continued output of dioxin was still observed. The study respondents never smoked, as they self-reported in the of the present -day chemical production technologies interview. revealed that dioxins and similar compounds can be formed in the production of methyl chloroform, vinyl chloride, dichlorpropionic acid, hexachlorethane, sodi- 2.2. Blood um pentachlorphenolate and polychloroform )Environ- ment and public health in Chapaevsk city, 2000). Blood samples were taken from 14 people. The A large network of industrial plants was created blood was centrifuged, frozen and transported on dry during industrialization in Russia, intended for the ice. Ninety percent of women lived in Chapaevsk for production of toxic agents with high chlorine content. more than three years and 75% of them for more than One such plant was founded in Chapaevsk, Samara ®ve years. Income for one member of a family in these Region. Industrial plants, mainly related to the military- three groups was nearly the same. A detailed inquiry industrial complex, occupied 51% of the total region into diet did not ®nd great di€erences between the area. These plants produced 86% of the city's income. groups. They employed approximately half of the city's popu- lation. 2.3. Cow's milk Beginning in 1989, a stable trend towards reduced production has been observed in the city, as well as in Samples were taken from private households of the country as a whole. The greatest reduction of more Chapaevsk residents. Residents use vacant lots in the than 83% took place at the defense plants. The chemical city as cow pastures, including areas near the chemical industry reduced production by more than 50%. The plant. reduced volume of production in Chapaevsk is higher than in and in Russia on the whole. The ®rst results of dioxin analysis in soil samples 2.4. Methods of dioxin analysis indicated high concentrations. High levels of dioxin were registered in soils at the city center, in the soils of gar- The technique for the isomer-speci®c analysis of dens and agricultural ®elds. This led the Chapaevsk City PCDDs and PCDFs in complex lipophilic matrices Administration to begin studies to assess the impact of consists of ecient extraction involving a salting out dioxin on human health with the following aims: procedure, which is followed by the clean-up on the 1. to estimate environmental exposure to dioxin; carbon microcolumn that permits to separate lipids. The 2. to estimate blood and milk levels of dioxin; ®nal puri®cation is done using an aluminum column. B. Revich et al. / Chemosphere 43 62001) 951±966 953

2.5. Sample extraction of milk e€ects, 369 children were examined who were born be- tween 1990 and 1995. All these children go to kinder- 13 One hundred milliliter of milk forti®ed with C12- gardens in Chapaevsk at locations in di€erent districts of labeled surrogate standards were mixed with 100 ml the city. In order to obtain the most accurate and acetone and 100 ml hexane and swirled by a homoge- complete information on the birth of children with nizer for 3 min until a homogeneous medium was congenital malformations )CMF), an analysis of the formed. After the addition of 70 g ammonium sulfate, medical records was carried out in all the obstetric and the mixture was shaken until all the ammonium sulfate treatment centers, as well as at prevention centers )ma- was dissolved. When the layers separated )5 min), the ternity hospitals, ambulatory care, and pathology de- precipitation was ®ltered through a glass ®lter using a partments) in the city. After identifying children with gentle vacuum. The precipitant was washed two times CMF based on all available sources of information, each with 10 mls hexane-acetone )1:1), and the rinses were case was recorded by the last name, diagnosis, place of added to the main extract. The organic layer )c. 300 ml) residence, and birth date. Cases which were recorded was separated using the separatory funnel; 20 ml acetone twice were deleted. All diagnoses made in the maternity were added. The aqueous layer was discarded. hospital were con®rmed. If they were not con®rmed, they were excluded. A standard form was completed for 2.6. Carbon microcolumn every identi®ed case, born with CMF.

