GSTT1 and CYP2E1 polymorphisms and trihalomethanes in drinking water: effect on childhood leukemia. (Children's Health Articles).The purpose of the study was to determine whether the risk of childhood acute lymphoblastic leukemia acute lymphoblastic leukemia n. Abbr. ALL Lymphoblastic leukemia occurring mainly in older adults, characterized by rapid onset and progression of symptoms. Also called acute lymphocytic leukemia. (ALL) associated with drinking water drinking water supply of water available to animals for drinking supplied via nipples, in troughs, dams, ponds and larger natural water sources; an insufficient supply leads to dehydration; it can be the source of infection, e.g. leptospirosis, salmonellosis, or of poisoning, e.g. disinfection disinfection, n the process of destroying pathogenic organisms or rendering them inert. disinfection, full oral cavity, n a procedure used to reduce active periodontal disease, usually completed within a certain short time frame. by-products was modified in the presence of variants in genes involved in the metabolism of trihalomethanes (THMs). We included a subset of cases from a population-based 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. in a case-only study to estimate the interaction odds ratios (IORs) between prenatal and postnatal postnatal /post·na·tal/ (-na´t'l) occurring after birth, with reference to the newborn. post·na·tal adj. Of or occurring after birth, especially in the period immediately after birth. exposure to THMs and polymorphisms in the GSTT GSTT Generation Skipping Transfer Tax GSTT Geological Society of Trinidad & Tobago 1 and CYP CYP In currencies, this is the abbreviation for the Cyprus Pound. Notes: The currency market, also known as the Foreign Exchange market, is the largest financial market in the world, with a daily average volume of over US $1 trillion. 2E1 genes. We compared cases with and without a given variant regarding their exposure to THMs using unconditional logistic regression In statistics, logistic regression is a regression model for binomially distributed response/dependent variables. It is useful for modeling the probability of an event occurring as a function of other factors. . The IOR IOR Indian Ocean Region IOR Improved Oil Recovery IOR Interoperable Object Reference IOR Istituto Ortopedico Rizzoli (Rizzoli Orthopaedic Institute, Italy) IoR Institute of Refrigeration (UK) for a postnatal average of total THM above the 95th percentile with GSTT1 null genotype was 9.1 [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%. (95% CI), 1.4-57.8]. With CYP2E1 (variant G-1259C, known as the allele allele (əlēl`): see genetics. allele Any one of two or more alternative forms of a gene that may occur alternatively at a given site on a chromosome. CYP2E1*5), the effect of exposure during pregnancy for an average exposure to total THM at or above the 75th percentile was 9.7 (95% CI, 1.1-86.0). These results contrast strongly with those from our case-control analysis, in which we considered the exposure to THMs only in relation with ALL, and observed no increase in risk or very moderate ones. The present preliminary study shows suggestive but imprecise results. We found no similar results in the literature, underscoring the need for other studies as well as the potential usefulness of combining exposure and relevant genetic information in such studies. Key words: childhood leukemia, CYP2E1, disinfection by-products, drinking water, genetic polymorphisms, GSTT1, trihalomethanes. Environ Health Perspect 110:591-593 (2002). [Online 25 April 2002] ********** Trihalomethanes (THMs), such as chloroform chloroform (klôr`əfôrm) or trichloromethane (trī'klôrōmĕth`ān), CHCl3 , are chlorination chlorination Public health Addition of chlorinated compounds to drinking water as disinfectants. Cf Ozonation. by-products of drinking water resulting from the reaction of chlorine with organic material in the water. THMs have been found to be associated with tumors in animal studies (1). In addition, epidemiologic studies in adults potentially exposed to THMs have shown excesses of colon, rectum, and bladder cancer bladder cancer Malignant tumour of the bladder. The most significant risk factor associated with bladder cancer is smoking. Exposure to chemicals called arylamines, which are used in the leather, rubber, printing, and textiles