SCIENTIFIC ARTICLES. Dynamics of thyroid cancer incidence in Russia following the Chernobyl accident: eco-epidemiological analysis

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1 SCIENTIFIC ARTICLES Dynamcs of thyrod cancer ncdence n Russa followng the Chernobyl accdent: eco-epdemologcal analyss Ivanov V.K., Tsyb A.F., Gorsky A.I., Maksoutov M.A. Medcal Radologcal Research Center of RAMS, Obnnsk The paper presents the analyss of thyrod cancer ncdence n the terrtores of Russa that were most contamnated after the Chernobyl accdent. Incdence data n the Bryansk, Kaluga, Orel and Tula regons (,9 thousand persons) are used. Informaton on ncdence has been obtaned from regonal oncologcal dspensares (state health nsttutons nvolved n dagnoss and treatment of malgnant neoplasms). Altogether,,99 cases of thyrod cancer are consdered from 9 to 99. Of them, cases were among chldren and adolescents and among the populaton who were chldren and adolescents at the tme of the accdent n 9. The study s performed for both sexes. The study compares the dstrbuton of thyrod cancer cases by age at dagnoss and age at exposure. It has been shown that snce 99 the age structure of the ncdence has changed sgnfcantly wth the growng proporton of cases among chldren and adolescents. The change n the structure occurred due to the radaton factor, specfcally as a result of exposure of thyrod to ncorporated I. A dependence of rsk of cancer on age at exposure has been derved. For chldren of - years at exposure the rsk of nducton of radogenc thyrod cancer s - tmes hgher than n adults. On the average, the rsk co-effcent n chldren and adolescents at the tme of exposure s about tmes hgher than that n adults. The analyss of tme trend n thyrod cancer ncdence has shown that the ncdence rate observed n the perod from 99 to 99 n the age groups up to years s expected to be mantaned n the near future. Introducton As a result of the Chernobyl accdent extensve areas of Russa (more than thousand km ) were affected by the radoactve contamnaton. The most contamnated was the terrtory of western areas of the Bryansk regon where the maxmum densty of 7 Cs sol contamnaton s as hgh as MBq/m. Somewhat lower, yet a rather sgnfcant contamnaton was reported n the Kaluga, Tula and Orel regons. The maxmum sol contamnaton wth 7 Cs n these areas was. MBq/m. The most sgnfcant dstant medcal consequences are exposure of thyrod n the resdents of the contamnated areas to ncorporated I whch enters the body by nhalaton or per orally. Ths problem s partcularly urgent for those resdents of the contamnated areas who were chldren and adolescents durng the exposure, as the rsk of developng cancer (as well as dose) s strongly dependent on the age at exposure. Unfortunately, to date no detaled pcture of I depostons n the terrtory of Russa s avalable, but the maxmum I deposton densty n Bryansk regon s known to be MBq/m, as of May 9. Under these crcumstances t s of partcular mportance to conduct epdemologcal analyss of thyrod cancer ncdence n the populaton of the most contamnated regons of Russa (Bryansk, Kaluga, Tula, Orel). There are a large number of publcatons on radaton nduced thyrod cancers [-]. These publcatons also nclude all necessary references. However, most of these studes focus on the effects of external exposure on thyrod cancer ncdence. The effect of nternal rradaton of the thyrod n chldren and adolescents due to ncorporated to I was studed n references [-7] based on a lmted number of cases (- cases). For these reasons the derved estmates are characterzed by sgnfcant errors. The purpose of the present work s to analyze the dynamcs and structure of thyrod cancer ncdence n four regons of Russa wth the populaton of,9 thousand people n The analyss s based on data of,99 cases of thyrod cancer durng ths perod of tme. Of them, cases were among chldren and adolescents at the tme of dagnoss and 9