The carbon microcolumn was made from a glass pi- pette )ID ˆ 3.5 mm) packed with 20 mg activated carbon FAS-MD on 200 mg Celite. The length of the sorbent 3. Results layer was 2.5 cm. Sorbent was ®xed at two ends by glass In 1994 the average concentration of dioxins in air ®ber plugs. The extract was transferred to the carbon 3 column under a pressure of 0.5±1.5 atmospheres. The was 0:116 pg=m . The calculations were made when the column was washed with 20 ml hexane-acetone )1:1). plant worked at 20% capacity, so one can extrapolate PCDD and PCDF were eluted in the reverse direction that dioxin air emissions had been higher previously. with 10 ml toluene at 80°C. Heat was produced by a Moving away from the plant one can see a decrease in microstove made from resistor )15 RUS). the dioxin levels ± down to 36.8 ng/kg in downtown )2.7 km from the plant); down to 3.9 ng/kg in the southern part of the city; down to 0.9 ng/kg at 10±15 km from the 2.7. Alumina column plant )Table 1). Private home owners )18,000 in Chap- aevsk) grow essentially all their vegetables and fruit for 5 ml of toluene eluate was mixed with 95 ml of their own use, thus receiving an additional dioxin load. hexane and placed on the aluminum column with 4 g of The TEQ values were calculated using the WHO-TEF sorbent. The column was washed with 20 ml of hexane, for dioxin-like compounds for human and wildlife ac- 30 ml methylene chloride-hexane )5:95), 50 ml methylene cording to Ahlborg et al. )1994). chloride-hexane )50:50) and 50 ml methylene chloride- We compared the data on dioxin content in soil to methanol )50:50), sequentially. The methylene chloride- other regions of Russia, where there are similar pro- hexane )50:50) fractions were collected and evaporated duction facilities. We summarize the information as: under vacuum gauge under heating to 40°C. 0.4±76.7 ng TEQ/kg in Arkhangelsk Region )Yu®t et al., 1998); 0.94±5.9 ng TEQ/ kg in Vladimir Region )Kly- 2.8. GC-HRMS analysis uyev et al., 1998); 0.05±11.3 in Astrakhan Region )Michaylov et al., 1998); 1±20 ng TEQ/kg in Bashkiria Analysis was produced using Finnigan MAT HSQ )Maystrenko et al., 1998). mass spectrometer at resolution 10,000. Silica capillary The town's drinking water source is groundwater. column HP-5 50 m  0; 20 )®lm thickness 0; 33 lm) was The water distribution pipes are old and su€er from used, temperature was programmed from 170°C )hold many breaks )120±225 per year) due to poor technical time 1,5 min) to 230°C, with rate 15°C=min )hold time maintenance. This is an ongoing cause of underground 1 min). Then to 280°C with rate 4°C=min )hold time water pollution. Dioxin analysis of three samples of 7 min). Injector temperature 250°C. drinking water from di€erent areas of the town was done in 1998. The results showed high levels of dioxin cong- 2.9. Public health eners OCDD and HpCDD, and relatively low concen- trations of other congeners )Table 2). It can be assumed To assess indicators of public health in Chapaevsk, that such a situation was caused by wastes discharged routine demographic and medical statistics were used. from the chemical production of pentachlorophenol. For the determination of congenital, morphogenetic The total content of PCDD and PCDF exceeds the 954 B. Revich et al. / Chemosphere 43 62001) 951±966

Table 1 Dioxin content in Chapaevsk soils and vegetables, di€erent distances from the plant, 1992±1994 Distance from the plant Dioxin content Soils )ng TEQ/kg) Vegetables )pg TEQ/kg) Minimum Maximum Mean Carrots mean Potatoes mean Less than 2 km 40.4 298.0 141.3 0.07 0.021 2±7 km 8.9 71.2 36.8 0.78 2.0 7±10 km Not avail. Not avail. 3.9 0.12 0.005 Outside the city, 10±15 km 0.1 3.6 0.9 0.001 0.009

Table 2 Contents PCDD/PCDF in drinking water, pg/liter, July 1998 Congeners 6±8 km from the plant City center Sample 1 Sample 2 2,3,7,8-TCDD less 2 less 2 5,0 1,2,3,7,8-PeCDD less 5 less 5 less 5 1,2,3,4,7,8-HxCDD less 10 less 10 less 10 1,2,3,6,7,8-HxCDD less 10 less 10 18,5 1,2,3,7,8,9-HxCDD less 10 less 10 less 10 1,2,3,4,6,7,8-HpCDD 166,4 291,0 70,0 OCDD 26,789,2 78,549,1 32,887,0 2,3,7,8-TCDF less 2 9,1 less 2 1,2,3,7,8-PeCDF less 5 less 5 64,5 2,3,4,7,8-PeCDF less 10 less 5 34,6 1,2,3,4,7,8-HxCDF less 10 57,2 131,4 1,2,3,6,7,8-HxCDF less 10 61,2 37,0 1,2,3,7,8,9-HxCDF less 10 less 10 less 10 2,3,4,6,7,8-HxCDF less 10 less 10 less 10 1,2,3,4,6,7,8-HpCDF less 20 less 20 less 20 1,2,3,4,7,8,9-HpCDF less 20 less 20 less 20 OCDF less 50 less 50 less 50 Other TCDD less 2 less 2 less 2 Other PeCDD less 5 less 5 less 5 Other HxCDD less 10 less 10 less 10 Other HpCDD less 20 106,9 76,5 Other TCDF less 2 9,0 13,2 Other PeCDF less 5 less 5 99,4 Other HxCDF 53,7 39,5 84,6 Other HpCDF less 20 less 20 less 20 Total PCDD/PCDF, TEQ 28.45 102.40 74.10 maximum allowable concentration of dioxin in drinking 3.1. Dioxin in cow's milk water in the US )0.013 pg/liter), in Germany and Can- ada )0.01 pg/liter) and in Italy )0.05 pg/liter). Dioxins were found in all samples of cow milk: The highest dioxin concentrations were found in 2,3,7,8-TCDD was 17.32 pg TEQ/g fat; 1,2,3,7,8-PeC- samples taken from the city center ± 102.4 and 74.1 pg/ DD was 61 pg TEQ/g fat. In most samples there liter. Signi®cantly lower levels were detected in the were 1,2,3,4,7,8-, 1,2,3,6,7,8- and 1,2,3,7,8,9-HxCDD, drinking water of the residential area 5±8 km from the 1,2,3,4,6,7,8-HxCDD and furans 1,2,3,4,6,7,8-, 1,2,3,6,7, plant )28.4 pg/liter). Such high levels of dioxins have 8,- and 1,2,3,7,8,9-HxCDF detected. The rest of the never been found in Russia, including in Bashkiria from congeners were on the edge of the detection limit. Dioxin 1994 to 1997. In 1989 there was an accident in Bashkiria and furan contents in cow's milk are signi®cantly higher at a chemical plant and drinking water was heavily than the accepted regulatory standard in Russia )5.2 pg contaminated by dioxin. TEQ/g fat). B. Revich et al. / Chemosphere 43 62001) 951±966 955