industries, is another risk factor. (1). Most environmental chemicals must be biotransformed to have toxic effects. This bio-transformation is a two-stage process carried out by phase I and phase II metabolizing enzymes (2). Phase I enzymes such as those belonging to the cytochrome cytochrome (sī`təkrōm'), protein containing heme (see coenzyme) that participates in the phase of biochemical respiration called oxidative phosphorylation. P-450 (CYP) family are involved in the initial oxidation, reduction, or dealkylation of carcinogens Carcinogens Substances in the environment that cause cancer, presumably by inducing mutations, with prolonged exposure. Mentioned in: Colon Cancer, Rectal Cancer ; this phase generally leads to the production of active intermediate metabolites Metabolites Substances produced by metabolism or by a metabolic process. Mentioned in: Interactions . Phase II enzymes such as those belonging to the glutathione S-transferase The glutathione S-transferase (GST) family of enzymes comprises a long list of cytosolic, mitochondrial, and microsomal proteins which are capable of multiple reactions with a multitude of substrates, both endogenous and xenobiotic. (GST GST abbr. Greenwich sidereal time GST (in Australia, New Zealand, and Canada) Goods and Services Tax ) family convert the active metabolites produced during phase I reactions into water-soluble and excretable products. Individual variation in the genes encoding these enzymes These Enzymes is an American hardcore/punk band featuring members of the All-American Rejects and Sons of Abraham. Biography These Enzymes was formed in late 2003 by All-American Rejects members Mike Kennerty (guitar) and Chris Gaylor (drums) along with former Sons of could modify the effects associated with specific exposures and thus influence susceptibilities to cancer, including childhood leukemia (3). Recent studies have shown that the enzymes CYP2E1 and GSTT1 are involved in the metabolism of THM, the latter in particular with brominated THM (4-6). Therefore, studying whether the risk for cancer associated with exposure to THMs in drinking water is modified by polymorphisms in the genes encoding these particular enzymes would seem relevant. We recently performed a case-control study investigating the risk for acute lymphoblastic leukemia (ALL) associated with exposure to THMs in drinking water in children 0-9 years old (7). We studied the risk for ALL from exposure to THMs during the prenatal and the postnatal periods and found that odds ratios (ORs) were generally not increased for the prenatal period and when using average levels of exposure. However, postnatal cumulative exposure for total THM above the 95th percentile of the distribution for cases and controls was associated with an OR of 1.54 [95% confidence interval (95% CI) = 0.78-3.03]; for that same period, risk associated with exposure to chloroform was increased (OR = 1.63; 95% CI, 0.84-3.19). To clarify further whether risk for ALL in these children was modified by DNA DNA: see nucleic acid. DNA or deoxyribonucleic acid One of two types of nucleic acid (the other is RNA); a complex organic compound found in all living cells and many viruses. It is the chemical substance of genes. variants in the genes encoding enzymes involved in the metabolism of THM such as chloroform, we performed a case-only study on a subset of the cases selected for the original case-control study. Materials and Methods Case-control study. Details of the case-control study are provided elsewhere (7). In brief, we recruited patients with ALL between 0 and 9 years old diagnosed between 1980 and 1993 in the Province of Quebec from tertiary care centers tertiary care center Hospital care A hospital or medical center for Pts often referred from secondary care centers, which provides subspecialty expertise Tertiary care center Surgery designated by governmental policy to hospitalize hos·pi·tal·ize tr.v. hos·pi·tal·ized, hos·pi·tal·iz·ing, hos·pi·tal·iz·es To place in a hospital for treatment, care, or observation. and treat children with cancer in the province. Tracing cases from these hospitals is equivalent to population-based ascertainment. We selected controls for these cases from family allowance files and matched them to each patient for age, sex, and region of residence (we based the definition of these regions on administrative and