Sex ratios of children of Russian pesticide producers exposed to dioxin. (Childrens's Health Articles).We investigated the sex ratio of children of pesticide workers who produced the biocide biocide (bī`əsīd'), synonym for pesticide. trichlorophenol trichlorophenol a wood preservative with fungistatic activity. Causes poisoning as with pentachlorophenol. and the herbicide herbicide (hr`bəsīd'), chemical compound that kills plants or inhibits their normal growth. A herbicide in a particular formulation and application can be described as selective or nonselective. 2,4,5-trichlorophenoxy acetic acid acetic acid (əsē`tĭk), CH3CO2H, colorless liquid that has a characteristic pungent odor, boils at 118°C;, and is miscible with water in all proportions; it is a weak organic carboxylic acid (see carboxyl group). from 1961 to 1988 in the city of Ufa, Bashkortostan, Russia. We measured exposure of the two related cohorts to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD TCDD tetrachlorodibenzodioxin. ) and other dioxins by analyzing 84 blood samples, which produced median TCDD toxic equivalents blood lipid values of 240 ng/kg, which are more than 30 times higher than background or normal exposure from the region. The sex ratio (fraction male) of the combined cohort of 227 children from 150 male and 48 female workers was 0.40, significantly lower (z-test for proportions = 3.21; p < 0.001) than those for the city of Ufa (0.512) and elsewhere worldwide. When we analyzed the sex ratio of the children according to maternal or paternal exposure, we observed a decrease in the number of boys (ratio 0.38) for fathers and a normal number (ratio 0.51) for the mothers. Human exposure of these pesticide producers to high levels of dioxins is associated with the birth of more girls, but only for paternal exposures. Key words: dioxin exposure, Russian chemical producers, sex ratio. Environ Health Perspect 110:A699-A701 (2002). [Online 10 October 2002] http://ehpnet1.niehs.nih.gov/docs/2002/110pA699-A701ryan/abstract.html ********** Workers who produce chlorine-containing chemicals have always been at risk from exposure to and health effects of the persistent and bioaccumulative microcontaminants chlorinated chlorinated /chlo·ri·nat·ed/ (klor´i-nat?ed) treated or charged with chlorine. chlorinated charged with chlorine. chlorinated acids some, e.g. dibenzo-p-dioxins and furans. Historically, the effects of dioxin-like compounds focused on their acute toxicity acute toxicity Pharmacology Illness caused by a single exposure to a toxic substance and carcinogenicity carcinogenicity /car·ci·no·ge·nic·i·ty/ (kahr?si-no-je-nis´i-te) the ability or tendency to produce cancer. carcinogenicity the ability or tendency to produce cancer. , but lately the more subtle and sensitive effects of altered development and reproduction have been recognized (Schecter 1994; U.S. EPA EPA eicosapentaenoic acid. EPA abbr. eicosapentaenoic acid EPA, n.pr See acid, eicosapentaenoic. EPA, n. 2000). This reasoning has been fortified fortified (fôrt  ´fīd),adj containing additives more potent than the principal ingredient. by the report (Mocarelli et al. 1996) of a skewed skewed curve of a usually unimodal distribution with one tail drawn out more than the other and the median will lie above or below the mean. skewed Epidemiology adjective Referring to an asymmetrical distribution of a population or of data offspring ratio (65% girls) from individuals highly exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as a result of an accidental exposure at Seveso in northern Italy in July 1976. Further study of the Seveso cohort revealed that the effect was associated with paternal, not maternal, TCDD exposure (Mocarelli et al. 2000). However, this biased sex ratio has not been consistent among exposed cohorts. Moshammer and Neuberger (2000) reported a small difference of 0.46 in an Austrian worker cohort; Rogan et al. (1999) found a slightly higher value of 0.49 in the Yu-cheng rice oil victims; and Michalek et al. (1998) found no effect for this outcome in the lowly exposed Ranch Hand cohort by American Vietnam veterans who sprayed Agent Orange. In a conflicting study, no effect on the sex ratio was detected in a recent publication (Schnorr et al. 2001) from producers of pesticides in two U.S. cohorts that had high TCDD exposure. The city of Ufa is situated at the eastern edge of Europe in the Bashkortostan Republic of Russia, just west of the Ural Mountains. It was the site of one of the state agrochemical agrochemical Any chemical used in agriculture, including chemical fertilizers, herbicides, and insecticides. Most are mixtures of two or more chemicals; active ingredients provide the desired effects, and inert ingredients stabilize or preserve the active ingredients or aid plants called Khimprom, which has operated since the early 1940s. From 1961 to 1988, over 