Dapsone

Carcinogenicity

Description of key information

Dapsone (4,4 -DDS) was tested in a cancer bioassay as part of the US Government carcinogenesis bioassay program in male and female F344 rats (NIH 77-820). Fibrosarcomas in the spleen were observed in male F344 rats treated with 600 or 1200 ppm dapsone in diet for 78 weeks followed by observation for 27-28 weeks. The number of tumors were dose dependent. No tumors were found in female F344 rats or B6C3F1 mice.

In a follow-up study as part of the US Government carcinogenesis bioassay program dapsone was tested in male and female F344 rats along with five structurally related substances which had previously also shown the induce sarcomas in the spleen. The formation of a variety of sarcomas in the spleen of male rats combined with fibrosis was found (Goodman et al. 1984).

Dapsone was tested for possible carcinogenesis in a long-term study in BDIV rats conducted by Gricuite and Tomatis in 1980. Treatment was started in pregnant females during the last part of pregnancy, continued during lactation, then given to offspring after weaning, five times a week for 104 weeks at 100 mg/kg. Spleen sarcomas (related to severe fibrosis of the spleen) were observed in male rats. Although the increase in incidence of tumors in dapsone-treated animals compared to untreated controls was statistically significant it was relatively low overall. The tumors appeared after life-time treatment with maximum tolerated doses and spleen sarcomas were observed mostly in male rats. The results provide only limited evidence of carcinogenicity of dapsone in rats.

Splenic sarcomas are rare, the spleen is usually not a target organ for chemical carcinogenicity. Dapsone did not show mutagenic potential in an Ames bacterial gene mutation assay conducted according to OECD TG471 and in a mammalian gene mutation test according to OECD TG476 (Mouse Lymphoma Assay) in the absence or presence of metabolic activation. Dapsone was found to induce chromosomal aberrations in an in vitro chromosomal aberration study in peripheral human lymphocytes according to OECD TG473 after 3 hours exposure in the absence of metabolic activation. In an in vivo mammalian erythrocyte micronucleus study in mice according to OECD TG474 no potential for the induction of micronuclei was found for dapsone. The absence of clastogenicity potential under in vivo conditions is of higher relevance in the overall assessment of the potential gentoxicity of dapsone to human and therefore it can be concluded that overall, dapsone can be considered as not having genotoxicity potential under in vivo conditions. Therefore, a non-genotoxic mechanism is likely to be the cause for the induction of splenic sarcomas in male rats.

Several structurally related aromatic amines induce the same type of fibrosarcomas in the spleen in the male rat and a common mechanism is proposed as follows: metabolic activation to the corresponding hydroxylamine followed by methemoglobinaemia. Splenic haemosiderosis could be a result of the methemoglobinaemia and may cause splenic fibrosis, formation of splenic sarcomas and finally metastatic sarcomas of different kinds (Goodman et al. 1984).

Long-term health effects from exposure to Dapsone were assessed in a retrospective cohort study on Army Vietnam veterans including a total of 40,207 Army Vietnam veterans : 16,945 veterans who were not exposed to Dapsone and 23,262 veterans who were exposed (Wilson et al. 2007).

In this study, mortality was assessed for over 30 years since exposure and cancer incidence follow-up was studied for 19 years. There was no statistically significant difference in non-cancer mortality between those who consumed Dapsone and those who did not. Dapsone was given in combination with different other medications at 25 mg/day for 30 days or longer. Dapsone use was discontinued during the dry season. Among the 57.8 % of veterans who took Dapsone medication 13.9 % took up to 80 doses, 13.3 % between 80-159 doses, 16.6 % 160-239 doses and 14 % more than 240 doses of 25 mg daily.

There was a modest but statistically significant lower than expected overall cancer incidence, and for some specific cancers, a lower than expected mortality for the Dapsone exposed group. There was a modest but statistically significant lower than expected overall cancer incidence, and for some specific cancers, a lower than expected mortality for the Dapsone exposed group.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

other: retrospective cohort study

Adequacy of study:

key study

Study period:

1973-2001

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Principles of method if other than guideline:

Retrospective cohort study on Army Vietnam veterans including a total of 40,207 Army Vietnam veterans : 16,945 veterans who were not exposed to Dapsone and 23,262 veterans who were exposed.

GLP compliance:

no

Remarks:

not applicable

Species:

other: Human

Sex:

male

Details on test animals or test system and environmental conditions:

Australian Vietnam veteran study cohort:
All male Australian members of the defence forces and the Citizen Military Forces (CMF) who were allotted or deemed allotted for service in Vietnam; all Australian members of the defence forces who landed in Vietnam including those who were seconded to the Army of the Republic of Vietnam (ARVN), the United States Air Force (USAF), the United States Navy (USN) and any other allied service; all members of the Australian Army Training Teams Vietnam (AATTV); who saw service in Vietnam during the period between 23 May 1962 and 1 July 1973.
The mean age for those determined to be alive at the end of the study period was 56 years (range 47-90); 59 years for non-exposed and 55 years for those exposed.

