Risk of Cancer in an Occupationally Exposed Cohort with Increased Level of Chromosomal Aberrations.We used cytogenetic cytogenetic /cy·to·ge·net·ic/ (-je-net´ik) 1. pertaining to chromosomes. 2. pertaining to cytogenetics. cytogenetic pertaining to or originating from the origin and development of the cell. analysis to carry out a cohort study A cohort study is a form of longitudinal study used in medicine and social science. It is one type of study design. In medicine, it is usually undertaken to obtain evidence to try to refute the existence of a suspected association between cause and disease; failure to refute in which the major objective was to test the association between frequency of chromosomal aberrations Noun 1. chromosomal aberration - any change in the normal structure or number of chromosomes; often results in physical or mental abnormalities chromosomal anomaly, chromosonal disorder, chrosomal abnormality and subsequent risk of cancer. In spite of the extensive use of the cytogenetic analysis of human peripheral blood lymphocytes Peripheral Blood Lymphocytes (PBL): These are the mature lymphocytes (small white immune cells) that are found circulating in the blood, as opposed to organs, such as the lymph nodes, spleen, thymus, liver or bone marrow. These cells consist of T cells, NK cells and B cells. in biomonitoring of exposure to various mutagens and carcinogens Mutagens and carcinogens A mutagen is a substance or agent that induces heritable change in cells or organisms. A carcinogen is a substance that induces unregulated growth processes in cells or tissues of multicellular animals, leading to cancer. on an ecologic level, the long-term effects of an increased frequency of chromosomal aberrations in individuals are still uncertain. Few epidemiologic studies epidemiologic study A study that compares 2 groups of people who are alike except for one factor, such as exposure to a chemical or the presence of a health effect; the investigators try to determine if any factor is associated with the health effect have addressed this issue, and a moderate risk of cancer in individuals with an elevated frequency of chromosomal aberrations has been observed. In the present study, we analyzed data on 8,962 cytogenetic tests and 3,973 subjects. We found a significant and strong association between the frequency of chromosomal aberrations and cancer incidence in a group of miners exposed to radon, where a 1% increase in frequency of chromosomal aberrations was followed by a 64% increase in risk of cancer (p [is less than] 0.000). In contrast, the collected data are inadequate for a critical evaluation of the association with exposure to other chemicals. Key words: cancer incidence, chemical mutagens, chromosome aberrations Chromosome aberration Any numerical or structural change in the usual chromosome complement of a cell or organism. HeteroploidyNumerical changes (heteroploidy) are of two types, polyploidy and aneuploidy. , radon, risk. Environ Health Perspect 109:41-45 (2001). [Online 12 December 2000] http://ehpnet1.niehs.nih.gov/docs/2001/109p41-45smerhovsky /abstract.html Cytogenetic analysis of peripheral blood lymphocytes (PBLs), a sensitive assay to detect exposures to mutagens and carcinogens in occupational settings, has been used in the Czech Republic Czech Republic, Czech Česká Republika (2005 est. pop. 10,241,000), republic, 29,677 sq mi (78,864 sq km), central Europe. It is bordered by Slovakia on the east, Austria on the south, Germany on the west, and Poland on the north. since 1975. Its validity at an ecologic level has been confirmed by numerous biomonitoring studies (1-10). Cytogenetic analysis is a valuable tool widely applied in the field of occupational health in the Czech Republic. Since 1975, several thousand employees exposed to carcinogens Carcinogens Substances in the environment that cause cancer, presumably by inducing mutations, with prolonged exposure. Mentioned in: Colon Cancer, Rectal Cancer , mostly in chemical industries, have been assayed, many of them repeatedly. This has made it possible to assemble a retrospective cohort large enough to carry out an epidemiologic study in which the major objective is to test for an association between the frequency of chromosomal aberrations (CAs) and a subsequent risk of cancer. In spite of the extensive use of the cytogenetic analysis in biomonitoring of exposure on an ecologic level, the long-term effects of an increased frequency of CAs in individuals are still uncertain. Only a few epidemiologic studies have attempted to address the problem of the predictive value pre·dic·tive value n. The likelihood that a positive test result indicates disease or that a negative