2 cases among the populaton who were chldren and adolescents at the tme of the accdent n 9. Snce ndvdual radaton doses cannot be estmated on such a large scale, an eco-epdemologcal method s used. One of the major lmtatons of the approach used s a possble bas n the derved values of radaton rsk due to changng ntensty of screenng of thyrod cancers n the post-chernobyl perod and n the determnaton of controls. For ths reason, the work places partcular emphass to these matters. At the same tme, an advantage of the approach s takng nto account of all detected cases of thyrod cancer n the four most contamnated regons of Russa to estmate ndcators of ncdence n dfferent age groups pror to the Chernobyl accdent and after t. Methods and materals General descrpton of medcal and demographc data The prmary source of demographc nformaton was the data of federal state statstc bodes and regonal statstc commttees. Table shows the demographc characterstcs of the populaton n the Russan regons under consderaton n 9 (at the tme of the Chernobyl accdent). Populaton n the regons of Russa that were studed Table Regon Bryansk Kaluga Tula Orel Total Number of chldren (- years) and adolescents (-7 years), thousand Boys 9 97 Grls Number of adults, thousand s 7 s 9 7 Mean age of populaton s s Table Number of thyrod cancer cases among resdents of the Bryansk, Kaluga, Tula and Orel regons Regon Bryansk Kaluga Tula Orel Total Number of cases among chldren and adolescents at dagnoss (9-9) Boys Grls Number of cases among adults at dagnoss (9-9) s s 7 Number of cases among chldren and adolescents at dagnoss (9-99) Boys Grls Number of cases among adults at dagnoss (9-99) s s Number of cases among chldren and adolescents at dagnoss (99-99) Boys 9 Grls Number of cases among adults at dagnoss (99-99) s s Number of cases among chldren and adolescents at exposure Boys 9 Grls

3 Num ber of cases Grls Boys Age at exposure Fg.. Number of cases as a functon of age at exposure. Number of cases Grls Boys 7 9 Tme snce exposure (years) Fg.. Number of cases as a functon of tme after exposure. Table contans the number of detected cases of thyrod cancers as a functon of regon, tme nterval and age durng dagnoss and age at exposure. These are offcal data of oncologcal dspensares n Bryansk, Kaluga, Tula and Orel regons n charge of regstraton of oncologcal patents n accordance wth regulatons of Mnstry of Health of Russa. A total of,99 cases were detected from 9 to 99. Among them, cases are among females ( cases among grls of -7) and 7 cases among males ( cases among boys of -7). There were cases among persons born n 99-9, who were chldren and adolescents at the tme of exposure (9 boys and grls). Fgures and shows the number of cases among chldren and adolescents at the tme of exposure as a functon of age durng exposure and the tme after exposure. Among the chldren born (after the accdent) from 97 to 99 no cases of thyrod cancer have been reported (the begnnng of the perod s chosen to nclude fetal exposure). The most common knds of cancer among the populaton of the above four regons of Russa n 9-99 were papllary and follcular cancers (% and % n males and 7% and % n females, respectvely, of the total number of cases). Fgure shows the relaton of the frequency of thyrod cancer ncdence n females to that n males n dfferent age groups n Russa and some known cancer regstres [, 9]. In Fgure the value of ths rato s gven for the whole of Russa and for the populaton of the four regons under consderaton. For Russa as a whole the frequency rato attans a maxmum of n the age range of -9 years. For other cancer regstres, the maxmum of the rato occurs n the age range of -9 years. As can be seen from Fgure, the female/male rato of frequency of thyrod cancer n Russa as a whole and the four contamnated regons s n agreement wthn a standard error. The dynamcs of thyrod cancer ncdence n the study regons n comparson wth Russa s presented n Fgures and. Fgure presents a standardzed rato of ncdence wth 9% confdence ntervals (

4 = observed number of cases/expected number of cases) for each regon separately and Fgure - for all four regons altogether. The confdence levels are calculated accordng to []. The dynamcs of the Standard Incdence Rato () n 9-99 n Bryansk, Tula and Orel regons (Fgure ) reveals an nterestng feature. Ths feature s evdent from Fgure showng the dynamcs of the for the four regons. Indeed, n 9-9 the thyrod cancer ncdence, both n males and females, was lower than n Russa (Russa as a whole s taken as control). In 9-9 was <. In the second perod 97-99, as can be seen from Fgures and,, on the average, s more than,.e. the ncdence n the four regons becomes hgher than n Russa as a whole. As the perod s a latent perod for nducton of thyrod cancer by radaton, the growth of ncdence n ths perod can be attrbuted to ntroducton of a specalzed examnaton system n these regons (the screenng effect). As can be seen from Table n the above four regons n the perod 9-9, on the average, 9 cases of thyrod cancers were reported and n 9-99 cases were detected annually (. tmes hgher). It s nterestng to note that n the prevous work on thyrod cancer among Chernobyl accdent emergency workers [] we also demonstrated the screenng effect wth the coeffcent of.. After 99, as can be seen from Fgure, a certan growth of thyrod cancer ncdence n the four regons of Russa under study s observed. /male Russa Belarus USA England Fnland Age group Fg.. /male rato of thyrod cancer ncdence as a functon of age at dagnoss n Russa and usng data of world cancer regstres. Russa Regons(9-99) fem ale/male Age group Fg.. /male rato of thyrod cancer ncdence as a functon of age at dagnoss n Russa as a whole and among the populaton of the four regons.