600 workers in this chemical factory produced 2,4,5-trichlorophenol (TrCP) that was used as a wood preservative wood preservative substances used as dressing for lumber to protect it against mold, insects, pests, fire, etc. Animals housed in pens made of wood which has been treated with wood preservatives may be poisoned by these compounds if they chew the wood. and as an intermediate in the further production of both the germicide germicide (jûr`mĭsīd), chemical substance capable of killing many different types of microorganisms; also called disinfectant. hexachlorophene hexachlorophene /hexa·chlo·ro·phene/ (hek?sah-klor´o-fen) an antibacterial effective against gram-positive organisms; used as a local antiseptic and detergent for application to the skin. and the phenoxy herbicide 2,4,5-trichlorophenoxy acetic acid (2,4,5-T). More than 250 workers produced 2,4,5-T itself for about two years, between late 1964 and the end of 1967. Most of the workers were young men in their early twenties and recently graduated from technical school, but about 13% of the 2,4,5-T and 30% of the TrCP work force were young women. In September 1992, about 25 years after the 2,4,5-T herbicide production had ceased, blood sampling and analysis of about 60 men, women, and children from this factory and the city of Ufa took place. For the 2,4, 5-T producers, the results showed high exposure (Ryan and Schecter 2000) to both TCDD and significant amounts of the equally toxic 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PnCDD). The TCDD blood concentrations were more than 30 times greater than contemporary blood values from the Bashkortostan region. Blood dioxin levels for the TrCP workers were originally obtained from a small sampling in 1992 which indicated a higher overall toxic equivalent (TEQ TEQ Toxicity Equivalent TEQ Time Domain Equalizer TEQ Teacher Education Quarterly TEQ Terra Est Quaestuosa (web-based game, Spanish: Lland is Profitable) TEQ The Evil Quakkers (gaming clan) ) exposure along with the presence of the toxic PnCDD congener congener /con·ge·ner/ (kon´je-ner) something closely related to another thing, as a member of the same genus, a muscle having the same function as another, or a chemical compound closely related to another in composition and exerting . We now describe further blood measurements of these two cohorts which have been made in the intervening years by the Bashkortostan Republic Environmental Centre (BREC BREC Busqueda y Rescate en Estructuras Colapsadas (Guatemala) BREC Recreation and Park Commission for the Parish of East Baton Rouge BRec Bachelor of Recreation BREC Birch Run Expo Center (Birch Run, Michigan) ). Using these additional blood data and in light of the positive association of high dioxin values on a skewed sex ratio for the Seveso cohort in Italy and a lack of such finding in other dioxin cohorts, we report also on the sex ratio for the highly exposed Ufa Russian chemical workers. Materials and Methods Blood lipid exposure. In addition to the more than 60 samples obtained in 1992 whose dioxin values were reported previously (Ryan and Schecter 2000), further whole blood samples were obtained with consent from the cohort workers. These included 20 samples from the 2,4,5-T group taken in 1997-2000 and 23 samples collected in 1997-2001 from the more numerous and longer existing TrCP cohort. These blood samples were analyzed by BREC using sample enrichment and isotope dilution high resolution mass spectrometry mass spectrometry or mass spectroscopy Analytic technique by which chemical substances are identified by sorting gaseous ions by mass using electric and magnetic fields. techniques similar to those used by Ryan and Schecter (2000). Both laboratories have participated in World Health Organization-sponsored interlaboratory studies to check the reliability and consistency of human PCDD/polychlorinated dibenzofurans (PCDF PCDF Polychlorinated Dibenzofurans PCDF Polychlorodibenzofuran PCDF People Centered Development Forum ) determinations. In addition, both laboratories have successfully exchanged laboratory biota biota /bi·o·ta/ (bi-o´tah) all the living organisms of a particular area; the combined flora and fauna of a region. bi·o·ta n. The flora and fauna of a region. samples and compared results as part of normal quality control laboratory procedures. Workers and their children. Company archival records of the individual workers were consulted for age, sex, time of working in the designated shop, and number, sex, and date of birth of children. Verification of company information and additional data on date of birth and sex of all live-born children were obtained by interview either by personal contact or by telephone with each worker or a close relative. Through company information and public meetings, workers from whom blood was not obtained or requested were aware of the health outcome