geographical criteria, and they cover wide territories). The family allowance is a government stipend awarded to all families with children living legally in Canada and was the most complete census of children available for the study years. Participation rates were 96.3% among cases and 83.8% among controls. We analyzed 491 cases and 491 controls. The ethical review board of each participating hospital approved the project for recruitment of cases, whereas that for controls was approved by the provincial paragovernmental agency regulating access to databases with personal identifiers. Sources of data for exposure measurement and exposure matrix. Extensive details on the exposure assessment method are given in (7). Briefly, to determine exposure to THMs in drinking water, we developed a municipality-exposure matrix. To do so, we used a) information from interview of parents where child's residential history covering the pregnancy period up to the time reference date was collected, b) historical data provided by municipalities and the ministry of environment, and c) a tap water survey carried out in 227 homes. We used all these sources of data to fill the cells of the matrix, which we defined by rows of municipalities and columns of specific contaminants; a third dimension was the calendar year. For cells with a missing value, we imputed Attributed vicariously. In the legal sense, the term imputed is used to describe an action, fact, or quality, the knowledge of which is charged to an individual based upon the actions of another for whom the individual is responsible rather than on the individual's the closest available annual average measurement (before or after a missing year). For the prenatal period, 21% of person-years of exposure had their value assigned from the current year (i.e., no imputation IMPUTATION. The judgment by which we declare that an agent is the cause of his free action, or of the result of it, whether good or ill. Wolff, Sec. 3. ), whereas 52% of person-years of exposure were assigned from the nearest 6 years or less. For the postnatal period, these figures were 26% and 61%, respectively. In the end, some data were available on THMs for 436 of cases and 422 controls during the prenatal period, and for 457 cases and 441 controls during the postnatal period. We used three exposure indices in the analysis. A first index was, over the exposure period, whether drinking water was never chlorinated chlorinated /chlo·ri·nat·ed/ (klor´i-nat?ed) treated or charged with chlorine. chlorinated charged with chlorine. chlorinated acids some, e.g. , chlorinated part of the time, or always chlorinated. A second index was the average level of exposure over the period [[SIGMA]([concentration.sub.j] x [duration.sub.i] in days) / total duration]; we then categorized it at > 95% percentile of the distribution for cases and controls. We also categorized the average level into three categories: [less than or equal to] 24th percentile, 25th to 74th percentile, and [greater than or equal to] 75th percentile. A third index was the cumulative weighted sum over the exposure period [[SIGMA] ([concentration.sub.j] x [duration.sub.i] in days)], which we then categorized as above. In the present report we use the second and third indices of exposure. Case-only study. The case-only study has been recently proposed as an efficient design for studying gene-environment interactions (8). Based only on cases, the OR measuring the association between the gene of interest and the particular environmental exposure among these cases is a measure of the interaction parameter. The latter is an efficient estimate of the interaction odds ratio (IOR) one would obtain from the case-control study and is a valid estimate of this quantity if the exposure and the genotype in the population are independent (9). For this study, we used 170 cases from the set of 491 cases; these came from the largest pediatric pediatric /pe·di·at·ric/ (pe?de-at´rik) pertaining to the health of children. pe·di·at·ric adj. Of or relating to pediatrics. cancer-treating center in the province where genotyping of all ALL cases has been systematically initiated. All parents signed a consent form for our use of DNA material that was already provided for diagnostic and therapeutic purposes. The cases included here are all of French-Canadian origin (French-Canadians make up