5 7 Bryansk oblast Kaluga oblast female male female male Calendar years Calendar years Tula oblast 7 Orel oblast female male female male Calendar years Calendar years Fg.. Dynamcs of standardzed thyrod cancer ncdence rato n Bryansk, Kaluga, Tula and Orel regons (raton control - Russa)... Four Regons Calendar year Fg.. Dynamcs of standardzed thyrod cancer ncdence rato n the four regons under consderaton together (raton to control - Russa). Methodology of the study The man dea of the present study s the comparson of age dstrbutons of thyrod cancer cases n

6 exposed and unexposed (control) populatons. The rsks of nducton of radogenc cancers at the same dose and dose rate are known to depend on age at exposure [, ]. For malgnant neoplasms at most stes, the decrease n age at exposure leads to an ncrease n the rsk of cancer. Ths equally apples to radogenc thyrod cancer [-]. The above rsk dependence wll be better defned n case of thyrod exposure to ncorporated I, as n ths case; the thyrod exposure dose wll depend on age at exposure [,, ]. So, nducton of radogenc cancers should change the shape of age dstrbuton of cancers. The regons of Russa under study (Bryansk, Kaluga, Tula and Orel regons) are smlar n geography, demography and soco-economcal development. The data of state statstcs suggest that the sex-age structure of the populaton n the postaccdent perod n the regons under study and Russa n general remaned practcally unchanged. Therefore, t can be expected that dependences of thyrod cancer ncdence on age pror to exposure and n the latent perod of radogenc cancer development wll be close to dependences for the Russa n general. Besdes, t may be assumed that the observed regonal dfference n thyrod cancer ncdence n the regons under study, accurate to a constant factor, does not change the dstrbuton form. Of course, the queston arses as to the qualty of data on thyrod cancer n Russa used as control and on the objectvty of assumptons concernng dstrbuton forms. For analyss of data qualty, we use such nformaton of medcal statstcs n Russa for 99 [] and world oncologcal statstcs [9]. Informaton on thyrod cancer ncdence for major cancer regstres of UK, USA (SEER, whtes), Belarus and Fnland for 9-97 was borrowed from [9]. Fgure 7 shows the dstrbuton densty f ( x ) λ λ = wth respect to age, where λ s ncdence rate n the -the age group of a specfc country; λ s ncdence ndcator n the -th age group of the country selected as control. We took the regstry of UK as a control for the analyss of the completeness of Russan data. Ths control was selected because the cancer regstry of UK s farly representatve (about mllon people) and covers a long observatonal perod (we used data for 97-97) [9, ]. Besdes, the analyss of ncdence dstrbuton by age n the Brtsh regstry n 97-9 and 9-97 has shown a very close agreement n dstrbutons, whch suggests the relablty of ths regstry data. Dfferent age ranges n Fgure 7 (- years for males and - years for females) are due to the data avalable n [9]. Fem ale 7 Russa Belarus USA England(control) Fnland 7 Russa Belarus USA England(control) Fnland Rate relaton Rate relaton Age Age Fg. 7. Densty dstrbuton of thyrod cancer ncdence rato as a functon of age. Wthn the hypothess proposed above about stablty of the forms of the ncdence age dstrbuton, the rato of rates of thyrod cancer ncdence characterzes detectablty of cancer n dfferent age group wth respect to control. It can be seen from Fgure 7 that for most age groups the detectablty s almost dentcal for a gven regstry, though the value s dfferent from the control value, ths dfference can be attrbuted to both the dfference n detectablty levels for the populaton n general and to the dfference n actual ncdence levels. The excepton s dstrbuton for females of Russa. The maxmum (-9 years) and mnmum (- years) rato of ncdences n ths case dffer by a factor of, whle the detectablty wth respect to the control ncreases monotoncally to the age of -9 years, at whch the ncdence accordng to the data of Russan statstcs s maxmum too. The above dstrbutons can be used to estmate a potental effect of n-depth screenng. It s unlkely that the maxmum detectablty of cancer s due to hyper dagnoss. Therefore, the rato of maxmum and mnmum detectablty for a specfc country can serve as an estmate of a potental screenng effect wth respect to the control n dfferent age groups. In addton to dstrbuton densty, we use the functon of dstrbuton by age for analyss of oncologcal nformaton:

7 F( x ) k = = N k = f ( x f ( x k k ) u ) u Where =,,...,N and N s the number of age ntervals; u k s wdth of the k-th age nterval. Unlke for densty, we compensate for possble regonal dfferences n actual ncdence and cancer detectablty n the dstrbuton. Fgure shows one age dstrbuton (up to years) of ncdence rate ratos for dfferent regstres. It s obvous that for the control populaton (UK regstry) the dstrbuton densty wll be unform and the dstrbuton - lnear. The lnear form s convenent for comparson and analyss of cancer data qualty. It can be seen that, by and large, the dstrbutons for males are close (ncludng those for Russa). The excepton s k k, the dstrbuton for the USA populaton. For ths regstry the dstrbuton s close to lnear (detactablty n dfferent age groups s about the same) and the dfference s prmarly due to the shft (lack of data) n the age group of -9 years. For females all dstrbutons, except Russa, are well consstent. The reasons of the dfference n the Russan dstrbuton possbly relate to poor cancer detectablty young age. The smlarty n age structure of ncdence for the regstres under consderaton s also confrmed by the mean age of cancer development u (Table ) derved from the rato: u = to years. λ λ, summaton s made by all ages,, Fracton below specfed age,,,, Russa Belarus USA England(control) Fnland Fracton below specfed age,,,, Russa Belarus USA England(control) Fnland, age, age Fg.. Dstrbuton of thyrod cancer ncdence rato as a functon of age (to years). Mean age of thyrod cancer development accordng to data of dfferent cancer regstres (age to years) Table Countres s s Russa. 9. Belarus..9 UK 9.7. USA. 7.9 Fnland.. As the form of the theoretcal dstrbuton n the populaton, selected as control, s known to be lnear, t s convenent to use the Kolmogorov crteron as a crteron of agreement between the selected and theoretcal dstrbutons [7]. In calculatons of probablty P that the maxmum dscrepancy between the selected dstrbuton F (x) and the theoretcal dstrbuton F(x) n the control populaton wll be not less than the observed one, the value α = D N s used as a parameter. D s defned by the quarter * D = max F ( x ) F( x ) - or n words, the maxmum of the module of dfference between the selected and theoretcal dstrbuton functon and N s the number of age dstrbutons. Calculatons of P for dfferent regstres are presented n Table. As the rsk of nducton of radogenc cancers at thyrod exposure to ncorporated I s strongly dependent on age at exposure and ncreases at young, age we study the qualty of data on ncdence for the age less than years. As s shown n [,, ], for older age the thyrod dose s practcally ndependent of age and determned by the amount of ncorporated radonucldes only. The dstrbuton functons for