3.2. Human milk chemical poisoning by mustard, lewisite and their mix- ture. The analysis of dioxins in seven pooled samples of In 1969, the Gorky Institute of Hygiene made the human milk )40 individual trials) has been carried out. ®rst assessment of the plant workers'health. At that time The results of dioxin and furan contents in human breast the plant produced hexachlorane. Out of 55 exam- milk are shown in Table 3. ined workers, 32 su€ered from chronic dermatitis ± chloracne. In 1973±1974 the workers participated in follow-up medical examinations. At that point, chronic 3.3. Blood chloracne was found in 52 cases out of 119. Mortality rates from all causes in Chapaevsk for The analysis of blood serum for dioxin con®rmed the 1995±1997 were higher than in the Samara Region on excess dioxin concentration in the breast milk samples. the average and higher than in the other towns of the A comparison of the dioxin contents in the blood of region. Analysis of mortality is based on the ocial di€erent groups of the population shows considerably statistical data. Life expectancy declined considerably higher levels of dioxin, especially of 2,3,7,8-TCDD and over the last decade. In 1995, it was 60.7 years for men 1,2,3,7,8-PeCDD in female workers' blood )Table 4). and 74.1 for women. As the main causes of death, car- There are distinct di€erences in the levels of dioxin in diovascular diseases are the most predominant, cancer is women living in two di€erent regions of the town. second, and third are trauma and accidental causes. Cardiovascular diseases were the cause of 65±67% of women's deaths and 41±49% of men's deaths in 1990± 4. Public health 1997, and the latter rate is growing from year to year, particularly for men of 50±59 years of age and 30±39 4.1. The chemical fertilizer plant workers years of age. Women's deaths in Chapaevsk related to cardiovascular diseases are also increasing. In Chap- The group most exposed to dioxin are the workers at aevsk, male mortality due to cardiovascular diseases is the chemical fertilizer plant. The plant produced toxic 1.14 times higher than in Russia. The greatest di€erences compounds during World War II. There is little pub- are observed between the ages of 30 and 49. The com- lished information on the working conditions in those parison of observed and expected )according to Samara years. The newspaper ``Chapaevsk Worker'' reported Region mortality rates) cardiovascular-related deaths mustard gas concentrations in the air of the working also shows a higher mortality rate in Chapaevsk. The area as being 500 times or higher than the Russian trend in mortality from cardiovascular disease is directly threshold limit value. More than 30 workers died of related to the trends in unemployment.

Table 3 PCDD/PCDF content in human milk of 40 women )seven pooled samples) form Chapaevsk )ng/liter and pg/g fat) Congeners TEF )Ahlborg et al., 1994) Contents ng/liter TEQ pg/g fat pg TEQ/g/fat 2,3,7,8-TCDD 1.0 0.88 0.88 23.2 23.2 1,2,3,7,8-PeCDD 1.0 0.30 0.30 7.88 7.88 1,2,3,4,7,8-HxCDD 0.1 0.125 0.0125 2.78 0.28 1,2,3,6,7,8-HxCDD 0.1 0.91 0.09 26.5 2.65 1,2,3,7,8,9-HxCDD 0.1 0.08 0.008 4.27 0.43 1,2,3,4,6,7,8-HpCDD 0.01 0.405 0.004 10.3 0.10 OCDD 0.0001 15.75 0.0016 426.4 0.04 2,3,7,8-TCDF 0.1 0.515 0.051 1.87 0.19 1,2,3,7,8-PeCDF 0.05 0.37 0.018 9.08 0.45 2,3,4,7,8-PeCDF 0.5 0.285 0.143 6.73 3.37 1,2,3,4,7,8-HxCDF 0.1 0.64 0.064 16.97 1.70 1,2,3,6,7,8-HxCDF 0.1 0.41 0.041 11.35 1.13 1,2,3,7,8,9-HxCDF 0.1 0.08 0.008 7.88 0.79 2,3,4,6,7,8-HxCDF 0.1 0.32 0.032 3.02 0.03 1,2,3,4,6,7,8-HpCDF 0.01 0.08 0.0008 1.87 0.02 1,2,3,4,7,8,9-HpCDF 0.01 0.08 0.0008 1.87 0.0002 OCDF 0.0001 0.08 0.000008 2 0.000008