test result excludes disease. predictive value a measure used by clinicians to interpret diagnostic test results. of the CA assay in PBLs. A modest increase in total cancer incidence rate [incidence ratio = 2.08; 95% confidence interval confidence interval, n a statistical device used to determine the range within which an acceptable datum would fall. Confidence intervals are usually expressed in percentages, typically 95% or 99%. (CI), 1.26-3.40] was observed in individuals assigned to the high CA frequency category in the Nordic cohort (11-14). The results of the Italian cohort (14-16) suggest an association between the frequency of PBL PBL Problem-Based Learning PBL Phi Beta Lambda PBL Performance Based Logistics PBL Planetary Boundary Layer PBL Publishing and Broadcasting Limited (Australia) PBL Philippine Basketball League PBL Peripheral Blood Leukocyte CAs and cancer mortality rates The introduction to this article provides insufficient context for those unfamiliar with the subject matter. Please help [ improve the introduction] to meet Wikipedia's layout standards. You can discuss the issue on the talk page. . In that case, the mortality ratio for individuals with a high frequency of CAs in PBLs was estimated to be 2.56 (95% CI, 1.35-4.86) for total cancer, 4.2 (95% CI, 1.14-4.38) for lung cancer lung cancer, cancer that originates in the tissues of the lungs. Lung cancer is the leading cause of cancer death in the United States in both men and women. Like other cancers, lung cancer occurs after repeated insults to the genetic material of the cell. , and 4.36 (95% CI, 1.18-11.1) for cancers of lymphatic lymphatic /lym·phat·ic/ (lim-fat´ik) 1. pertaining to lymph or to a lymphatic vessel. 2. a lymphatic vessel. lym·phat·ic adj. and hematopoietic hematopoietic /he·ma·to·poi·et·ic/ (-poi-et´ik) 1. pertaining to hematopoiesis. 2. an agent that promotes hematopoiesis. hematopoietic 1. pertaining to or affecting the formation of blood cells. tissues (14-16). Also, in a nested case-control study A nested case-control study is a type of study design where new case controls are applied into cohorts which were defined before the study begins. Compared with case-control study, nested case-control study can reduce 'recall bias' and temporal ambiguity, and compared with carried out in a blackfoot endemic area Endemic area A geographical region where a particular disease is prevalent. Mentioned in: Leprosy, Scrub Typhus , Liou et al. (17) found a statistically significant association between chromosome type-aberrations and cancer. Kleinerman et al. (18) noted a correlation between the CA frequency in PBLs and cancer risk in women who received different therapeutic doses of ionizing radiation i·on·i·zing radiation n. High-energy radiation capable of producing ionization in substances through which it passes. Ionizing radiation . Recently published outcomes of the case-control study case-control study, n an investigation employing an epidemiologic approach in which previously existing incidents of a medical condition are used in lieu of gathering new information from a randomized population. nested within the Nordic and Italian cohorts confirmed previous outcomes; furthermore, Bonassi et al. (19) found that the association between the CA frequency and cancer did not appear to be modified by sex, age, or time since the CA assay. Because better understanding of the nature of the relationship of CA frequency in PBLs to cancer risk is not only a scientific issue but also a matter of public health concern, we chose to discuss the results of ongoing epidemiologic research in the Czech Republic. Contrary to previously published studies, in the Czech cohort, we could treat the frequency of CAs as a continuous variable. Furthermore, in addition to the variables such as age at cytogenetic analysis, time since testing, and sex, we could control for the type of occupational exposure. Finally, as far as power considerations are of interest, the present study is based on the largest study population hitherto studied. Methods Study Population The study base consists of individuals examined between May 1975 and October 1998 for the frequency of CAs in PBLs in four cytogenetic laboratories (the Cytogenetic Laboratory of the South Moravian Regional Institute of Hygiene, the Cytogenetic Laboratory of the North Bohemian Regional Institute of Hygiene, the Cytogenetic Laboratory of the Municipal Institute of Hygiene at Brno, and the Cytogenetic Laboratory of Institute of Hygiene of the Capital, Prague). The subjects were selected for cytogenetic analysis because of their exposures to various occupational mutagens and carcinogens. Radon. The radon group consists of underground miners exposed to radon gas in one ore mine. Participants were examined for the CA frequency in PBL in May 1975-December 1990. Radiation. The radiography radiography: see X ray. ward group consists of staff of the X-ray and radiotherapeutic ra·di·o·ther·a·peu·tic adj. Relating to radiotherapy or to radiotherapeutics. wards. Subjects were examined in February 1989-August 1998. Cytostatic cytostatic /cy·to·stat·ic/ (sit?ah-stat´ik) 1. suppressing the growth and multiplication of cells. 2. an agent that so acts. cy·to·stat·ic adj. 1. drugs. The cytostatic drug group consists of personnel exposed during cytostatic drug production and medical personnel who handled cytostatics. They were examined in October 1981-October 1998. Bis(chloromethyl) ether ether, in chemistry ether, any of a number of organic compounds whose molecules contain two hydrocarbon groups joined by single bonds to an oxygen atom. . The bis(chloromethyl) ether (BCME BCME Bis(Chloromethyl) Ether BCME Beverage Can Makers Europe BCME Battle Command & Mission Execution (subset of Future Combat Systems) ) group includes workers exposed to BCME in one chemical plant. Subjects were examined November 1975-November 1987. Coal gasification Coal gasification The conversion of coal or coal char to gaseous products by reaction with steam, oxygen, air, hydrogen, carbon dioxide, or a mixture of these. . The coal gasificication group is composed of workers who were exposed to by-products of hard pressure coal gasification in one gasworks gas·works pl.n. (used with a sing. verb) A factory where gas for heating and lighting is produced. Also called gashouse. gasworks Noun a factory in which coal gas is made . They were examined January 1980-May 1992. Polyaromatic hydrocarbons hydrocarbons (hīˈ·drō·kärˑ·b  nz),n. . Members of the polyaromatic hydrocarbon hydrocarbon (hī'drōkär`bən), any organic compound composed solely of the elements hydrogen and carbon. The hydrocarbons differ both in the total number of carbon and hydrogen atoms in their molecules and in the proportion of hydrogen (PAH PAH, PAHA aminohippuric acid. PAH abbr. para-aminohippuric acid PAH 1 Polycyclic aromatic hydrocarbon, see there 2. Pulmonary artery HTN ) group were workers who had been exposed to different PAHs generated mostly by burning processes. They were examined April 1983-October 1990. Nonexposed. The nonexposed matched referent ref·er·ent n. A person or thing to which a linguistic expression refers. Noun 1. referent - something referred to; the object of a reference group is made up of a small group of subjects who were examined January 1981-October 1998. Other chemicals. The other chemicals group includes individuals exposed to miscellaneous chemicals or mixtures of chemicals for whom the numbers of participants were too small to create meaningful strata. These subjects were examined from July 1978 to October 1998. We retrieved data on 4,288 individuals from laboratory records. Because of insufficient personal identification, 231 (5.39%) were excluded. Furthermore, we did not include 28 (0.65%) subjects with cancer onset before the date of cytogenetic analysis and 56 (1.31%) subjects with [is less than] 100 metaphases scored, leaving 3,973 (92.66%) subjects in the study. All subjects were at least 17 years of age at the date of cytogenetic analysis. Because many of the subjects included in the study were repeatedly examined for the frequency of CAs, altogether 8,962 cytogenetic tests were available for the epidemiologic analysis. Basic descriptive characteristics of the cohort are presented in Tables 1-3.
Table 1. Distribution of the chromosomal aberrations.
Percentiles of CA
No. of
Exposure subjects 10th 50th 90th
Radon 236 1.50 2.38 4.00
Radiography wards 73 1.00 2.00 5.00
BCME 244 1.23 2.66 4.67
Cytostatic drugs 1,297 0.67 2.00 4.00
Coal gasification 217 1.00 2.00 4.00
PAHs 365 1.00 2.00 5.00
Referents 336 0.00 2.00 4.00
Other chemical substances 1,205 0.00 2.00 5.00
Total 3,973 1.00 2.00 4.25
Table 2. Distribution of sex, cases, and deaths.
Cases
No. of Percent Percent
Exposure subjects of total male No. Percent
Radon 236 5.9 97.0 33 14.0
Radiography wards 73 1.8 30.1 3 4.1
BCME 244 6.1 87.7 12 4.9
Cytostatic drugs 1,297 32.6 16.6 13 1.0
Coal gasification 217 5.5 87.6 16 7.4
PAHs 365 9.2 91.8 7 1.9
Referents 336 8.5 45.2 15 4.5
Other chemical 1,205 30.3 63.6 45 3.7
substances
Total 3,973 100.0 53.4 144 3.6
Deaths(a)
Exposure No. Percent
Radon 27 11.4
Radiography wards 0 0.0
BCME 9 3.7
Cytostatic drugs 3 0.2
Coal gasification 10 4.6
PAHs 15 4.1
Referents 6 1.8
Other chemical 24 2.0
substances
Total 94 2.4
(a) Deaths from causes other than cancer.
Table 3. Distribution of age at testing and the length of follow-up.