8 ncdence ratos n ths range and P values are presented n Fgure 9 and Table. It can be seen from the data presented thus, that for females n the Russan populaton the dstrbuton n the age range - years s n good agreement wth the control and most of other regstres. For males the agreement s not that good, whch s probably because of rare cases of cancers. However, the value of probablty P for ncdence dstrbuton among males of Russa s close to unty (.99). Most of the regstres under consderaton do not nclude data on ncdence for the range of - years, n whch the effect of radaton exposure to the thyrod may be maxmum except for nformaton on boys n the UK regstry and Russan data obtaned for the whole populaton of Russa (ths age group ncludes about mllon people). The comparson of Russa data wth the data of UK regstry shows that the value P for the range - years s rather consderable:.. The above results show that n the age range to years the data on thyrod cancer ncdence ncluded n the state medcal statstcs of Russa can be used as a control n ths study. Herenafter, control wll be understood as one Russan populaton. P probablty values for dfferent regstres Table Sex s s Age nterval Russa Belarus USA Fnland ,, Fracton below specfed age,,,, Russa Belarus USA England(control) Fnland Fracton below specfed age,,,, Russa Belarus USA England(control) Fnland, age, age Fg. 9. Dstrbuton of thyrod cancer ncdence rato as a functon of age (to years). Results The data on thyrod cancer cases n 9-99 n the terrtores under study were represented as a matrx M j, ndex s age at dagnoss or age range and j s tme after exposure. Each matrx element s the rato of thyrod cancer rate n the age group under study at a certan tme moment and control - the populaton of Russa λ. j c, j n, j, where c,j s the number of cases at age n j years after exposure; n,j s number of age group n j years after exposure; λ,j s thyrod cancer rate n Russa. Two tme ntervals were consdered: the frst perod from 9 to 99 ncluded a pre-accdent tme perod from 9 to 9 and the latent perod of years from 9 to 99 nclusve. Ths was assumed to be the perod of spontaneous cancers. The second (postlatent) perod covered from 99 to 99 when radogenc cancers could be nduced. The age scale for ths perod starts from years to exclude chldren born after the accdent. The correctness of dvdng nto the above tme ntervals s confrmed by the dynamcs of standardzed ncdence rato () of thyrod cancer n the regons under study as compared to Russa (Fgure ). The results of calculatng dstrbutons of ncdence relatons n the regons under study and Russa as a functon of age (age at dagnoss) and calendar perod are shown n Fgure. It can be seen that after 99 a radcal change occurred n the age structure of thyrod cancer ncdence for the consdered age range and the dstrbuton n ths tme perod dffers consderably from the Russan one. The curve shape n the perod after 99 (above the Russan dstrbuton)

9 reflects a consderable ncrease n ncdence at younger age as compared to Russa. On the other hand, for older age the dstrbutons n the tme perods under consderaton are about dentcal, for example, for females of - years (Fgure ). Ths result s confrmed by for all the regons that are consdered as functon of age at dagnoss, as s shown n Fgure. Thus, n the post-latent perod, a radcal charge n age structure of thyrod cancer ncdence occurs for chldren and adolescents.,, Fracton below specfed age,9,,7,,,,,, 9-99 (p=.) Control (p=.) Fracton below specfed age,9,,7,,,,,, 9-99 (p=.9) Control (p=.), Age at dagnoss, Age at dagnoss Fg.. Dstrbuton functon for thyrod cancer ncdence rato as a functon of age and sex., Fracton below specfed age,,,, (p=.) Control 9-99 (p=.9), Age at dagnoss Fg.. Dstrbuton functon for thyrod cancer ncdence rato among females as a functon of age (- years). 7

10 Age at dagnoss Age at dagnoss - - Fg.. dstrbuton as a functon of age at dagnoss. If ths s a consequence of radaton exposure to the thyrod, then changes n age structure of ncdence should be maxmum for those who were chldren and adolescents at exposure tme. To prove ths statement we use two tme ntervals: the frst m=9 years (9 to 99) and n= years (99 to 99). Let us consder the rato of observed and expected (n Russa n general) ncdences n the consdered tme ntervals among ndvduals of age at the begnnng of each tme nterval: observed RR = = expected k λ k c, + k, + k n, + k, k=,,...,m for the frst observatonal, k=,,...,n for the second, and (+k) s age dagnoss. The quantty of RR for ndvduals of age n 9 s an estmate of relaton of relatve rsk of nducton of radogenc cancer and age at exposure. Fgure presents the results of calculatng the rsk of nducton of radogenc thyrod cancer n chldren and adolescents wth respect to adults wth 9% confdence ntervals. The rsk dstrbuton s normalzed to the mean-weghted rsk among adults wth consderaton of sze of correspondng age groups. It should be noted that wth such normalzaton the regonal dfferences n ncdence are compensated. The summaton of RR relaton over all the regons s competent n ths case, as the age structure of populaton s approxmately the same and dstrbutons of RR for each regon wll be smlar wth accuracy to a constant factor descrbng the total contamnaton of the regon wth I. The 9% confdence ntervals have been calculated accordng to []. In [,, ] the relaton of thyrod dose D and unt actvty of ncorporated I has been derved as a functon of age at the tme of the Chernobyl accdent. It has been shown that the dfference n absorbed doses of younger age groups can occur earler than at the age of - years at exposure. The dstrbuton of dose D s also shown n Fgure. The dose s normalzed to unty at age at exposure - years. Relatve rsk, Dose Dose Rsk Relatve rsk, Dose Dose Rsk Age at exposure Age at exposure -9 - Fg.. Ratos of rsks (RR) and doses (D) as a functon of age at exposure and calendar perod. It can be seen that the relatons for both sexes n the perod of spontaneous cancers are close to unty and dffer sgnfcantly from unty n the assumed perod of nducton of radogenc cancers (99-99)