Total PCDD/PCDF 1.55 42.26 956 B. Revich et al. / Chemosphere 43 62001) 951±966

Table 4 PCDD/PCDD in female workers'blood )serum), pg TEQg/ lipid Congeners TEF, WHO Chapaevsk, 1998 Workers n ˆ 4 1±3 km n ˆ 6 5±8 km n ˆ 4 2,3,7,8-TCDD 1.0 80.5 46.4 <2.5 1,2,3,7,8-PeCDD 1.0 164.9 8.6 <7.5 1,2,3,4,7,8-HxCDD 0.1 5.8 1.8 <1.0 1,2,3,6,7,8-HxCDD 0.1 15.7 4.8 6.1 1,2,3,7,8,9-HxCDD 0.1 5.2 1.3 <1.0 1,2,3,4,6,7,8-HpCDD 0.01 1.45 0.9 0.49 OCDD 0.0001 0.18 0.14 0.08 2,3,7,8-TCDF 0.1 3.86 0.78 <0.25 1,2,3,7,8-PeCDF 0.05 1.84 0.41 <0.12 2,3,4,7,8-PeCDF 0.5 89.0 <0.25 <1.25 1,2,3,4,7,8-HxCDF 0.1 13.6 3.8 <1.0 1,2,3,6,7,8-HxCDF 0.1 27.8 2.86 <1.0 1,2,3,7,8,9-HxCDF 0.1 <1.0 <1.0 <1.0 2,3,4,6,7,8-HxCDF 0,1 1.37 <1.0 <1.0 1,2,3,4,6,7,8-HpCDF 0.01 <0.12 0.1 <0.1 1,2,3,4,7,8,9-HpCDF 0.01 <0.12 <0.12 <0.1 OCDF 0.0001 0.0025 0.0025 0.0025

Total PCDD/PCDF 412.4 75.2 24.5

Cancer mortality. In Chapaevsk, cancer mortality teractive Modeling. To evaluate the Chapaevsk cancer constitutes 17.5% of all deaths. Every year 210 people mortality rate, we chose corresponding regional rates for die of malignant tumors in Chapaevsk, which is equal to control. 4 deaths a week. Most likely, lower mortality rates in Table 5 reports the results of mortality analysis. In cases of malignant tumors can be associated with earlier general, the male cancer mortality observed rate in diagnoses and therefore higher treatment eciency. Chapaevsk is higher than expected. The highest risk was Male cancer mortality in Chapaevsk is 1.2 times estimated for lung cancer )3.1), urinary organs )2.6), higher than the average for the Samara Region and 1.3 digestive organs )2.0), and stomach )1.7). Chapaevsk times higher than for Russia. It is 1.4 times higher than women have a higher risk overall due to breast cancer in the US. We estimated expected number of cases and )2.1) or cervix cancer )1.8). The risk of dying from these relative risks )including con®dence intervals) for each forms of cancer is signi®cantly higher than for Samara cancer cause by gender, using Generalized Linear In- Region. The relative risk of death from malignant

Table 5 The deaths for selected cancers in Chapaevsk, 1995±1998a Cause of death )cancer site) Males Females Observed SMRb 95% CI Observed SMR 95% CI All cancers 427 1.8 1.6±1.9 376 0.9 0.8±1.1 Intestine 8 1.7 0.7±3.3 5 0.6 0.2±1.4 Stomach 59 1.7 1.3±2.2 45 0.7 0.5±0.9 Colon 17 1.3 0.8±2.2 24 1.0 0.7±1.5 Rectum 21 1.5 1.0±2.4 24 0.9 0.6±1.4 Larynx 13 2.3 1.2±3.8 1 0.1 0.0±0.6 Lung 168 3.1 2.6±3.5 40 0.4 0.3±0.6 Bones, soft tissues 7 2.1 0.9±4.4 7 1.4 0.6±3.0 Breast 58 2.1 1.6±2.7 Cervix 13 1.8 1.0±3.1 Urinary organs 31 2.6 1.7±3.6 17 0.8 0.5±1.3 Leukemia 11 1.5 0.8±2.7 15 1.5 0.8±2.4 Lymphomas 6 1.1 0.4±2.3 9 1.1 0.5±2.1 a Standard ˆ death rates in Samara Region. b SMR ± standardized mortality ratio. B. Revich et al. / Chemosphere 43 62001) 951±966 957 tumors in bones and tissue is also elevated for the In Chapaevsk, the cancer incidence rates for all types population of Chapaevsk. in 1998 are 1.3 times higher in males compared to Russia Cancer-related deaths annually cost Chapaevsk more and 1.2 times higher compared to the Samara Region than 2.8 million person-years of life lost. Among them )for females they are 1.5 and 1.4 times higher, respec- are: lung cancer )663.700), stomach cancer )400.000), tively). As compared to Russia and Samara Region, the breast cancer )187.000), leukemia and lymphomas lung cancer incidence in Chapaevsk is the highest )146.800 person-years). To compare Chapaevsk's losses )Table 6, Fig. 1). The lung cancer incidence rates were in person-years with the averages for the region, stan- higher for males in all age groups compared to Russia dard age rates were calculated. Losses in male person- and Samara Region in 1998. After 45 years a man in years )42.1) in Chapaevsk are twice as great as losses in Chapaevsk has an increased risk of these diseases. In female person-years )21.1). Lung cancer related deaths males, relatively elevated rates were also registered for constitute the highest rates )14.2 for male, 1.7 for fe- malignant tumors of the colon, liver and bladder. For male), stomach cancer )5.3 and 3.2). Chapaevsk has females these localizations were: stomach, skin including twice as many cancers of the digestive organs )male and melanoma, breast, cervix, leukemia and lymphomas. female) as the average regional rates. The same is true Age-speci®c incidence rates for female breast cancer are about breast cancer )female), throat and lung cancer. shown in Fig. 2. Cancer mortality reduces male average life expec- tancy by 2.3 years, and women's by 1.9 years. Lung 4.2. Reproductive health cancer has the highest impact on average male life ex- pectancy )0.77 year), stomach cancer )0.28 year), leu- To assess reproductive health status, ocial medical kemia and lymphomas )0.17 year). The average statistical information was used. Signi®cant disruptions woman's life span is: 0.29 years shorter in the case of in reproductive function were detected. stomach cancer; 0.27 years shorter in the case of breast Spontaneous abortions. In cases of pregnancy in cancer; 0.15 years in the case of lung cancer; and 0.11 Chapaevsk women, there are usually development years in the case of hemoblastoses. problems. There are a greater number of spontaneous Cancer morbidity. The absolute number of new cases abortions as compared to other cities in the region. The of cancer in Russia increased in 1998 by 75% compared mean frequency of spontaneous abortions in the to the 1980 level )deaths about 80%), )Trapeznikov and last seven years was 24.4% in Chapaevsk; 15.2% in Sa- Aksel, 1999). mara; 10.6% in Toliatti; 15.6% in ; 16.9% in