Age at testing Follow-up
(years) (person-years)
No. of
Exposure subjects 10th 50th 90th 10th 50th 90th
Radon 236 29 38 54 9 17 22
Radiography wards 73 24 40 52 3 9 10
BCME 244 22 31 47 13 18 22
Cytostatic drugs 1,297 21 33 51 1 4 11
Coal gasification 217 27 39 52 8 13 17
PAHs 365 24 38 50 9 12 15
Referents 336 22 36 51 1 10 15
Other chemical 1,205 25 38 53 2 10 16
substances
Total 3,973 22 36 52 1 9 17
Total
Exposure follow-up
Radon 3,792
Radiography wards 592
BCME 4,344
Cytostatic drugs 6,771
Coal gasification 2,948
PAHs 4,267
Referents 2,960
Other chemical 12,101
substances
Total 37,775
Cytogenetic Analysis The cytogenetic analysis of human PBLs followed the same protocol in all participating cytogenetic laboratories. We used the conventional modified Hungerford method on short-term cultures for 52 hr, with all cells being in the first division. The peripheral blood peripheral blood Cardiology Blood circulating in the system/body was collected by venipuncture venipuncture /veni·punc·ture/ (ven?i-pungk´chur) surgical puncture of a vein. ve·ni·punc·ture or ve·ne·punc·ture n. in heparinized tubes, and whole-blood cultures were established from the collected blood within 24 hr. Before culturing, we stored the tubes containing heparinized blood at 4-8 [degrees] C. The cultures were set up in RPMI RPMI Rapid Prototyping & Manufacturing Institute RPMI Roswell Park Memorial Institute RPMI Royal Park Memorial Institute (culture medium) 1640 medium supplemented with 20% calf serum and 1% phytohemagglutinin phytohemagglutinin /phy·to·hem·ag·glu·ti·nin/ (-hem?ah-glldbomact´in-in) a hemagglutinin of plant origin. phy·to·he·mag·glu·ti·nin n. Abbr. . We added colchicin 2 hr before harvesting. The cells were collected by centrifugation Centrifugation A mechanical method of separating immiscible liquids or solids from liquids by the application of centrifugal force. This force can be very great, and separations which proceed slowly by gravity can be speeded up enormously in centrifugal , resuspended in a prewarmed hypotonic hypotonic /hy·po·ton·ic/ (-ton´ik) 1. denoting decreased tone or tension. 2. denoting a solution having less osmotic pressure than one with which it is compared. solution (0.075 M KCl) for 20 min, and fixed in 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). :methanol methanol, methyl alcohol, or wood alcohol, CH3OH, a colorless, flammable liquid that is miscible with water in all proportions. Methanol is a monohydric alcohol. It melts at −97. (1:3, v:v). The slides were prepared by air drying and stained with a 5% Giemsa solution (pH 6.8). Slides from each culture were randomly numbered and scored "blind" in numerical order. We examined at least 100 well-spread metaphases with 46 [+ or -] 1 centromeres per donor on coded slides (10,20). The National Reference Laboratory of Genetic Toxicology toxicology, study of poisons, or toxins, from the standpoint of detection, isolation, identification, and determination of their effects on the human body. Toxicology may be considered the branch of pharmacology devoted to the study of the poisonous effects of drugs. of the National Institute of Public Health, Prague, coordinated the effort of all participating cytogenetic laboratories. The National Reference Laboratory has been responsible for the standardization standardization In industry, the development and application of standards that make it possible to manufacture a large volume of interchangeable parts. Standardization may focus on engineering standards, such as properties of materials, fits and tolerances, and drafting (development of standard methods, supply media, and training of new personnel) and control (quality control of field laboratory workers by assessing the cytogenetic analysis results on coded slides, blood sampling and handling, and preparation of cell cultures, etc.). This method ensured the comparability of cytogenetic analysis results of all laboratories (10). We evaluated the four categories of CAs: chromatid chromatid (krō`mətəd): see chromosome; crossing over. and chromosome breaks and chromatid and chromosome exchanges. Gaps were not scored as aberrations. Cells bearing breaks or exchanges were considered as aberrant aberrant /ab·er·rant/ (ah-ber´ant) (ab´ur-ant) wandering or deviating from the usual or normal course. ab·er·rant adj. 1. cells. We treated the frequency of CAs enumerated This term is often used in law as equivalent to mentioned specifically, designated, or expressly named or granted; as in speaking of enumerated governmental powers, items of property, or articles in a tariff schedule. as a percentage of aberrant lymphocytes Lymphocytes Small white blood cells that bear the major responsibility for carrying out the activities of the immune system; they number about 1 trillion. as continuous variable. To account for possible differences in mechanisms of inducing CAs in relation to the type of exposure and for the sake of some statistical procedures as well as comparability of the results with previously published studies, the subjects were also categorized cat·e·go·rize tr.v. cat·e·go·rized, cat·e·go·riz·ing, cat·e·go·riz·es To put into a category or categories; classify. cat into the terciles and/or quartiles. Cutoff points Cutoff point The lowest rate of return acceptable on investments. are presented in Table 4 and may differ for specific occupational exposure subgroups as well as for the whole cohort.
Table 4. Categorization of subjects according to chromosomal aberration
frequency (%).