studies. The number and sex of live children born any time after 9 months for which the worker was first employed in either of the two factory shops were used for calculation. Any children born before the parent's employment in either shop were excluded from analysis. Also included were data on any offspring who were born live but were deceased in the interim. Most of the children were born between 1965 and 1972, with smaller numbers born through 1991. The sex ratio or fraction male is the number of males (M) divided by the total number of male and female (F) children--i.e., M/(M + F). Comprehensive data on the number and sex of live births in the years 1959-1996 from the city of Ufa and the Republic of Bashkortostan were available from the State Regional Statistical Department of the Republic. Birth numbers from five individual years approximately spaced between 1959-1996 were averaged for the city of Ufa (34,132 males; 32,563 females; proportion males, 0.512; 105 M/100 F) and used as the basis for comparison to those obtained from the workers. The Republic of Bashkortostan, much larger in population, showed virtually identical sex ratios for the same time period. Statistical treatment. Descriptive statistics descriptive statistics see statistics. (mean, median, variance etc) were conducted on the blood data normalized as to lipid content by standard methods using SigmaStat (SPSS A statistical package from SPSS, Inc., Chicago (www.spss.com) that runs on PCs, most mainframes and minis and is used extensively in marketing research. It provides over 50 statistical processes, including regression analysis, correlation and analysis of variance. Science, Chicago, IL). Differences between the proportions of boys and girls boys and girls mercurialisannua. were performed with the z-test for ratios and [chi square chi square (kī), n a nonparametric statistic used with discrete data in the form of frequency count (nominal data) or percentages or proportions that can be reduced to frequencies. ] analysis of contingency. The z-test was performed with both two-tailed and one-tailed tests with the null hypothesis null hypothesis, n theoretical assumption that a given therapy will have results not statistically different from another treatment. null hypothesis, n being differences in the ratio of boys between the exposed population and the control population from the city of Ufa. Results Table 1 gives the number of workers in both cohorts, their blood lipid exposure expressed in TCDD TEQs, and the number and sex of their children. The sex ratio is compiled for both cohorts separately and combined, and is further separated between mother and father worker. The new blood data by BREC confirmed the even higher TEQ exposure for the TrCP cohort with the appreciable presence of PnCDD. For both cohorts, more than 70% of the worker blood TEQ originates from TCDD, with significant contribution from the equally toxic PnCDD. The TEQ values from blood samples collected many years after initial exposure are one to two orders of magnitude higher than background or normal concentrations from this region or elsewhere worldwide, attesting to the overall elevated exposure to dioxins. The blood lipid TEQ values for the TrCP cohort are more than three times higher than the 2,4,5-T group. However, some of this exposure difference is due to a) the date of blood sampling, which for the TrCP cohort was closer in time to the actual date of chemical production, and b) to the longer time individuals spent in the TrCP shop that manufactured this chemical. When the z-test is used for proportions, the ratio of male children for both cohorts (0.40) is statistically different (z = 3.21; p < 0.001) from normal live births in this region and worldwide (about 105 males for 100 females). Differentiating the children according to either their exposed mother (n = 48) or father (n = 150) shows a further decrease in the number of boys for the fathers (ratio 0.38) and a normal number (ratio 0.51) for the mothers. The ratio of boys for the fathers only is significantly different (z = 3.60; p < 0.001) from those of the control populations. The degree of exposure as indicated by the blood lipid values was virtually the same for the mothers and fathers in both groups. The sex ratio is as low as 0.23 (7 M/23 F) for those fathers from the TrCP cohort with measured blood values (median of 715 ppt ppt abbr. 1. parts per thousand 2. parts per trillion TEQ blood lipid). The sex of the 188 children fathered by the 150 male workers is presented in Figure 1. This histogram histogram or bar graph Graph using vertical or horizontal bars whose lengths indicate quantities. Along with the pie chart, the histogram is the most common format for representing statistical data. shows visually the preponderance of girls over boys. Both of these results--the altered sex ratio and the association