Cobalt sulphate

Direct observations: clinical cases, poisoning incidents and other

Administrative data

Endpoint:

direct observations: clinical cases, poisoning incidents and other

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

not stated

Reliability:

other: not rated acc. to Klimisch

Rationale for reliability incl. deficiencies:

other: Any kind of reliability rating is not considered to be applicable, since human studies/reports are not conducted/reported according to standardised guidelines.

Data source

Reference

Reference Type:

publication

Title:

Human metabolism of orally administered radioactive cobalt chloride

Author:

Holstein, H. et al.

Year:

2015

Bibliographic source:

Journal of Environmental Radioactivity 143: 1 - 7.

Materials and methods

Study type:

study with volunteers

Endpoint addressed:

basic toxicokinetics

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

This study investigated the human gastrointestinal uptake, whole-body retention, and excretion of or all administered radioactive cobalt. Eight volunteers (6 males / 2 females) were given a 57CoCl2 so lution containing a stable cobalt carrier (t1/2 = 272 days) and/or a carrier-free 58CoCl2 solution (t1/2 = 71 days). The administered activities ranged between 25.3 and 103.0 kBq.

GLP compliance:

not specified

Remarks:

not specified in the publication

Test material

Test material information

Constituent 1

Reference substance name:

Cobalt dichloride

EC Number:

231-589-4

EC Name:

Cobalt dichloride

Cas Number:

7646-79-9

Molecular formula:

CoCl2

IUPAC Name:

Cobalt dichloride hexahydrate

Test material form:

not specified

Details on test material:

not specified

Specific details on test material used for the study:

RADIOLABELLING INFORMATION
Two solutions of radioactive cobalt chloride were used in this study. A carrier-loaded cobalt solution contained 57Co, which has a physical half-life (T1/2) of 272 days, and main primary photon energies (Eγ) of 122 keV (nγ = 85.6%) and 137 keV (nγ = 10.6%). The solution contained 1.35 μg stable cobalt per unit MBq of 57Co. The other CoCl2-solution contained the radionuclide 58Co (T1/2 = 71 days; Eg = 811 keV; nγ = 0.99), but included no stable cobalt.

Method

Type of population:

general

Subjects:

- Number of subjects exposed: 8 volunteers
- Sex: 6 males / 2 females
- Age: males: 24 - 68 year old; females: 25 and 27 years old
- Height: males: 1.75 - 1.93 m; females: 1.67 m (both)
- Weight: males: 75 - 103 kg; females: 58 and 60 kg
- Volunteers lived and worked in the vicinity of Malmo, in the southern part of Sweden

Ethical approval:

not specified

Route of exposure:

oral

Reason of exposure:

intentional

Exposure assessment:

measured

Details on exposure:

TYPE OF EXPOSURE / EXPOSURE LEVELS: volunteers ingested portions of carrier loaded 57CoCl2 and/or carrier-free 58CoCl2 with well-determined activity (relative uncertainty: 2 SD < 5%).
For the ingestion experiment, varying amounts of the cobalt chloride solutions were mixed with fruit-flavored beverages or soda (final volume: about 200 mL), which were consumed together with a meal (ascorbic acid > 150 mg/portion). Prior to ingestion, the activity of the beverage was measured by high-resolution gamma ray spectrometry using a High Purity Germanium detector (efficiency 56%@1332 keV). The administered activities were as follows:
males:
57Co: 67.1 to 101.1 kBq (5 males)
58Co: 25.3 to 103.0 kBq (5 males)
females:
Co57: 58.7 and 86.4 kBq (2 females)
Co58: 60.1 kBq (1 female)

For the subjects who ingested both 57Co and 58Co, the solutions were administered with at least six months between the occasions, beginning with the carrier-free 58CoCl2, in order to minimize interference between the two isotopes. The adminstered carrier loaded 57CoCl2 portions contained about 0.1 - 0.2 μg stable cobalt/participant. Some of the volunteers could not participate in the intake of both nuclides.