about 80% of the population in the Province of Quebec). The polymorphism polymorphism, of minerals, property of crystallizing in two or more distinct forms. Calcium carbonate is dimorphous (two forms), crystallizing as calcite or aragonite. Titanium dioxide is trimorphous; its three forms are brookite, anatase (or octahedrite), and rutile. deletion in the GSTT1 gene was revealed by a polymerase chain reaction polymerase chain reaction (pŏl`ĭmərās') (PCR), laboratory process in which a particular DNA segment from a mixture of DNA chains is rapidly replicated, producing a large, readily analyzed sample of a piece of DNA; the process is (PCR PCR polymerase chain reaction. PCR abbr. polymerase chain reaction Polymerase chain reaction (PCR) )-based assay using internal controls (10). PCR allele-specific oligonucleotide hybridization hybridization /hy·brid·iza·tion/ (hi?brid-i-za´shun) 1. crossbreeding; the act or process of producing hybrids. 2. molecular hybridization 3. assays have been used to genotype the polymorphism G-1259C (a G-to-C substitution at position -1259 in the promoter) that defines the allele CYP2E1*5 (11). Statistical analysis. We used unconditional logistic regression to estimate the IORs and their 95% confidence intervals. The IOR is defined as O[R.sub.ge]/(O[R.sub.g] x O[R.sub.e]) x Z, where g stands for genotype, e for exposure, and Z for the OR between exposure and genotype in the controls, assumed to be 1 based on the independence assumption. Results Among the 170 genotyped cases, 161 cases also had exposure data. We compared the age and sex distributions (confirmed risk factors for ALL) of the 161 genotyped subjects entering the analysis with those of the entire set of cases and found that 57% were boys in comparison with 56% among all 491 cases, and 58% were < 5 years old in comparison with 66% among all cases. In the present study, we analyzed the GSTT1 polymorphism with the index measuring average as well as the cumulative level of exposure for total THM > 95th percentile and likewise for bromoform at [greater than or equal to] 75th percentile; for CYP2E1*5, we used the average as well as the cumulative level at [greater than or equal to] 75th percentile. We based the percentile distributions on the complete set of subjects, as previously described, but for some situations in the present analysis we had too few subjects > 95th percentile to use that category; instead, we used a broader category ([greater than or equal to] 75th percentile). To evaluate latency, we determined average and cumulative exposure for the period ranging from pregnancy to 1 year before diagnosis or reference date for controls. For study subjects younger than 1 year old, we did not apply the latency period latency period n. In psychoanalytic theory, the fourth stage of psychosexual development, extending from about age 5 to puberty, when a child apparently represses sexual urges and prefers to associate with members of the same sex. ; four cases were in this category in the present analysis. Table 1 shows that the IOR was increased with the GSTT1 null genotype in the postnatal period using the average level of total THM and likewise for the complete period. Using the cumulative THM level, risks were only moderately increased and all confidence intervals included the null value. Results with the average as well as the cumulative values for bromoform suggested a nonsignificant non·sig·nif·i·cant adj. 1. Not significant. 2. Having, producing, or being a value obtained from a statistical test that lies within the limits for being of random occurrence. protective effect associated with the null genotype. IORs were increased with the CYP2E1*5 allele using the average or the cumulative level for total THM and for chloroform; risks were generally comparable for the pregnancy and the postnatal period. Discussion Using the case-only methodology, we observed that risk for ALL associated with exposure to total THM was elevated among children homozygous ho·mo·zy·gous adj. Having the same alleles at one or more gene loci on homologous chromosome segments. Homozygous Identical genes controlling a specified inherited trait. for GSTT1 deletion (null genotype) but below the null value with exposure to bromoform; risks for those carrying the CYP2E1 variant G-1259C (allele *5) were elevated for exposure occurring during the prenatal as