with the father and not the mother--are identical to what was found in the Seveso incident (Mocarelli et al. 1996, 2000) and differ from what has been reported for the U.S. chlorophenol cohort (Schnorr et al. 2001). [FIGURE 1 OMITTED] Discussion These results, comprising relatively large numbers of blood exposure values and sizeable numbers of offspring, show that the Ufa workers produced an excess of female children associated with their fathers' exposure to dioxins. Worldwide the ratio of live-born male to total births in the general human population is remarkably constant (James 1996), fluctuating around 0.51 (104-106 boys/100 girls) even when changes are noted with large sample sizes or over long periods of time (Allan et al. 1997). Both the city of Ufa and the surrounding Republic of Bashkortostan have shown this sex ratio in the years 1959-1996. We attribute the exposure to TCDD as the most likely cause of the altered sex ratio. However, in most studies of the association between environmental chemicals and altered sex ratio, humans are exposed to many chemicals. In the Ufa cohort as well as those of Seveso, Italy, and the United States (Schnorr et al. 2001), significant exposure to chlorinated phenols phenols (fēˑ·n  lz),n. and phenoxy pesticides occurred. These compounds have short half-lives in humans, so a retrospective study retrospective study, a study in which a search is made for a relationship between one phenomenon or condition and another that occurred in the past (e.g. of exposure is not possible. However, these less persistent compounds are still candidates as endocrine-disrupting chemicals in these episodes. In this article we present measured blood data on 84 individuals many years after their exposure in chemical manufacturing. We have not attempted to back-calculate to estimate the blood dioxin content at the time of the workers' employment, when their blood levels would have been considerably higher. These estimates usually have a high degree of uncertainty because mostly single blood measurements are available and the rate of elimination of dioxins in humans is nonlinear (Carrier et al. 1995) with short half-lives at higher exposure. In addition, the dates of beginning and ending employment vary among individuals, as does possible and unknown dioxin exposure subsequent to employment. Nevertheless, the effect we show here indicates that dioxins act as endocrine disruptors and cause some type of hormonal imbalance. A plausible biologic explanation for the change in sex ratio is not obvious. Mocarelli et al. 2000 have suggested that early age of exposure of the parent may be a factor. We are unable to test this hypothesis in our study because the mean age of the parents at birth of their children was about 29 (range 20-43) years. Other hypotheses that have been suggested to explain the low sex ratio are an antiandrogenic effect of dioxin that alters sperm transit time transit time the time required for ingesta to pass through the gastrointestinal tract; a shorter transit time is seen in conditions associated with gut hypermotility, such as diarrhea. Delayed passage from any cause results in a longer transit time. , with resultant delay of fertilization of the oocyte oocyte /oo·cyte/ (-sit) the immature female reproductive cell prior to fertilization; derived from an oogonium. It is a primary o. prior to completion of the first maturation division, and a secondary o. (Jongbloet et al. 2002). At present, data to support or refute this explanation are limited. Nor can we offer a causal explanation for the consistency of our results with those of Seveso and for their difference with the U.S. cohort. The chemical exposure of the Russian workers to dioxins was probably somewhat higher than in both the Seveso incident and the U.S. workers, when one considers the time of blood sampling and, for the latter cohort, the number of years working. However, all three cohorts have substantial elevated exposure to TCDD and related compounds. A more plausible explanation for the low sex effect in the Yu-cheng poisoning is available. In that episode, exposure was to heat-degraded PCBs containing elevated levels of PCDFs; but the cohort studied was comprised mostly of women, and indications are that maternal exposure is not critical in sex alteration of these environmental chemicals. The different results among all the described cohorts underline the uncertainty of epidemiology in the study of adverse effects that may be subject to undetected effect modification effect modification Epidemiology An interaction among multiple possible cause-and-effect relationships, where the estimate of the effect of one factor on a disease process depends on other factors in the study . Further study of these groups and of related chemicals is necessary for understanding the effect of chemical exposure on human reproduction.