Table 6 Cancer incidence rates in Russia, Samara Region and Chapaevsk, 1998a Cancer site Males Females Russia Samara Region Chapaevsk Russia Samara Region Chapaevsk All cancers 360.8 403.0 480.1 231.6 257.1 350.8 Lip 7.2 11.5 16.1 1.2 1.5 4.3 Oral cavity 7.6 7.1 13.1 1.5 1.3 1.9 Pharynx 5.9 2.3 2.2 0.7 0.6 2.1 Esophagus 10.2 4.0 4.1 1.8 1.4 0.0 Stomach 48.1 44.0 45.3 20.7 17.6 33.9 Colon 17.9 21.7 22.7 14.1 15.4 13.3 Rectum 16.6 17.1 15.3 10.3 11.2 7.0 Liver 7.5 6.6 13.5 5.8 2.7 5.9 Larynx 11.3 18.0 0.4 1.1 Lung 89.4 102.4 164.5 9.8 11.1 19.6 Skin 36.4 55.7 55.9 27.5 47.6 64.0 Melanoma 3.6 5.1 4.2 4.0 3.5 8.9 Prostate 19.6 22.0 7.0 )) ) Breast )) )46.2 50.7 69.6 Cervix )) )13.2 11.7 20.7 Bladder 16.2 19.8 40.2 2.2 2.3 3.9 Kidney 11.8 12.8 12.3 5.8 7.3 6.1 Thyroid gland 1.5 1.3 2.1 6.3 4.4 2.2 Leukemia and 15.2 14.6 2.4 10.7 13.9 19.0 Lymphoma a Adjusted for age to the Russian standard population. 958 B. Revich et al. / Chemosphere 43 62001) 951±966

Fig. 1. Male age-speci®c lung cancer incidence rates in Chapaevsk, Samara Region and Russia )1998).

Fig. 2. Age-speci®c female breast cancer incidence rates in Chapaevsk, Samara Region and Russia )1998).

Table 7 Spontaneous abortions frequency in the towns of Samara Region, 1991±1997 Towns Total number Spontaneous abortions rate per 100 95% CI )1991±1997) pregnancies ®nished by delivery Chapaevsk 951 24.4 20.0±29.5 Samara 8035 15.2 14.3±16.1 5376 10.6 9.8±11.5 Syzran 1701 15.2 13.4±18.1 Novokuibyshevsk 1174 16.9 14.0±20.3 Small towns 993 11.4 9.4±13.8

Table 8 Frequency of Late gestoses in the towns of Samara Region, 1994±1997 Towns Total number Late gestoses Rate 95% CI )1994±1997) per 100 pregnant Chapaevsk 1005 44.1 37.9±51.2 Samara 12,082 33.8 32.5±35.2 Tolyatti 5237 20.6 19.4±21.6 Syzran 968 18.1 15.6±21.0 Novokuibyshevsk 807 21.2 18.0±25.0 Small towns 439 27.4 21.1±34.8

Novokuibyshevsk; and 11.3% in small towns as shown Preterm delivery. Half of pregnant women in Chap- in Table 7. aevsk su€er from this condition which leads to serious Gestoses. Late gestoses is statistically lower in Chap- delivery complications. The average rate of preterm aevsk than in other Samara Region towns )Table 8). delivery was 45.7 per 1000 women in Chapaevsk B. Revich et al. / Chemosphere 43 62001) 951±966 959

Table 9 Frequency of newborns with low birth weight 1995±1997 Towns Total number Newborns with low birth weight 95% CI )1995±1997) per 100 newborns Chapaevsk 98 7.40 6.04±9.92 Samara 2177 6.60 6.20±7.02 Tolyatti 1200 5.98 5.62±6.27 Syzran 97 5.11 4.18±6.23 Novokuibyshevsk 133 5.78 4.88±6.84 Small towns 202 5.82 5.05±6.70