11 for chldren and adolescents. The ponts on the plot are shfted to reveal the bas n the values. The shape of the curve of relatve rsk n post latent perod s n good agreement wth the dose rato. As s seen from Fgure, the relatve rsk of nducton of radogenc cancer for chldren of - years age at exposure s - tmes and for those of -9 years - - tmes hgher the rsk for adults n the consdered perod The values of rsk for both sexes are approxmately the same, whch s n agreement wth result of [-, ]. The comparson of the presented dstrbutons of relatve rsk and dose dstrbuton leads us to conclude that the excessve rsk among chldren and adolescents n the consdered tme perod after exposure s prmarly due to a hgh dose, rather than an ncreased radaton senstvty. The above results gve enough grounds to assume that the change n the age structure of thyrod cancer ncdence between 99 to 99 s attrbuted to the radaton factor. A convncng evdence of ths s the fact that among the chldren born after 97 fallng n the age range of -9 years at dagnoss no thyrod cancer cases have been detected as compared to 7 cases among chldren born pror to the accdent and fallng n the same age range after 9, gven smlar screenng depth and coverage. Clearly, t s mportant to study tme trends n thyrod cancer ncdence. Fgure shows lnear trends (wth 9% confdence ntervals) n cancer ncdence as a functon of age at exposure and calendar perod. In calculatons we used a standard procedure of the weghted least square method. To assgn a larger weght to observatons wth a lesser varance a weghtng factor n nverse proporton to varance was used. As follows from the fgure, the lnear trend n the frst perod (9-99) s close to zero n most age groups and s more than zero n the post latent perod, though the statstcally sgnfcant dfference s reported n the group - for boys and n the group -9 for grls. The presented results make us to conclude that at least n the near future one should not expect a notceable ncrease n thyrod cancer ncdence rate n the age groups under study Trend Trend Age at exposure Age at exposure - Fg.. Tme trend n thyrod cancer ncdence as a functon of age at exposure. Dscusson and concluson In concluson, let us formulate agan the man results: - the analyss of one age dstrbuton of thyrod cancer cases based on Russan statstcs and major foregn cancer regstres shows that n ecoepdemologcal study data of thyrod cancer ncdence for the entre Russa can be taken as control n the age range - years; - t has been establshed that of thyrod cancer ncdence n Bryansk, Tula and Orel regons n relaton to control s characterzed by statstcally sgnfcant growth snce 99 on completon of the latent perod; - there s a major change n the age structure of ncdence snce 99 due to the ncrease n thyrod cancer ncdence n chldren and adolescents; - the hghest rsk of developng thyrod cancer has been found n chldren up to years at exposure (for them the rsk s - tmes hgher than that for adults); - the rsk for chldren born pror to the Chernobyl accdent s n good agreement wth the age dependence of thyrod doses from ncorporated I; - the screenng effect wth the coeffcent. has been establshed for thyrod cancer; - no thyrod cancers were detected n chldren born after the Chernobyl accdent. Thus, the eco-epdemologcal analyss of thyrod cancer ncdence n the terrtores of Russa sgnfcantly contamnated after the Chernobyl accdent ndcates convncngly the radaton nature of the detected cancers n chldren and adolescents. At the same tme, some mportant problems reman unresolved related to estmaton of radaton doses and ther uncertantes, determnaton of dose dependence n nducton of thyrod cancers, nfluence of factors modfyng radaton effects (odne endema, genetc predsposton). References

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