Tercile
1st 2nd 3rd
Exposure (low) (medium) (high)
Radon < 2.00 2.00- < 2.88 [is greater than or equal
to] 2.88
Radiography wards < 2.00 2.00- < 3.00 [is greater than or equal
to] 3.00
BCME < 2.10 2.10- < 3.11 [is greater than or equal
to] 3.11
Cytostatic drugs < 1.50 1.50- < 2.50 [is greater than or equal
to] 2.50
Coal gasification < 1.78 1.78- < 2.57 [is greater than or equal
to] 2.57
PAHs < 2.00 2.00- < 3.00 [is greater than or equal
to] 3.00
Referents < 1.00 1.00- < 3.00 [is greater than or equal
to] 3.00
Other chemical < 2.00 2.00- < 3.00 [is greater than or equal
substances to] 3.00
Chemicals -- -- --
Total < 1.89 1.89- < 2.99 [is greater than or equal
to] 3.00
Quartile
1st 2nd (lower 3rd (upper 4th
Exposure (low) intermediate) intermediate) (high)
Radon < 1.87 1.87- < 2.38 2.38- < 3.00 [is
greater
than or
equal to]
3.00
Radiography wards -- -- -- --
BCME -- -- -- --
Cytostatic drugs -- -- -- --
Coal gasification -- -- -- --
PAHs -- -- -- --
Referents -- -- -- --
Other chemical -- -- -- --
substances
Chemicals < 1.00 1.00- < 2.00 2.00- < 3.00 [is
greater
than or
equal to]
3.00
Total -- -- -- --
For subjects who had been examined for CAs more than once, we used mean scores for all computations. Cancer Incidence and Total Mortality We obtained the information on the incidence of cancer and the specific mortality in the cohort up to 31 March 1999 (the end of the overall follow-up period) from the National Oncological on·col·o·gy n. The branch of medicine that deals with tumors, including study of their development, diagnosis, treatment, and prevention. [Greek onkos, mass, tumor; see nek- Registry maintained by the Institute of Health Information and Statistics of the Czech Republic. The critical point in the identification of the cancer cases in the Oncological Registry is the knowledge of a birth number, which is the unique personal identification in the Czech Republic. In cases of uncertainty, we checked the accuracy of the birth numbers in records maintained by employers and crosschecked the numbers in the Central Registry of Inhabitants
The game is based loosely on the concepts from SameGame. of the Czech Police. The Central Registry of Inhabitants also confirmed the accuracy of mortality data. Statistical Methods We calculated the expected numbers of cancer cases, the standardized standardized pertaining to data that have been submitted to standardization procedures. standardized morbidity rate see morbidity rate. standardized mortality rate see mortality rate. incidence ratios (SIRs), and the 95% confidence intervals for SIRs on basis of the distribution of age- and sex-specific rates within the cohort. We used the Kaplan-Meier survival analysis to describe the differences in total cancer incidence during the follow-up period and plotted Kaplan-Meier survival curves. We used Cox regression (21) to model the associations between cancer incidence, the CA frequency, age at first testing, and sex. For a dependent time variable, we used either a) the time from the first test until the diagnosis of malignant neoplasm neoplasm or tumor, tissue composed of cells that grow in an abnormal way. Normal tissue is growth-limited, i.e., cell reproduction is equal to cell death. or death for causes other than cancer or b) the end of the follow-up period. The stratification stratification (Lat.,=made in layers), layered structure formed by the deposition of sedimentary rocks. Changes between strata are interpreted as the result of fluctuations in the intensity and persistence of the depositional agent, e.g. on the types of occupational exposure allowed for different shapes of baseline hazard function in each occupational exposure subgroup sub·group n. 1. A distinct group within a group; a subdivision of a group. 2. A subordinate group. 3. Mathematics A group that is a subset of a group. tr.v. . Routine diagnostic tests did not detect any substantial violation of underlying assumptions of Cox regression. Results At time of the analyses, there were data on 3,973 subjects, who contributed with 37,775 person-years to the total follow-up time. All subjects were divided into eight occupational groups by type of occupational exposure. In the cohort, there were 144 cases of cancer, shown in Table 5; 94 subjects were censored cen·sor n. 1. A person authorized to examine books, films, or other material and to remove or suppress what is considered morally, politically, or otherwise objectionable. 2. because their deaths were not caused by cancer. Of the participants, 53.4% were male; however, the sex distribution was not proportional. Males were overrepresented o·ver·rep·re·sent·ed adj. Represented in excessive or disproportionately large numbers: "Some groups, and most notably some races, may be overrepresented and others may be underrepresented" in several occupational groups (exposure to radon and PAHs), but females represented a larger portion of the group exposed to cytostatic drugs. The age distribution at the time of cytogenetic analysis and at follow-up are presented in Table 3. In spite of the fact that the subjects' ages were similar when the follow-up began (overall median 36 years of age), the length of the follow-up was significantly different. For example, the medians of follow-up periods in the radon and BCME groups were 17 and 18 years, respectively; in contrast, the median follow-up period was only 4 years in the cytostatic drug group. The distribution of CA frequencies and cutoff points used to classify study subjects into the specific CA frequency groups are shown in Tables 1 and 4. The overall median CA frequency (2%) was found in the cohort (10th percentile percentile, n the number in a frequency distribution below which a certain percentage of fees will fall. E.g., the ninetieth percentile is the number that divides the distribution of fees into the lower 90% and the upper 10%, or that fee level = [is less than] 1.00%, 90th percentile = [is less than] 4.25%). Descriptive characteristics of the cohort are presented in Tables 1-3.
Table 5. Classification of neoplasms according to International
Classification of Diseases, Revision 10 (ICD-10).