Route of administration:

oral: unspecified

Details on exposure:

25 mg Dapsone preparation drug

Duration of treatment / exposure:

In 1966 : triple-drug regimen consisting of quinine, pyrimethamine and Dapsone.
In 1967, Quinine dihydrochloide (1.8g per day) was given for 3 days and Dapsone (25mg per day) for 30 days.
In November 1968, 25 mg Dapsone was given with the morning Paludrine tablet (Proguanil) from November 1968.
Supplementation was discontinued during dry season as the risk of malaria was much lower, 200 mg Paludrine treatmant (one 100mg tablet in the morning and one in the evening) only was felt sufficient.

Frequency of treatment:

daily

Remarks:

Doses / Concentrations:
25mg
Basis:
actual ingested

No. of animals per sex per dose:

23 262 members of the Australian Army who served in Vietnam were exposed to Dapsone.
16 945 Army veterans who served in Vietnam while Dapsone prophylaxis was not in use received no Dapsone.

Control animals:

yes, concurrent no treatment

Statistics:

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). The indirect comparison was the method used in the first two volumes of this series on Vietnam veteran health. Lastly, regression analysis was used to assess whether a doseresponse relationship between total cumulative Dapsone dose and mortality or cancer incidence exists.

Relevance of carcinogenic effects / potential:

No carcinogenic effect

Key result

Dose descriptor:

NOAEL

Effect level:

> 25 other: mg/day

Based on:

act. ingr.

Remarks:

25 mg Dapsone as daily therapeutic dose

Basis for effect level:

other:

Direct comparison :

The all cause mortality did not differ between the two exposure groups, RR = 1.00 (95% CI 0.94, 1.07). Nor were there statistically significant differences in mortality between the groups for any of the causes of death analysed. When direct comparison between the exposure groups was calculated, overall cancer incidence was 10% lower amongst the Dapsone exposed group compared to the nonexposed veterans, RR = 0.90 (95% CI 0.83, 0.97). All calculations were adjusted for age. There were no cancer types for which the incidence was significantly elevated amongst the Dapsone exposed veterans. The incidence of connective soft tissue cancer, lung cancer and genitourinary cancer was significantly lower amongst those Army veterans exposed to Dapsone.

Dose response :

There was no significant relationship between increasing Dapsone dose and all cause mortality or cancer mortality. There was a borderline significant inverse relationship between Dapsone dose and cancer incidence. That is, with increasing total cumulative Dapsone dose there was a small decrease in the incidence of cancer.

Conclusions:

This study concludes that those who took the anti-malarial Dapsone/Paludrine prophylaxis have not experienced adverse health, as measured by mortality and cancer incidence, compared to those veterans who took anti-malarial treatment without Dapsone.

Executive summary:

In this study assessing long term health effects from exposure to Dapsone during Vietnam service, mortality was assessed for over 30 years since exposure and cancer incidence follow-up was for 19 years. There was no statistically significant difference in non-cancer mortality between those who consumed Dapsone and those who did not. There was a modest but statistically significant lower than expected overall cancer incidence, and for some specific cancers, a lower than expected mortality for the Dapsone exposed group.

This study concludes that those who took the anti-malarial Dapsone/Paludrine prophylaxis have not experienced adverse health, as measured by mortality and cancer incidence, compared to those veterans who took anti-malarial treatment without Dapsone.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Study duration:

chronic

Species:

other: retrospective cohort study on Australian Army veterans

Mode of Action Analysis / Human Relevance Framework

Dapsone has limited carcinogenic potential in male rats. Rare sarcomas of the spleen along with fibrosis are found in male rats after long-term treatment at doses close to the maximum tolerated dose. Tumor formation is suspected to follow a non-genotoxic mechanism and is initiated by the toxic hydroxylamine metabolite. Sustained methemoglobinemia may cause splenic hemosiderosis which in turn may lead to splenic fibrosis ultimately splenic sarcomas and metastatic sarcomas.

No increase in cancer incidence could be found in a well-documented large retrospective study in human after dapsone medication at 25 mg/day for up to and exceeding 240 doses. Therefore, findings from the studies in male rats are not considered to not be human relevant at therapeutic doses (25 mg/day or 0.35 mg/kg bw/day).

Several structurally related aromatic amines induce the same type of fibrosarcomas in the spleen in the male rat and a common mechanism is p

Justification for classification or non-classification

Dapsone has limited carcinogenic potential in male rats. Rare sarcomas of the spleen along with fibrosis are found in male rats after long-term treatment at doses close to the maximum tolerated dose. Tumor formation is suspected to follow a non-genotoxic mechanism and is initiated by the toxic hydroxylamine metabolite. Sustained methemoglobinemia may cause splenic hemosiderosis which in turn may lead to splenic fibrosis ultimately splenic sarcomas and metastatic sarcomas.

No increase in cancer incidence could be found in a well-documented large retrospective study in human after dapsone medication at 25 mg/day for up to and exceeding 240 doses. Therefore, findings from the studies in male rats are not considered to not be human relevant at therapeutic doses (25 mg/day or 0.35 mg/kg bw/day).

A classification as carcinogen according to EU CLP (Regulation (EC) No 1272/2008) paragraph 3.6.2 or UN GHS paragraph 3.6.2 is not warranted.