Methyl isothiocyanate

Immunotoxicity

Administrative data

Endpoint:

immunotoxicity: short-term oral

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study well documented, meets generally accepted scientific principles, acceptable for assessment.

Data source

Reference

Reference Type:

publication

Title:

Role of decomposition products in sodium methyldithiocarbamate-induced immunotoxicity.

Author:

Keil DE, Padgett EL, Barnes DB, Pruett SB.

Year:

1996

Bibliographic source:

Journal of Toxicology and Environmental Health, 47 ; 479-492.

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

MITC was administered to mice and the immune parameters known to be most affected by sodium methyldithiocarbamate (SMD) was evaluated.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Methyl isothiocyanate

EC Number:

209-132-5

EC Name:

Methyl isothiocyanate

Cas Number:

556-61-6

Molecular formula:

C2H3NS

IUPAC Name:

isothiocyanatomethane

Details on test material:

MITC provided from Sigma Chemical CO., St Louis, MO.

Test animals

Species:

mouse

Strain:

B6C3F1

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: National Cancer Institute's animal program
- Age at study initiation: 8-10 wks
- Weight at study initiation: 17-22g
- Fasting period before study: no data
- Housing: in AAALAC
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: at least 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-26
- Humidity (%): 40-60
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: hank balanced salt solution

Details on exposure:

Results with vehicle group were consistently similar for all vehicle groups used for this study (several chemicals, several vehicles), suggesting no vehicle-specific zffects in these studies. The volume of vehicle administered was equal to the volume of mITC required for the highest dosage.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

5 days

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
15, 30, 45 mg/kg/d
Basis:
actual ingested

No. of animals per sex per dose:

5 animals / dose

Control animals:

yes, concurrent vehicle

Details on study design:

no

Examinations

Observations and clinical examinations performed and frequency:

Blood was collected on day 6.
On day 8, the mice were sacrified and the thymus was removed.

Sacrifice and pathology:

no data

Cell viabilities:

After sacrifice, the thymus and spleen of each mouse were removed and weighed at the end of the experiment.
THYMUS: Yes
- Method: Fluorescent-labeled monoclonal antobodies were used to quanfify lymphocyte subpopulations in the thymus.

Humoral immunity examinations:

no

Specific cell-mediated immunity:

no

Non-specific cell-mediated immunity:

NATURAL KILLER (NK) CELL ACTIVITY: Yes
- Method: by measuring the lysis of 51Cr-labeled YAC-1 tumor cells by splenocytes in complete RPMI 1640 medium supplemented with 10% FCS.

Other functional activity assays:

no

Other examinations:

no

Positive control:

no

Statistics:

Data were analyzed by one-way analysis of variance followed by Dunnett's t-test. Differences were considered significant at a probability level less than of equal to 0.05.

Results and discussion

Results of examinations

Clinical signs:

not examined

Mortality:

not examined

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Gross pathological findings:

not examined

Details on results:

Body weight decreased by less than 10% of initial body weight for all mice.
Significant changes in thymus weight, white blood cell (WBC) differentials, and thymus subpopulations were noted in mice that were given MITC at 45 mg/kg/d. Total WBC counts were not significantly different in mice treated with MITC (45 mg/kg/d) for 5 d. MITC caused an increase in the percentage of neutrophils in blood to 22.6 ± 3.0%y, as compared to the control value of 11.6% ± 1.6%. The percentage of lymphocytes in the blood decreased to 72.8 ± 4.6% in MITC-treated mice. Mice treated with vehicle had 86.2 ± 1.5% lymphocytes in the peripheral blood. MITC decreased the thymus weight to 18.0 ± 2.7 mg, after 5 d of dosing (vehicle = 47.6 ± 4.4 mg). There were no significant changes in spleen weight or in NK cell activity. Flow cytometric analysis of thymus cells indicated a relatively selective loss of CD4*CD8+ thymocytes and an increase in the percentage (but not the absolute number) of CD4-CD8- thymocytes in MITC-treated mice.

Specific immunotoxic examinations

Cell viabilities:

effects observed, treatment-related

Humoral immunity examinations:

not examined

Specific cell-mediated immunity:

not examined

Non-specific cell-mediated immunity:

no effects observed

Other functional activity assays:

not specified

Other findings:

not specified

Effect levels

Dose descriptor:

LOAEL

Effect level:

15 mg/kg bw/day

Sex:

female

Basis for effect level:

other: Decomposition products on lymphocytes and neutrophiles

Applicant's summary and conclusion

Conclusions:

MITC produced changes that were comparable to those produced by SMD in differential blood leukocyte counts, thymus weight and cellularity, and thymus lymphocyte subpopulations. In addition, mITC produced an increased blood leukocyte numbers (not observed with SMD). However, MITC does not account for all immunological changes noted with SMD. MITC and SMD have immunotoxic effects.

Executive summary:

MITC was administered during 5 days to mice (5 females/dose) and the immune parameters known to be most affected by sodium methyldithiocarbamate (SMD) was evaluated. MITC produced changes that were comparable to those produced by SMD in differential blood leukocyte counts, thymus weight and cellularity, and thymus lymphocyte subpopulations. In addition, mITC produced an increased blood leukocyte numbers (not observed with SMD). However, MITC does not account for all immunological changes noted with SMD. MITC and SMD have immunotoxic effects.