Table 1. Numbers, TEQ dioxin exposure, and sex of offspring of Russian
chemical producers.
Cohort 2,4,5-T
Workers
No. for whom birth data available/total 88/> 250
Sex (M/F) of workers with birth data (74/14)
Worker exposure
No. blood samples analyzed 55
Sex (M/F) of donors (43/12)
Years since exposure (median) 23
Years worked in shop (median) (5.5)
TEQ (a) (median) 177
(Range) (17-1,930)
TCDD/PnCDD values 124/35
TEQ (TCDD mean values)
Bashkortostan residents
Ufa residents
Children of workers
Born during and after worker exposure 126
No. children by sex (M/F) 52/74
Sex ratio (M/M + F) with both parents 0.41
Fathers only (n) 74
No. children by sex (M/F) 44/66
Sex ratio using fathers 0.40
Mothers only (n) 14
No. children by sex (M/F) 8/8
Sex ratio using mothers 0.50
Sex ratio Ufa city
1959-1996; n = 66,700 exposed children
Cohort TrCP Combined
Workers
No. for whom birth data available/total 110/> 600 198/> 850
Sex (M/F) of workers with birth data (76/34) (150/48)
Worker exposure
No. blood samples analyzed 29 84
Sex (M/F) of donors (22/7) (67/19)
Years since exposure (median) 12 --
Years worked in shop (median) (13)
TEQ (a) (median) 672 243
(Range) (87-8,520) (17-8,520)
TCDD/PnCDD values 40/168 --
TEQ (TCDD mean values)
Bashkortostan residents 27 (4.8)
Ufa residents 47 (17)
Children of workers
Born during and after worker exposure 101 227
No. children by sex (M/F) 39/62 91/136
Sex ratio (M/M + F) with both parents 0.39 0.40 *
Fathers only (n) 76 150
No. children by sex (M/F) 27/51 71/117
Sex ratio using fathers 0.35 0.38 **
Mothers only (n) 34 48
No. children by sex (M/F) 12/11 20/19
Sex ratio using mothers 0.52 0.51
Sex ratio Ufa city 0.512
1959-1996; n = 66,700 exposed children (105 M/lO0 F)
(a) Values in nanograms TEQ per kilogram blood lipid (ppt). * z-test
for proportions = 3.21 (p < 0.001); ** z = 3.60 (p < 0.001).