Occupational exposure
Radiography Cytostatic
ICD-10 code Radon wards BCME drugs
00-14 Lip, oral cavity, 1 -- -- 1
and pharynx
15-26 Digestive organs 6 -- 4 1
30-39 Respiratory and 18 -- 1 --
intrathoracic organs
40-43 Skin 3 1 2 2
45-49 Mesothelium and -- -- 1 1
soft tissue
50 Breast -- 1 -- 2
51-58 Female genital -- -- -- 4
organs
60-63 Male genital organs 1 -- 2 --
64-68 Urinary tract 2 1 2 1
69-72 Eye, brain, and 1 -- -- --
other parts of CNS
73-75 Thyroid and other -- -- -- --
endocrine glands
76-80 Malignant neoplasms -- -- -- --
of ill-defined,
secondary, and
unspecified sites
91-96 Lymphoid, 1 -- -- 1
hematopoietic, and
related tissue
Total 33 3 12 13
Occupational exposure
Coal
gasifi- Refe- Other
ICD-10 code cation PAHs rents chemicals Total
00-14 Lip, oral cavity, -- 2 1 -- 5
and pharynx
15-26 Digestive organs 3 1 2 8 25
30-39 Respiratory and 5 1 3 7 35
intrathoracic organs
40-43 Skin 3 1 3 11 26
45-49 Mesothelium and -- -- -- -- 2
soft tissue
50 Breast -- -- -- 2 5
51-58 Female genital 1 1 3 4 13
organs
60-63 Male genital organs -- -- -- 4 7
64-68 Urinary tract 3 1 1 3 14
69-72 Eye, brain, and -- -- 1 1 3
other parts of CNS
73-75 Thyroid and other -- -- -- 2 2
endocrine glands
76-80 Malignant neoplasms 1 -- -- -- 1
of ill-defined,
secondary, and
unspecified sites
91-96 Lymphoid, -- -- 1 3 6
hematopoietic, and
related tissue
Total 16 7 15 45 144
CNS, central nervous system.
Differences in SIRs and in Kaplan-Meier survival analyses did not indicate an association between CA frequency and cancer incidence in pooled data. Although the SIR was elevated for high CA frequency (1.20; 95% CI, 0.94-1.52), the difference was not statistically significant (p [is greater than] 0.1). We found no increase in the SIR (0.94; 95% CI, 0.67-1.28) in the medium CA frequency group. There were also no statistically significant trends in SIR (p [is greater than] 0.05). This is consistent with the result of the Kaplan-Meier survival analysis shown in Figure 1. However, the more sophisticated Cox regression model, which accounted for the age at the time of the test, sex, and the type of occupational exposure, showed a statistically significant increase in the hazard ratio The hazard ratio in survival analysis is the effect of an explanatory variable on the hazard or risk of an event. For a less technical definition than is provided here, consider hazard ratio to be an estimate of relative risk and see the explanation on that page. (HR) in the high CA frequency group (1.6; 95% CI, 1.01-2.37; Table 6). [GRAPH OMITTED]
Table 6. Cox regression analyses for the whole cohort.
95% CI for HR
Variable HR Significance Lower Upper
CA frequency 0.079
Low 1.0 -- -- --
Medium 1.1 0.679 0.69 1.76
High 1.6 0.044 1.01 2.37
Age at testing (years) 1.1 0.000 1.07 1.10
Sex (1 for female) 0.8 0.321 0.50 1.25
Overall significance 0.000
The model was adjusted for the type of occupational exposure.
The stratification of the data on occupational exposures brought more insight into the nature of the association between CA frequency and cancer incidence. We constructed Kaplan-Meier survival curves for each occupational group; there was an apparent association between CA frequency and total cancer incidence in the group of miners exposed to radon (Figure 2). In the other occupational groups, we found no similar pattern of an association between CA in PBL and cancer. Therefore, only the results of the Kaplan-Meier survival analysis of combined groups that included only subjects with a history of chemical exposure and referents is shown in Figure 3. [GRAPHS OMITTED] This finding was confirmed in models with several explanatory variables. Two Cox regression models of the association between CA frequency and total cancer incidence in the radon-exposed group are presented in Table 7. When we allocated the radon-exposed subjects into the CA frequency groups according to according to prep. 1. As stated or indicated by; on the authority of: according to historians. 2. In keeping with: according to instructions. 3. quartiles, there was a statistically significant excess in HR in the high CA frequency group (8.0; 95% CI, 2.42-26.13). Moreover, an increase in CA frequency was followed by an increase in the HR. If the model was simplified using a continuous term describing CA frequency instead of the dummy variables This article is not about "dummy variables" as that term is usually understood in mathematics. See free variables and bound variables. In regression analysis, a dummy variable , the association between CA frequency and total cancer incidence remained statistically significant.
Table 7. Cox regression analyses for radon-exposed miners.