Examinations:

1) Whole-body counting
Whole-body counting was performed in a low-background room. The subjects were scanned in a lying bed geometry, with two NaI(Tl) detectors positioned above and below the patient couch. The scan started above the jugulum and continued for 150 cm in the caudal direction (scanning duration: 1000 seconds). Two consecutive scans were performed. The detectors were connected to a multichannel analyze, and the resulting spectra were evaluated.
To ensure that the volunteers were not contaminated prior to cobalt isotope ingestion, background measurements were performed before oral intake of the solutions. Directly after radiocobalt ingestion, the volunteers were subjected to whole-body scans, providing an individual calibration factor between the number of counts and the activity administered to each volunteer. During the first week after in gestion, scans were performed twice daily, Monday to Friday. After the first week, scans were performed one to three times per week until the primary gamma rays of 57Co and 58Co could no longer be discerned from the background. The whole-body counting data were decay-corrected to the date of ingestion, and then normalized to the ingested amount to obtain each volunteer's retention curve, q(t). These curves were used to evaluate the gastro-intestinal-uptake fraction (f1) and the biological half-time(s) Tb,short, Tb,med and Tb,long.

2) Excretion
Before cobalt solution intake, a diurnal urine sample was collected from the volunteers to determine any presence of gamma-emitting radionuclides that could perturb the excretion study by using a gamma spectrometry system and sample geometry for evaluation. During the first 3 - 5 days after cobalt solution intake, urine was collected daily. Over the following two weeks, diurnal urine was collected 1 – 4 times/week, after which occasional samples were collected until there remained no statistically significant peaks of the primary gamma rays from 57Co or 58Co. The activity in urine was determine d using the gamma spectrometry system. Gamma spectrum acquisition times were set to achieve a counting uncertainty of less than 10%.
The creatinine content in the sampled urine was determined to enable control of and correction for in complete diurnal urine sampling. If a participant has missed to collect one or more urinary fractions of the 24 h urine, it is expected that the urine samples exhibits a significantly lower creatinine content than the standard diurnal excretion rates of this substance, being 14.8 mmol/day d_1 for males and 9.5 mmol/day for females (Rääf et al., 1999)*. A correction of the measured cobalt in the diurnal urine sample was therefore performed in cases where the creatinine content was <90% of the standard diurnal creatinine excretion.

3) Gastro-intestinal uptake
Gastro-intestinal (GI) uptake (f1) has been estimated by taking the retention (=observed whole-body a ctivity divided by the ingested amount of activity of the radionuclide), q(t) at some time within the first few days upon ingestion, and then adding the total fraction of the cobalt found in the accumulated urine samples, f(urine;t), found in the same period: f1 = q(t) + f(urine;t), where q(t) is the fraction of the cobalt radionuclide remaining in the body after a given time (t).
Initially, a time period t = 3 days in the aforementioned equation was chosen as to correspond to the typical GI transit times in humans (Degen and Phillips, 1996.)*. Since the accumulated urinary excretion sampling in some cases extended up to 6 days, an alternative time period of 6 days in equation was set in order to ascertain that q(t)-values were not affected by any remaining unabsorbed cobalt in the GItract. This requires that one takes into account for the fraction of absorbed cobalt being recirculated into GI-tract and excreted through faeces. According to Smith et al. (1972)*, as much as 15% of the initially absorbed inorganic cobalt is excreted via feces during the first few days upon administration.Hence, the equation was modified in order to estimate the total fraction absorbed through GI-tract from urinary and whole-body data: f1 = q(t) + 1.15*f(urine; t).

4) Area-under-curve estimates:
The retention curves of the two radiocobalt nuclides were analyzed to obtain the time-integrated retention at various periods after ingestion. The time-integrated retention components were here denoted as “area-under-curve” (AUC). The AUC-estimations were used to estimate the absorbed dose contributions to the whole-body from the various components observed, represented by the biological half-times Tb,short, Tb,med and if observed, Tb,long. Since the radionuclide concentrations in the specific organs were too small to be measurable, it was assumed that the all components were homogeneously distributed, except the initial one associated with the passage of cobalt through the GI tract. To estimate the absorbed dose, theS-factors (mGy/(Bq d)) were used, which were taken from Snyder et al. (1975)*. The S-factor relates the time-integrated activity concentration of a given radionuclide in an organ or body compartment to an associated absorbed dose.

