Registration Dossier

Administrative data

Endpoint:
epidemiological data
Type of information:
other: epidemiological study in Humans
Adequacy of study:
key study
Study period:
2009
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Professionally performed and reported epidemiological study with a large number of "patients" and survaillance period of >20 years

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2005

Materials and methods

Study type:
cohort study (retrospective)
Endpoint addressed:
carcinogenicity
Test guideline
Guideline:
other: none
Principles of method if other than guideline:
The aim of this study was to assess and quantify any association between cancer incidence and exposure to dapsone and to Vietnam service among Australian Army servicemen who served in Vietnam during the Vietnam war.
The study cohort ('servicemen') consisted of all 115,407 males who served in the Australian Army for at least one year between 1965 and 1972. Identification of servicemen, those who had been exposed to dapsone, and those treated for malaria was done through Army records. Cancer incidence was determined by reference to State and Territory cancer registry records for the period 1972 to 1989, although not all registries had complete coverage for all of this period. Cancer incidence was examined for all cancers, and for 28 sites of cancer that included the cancers of a priori interest as well as groupings with more than 30 incident cases.
Cancer incidence rates, controlling for age and calendar year, were compared for several subgroups of servicemen:
• dapsone-exposed Vietnam veterans compared with non-exposed Vietnam veterans;
• for dapsone-exposed Vietnam veterans, those with the higher exposures compared with those with the lower exposures;
• Vietnam veterans with malaria compared with other Vietnam veterans;
• Vietnam veterans compared with non-veterans;
• dapsone-exposed Vietnam veterans compared with non-veterans;
• servicemen compared with other males in the Australian population.
Where possible, these comparisons were made separately for National Service (conscript) and Australian Regular Army (volunteer) servicemen.
Cancer mortality was not directly assessed.
GLP compliance:
no
Remarks:
Good Epidemiological Practice Standards applied

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
not specified.

Method

Type of population:
other: vietnam veterans
Ethical approval:
confirmed and informed consent free of coercion received
Details on study design:
The retrospect study cohort ('servicemen') consisted of all 40,207 males who served in the Australian Army for at least one year between 1 January 1965 and 1 March 1972. Identification of servicemen, those who had been exposed to dapsone, and those treated for malaria was done through Army records. Cancer incidence was determined by reference to State and Territory cancer registry records for the period 1972 to 1989, although not all registries had complete coverage for all of this period. Cancer incidence was examined for all cancers, and for 28 sites of cancer that included the cancers of a priori interest as well as groupings with more than 30 incident cases.
Cancer incidence rates, controlling for age and calendar year, were compared for several subgroups of servicemen:
• dapsone-exposed Vietnam veterans compared with non-exposed Vietnam veterans;
• for dapsone-exposed Vietnam veterans, those with the higher exposures compared with those with the lower exposures;
• Vietnam veterans with malaria compared with other Vietnam veterans;
• Vietnam veterans compared with non-veterans;
• dapsone-exposed Vietnam veterans compared with non-veterans;
• servicemen compared with other males in the Australian population.
Where possible, these comparisons were made separately for National Service (conscript) and Australian Regular Army (volunteer) servicemen.
Cancer mortality was not directly assessed.
Sites of cancer (known) are non-Hodgkin's lymphoma, Hodgkin's disease, oral cancer, kidney cancer, bladder cancer and leukemia, soft tissue and other sarcoma, nasal cancer, nasopharyngeal, thyroid cancer, testis cancer and primary liver cancer.
General dosing : 50 - 300 mg/person /day or 1 -2 mg/kg bw /days
Exposure assessment:
measured
Details on exposure:
In this study cohort, a total of 23,262 members of the Australian Army who served in Vietnam were exposed to Dapsone, 25 mg/person/day , while a total of 16,945 Army veterans who served in Vietnam while Dapsone prophylaxis was not in use received no Dapsone. Thus
this is a large population exposed to Dapsone, with a large and appropriately matched control group.
Statistical methods:
This study used three methods to analyse the mortality and cancer incidence experience of the Army veterans. A direct comparison between the Dapsone exposed veterans and the non-exposed veterans was used to calculate Relative Rate (RR). An indirect comparison was also used in which the mortality and cancer incidence of the exposed veterans and the non-exposed veterans was compared to the male Australian population
and is presented as Standardised Mortality or Incidence Ratios (SMR/SIR). Lastly, regression analysis was used to assess whether a doseresponse
relationship between total cumulative Dapsone dose and mortality or cancer incidence exists.

Results and discussion

Results:
509 cancers were identified; 247 exposed veterans, 262 non-exposed veterans.
Cancer incidence rate at ALL sites : 0.88 (general population the respective states : 0.74 / 1.05)
Result: overall no increase in cancer incidences.
None of the specific cancer sites investigated showed a significant increase in Dapsone exposed veterans versus non-exposed veterans, or versus or the population in the homeland.
Confounding factors:
Low power of significance due to the low number of cancer incidences in total and the wide confidence intervals for some comparisons.
Strengths and weaknesses:
Strenghts: Very high number of exposed persons evaluated. Similar size of treated and control group. Detailed records on exposure. Surveillance period is > 24 years.
Weakness: Exposure period is 1 year.

Applicant's summary and conclusion

Conclusions:
The study revealed no evidence that dapsone exposure was associated with an increase in total cancer incidence. Cancer incidence was assessed at six sites that had been suggested in previous publications as those for which an effect of dapsone was most likely. The study does not provide definite evidence of increased cancer incidence at these sites. Similar conclusions apply to the other 22 sites that were examined.
The study revealed no definite evidence that Vietnam service was associated with an increase in total cancer incidence. Cancer incidence was assessed at eight sites that had been suggested in previous publications as those for which an effect of exposure to herbicides was most likely. The study does not provide definite evidence of increased cancer incidence at these sites. Similar conclusions apply to the other 20 sites that were examined.
For those sites of cancer with few cases the confidence intervals were wide. The study results cannot therefore rule out an increased incidence at one or more of these sites.
The most recent cancer registration used in this study was for 1989, 24 years after first exposure to dapsone or service in Vietnam. Accordingly, this study cannot detect cancers that may arise at greater latencies after exposure to dapsone or Vietnam service.
Executive summary:

23,262 Australian army associates have been treated during their service in Vietnam (1965 -1972) with dapsone for malaria prophylaxis. Each service was for at least one year. Relative mortality and cancer incidence rates were calculated for Army personnel who served in Vietnam and consumed dapsone as part of the malarial prophylaxis treatment compared to Army personnel who did not consume dapsone during their Vietnam service. Standardised ratios comparing the two treatment groups to the Australian population were also calculated. The retrospect study shows no effect of dapsone exposure (25 mg/day, ~ 1 year) on mortality rate.

The retrospective cohort studies performed revealed no evidence that dapsone exposure was associated with an increase in total cancer incidence. Cancer incidence was assessed in detail at six sites that had been suggested in previous publications as those for which an effect of dapsone was most likely. The study does not provide definite evidence of increased cancer incidence at these sites. Similar conclusions apply to the other 22 sites that were examined. Cancer incidence was assessed at eight sites that had been suggested in previous publications as those for which an effect of exposure to herbicides was most likely. The study does not provide definite evidence of increased cancer incidence at these sites. Similar conclusions apply to the other 20 sites that were examined. For those sites of cancer with few cases the confidence intervals were wide. The study results cannot therefore rule out an increased incidence at one or more of these sites. The most recent cancer registration used in this study was for 1989.