well as the postnatal period. Many of these observations were imprecise because of the relatively small number of genotyped subjects. The data are quite preliminary and will need to be replicated before any strong conclusion is reached. However, we have established that carcinogenic carcinogenic having a capacity for carcinogenesis. risks from exposure to environmental toxicants can be modified by genetic risk factors such that certain individuals are more or less susceptible as a result of DNA variants in the genes encoding xenobiotic xen·o·bi·ot·ic adj. Foreign to the body or to living organisms. Used of chemical compounds. n. A xenobiotic chemical. xenobiotic any substance, harmful or not, that is foreign to the animal's biological system. metabolizing enzymes. Because the tested variant in the regulatory region of the CYP2E1 gene is associated with an increased transcriptional activity (12), individuals with this polymorphism would be expected to show enhanced metabolism of THM and chloroform that in turn would result in more activated metabolites. Similarly, individuals lacking GSTT1 enzyme activity Enzyme activity A measure of the ability of an enzyme to catalyze a specific reaction. Mentioned in: Glucose-6-Phosphate Dehydrogenase Deficiency (GSTT1 null genotype) would be at higher risk because they are less efficient in converting these reactive intermediates into soluble products. Studies investigating the risk of ALL from exposure to chlorination by-products in drinking water are scarce. To our knowledge, no study has investigated the joint contribution of DNA variants in xenobiotic metabolizing enzymes and exposure to THMs in the pathogenesis of ALL, and only two other studies have evaluated the association between leukemia and drinking water contamination, both ecologic: one study (13) reported an inverse relationship between exposure to THMs and leukemia for adults, and the other (14) observed no relation for ALL and exposure to THMs. The validity of the IORs obtained from case-only studies rests on the assumption of independence of exposure and genes in the population, such that individuals with certain DNA variants are not more or less likely to be exposed to environmental contaminants. We have no data to support the independence assumption in our study, but lack of independence would seem unlikely for maternal exposure given unknown child genotype and likewise for the child postnatally given the nature of the exposure. The interpretation of the measures of effects for candidate genes in an association study must be made with caution because alternative explanations need to be considered. Although the studied gene could be involved in causing the disease, another interpretation is that the candidate gene is not itself causally involved but rather is in linkage disequilibrium linkage disequilibrium n. The nonrandom association between two or more alleles such that certain combinations of alleles are more likely to occur together on a chromosome than other combinations of alleles. with (very close to) a causal gene. A third possibility is that the study is affected by a population structure bias (15) whereby many ethnic subgroups with different allelic al·lele n. One member of a pair or series of genes that occupy a specific position on a specific chromosome. [German Allel, short for Allelomorph, allelomorph, from English distributions are pooled in the analysis, a potential bias that can affect case-only studies (9). The latter explanation for our results is unlikely because all genotyped cases were ethnically homogeneous. The possibility of linkage disequilibrium remains, and although we have no data to address this possibility, these closely linked genes, if any, must participate in or influence the metabolism of THM. In conclusion, although imprecise and preliminary, our results indicate that individual susceptibility as determined by DNA variants may play a role in the etiology of ALL. When considering the risk of ALL associated with exposure to drinking water contaminants, our results were not very suggestive (7); the present results, on the other hand, if validated in future studies, highlight the importance of considering genetic variation with exposure to contaminants to determine associations.
Table 1. IORs and 95% CIs for exposure to THMs and GSTT1 and CYP2E1
genotypes among children with ALL.