95% CI for HR
Signifi-
Model Variable HR cance Lower Upper
Categorized Frequency of CA (%) 0.027
CA Low 1.0 -- -- --
frequency Lower intermediate 2.8 0.125 0.75 10.23
Upper intermediate 3.0 0.090 0.84 10.95
High 8.0 0.001 2.42 26.13
Age at testing (years) 1.1 0.000 1.07 1.15
Overall significance 0.000
Continuous Frequency of CA (%) 1.64 0.000 1.38 1.94
CA Age at testing (years) 1.10 0.000 1.07 1.14
frequency Overall significance 0.000
No statistically significant differences were detected in HR in the other occupational groups. Table 8 shows the results of Cox regression analysis In statistics, a mathematical method of modeling the relationships among three or more variables. It is used to predict the value of one variable given the values of the others. For example, a model might estimate sales based on age and gender. performed on the combined group of subjects exposed to chemicals or chemical mixtures and referents. Attempts to detect an association between CA frequency and a specific group of cancers failed.
Table 8. Cox regression analyses for individuals exposed to chemical
substances and referents.
95% CI for HR
Signifi-
Model Variable HR cance Lower Upper
Categorized Frequency of CA (%) 0.852
CA Low 1.0 -- -- --
frequency Lower intermediate 1.0 0.992 0.53 1.92
Upper intermediate 0.8 0.566 0.41 1.62
High 1.0 0.905 0.53 2.04
Age at testing (years) 1.1 0.000 1.06 1.10
Sex (1 for female) 0.9 0.835 0.54 1.65
Overall significance 0.000
Continuous
CA Frequency of CA (%) 0.96 0.602 0.84 1.11
frequency Age at testing (years) 1.08 0.000 1.06 1.10
Sex (1 for female) 0.94 0.815 0.54 1.63
Overall significance 0.000
Models were adjusted for the type of occupational exposure.
Discussion Cytogenetic analysis has been successfully used in occupational medicine for decades. On many occasions, it has been shown to be an effective tool to identify occupational exposures to mutagens and carcinogens. Nevertheless, at a time when the PBL CAs and other cytogenetic end points were conceptualized as biomarkers of early effects in the process of carcinogenesis car·ci·no·gen·e·sis n. The production of cancer. carcinogenesis production of cancer. biological carcinogenesis viruses and some parasites are capable of initiating neoplasia. , there was no empirical evidence of an association between cancer incidence and CAs. Until recently, few epidemiologic studies addressed that issue. The present study was designed to test the validity of CAs as the biomarker biomarker /bio·mark·er/ (bi´o-mahr?ker) 1. a biological molecule used as a marker for a substance or process of interest. 2. tumor marker. bi·o·mark·er n. 1. of early effect and as a predictive value for a subsequent risk of cancer. In the present study, there has been improvement over previous methods. First of all, in spite of the fact that the study includes subjects examined for CAs in four laboratories, the interlaboratory differences in the scoring of CAS have not been significant. The quality of performance of the cytogenetic laboratories was under the quality control program of the National Institute of Public Health in Prague since their establishment; this originally included a uniform laboratory protocol and classification and scorers' training. In the early 1980s, the quality control program gradually developed into a quality assurance/quality control system, which includes regular testing of reference samples (10). Second, the information on the occupational exposures of all subjects in the study was available. Finally, the study is based on the largest population examined systematically for CAs (3,973 subjects who underwent 8,962 cytogenetic analyses). The data analysis revealed strong associations between CA frequency and total cancer incidence in the group of underground miners exposed to radon. The validity of this finding is supported by the fact that, in that particular case, all subjects were examined for CA frequency in the same laboratory by the same personnel; therefore, interlaboratory bias could not affect this result. Also, the potential for other bias, such as selection or information bias, is very limited. All eligible workers were included in the study, and cytogenetic assays had been performed repeatedly in all miners. (It is important to note that all subjects in this subgroup worked in the same ore mine.) In contrast, we could not demonstrate any association between CAs and cancer in cases of other occupational exposures. If we exclude interlaboratory bias as an explanation for this finding, there are still other alternatives. The most probable explanation is that the most numerous subgroups in the study were relatively young and the length of follow-up has been too short to experience a sufficient number of cases. In contrast, in the occupational subgroups where the follow-up period is sufficiently long, there are few participants. Also, confounding confounding when the effects of two, or more, processes on results cannot be separated, the results are said to be confounded, a cause of bias in disease studies. confounding factor bias could have masked the association. Heterogeneity het·er·o·ge·ne·i·ty n. The quality or state of being heterogeneous. heterogeneity the state of being heterogeneous. caused by random factors is very likely to be substantial, decreasing the study power. In the Cox regression model, we have been able to account only for age at testing, sex, and the type of occupational exposure. Data on other potential confounders or modifying factors, such as the