)Samara is 39.9; Toliatti is 45.8, Novokuibyshevsk is Table 10 36.5; and small towns range from 30.0 to 38.4). In The distribution of all live newborns and sex ratio among them Chapaevsk, the frequency of preterm delivery is signi®- in Chapaevsk, 1983±1997 cantly higher than in most Samara Region towns, except Year All newborns Sex ratio )boys:girls) Toliatti. The same level of 45.7 per 100 and 43.5 per 100 1983 1111 0.95 was observed in Magnitogorsk )large industrial center in 1984 1123 1.04 Russia with high levels of air pollution). In Russia, this 1985 1034 0.97 rate were 37±42 preterm deliveries per 1000 labors. 1986 1111 1.06 Newborns with low birth weight. This measure is used 1987 964 1.27 as an indicator of environmental pollution. The fre- 1988 923 1.00 quency of newborns with this low birth weight was 7.1. 1989 1105 0.67 In Russia and in most of Samara Region towns, this rate 1990 709 0.79 1991 549 0.79 is lower )6.2±5.1%). But these rates are not statistically 1992 514 1.06 di€erent. Similarly this rate of 7.4 was registered in one 1993 381 1.20 of the most PCB-contaminated cities in Russia, Ser- 1994 377 1.00 pukhov )Revich et al., 1996) )see Table 9). 1995 380 1.27 According to data collected by the Maternity and 1996 386 1.02 Gynecology Department of Samara Medical Institute, 1997 423 1.08 babies born to mothers working at the chemical fertilizer 1983±1997 11,090 1.03 plant, display a more distinct reproduction pathology )number of prematurely born babies, inborn defects) than the city average indicators. 4.3. Congenital morphogenetic conditions 6CMGC) Sex ratio. It has been proposed that environmental chemicalization is responsible for the recent decline in The CMGC rate per child varied from 0 to 10. The male ratio among newborns. High concentrations of average number of CMGC per child was 4.5 for boys dioxins, such as those released in the Seveso incident in and 4.4 for girls. These values were more than those Italy in 1976, seem to be associated with fewer males obtained in other environmentally unfavorable regions born than were expected )Mocarelli et al., 1996). This )Bochkov et al., 1994) )Fig. 3). may be a threshold e€ect because the phenomenon was The following attributes are among the most fre- restricted to those families su€ering from extremely high quently occurring ones: sandals chack, epicanthus, dioxin exposure and was likely to be associated with a shawl scrotum )for boys), clinodactyly, broad ®rst ®n- marked induction of the microsomal oxidative enzymes gers of hands and others. Thus, it was established that that also metabolize steroid hormones. Heavy exposure the number of CMGCs is increasing for children ex- to a mixture of PCBs and PCDDs in Taiwan was not amined in Chapaevsk. According to international crite- followed by any similar major change in sex ratio ria, 87 children showed discernible CMGCs. The )Rogan et al., 1999). alternative evaluation of each trait was accomplished in We analyzed the sex ratio of births on the basis of the survey, that is, the extreme forms of a manifestation demographic data in Chapaevsk city. The distribution of of one attribute or another without anthropometry all live births is shown in Table 10 )1983±1997). The being taken into account. range of sex ratio among newborns in Chapaevsk )boys:girls) was from 0.79 to 1.27 with mean value 1,03. 4.4. Congenital malformations Our 15-year data are compatible with the hypothesis that the decrease in the ratio of male to female births in The comparison of the results of our investigation industrial countries is caused by environmental factors. with the data of the European register shows the 960 B. Revich et al. / Chemosphere 43 62001) 951±966

Fig. 3. Distribution of congenital morphogenetic conditions among 369 children )3±8 years old): A ± non-industrial towns; B ± in- dustrial towns; C ± . The most frequent CMGC: sandals chack; epicantus; shawl scrotum; clinodactyly, broad ®rst ®ngers of hands. identi®ed frequencies of CMF. The average frequency of agenesia and disgenesis of the kidney. The increasing CMF is 11.8 per 1000 births, and this value is lower rate of kidney agenesia and disgenesis in Chapaevsk was compared to European register data )23.5 per 1000 not statistically signi®cant. However, the observed ter- births). The exceptions are congenital hydrocephalus, atogenic e€ect of dioxins on animals )Bernes, 1998),

Fig. 4. Congenital malformations in Chapaevsk registered during the period 1982±1997 )columns) and EUROCAT'97 range )band), per 1000 births. B. Revich et al. / Chemosphere 43 62001) 951±966 961 leading to the development of renal e€ects cannot be Table 11. The higher concentrations of dioxins are neglected by looking at the frequency of CMFs )see found only in the milk of women, living close to cotton Fig. 4). ®elds in Kazakhstan. In the past these ®elds were treated with chlorine-containing pesticides )Hooper et al., 1999). 4.5. Discussion The elevation of dioxin levels in human milk in comparison with rural areas is characteristic of residents In comparison with the data on other cities of Russia of Usolye Sibersk in the Irkutsk Region as it is for and other countries, residents of Chapaevsk have Chapaevsk residents. considerably higher human milk levels of the more Comparative analysis of dioxin concentrations in the toxic congeners ± 2,3,7,8-TCDD, 1,2,3,7,8-PeCDD, blood of female workers at the chemical factory in 1,2,3,4,7,8-HcCDD, and also octa-dioxins. The results Chapaevsk and workers at other dioxin-generating of the dioxin analysis in human milk from Chapaevsk production facilities in various countries shows that residents and other populated areas are presented in some of the highest levels of these toxic substances are