Prenatal Postnatal
Gene/exposure IOR (95% CI) IOR (95% CI)
GSTT1 null (23 M; 131 N) (25 M; 136 N)
Total THM (> 95th percentile)
Average 2.40 (0.43-13.18) 9.13 (1.44-57.82)
Cumulative 2.40 (0.43-13.18) 2.51 (0.60-10.45)
Average for complete period
(a) 4.6 (0.96-21.97) --
Cumulative for complete
period (a) 2.23 (0.55-9.06) --
Bromoform (b) (> 75th
percentile)
Average -- 0.53 (0.17-1.52)
Cumulative -- 0.57 (0.18-1.64)
Average for complete period
(a) 0.37 (0.10-1.33) --
Cumulative for complete
period (a) 0.39 (0.11-1.38) --
CYP2E1*5 (12 M; 118 N) (12 M; 125 N)
Total THM
Average
25th-74th percentile 3.50 (0.40-31.54) 1.61 (0.28-9.25)
[greater than or equal to]
75th percentile 9.75 (1.10-86.01) 4.06 (0.76-21.50)
For complete period (a)
25th-74th percentile 1.56 (0.27-8.94) --
[greater than or equal to]
75th percentile 4.30 (0.81-22.77) --
Cumulative
25th-74th percentile 4.5 (0.52-39.12) 3.89 (0.45-33.67)
[greater than or equal to]
75th percentile 8.0 (0.88-72.51) 5.96 (0.66-53.82)
For complete period (a)
25th-74th percentile 1.74 (0.32-9.43) --
[greater than or equal to]
75th percentile 2.95 (0.53-16.24) --
Chloroform
Average
25th-74th percentile 3.48 (0.40-30.97) 3.80 (0.42-33.75)
[greater than or equal to]
75th percentile 10.17 (1.15-89.89) 8.20 (0.94-71.72)
For complete period (a)
25th-74th percentile 3.33 (0.37-29.60) --
[greater than or equal to]
75th percentile 8.57 (0.97-75.17) --
Cumulative
25th-74th percentile 4.60 (0.53-39.88) 5.47 (0.65-121.36)
[greater than or equal to]
75th percentile 7.69 (0.85-69.63) 7.31 (0.79-169.76)
For complete period (a)
25th-74th percentile 3.33 (0.37-29.60) --
[greater than or equal to]
75th percentile 6.91 (0.79-60.37) --
Abbreviations: M, mutant allele (GSTT1 null genotype, carrier of at
least one CYP2E1*5 allele); N, normal allele.
(a) From pregnancy to the year before diagnosis, (b) All subjects were
in the [greater than or equal to] 75th percentile category during
pregnancy.
REFERENCES AND NOTES (1.) Mills CJ, Bull RJ, Cantor KP, Reif J, Hrudey SE, Huston P, and an Expert Working Group. Workshop report: Health risks of drinking water chlorination by-products: report of an expert working group. Chronic Dis Can 19:91-102 (1998). (2.) Hirvonen A. Polymorphisms of xenobiotic-metabolizing enzymes and susceptibility to cancer. Environ Health Perspect 107(suppl 1):37-47 (1999). (3.) Sinnett D, Krajinovic M, Labuda D. Genetic susceptibility to childhood lymphoblastic leukemia lymphoblastic leukemia n. A type of lymphocytic leukemia characterized by abnormal, often immature, lymphocytic cells or by the presence of unusually large numbers of immature lymphocytes occurring together with adult lymphocytes. . Leukemia Lymphoma 38:447-462 (2000). (4.) Constan AA, Sprankle CS, Peters JM, Kedderis GL, Everitt JI, Wong BA, Gonzalez FL, Butterworth BE. Metabolism of chloroform by cytochrome P450 2E1 is required for induction of toxicity in the liver, kidney, and nose of the male mice. Toxicol Appl Pharmacol 160:120-126 (1999). (5.) Pegram RA, Andersen ME, Warren SH, Ross TM, Claxton LD. Glutathione glutathione: see coenzyme. S-transferase-mediated mutagenicity mutagenicity /mu·ta·ge·nic·i·ty/ (-je-nis´it-e) the property of being able to induce genetic mutation. mutagenicity the property of being able to induce genetic mutation. of thihalomethanes in Salmonella typhimuriurm: contrasting results with bromodichloromethane and chloroform. Toxicol Appl Pharmacol 144:183-188 (1997). (6.) Allis JW, Brown BL, Zhao G, Pegram RA. The effects of inhalation exposure to bromo-dichloromethane on specific rat CYP isoenzymes. Toxicol 161:67-77 (2001). (7.) Infante-Rivard C, Olson E, Jacques L, Ayotte P. Drinking water contaminants and childhood leukemia. Epidemiology 12:13-19(2001). (8.) Khoury