length and intensity of occupational exposures, diet or smoking, was not available at the time of analyses. The predictive value of a spot test on CAs is low. When we used predictor spot tests (the outcome of the first CA assay or the outcome of the highest CA assay observed in participant) in Cox regression models, the association between CA frequency and cancer incidence vanished even in the radon-exposed group. This is consistent with the early findings of high intraindividual variability in CA frequencies. Consequently, because the subgroups exposed to chemicals were not systematically examined and because the frequency of CAs per capita [Latin, By the heads or polls.] A term used in the Descent and Distribution of the estate of one who dies without a will. It means to share and share alike according to the number of individuals. is much lower than in the radon-exposed group, it may be difficult to detect an association between CA frequency and cancer. The frequency of CAs in PBLs is a surrogate surrogate n. 1) a person acting on behalf of another or a substitute, including a woman who gives birth to a baby of a mother who is unable to carry the child. 2) a judge in some states (notably New York) responsible only for probates, estates, and adoptions. measure of events, which may occur in other tissues. It is plausible to expect that changes in specific tissues are reflected in PBLs with a different intensity. Consequently, the association between CA frequency and specific cancers may be assumed to vary (11,12). However, we failed to demonstrate such specific association, probably because of the low number of different types of malignancies under scrutiny (Table 5). In conclusion, the present study has been, to a certain degree, consistent with previous observations. Also, this study has shown evidence that supports the association between CA frequency in PBLs and cancer incidence. However, more subjects are needed before analyses and conclusions can be completed. The study should be able to provide more information on the relationship between CAs and cancer after a substantial increase in the number of individuals in the study and a somewhat longer follow-up time. Furthermore, we have made an effort to collect additional data on potentially modifying factors and confounders such as smoking and the length of occupational exposures. We are interested in testing the independence of predictivity of CAs on radiation dose and cigarette smoking in the group of miners exposed to radon. REFERENCES AND NOTES (1.) Zudova Z, Landa K. Genetic risks of occupational exposures to haloethers. Mutat Res 46:242-243 (1977). (2.) Kucerova M, Zhurkov VS, Kuleshov NP. Mutagenic mutagenic inducing genetic mutation. effect of epichlorhydrin II. Analysis of chromosomal aberrations in lymphocytes of persons occupationally exposed to epichlorhydrin. Mutat Res 48:355-360 (1977). (3.) Sram RJ, Kuleshov NP. Monitoring the occupational exposure to mutagens by the cytogenetic analysis of human peripheral lymphocytes in vivo in vivo /in vi·vo/ (ve´vo) [L.] within the living body. in vi·vo adj. Within a living organism. in vivo adv. . Arch Toxicol Suppl 4:11-18 (1980). (4.) Sram RJ, Samkova I, Hola N. High-dose ascorbic acid prophylaxis prophylaxis (prō'fĭlăk`sĭs), measures designed to prevent the occurrence of disease or its dissemination. 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In: Acta Hygienica, Epidemiologica et Microbiologica, Appendix No 20/1989 Prague:National Institute of Public Health at Prague, 1989. (21.) Cox DR, Oakes D. Analysis of Survival Data. London: Chapman and Hall Chapman and Hall was a British publishing house, founded in the first half of the 19th century by Edward Chapman and William Hall. Upon Hall's death in 1847, Chapman's cousin Frederic Chapman became partner in the company, of which he became sole manager upon the retirement of , 1990. Zdenek Smerhovsky,(1) Karel Landa,(1) Pavel Rossner,(1) Marek Brabec,(1) Zdena Zudova,(2) Nora Hola,(3) Zdena Pokorna,(2) Julie Mareckova,(4) and Dana Hurychova(5) (1) The National Institute of Public Health, Prague, Czech Republic; (2) South Moravian Regional Hygienic hy·gien·ic adj. 1. Of or relating to hygiene. 2. Tending to promote or preserve health. 3. Sanitary. Station, Brno, Czech Republic; (3) North Bohemian Regional Hygienic Station, Usti nad Labem Ú·stí nad La·bem A city of northwest Czech Republic on the Elbe River near the German border. Population: 96,100. , Czech Republic; (4) Municipal Hygienic Station, Brno, Czech Republic; (5) Hygienic Station of the Capital, Prague, Czech Republic Address correspondence to Z. Smerhovsky, Group for Occupational and Environmental Epidemiology, Center for Industrial Hygiene and Occupational Diseases, National Institute of Public Health, Srobarova ul. 48, 100 42, Prague 10, Czech Republic. Telephone: +420 2 6708 2759. Fax: +420 2 6731 1236. E-mail: zdsm@szu.cz The project was funded by the Internal Grant Agency of the Ministry of Health of the Czech Republic, grant 9NJ5177-3. We thank P. Boffetta, International Agency for Research on Cancer The International Agency for Research on Cancer (IARC, or CIRC in its French acronym) is an intergovernmental agency forming part of the World Health Organisation of the United Nations. Its main offices are in Lyon, France. , and E. Fitzgerald through the Fogarty International Center for additional funding. Received 9 June 2000; accepted 24 August 2000. |
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