Table 11 Concentrations of PCDD and PCDF in human milk in various countries )TEF, Ahlborg et al., 1994) in pg TEQ/g fat Country, city, year n PCDD/PCDF Source Russia City with Chlorine Production Chapaevsk, 1998 40 43.3 Revich et al. )1999) Usolye-Sibersk, 1998 11 23.7 Schecter et al. )1999a,b,c) Dzerzhinsk 10 10.7 Traag and Yu®t )1997) Volgograd 10 9.1 Traag and Yu®t )1997) Bashkiria Amirova et al. )1999) 8 cities 43 15.9 Rural area 23 12.8 Large Cities without Chlorine Production±Irkutsk, Novosi- 62 From 8 to 17 Schecter et al. )1990), Schecter bersk, Nizhniy Taigil, Murmansk, Angarsk, Cheremkhovo et al. )1999a,b,c), Traag and Yu®t )1997), Amirova et al. )1999) and Mamontova et al. )1999)

Kazakhstan Hooper et al. )1999) 1. Areas close to cotton ®elds 16 74.0 2. Areas more than 10 kilometers from cotton ®elds 24 30.1 Uzbekistan 9 24.2 Hooper et al. )1999) Ukraine 1. Cities not indicated 5 10.0 Schecter et al. )1999a,b,c) 2. Kiev- city center 5 11 Sova and Snoz )1996) 3. Industrial districts 5 13 Sova and Snoz )1996) Lithuania Liem and Theelen )1997) 1. Vilnius 12 13.3 2. Palanga 12 16.6 Netherlands, various cities 17 23.5 Liem and Theelen )1997) Cities of Europe: Albania )Tirana), Austria )Vienna), Croatia 67 3.5± 4.7 Liem and Theelen )1997) )Zagreb), Czech Republic )Kladno), Hungary )Budapest), Germany )Berlin) Belgium )Brussels, Brabant. Lezh) 34 20.8±27.1 Liem and Theelen )1997) Denmark 7 regions 48 15.2 Liem and Theelen )1997) Italy, 4 regions 59 29.0 Schecter et al. )1999a,b,c) Spain, Biscay 19 19.4 Schecter et al. )1999a,b,c) Great Britain )Birmingham, Glasgow) 43 17.0 Schecter et al. )1999a,b,c) Finland, Helsinki 10 21.5 Schecter et al. )1999a,b,c) USA, Los Angeles 21 16.6 Schecter et al. )1990) Canada 225 10.8±21.1 Liem and Theelen )1997) Japan 125 16.0 Iida et al. )1999) South Korea, Seoul 11 24.1 Shin et al. )1999) 962 B. Revich et al. / Chemosphere 43 62001) 951±966