*Reference:
- Rääf, C.L., Thornberg, C., Mattsson, S., 1999. Urinary excretion measurements for the assessment of body burden of radiocaesium in man: differences between potassium and creatinine normalization. Appl. Radiat. Isot. 51 (1), 505 - 514.
- Degen, L.P., Phillips, S.F., 1996. Variability of gastrointestinal transit in healthy women and men. Gut 39, 299 - 305.
-Smith, T., Edmonds, C.J., Barnaby, C.F., 1972. Absorption and retention of cobalt in man by wholebody counting. Health Phys. 22, 359 - 367.
- Snyder, W.S., Ford, M.R., Warner, G.G., Watson, S.B., 1975. ‘‘S,’’ Absorbed Dose Per Unit Cumulated Activity for Selected Radionuclides and Organs. MIRD Pamphlet No. 11. Society of Nuclear Medicine, New York, NY.

Medical treatment:

not applicable

Results and discussion

Clinical signs:

not examined

Results of examinations:

1) Whole-body counting
- biological half-time (retention up to 7 days; Tb,short ): mean half time of 0.76 ± 0.14 days for carrier-associated 57Co and 0.68 ± 0.13 days for carrier-free 58Co was found (99.6 % and 99.5 % of intake, respectively)
- biological half-time (retention ranging from 7 to 40 days; Tb,med): mean half time of 32.0 ± 4.1 days for carrier-associated 57Co and 33.3 ± 6.8 days for carrier-free 58Co was found (0.34 % and0.46 % of intake, respectively).
- biological half-time (retention up to 40 days; Tb, long): in two males, a long-term component was discernable, albeit with high uncertainties. Tb,long for 58Co was 351 ± 520 days (0.27 % of intake) for one male and 81.5 ± 38.4 days (0.21 % of intake) for the second male. In the former male, an even slower long-term component was observed for 57Co retention (t1/2, long =720 ± 550 days; 0.17 % of intake).

2) Excretion measurement and gastro-intestinal uptake
- after 6 days post-ingestion, the average accumulated excretion (f(urine; t)) was 0.84 ± 0.15 for carrier associated 57Co and 1.02 ± 0.31 for carrier-free 58Co.
- a non-significant systematic difference (p > 0.05) between 57Co and 58Co was observed in the five subjects who ingested both nuclides.
- gastro-intestinal (GI) uptake was found to widely vary among the volunteers.
- after 6 day post-ingestion, the GI uptake was 0.016 ± 0.0021 for carrier associated 57Co and 0.028 ± 0.0048 for carrier-free 58Co (difference between 57Co and 58Co was not significant on a 95 % confidence level).
- after 3 day post-ingestion, the GI uptake was 0.061 ± 0.015 for carrier associated 57Co and 0.11 ± 0.032 for carrier-free 58Co. The GI uptake values were associated with larger individual variation than for the corresponding values for the 6 day post ingestion values, with 76 % and 49 % standard deviation of the mean, respectively.

3) Area-under-curve (AUC) estimates:
- for the short-lived cobalt isotopes 57Co and 58Co, the AUC for the first 7 days after ingestion accounted for 96% (range, 93 - 98%) and 97% (range, 96 - 99%) of the time-integrated absorbed doses for 57Co and 58Co, respectively

Effectivity of medical treatment:

not applicable

Outcome of incidence:

not applicable

Applicant's summary and conclusion

Conclusions:

The observed mean human gastrointestinal uptake, based on 6 days accumulated urinary excretion sampling and whole-body counting, was 0.028 ± 0.0048 for carrier-free 58Co, and 0.016 ± 0.0021 for carrier-associated 57Co. The time pattern of the total retention (including residual cobalt in the gastro-intestinal tract) included a short-term component with a biological half-time of 0.71 ± 0.03 days, an intermediate component with a mean half-time of 32 ± 8.5 days, and a long-term component (observed in two volunteers) with half-times ranging from 81.5 to 721 days for the two isotopes. In conclusion, for the short-lived 57Co and 58Co, more than 95% of the internal absorbed dose was delivered within 7 days following oral intake, with a high individual variation influenced by the transit time of the unabsorbed cobalt through the gastro-intestinal tract.