MJ, Flanders WD. Nontraditional epidemiologic approaches in the analysis of gene-environment interaction: case-control studies with no controls. Am J Epidemiol 144:207-213 (1996). (9.) Weinberg C, Umbach DM. Choosing a retrospective design to assess joint genetic and environmental contributions to risk. Am J Epidemiol 152:197-203 (2000). (10.) Krajinovic M, Labuda D, Richer C, Karimi S, Sinnett D. Susceptibility to childhood acute lymphoblastic leukemia: influence of CYP1A CYP1A Cytochrome P450 1A 1, CYP2D6, GSTM GSTM Gatespace Telematics (supplier of systems and components for telematics) GSTM General System Test Module 1 and GSTT1 genetic polymorphisms. Blood 93:1496-1501 (1999). (11.) Krajinovic M, Sinnett H, Richer C, Labuda D, Sinnett D. Role of NQ01, MP0 and CYP2E1 genetic polymorphisms in the susceptibility to childhood acute lymphoblastic leukemia. Int J Cancer 97:230-236. (12.) Hayashi SI, Watanabe J, Kawajiri K. Genetic polymorphism in the 5' flanking region change transcriptional regulation of the human cytochrome P450E1 gene. J Biochem 110:559-565 (1991). (13.) Fagliano J, Berry M, Bove F, Burke T. Drinking water contamination and the incidence of leukemia: an ecologic study. Am J Public Health 80:1209-1212 (1990). (14.) Foster AM, Prentice AG, Copplestone JA, Cartwright RA, Ricketts C. The distribution of leukaemia in association with domestic water quality in south west England South West England is one of the regions of England. It is the largest such region in terms of area, and extends from Gloucestershire and Wiltshire to Cornwall and the Isles of Scilly. This includes the area often known as the West Country, and much of Wessex. . Eur J Cancer Prey 6:11-19 (1997). (15.) Wacholder S, Rothman N, Caparoso N. Population stratification in epidemiologic studies of common genetic variants and cancer: quantification of bias. J Natl Cancer Inst 92:1151-1158 (2000). Claire Infante-Rivard, (1,2) Devendra Amre, (2,3) and Daniel Sinnett, (2,3) (1) Joint Departments of Epidemiology and Biostatistics, and Occupational Health, Faculty of Medicine, McGill University Montreal, Quebec, Canada; (2) Research Center, Hopital Sainte-Justine, Montreal, Quebec, Canada; (3) Department of Pediatrics, Universite de Montreal, Montreal, Quebec, Canada Address correspondence to C. Infante-Rivard, Joint Departments of Epidemiology and Biostatistics, and Occupational Health, Faculty of Medicine, McGill University, 1130 Pine Avenue West, Montreal, Quebec, Canada H3A 1A3. Telephone: (514) 398-4231. Fax: (514) 398-7435. E-mail: cirivard@epid.lan.mcgill.ca We thank the oncologists and hematologists J.-M. Leclerc (Hopital Sainte-Justine), M. Whitehead (Montreal Children's Hospital Montreal Children's Hospital is a pediatric health centre in Montreal and one of a few in Canada. It is affiliated with the McGill University Health Center. Although it is much smaller than its Montreal counterpart, the Centre hospitalier universitaire Sainte-Justine (144 ), L. Cote-Brisson (Centre Hospitalier de l'Universite Laval), J. Brossard (Centre Hospitalier de l'Universite de Sherbrooke), and R. Simard (Centre Hospitalier de Chicoutimi) for their collaboration, and the following members of the research team: M. Petitclerc, D. Hamer, A. Chartier, and E. Olson. This project was supported by grants from the National Research and Development Program (NHRDP NHRDP National Health Research & Development Program (Canada) ), Ottawa; the NHRDP-Saint-Laurent Vision 2000-Fonds de la Recherche en Sante du Quebec (FRSQ FRSQ Fonds de la Recherche en Santé du Québec ) program; and the Hydro-Quebec-FRSQ program on environment and child health. Received 17 July 2001; accepted 20 November 2001. |
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