Table 12 Concentrations of PCDD and PCDF in the serum of workers of some dioxin-generating production processes, pg/g lipids, TEQ WHO Country, city, years Type of production n Average concentration Source Russia: Chapaevsk, Production processes of hexachloro- 4 412.4 1997 cyclohexane, hexachlorobenzol, pentachlorphenolata sodium Ufa, 1996±1997 2,4,5-T 41 157 Amirova )1999) 2,4,5-TSR 4 490 2,4-D 24 243 Chlorbenzol 6 128 Shelekhovo, 1998 Fire®ghters 5 12.9 Schecter et al. )1999a,b,c) Austria, 1996 2,4,5-T, production stopped in 1973 50 465.5 Neuberger )1999) Germany: Hamburg Former workers from production of 290 104.7 Manz and Paepke herbicides and insecticides )1999) Japan, 1997 Workers from municipal waste in- 94 39.7/11.3±831.9/ Watanabe et al. cinerator )1999) observed in Chapaevsk. The highest concentration of sue sarcoma. But the study is continuing in an attempt dioxin was found in workers in the production of 2,4,5-T to overcome existing limitations: inadequate individual at the Khimprom factory in Ufa )Table 12). exposure data, short latency period, and small popula- The comparison of data on dioxin concentrations in tion size for certain cancer types )Bertazzi and Ilaria the blood of the residents of Chapaevsk will allow us to Bernucci, 1998). draw the following conclusions: Organochlorines a€ect or mimic sex hormones that 1. In comparison with the population of other cities of may be mentioned as causes of some types of cancer. Russia and a few countries, there are elevated dioxin Furthermore, they are excreted in breast milk, suggest- and furan concentrations in the blood of the residents ing that ductal and other cells in the breast are exposed of the area close to the chemical factory in directly. The results of epidemiological research on en- Chapaevsk. vironment risk factors and breast cancer vary, but in 2. Inside the city, there is a sharp di€erence in the levels certain case-control studies the role of these factors has of dioxin in the blood of the general population, been con®rmed )Kelsey and Bernstein, 1996; Laden and living close to the factory and far from the factory Hunter, 1998). Hunter et al. )1997), Lopez-Carillo et al. )Table 13). )1997) and van't Veer et al. )1997) showed no associa- In recent years, more studies have in fact demon- tion of organochlorines to breast cancer development. It strated small but statistically signi®cant increases in the is dicult to identify the unexposed population with number of cancer cases in groups exposed many years low-level exposure. The number of cases of breast cancer ago to high doses of dioxins. The focus has been on seems to be higher among wives of ®shermen on the east chemical industry workers. Among Seveso and Taiwan coast of Sweden )who eat relatively more Baltic ®sh with victims, two decades after the accidents in 1970s slight high levels of POPs) than the corresponding group on upward trends in cancer incidence have begun to the west coast )Bernes, 1998). Signi®cant elevated rates emerge. The World Health Organization's International of breast cancer have been found across the USA in Agency for Research of Cancer )IARC) recently decided Cape Cod, Massachusetts, Central Illinois, and San to include the dioxin congener TCDD to the list of Francisco. substances that can cause cancer in humans )Bernes, At the chemical factory in Chapaevsk, 560 people 1998). The fact that even in very small doses, dioxins are were exposed to dioxin and 35% of them were women. able to cause cancer in rats and mice has been reported The average term of employment is 11 Æ 0:5 years. It in many experimental studies. The results of incidence would be extremely interesting to assess the impact of and mortality analysis in Chapaevsk show an increased dioxins on this cohort of workers. occurrence of cancer at all sites including lung, gastro- It can be assumed that high levels and long-term intestinal, urinary organs, female breast cancer, cervix, dioxin pollution in¯uence to a certain degree the high leukemia and lymphoma. level of incidence and mortality from female breast Long-term investigations on cancer incidence and cancer. Many of these compounds bioaccumulate in the mortality were designed and implemented in Seveso. In food chain and persist in the human body and in the the ®rst decade after the accident, an incidence study environment. The presence of dioxins in breast milk of showed an increase in cancer at the gastrointestinal sites, women of Chapaevsk is higher than in majority of other lymphatic and haemopoietic neoplasms, and in soft tis- cities of Russia and other countries. Previous studies B. Revich et al. / Chemosphere 43 62001) 951±966 963

Table 13 Concentration of PCDD and PCDF in the blood of the residents of Chapaevsk and a few other cities, pg TEQ/g lipids Country, city, year Number of samples Average concentration Source Russia, Chapaevsk: 1997, 1±3 km 6 75.2 Revich et al. )1999) 5±8 km 4 24.5

Bashkiria Amirova )1999) 1. Industrial cities 124 39.8 2. Small cities 138 25.0 3. Rural areas 102 24.8

Irkutsk Oblast Schecter et al. )1999a,b,c) 1. Sayansk 1 37.3 2. Baikalsk 8 20.0 3. Angarsk 5 14.8

Sverdlovsk Oblast Amirova and Kruglov )1998) 1. Yekaterinburg 115 64.4 2. Kirovgrad 33 40.5 3. Kamensk-Uralsk 35 25.8 4. Nizhniy Taigil 34 21.7 Chuvashia, Novocheboksarsk 14 12.0 Amirova and Kruglov )1998) Saint Petersburg 60 29.8 Amirova and Kruglov )1998) Germany, 1999 30 18.2 Papke et al. )1999)

USA, 1996 100 30.6 Schecter and Papke )1998) 1. Residents near the Great Lakes 39 39.4 Anderson et al. )1998) 2. Control group in Arkansas 70 20.4

Italy, Seveso, 1998 Measured Calculation at Landi et al. )1996) conc. moment of accident 1. Zone of maximum contamination 7 53 230 2. Zone of medium concentration 51 11 47 3. Outside zone of contamination 52 4.9 ±

Spain Gonzalez et al. )1999) 1. 0.5±1.5 km from MWI 104 16.7 )I-TEQ) 2. 3.0 km, 1997 97 16.7 )I-TEQ)

Japan: 1. Furuoka 63 16.0 Matsueda et al. )1999) 2. Not indicated 30 15.0 Iida et al. )1999)

Vietnam Schecter et al. )1999a,b,c) 1. South 433 35 2. Central 183 57 3. North 82 17

New Zealand 2925 16±23 Bates et al. )1999) 964 B. Revich et al. / Chemosphere 43 62001) 951±966 have not revealed as high levels of organochlorines in carrying out this work, the Director of the Health Care breast milk and in blood, as in the women of Chapaevsk. Administration for the city, Vladimir Zeilert, has ac- The incidence rates are much higher in all age groups tively assisted us. We are also grateful to Jennifer Adibi from the age of 35±55 years. The observed number of and Dr. Russ Hauser of the Harvard School of Public deaths from breast cancer is signi®cant, as it is two times Health for their help in preparing this publication. greater than the expected number of deaths for Samara Region. This veri®es the need to study environmental risk factors and female breast cancer in Chapaevsk. References Only long-term prospective studies on a large popu- lation that cover two generations will be able to resolve Ahlborg, U.G., et al., 1994. 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