REFERENCES Allan BB, Brant brant or brant goose, common name for a species of wild sea goose. The American brant, Branta bernicla, breeds in the Arctic and winters along the Atlantic coast. R, Seidel sei·del n. A beer mug. [German, from Middle High German s  del, from Latin situla, bucket.]Noun 1. JE, Jarrell JR. 1997. Declining sex ratios in Canada. Can Med Assoc J 156:37-41. Carrier G, Brunet RC, Brodeur J. 1995. Modelling of the toxicokinetics of polychlorinated dibenzo-p-dioxins and dibenzo-furans in mammalians, including humans. I. Nonlinear distribution of PCDD/PCDF body burden between liver and adipose tissues. Toxicol Appl Pharmacol 131:253-266. James WH. 1996. Evidence that mammalian sex ratios at birth are partially controlled by parental hormone levels at the time of conception. J Theor Biol 180:271-286. Jongbloet PH, Roeleveld N, 6roenewoud HMM HMM heavy meromyosin. . 2002. Where the boys aren't: dioxin and the sex ratio. Environ Health Perspect 110:1-3. Michalek JE, Rahe AJ, Boyle CA. 1998. Paternal dioxin and the sex of children fathered by veterans of Operation Ranch Hand Operation Ranch Hand was a U.S. Military operation during part of the Vietnam War, lasting from 1962 until 1971. It involved spraying an estimated 19 million US gallons of defoliants over rural areas of South Vietnam in an attempt to deprive the Viet Cong of . Epidemiology 9:474-475. Mocarelli P, Brambilla P, Gerthoux PM, Patterson DG Jr, Needham LL. 1996. Change in sex ratio with exposure to dioxin. Lancet 348:409-410. Mocarelli P, Gerthoux PM, Ferrari E, Patterson DG Jr, Kieszak SM, Brambilla P, et al. 2000. Paternal concentrations of dioxin and sex ratio of offspring. Lancet 355:1858-1863. Moshammer H, Neuberger M. 2000. Sex ratio in the children of the Austrian chloracne chloracne /chlor·ac·ne/ (klor-ak´ne) an acneiform eruption due to exposure to chlorine compounds. chlor·ac·ne n. cohort. Lancet 356:1271-1272. Rogan WJ, Gladen BC, Guo Y-LL, Hsu C-C C-C Carbon-Carbon C-C Carotid-Cavernous (relating to the carotid artery and the sinuses) . 1999. Sex ratio after exposure to dioxin-like chemicals in Taiwan. Lancet 353:206-207. Ryan JJ, Schecter A. 2000. Exposure of Russian phenoxy herbicide producers to dioxin. Occup Environ Med 42:861-870. Schecter A, ed. 1994. Dioxins and Health. New York New York, state, United States New York, Middle Atlantic state of the United States. It is bordered by Vermont, Massachusetts, Connecticut, and the Atlantic Ocean (E), New Jersey and Pennsylvania (S), Lakes Erie and Ontario and the Canadian province of :Plenum Press. Schnorr TM, Lawson CC, Whelan EA, Kankovic DA, Deddens JA, Piacitelli LA, et al. 2001. Spontaneous abortion spon·ta·ne·ous abortion n. A naturally occurring termination of a pregnancy. Also called miscarriage. spontaneous abortion , sex ratio, end paternal occupational exposure to 2,3,7,8-tetrachlordibenzo-p-dioxin. Environ Health Perspect 109:1127-1132. U.S. EPA. 2000. Draft Exposure and Human Health Assessment of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) and Related Compounds. Part II. EPA/600/P-00/001Be. Washington, DC:U.S. Environmental Protection Agency Environmental Protection Agency (EPA), independent agency of the U.S. government, with headquarters in Washington, D.C. It was established in 1970 to reduce and control air and water pollution, noise pollution, and radiation and to ensure the safe handling and Office of Research and Development. John Jake Ryan, (1) Zarema Arnirova, (2) and Gaetan Carrier (3) (1) Health Products and Food Branch The Health Products and Food Branch (HPFB) of Health Canada manages the health-related risks and benefits of health products and food by minimizing risk factors while maximizing the safety provided by the regulatory system. , Health Canada, Ottawa, Canada; (2) Environmental Protection Centre of Bashkortostan, Ufa, Bashkortostan, Russia; (3) Departement de Sante environnmentale et sante au travail TRAVAIL. The act of child-bearing. 2. A woman is said to be in her travail from the time the pains of child-bearing commence until her delivery. 5 Pick. 63; 6 Greenl. R. 460. 3. , Universite de Montreal, Montreal, Quebec, Canada Address correspondence to J.J. Ryan, Health Products and Food Branch, Health Canada, Banting 2203D, Ross Avenue, Ottawa K1A 0L2, Canada. Telephone: 613-957-0978. Fax: 613-941-4775. E-mail: jake_ryan@hc-sc.gc.ca Received 9 April 2002; accepted 26 July 2002. |
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