NNNS: Adverse Effects (2011)

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:
To evaluate the risk of bladder cancer over some 30 to 35 years in the Danish population born during World War II. This population group experienced increased intrauterine exposure, compared with people born before the war. The artificial sweeteners, consumed during the war and to which fetuses were exposed, consisted almost exclusively of saccharine.
Inclusion Criteria:
  • 1930 to 1955 saccharine import and export figures
  • Consumption of sugar per inhabitant
  • Only tumors occurring in the age groups 20 to 24, 25 to 29 and 30 to 34 years.
Exclusion Criteria:
No epithelial tumors were recorded at younger ages in these cohorts and no sarcomas were seen in the cohorts born during 1941 to 1945, in contrast to five cases (four males and one female) in cohorts born during 1931 to 1940.
Description of Study Protocol:
None given.
Data Collection Summary:

Timing of Measurements

  • Incidence of malignant neoplasms of the bladder: Calculated on the basis of the number of cases of bladder tumors (including papillomas) reported to the Cancer Registry in the period of 1951 to 1976 for three five-year birth cohorts of the years 1931 to 1945, representing two pre-war (unexposed) and one wartime (exposed) group
  • Age- and sex-specific incidence rates: Calculated with population denominators from the census-based statistics of the same cohorts (Denmark Statistics 1950 to 1976). The age-specific rates for the cohorts born between 1931 and 1940 formed the basis for calculation of the expected number of bladder tumors in the 1941 to 1945 cohort.
Description of Actual Data Sample:
  • Initial N:
Person, Years At Risk In Five-Year Birth Cohorts Between 1931 and 1945, Distributed by Age and Sex
 
  Birth Cohorts Birth Cohorts Birth Cohorts Birth Cohorts Birth Cohorts Birth Cohorts
  1931 to 1935 1931 to 1935 1936 to 1940 1936 to 1940 1941 to 1945 1941 to 1945
Age Groups (years)
20 to 24 712,846 708,549 781,954 758,261 996,866 947,590
25 to 29 697,793 700,646 771,999 753,769 993,963 942,257
30 to 34 697,368 698,058 773,342 751,869 467,461 444,503
  • Ethnicity: Danish.

Summary of Results:

Other Findings

  • The shortage of natural sweeteners during World War II and in the immediate post-war years produced an increase in the importation of saccharin (over 500kg per year), especially in the first years of the war. Sugar consumption fell to about half the pre-war level. In the post-war period, the relatively low sugar intake continued until the mid 1950s. Import of saccharine was, on average, 4.5 times higher during the war in the previous decade.
  • No major differences are found between the observed and the expected number of cases and no trend emerges from the small numbers
  • Men: The risk of bladder tumors in men born 1941 to 1945 is identical with the risk for men born 1931 to 1940. Observed/expected was 22/21.0, RR=1.0 (95% CI: 0.7 to 1.6)
  • Women: The risk among women is reduced, but not statistically different from the risk in the pre-war cohort. Observed/expected was 3/8.9, RR=0.3 (95% CI: 0.1-1.9).
Observed and Expected Numbers of Bladder Tumors in Persons Born in Denmark, 1941 to 1945

 

 
  Males Females
Age Group (Years) Observed 41 to 45

Expected
31 to 35

Expected 36 to 40 Expected 31 to 40 Observed 41 to 45/ Expected 31 to 40 Observed 41 to 45

Expected
31 to 35

Expected 36 to 40 Expected 31 to 40 Observed 41 to 45/ Expected 31 to 40
20 to 24 1 5.61 5.12 5.33 0.2  1  1.3-1  0.02  0.73  1.4
25 to 29 13 10.0 6.4 8.1 1.6  2  2.7-  6.3  4.5  0.4
30 to 34 8 9.4 6.0 7.6 1.1  0  3.2-  4.1  3.7  -
20 to 34 22 25.0 17.5 21.0 1.0  3  7.2-  10.4  8.9  0.3

1: Expected numbers based on age-specific rates for 1931 to 1935 birth cohort.
2: Expected numbers based on age-specific rates for 1936 to 1940 birth cohort.
3: Expected numbers based on age specific rates for 1931 to 1940 birth cohort.

Author Conclusion:
  • This study of the Danish population born during World War II, which may be taken to have been exposed in utero to saccharine, shows no indication of an association with an increased risk for the development of bladder carcinoma during the first 30 to 35 years of life
  • Even though the size of the material cannot, with certainty, exclude a slight increase in risk, the wartime saccharin consumption has, so far, not influenced the bladder cancer rates of that generation
  • The result of this study corresponds with the majority conclusions of other epidemiological investigations regarding the absence or weakness of the risk of human bladder cancer associated with the use of saccharine or artificial sweeteners.
Funding Source:
Government: Danish Cancer Registry
Reviewer Comments:
None listed.
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
 
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? No
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) N/A
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) No
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? No
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) N/A
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? N/A
  4.4. Were reasons for withdrawals similar across groups? N/A
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? No
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? N/A
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) N/A
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? No
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? No
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? N/A
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? No
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? No
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? N/A
  6.6. Were extra or unplanned treatments described? N/A
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? N/A
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? No
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? No
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? No
  7.5. Was the measurement of effect at an appropriate level of precision? No
  7.6. Were other factors accounted for (measured) that could affect outcomes? No
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? No
  8.1. Were statistical analyses adequately described and the results reported appropriately? No
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? N/A
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? No
  8.6. Was clinical significance as well as statistical significance reported? No
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
9. Are conclusions supported by results with biases and limitations taken into consideration? No
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? No
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes