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Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well designed and documented study. Restrictions - no claims that the study had been conducted and reported according to internationally accepted guidelines or in compliance with the principles of GLP.

Data source

Reference
Reference Type:
publication
Title:
Old age and gender influence the pharmacokinetics of inhaled manganese sulfate and manganese phosphate in rats
Author:
Dorman DC, McManus BE, Marshall MW, James RA and Struve MF
Year:
2004
Bibliographic source:
Toxicol Appl Pharmacol 197:113-124

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Rat (M+F) exposed by inhalation (whole body) to air, or 0.01, 0.1, 0.5 mg Mn/m3 MnSO4 or 0.1 mg Mn/m3 hureaulite for 6h/day, 5 d/wk for 90d. Tissue Mn concs examined after 32 d and 91 d (M), 65 d (F) with 45 day post exposure period. Iv Mn Tracer study at 90-days to assess whole-body clearance rates.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Manganese (II) sulphate monohydrate (MnSO4.H20) was obtained from Aldrich chemical company,InC. Manganese(Mn2+) phosphate, in the mineral form hureaulite (Mn5(PO4)2[(PO3)OH]2.4H20), was obtained from Alfa Aesar.
Radiolabelling:
yes
Remarks:
54Mn

Test animals

Species:
rat
Strain:
other: CD
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories
- Age at study initiation: 16 months old
- Housing: Individually housed rats were maintained in stainless-steel cage with wire mesh floors or exposure cage rack units
- Diet (e.g. ad libitum): a pelleted, semipurified AIN-93G certified diet from Bioserv( Frenchtown, NJ) formulated to contain approximately 10ppm manganese and 35ppm iron was given ad libitum(except during inhalation exposures) throughout the study
- Water (e.g. ad libitum):Reverse-osmosis-purified water was available ad libitum
- Acclimation period:30 days before the start of inhalation exposure


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±4
- Humidity (%): 30-70
- Air changes (per hr): 10-15 air change per hour
- Photoperiod (hrs dark / hrs light): lights on approximately 0700-1900.


IN-LIFE DATES: From: To:

Administration / exposure

Route of administration:
inhalation: aerosol
Duration and frequency of treatment / exposure:
6h/day, 5 d/wk for 90d
Doses / concentrations
Remarks:
Doses / Concentrations:
0.01, 0.1, 0.5 mg Mn/m3 MnSO4 or 0.1 mg Mn/m3 hureaulite
No. of animals per sex per dose:
8
Control animals:
yes
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled : blood, lungs. liver, cerebellum and pancreas
- Time and frequency of sampling: Tissue Mn concs examined after 32 d and 91 d (M), 65 d (F) with 45 day post exposure period



Statistics:
The data for quantitative, continuous variables were compared for the exposure and control groups by tests for homogeneity of variance (Leven's test), analysis of variance(ANOVA), and Dunnett's multiple comparison procedure for significant ANOVA.

Results and discussion

Any other information on results incl. tables

The MMAD were 1.85, 1.92 and 2.03 um for the target 0.01, 0.1 and 0.5 Mn/m3 for the manganese sulphate dose groups. 

Gender and age did not affect manganese delivery to the striatum, a known target site for neurotoxicity in humans, but did influence manganese concentrations in other tissues. End-of-exposure olfactory bulb, lung, and blood manganese concentrations were higher in young male rats than in female or aged male rats and may reflect a portal-of-entry effect. Old male rats had higher testis but lower pancreas manganese concentrations when compared with young males. Young male and female rats exposed to MnSO4 at 0.5 mg Mn/m3 had increased (54)Mn clearance rates when compared with air-exposed controls, while senescent males did not develop higher (54)Mn clearance rates.

Table 1 Mean (±SEM) tissue manganese concentration (µg Mn g-1tissue wet weight) following subchronic exposure (90days) to MnSO4 or hureaulite by inhalation

 

Tissues

Exposure group(nominal exposure concentration mg Mn m-3

 

Air

MnSO4

Hureaulite

 

0

0.01

0.1

0

0.01

Young females

 

 

 

 

 

Olfactory bulb

0.58±0.02

0.65±0.02

0.99±0.11*

1.46±0.05*

0.77±0.03

Cerebellum

0.55±0.05

0.54±0.02

0.56±0.03

0.59±0.02

0.54±0.02

Striatum

0.54±0.08

0.48±0.03

0.67±0.09

0.73±0.05

0.90±0.24

Lung

0.21±0.04

0.18±0.01

0.22±0.01a

0.29±0.01

0.46±0.04*

Liver

2.33±0.14

2.23±0.11

2.27±0.11

2.53±0.09

2.33±0.09

Femur

0.61±0.05

0.68±0.08

0.68±0.09

0.69±0.06

0.60±0.04

Ovary

0.60±0.11

0.60±0.03

0.66±0.04a

0.61±0.03

0.52±0.02

Pancreas

2.47±0.04

2.24±0.22

2.44±0.09

2.84±0.13

2.46±0.06

Blood

0.04±0.01

0.02±0.01

0.04±0.01

0.03±0.01

0.04±0.02

Group size

8

8

8

8

8

Young males

 

 

 

 

 

Olfactory bulb

0.55±0.06

0.70±0.02*

1.25±0.06*a

1.95±0.09*

0.83±0.02*

Cerebellum

0.44±0.03

0.46±0.02

0.52±0.02 a

0.59±0.03*

0.47±0.02

Striatum

0.48±0.03

0.51±0.04

0.84±0.12*a

0.72±0.02*

0.51±0.01

Lung

0.18±0.01

0.27±0.03*

0.30±0.02*a

0.36±0.02*

0.64±0.05*

Liver

1.83±0.02

1.77±0.07

1.81±0.08

2.04±0.09

1.94±0.06

Femur

0.62±0.04

0.61±0.02

0.67±0.03

0.86±0.05*

0.67±0.03

Testes

0.29±0.02

0.32±0.02

0.31±0.02

0.35±0.02

0.31±0.01

Pancreas

2.15±0.06

2.49±0.07*

2.43±0.06*a

2.65±0.06*

2.24±0.04

Blood

0.05±0.02

0.05±0.02

0.07±0.01

0.08±0.02

0.03±0.01

Group size

8

8

8

8

8

Senescent males

 

 

 

 

 

Olfactory bulb

0.51±0.03

0.55±0.03

1.01±0.06*a

1.51±0.13*

0.66±0.04*

Cerebellum

0.46±0.02

0.51±0.01

0.54±0.02*

0.59±0.02*

0.49±0.01

Striatum

0.52±0.08

0.48±0.01

0.60±0.02

0.77±0.05*

0.55±0.04

Lung

0.26±0.07

0.21±0.01

0.29±0.02a

0.40±0.03

0.61±0.05*

Liver

1.87±0.09

1.64±0.09

2.02±0.13

2.08±0.05

2.05±0.14

Femur

0.54±0.07

0.53±0.02

0.51±0.02

0.50±0.03

0.51±0.03

Testes

0.40±0.05

0.33±0.03

0.35±0.03

0.40±0.02

0.30±0.04

Pancreas

1.69±0.13

1.60±0.28

2.04±0.16

2.12±0.14

1.89±0.13

Blood

0.03±0.01

0.05±0.01

0.03±0.01

0.03±0.01

0.05±0.02

Group size

7

7

7

7

7

 

a Tissue manganese concentration in rats exposed to MnSO4 at 0.1 mg Mn/m3 were significantly different from those seen in hureaulite exposed rats

* Significantly different when compared with air exposed control rats(P<0.05)

 

Table 2 Mean (±SEM) tissue manganese concentration (µg Mn g-1tissue wet weight) 45 days after the end of a 90-day inhalation exposure to MnSO4 or hureaulite

 

 

Tissues

Exposure group(nominal exposure concentration mg Mn m-3

 

Air

MnSO4

Hureaulite

 

0

0.01

0.1

0

0.01

Young females

 

 

 

 

 

Olfactory bulb

0.59±0.05

0.55±0.03

0.59±0.02

0.58±0.01

0.57±0.02

Cerebellum

0.53±0.02

0.51±0.01

0.51±0.01

0.52±0.01

0.50±0.01

Striatum

0.48±0.04

0.50±0.02

0.48±0.01

0.55±0.04

0.49±0.02

Lung

0.25±0.03

0.25±0.03

0.24±0.01

0.23±0.01

0.29±0.05

Liver

2.34±0.11

2.51±0.17

2.43±0.11

2.44±0.07

2.34±0.05

Femur

0.60±0.04

0.52±0.03

0.62±0.05

0.78±0.06*

0.55±0.03

Ovary

0.46±0.05

0.54±0.03

0.47±0.04

0.46±0.03

0.54±0.05

Pancreas

2.60±0.04

2.48±0.22

2.52±0.09

2.58±0.13

2.67±0.06

Blood

0.06±0.02

0.05±0.03

0.03±0.01

0.05±0.02

0.04±0.01

Group size

8

8

8

8

8

Young males

 

 

 

 

 

Olfactory bulb

0.65±0.07

0.69±0.06

0.68±0.02

0.81±0.04*

0.68±0.01

Cerebellum

0.52±0.03

0.55±0.02

0.56±0.02

0.63±0.05

0.54±0.03

Striatum

0.45±0.06

0.49±0.04

0.46±0.03

0.49±0.04

0.45±0.02

Lung

0.15±0.00

0.16±0.01

0.20±0.02

0.17±0.01

0.19±0.01

Liver

1.76±0.07

1.76±0.14

1.64±0.11

1.97±0.10

1.86±0.09

Femur

0.56±0.03

0.52±0.03

0.54±0.03

0.68±0.03*

0.54±0.03

Testes

0.25±0.02

0.28±0.01

0.26±0.02

0.25±0.02

0.26±0.01

Pancreas

2.18±0.02

2.17±0.11

2.02±0.24

2.27±0.04

1.97±0.22

Blood

0.06±0.02

0.04±0.01

0.06±0.01

0.05±0.01

0.05±0.01

Group size

8

8

8

8

8

Senescent males

 

 

 

 

 

Olfactory bulb

0.53±0.02

0.57±0.04

0.56±0.02

0.74±0.08*

0.53±0.02

Cerebellum

0.64±0.07

0.52±0.03

0.60±0.03

0.63±0.07

0.51±0.01

Striatum

0.48±0.02

0.50±0.02

0.51±0.02

0.57±0.02*

0.49±0.02

Lung

0.18±0.01

0.17±0.01

0.19±0.01

0.17±0.01

0.19±0.02

Liver

1.74±0.07

1.77±0.10

1.97±0.13

1.74±0.08

1.92±0.15

Femur

0.53±0.04

0.60±0.02

0.62±0.03

0.63±0.03

0.62±0.03

Testes

0.31±0.02

0.34±0.01

0.37±0.02

0.35±0.01

0.40±0.04

Pancreas

1.87±0.10

1.82±0.10

1.73±0.22

1.72±0.16

1.66±0.18

Blood

0.04±0.01

0.05±0.02

0.05±0.02

0.02±0.01

0.03±0.01

Group size

8

8

8

8

9

 

* Significantly different when compared with air exposed control rats(P<0.05)

 

Table 3:Selected pharmacokinetics parametersa(Mean±SEM) describing 54Mn elimination in rats following a subchronic 90-day inhalation exposure to MnSO4 or hureaulite

 

Tissues

Exposure group(nominal exposure concentration mg Mn m-3

 

Air

MnSO4

Hureaulite

 

0

0.01

0.1

0

0.01

Young females

 

 

 

 

 

A (kBq)

7.2±0.7

8.0±0.6

8.5±0.6

9.5±0.6

7.9±0.4

B(kBq)

16.2±0.7

15.3±0.6

14.9±0.6

14.0±0.6

15.5±0.4

T1/2α(days)

1.6±0.5

2.3±0.5

1.6±0.2

1.7±0.4

2.0±0.6

T1/2β(days)

21.3±0.9

22.4±0.7

21.3±0.8

20.7±0.6

21.3±0.7

Clb(kBq day-1* 10-3)

36.0±0.5

35.3±0.9

39.1±1.2

42.2±1.5*

37.2±1.0

AUC (kBq * day)

514±7

526±13

476±14

442±15*

500±13

Group size

8

8

8

8

8

Young males

 

 

 

 

 

A (kBq)

8.3±0.5

7.9±0.5

7.6±0.4

9.7±0.3

8.5±0.4

B(kBq)

14.9±0.5

15.4±0.5

15.7±0.4

13.6±0.4

14.8±0.4

T1/2α(days)

2.2±0.4

1.6±0.3

1.4±0.2

5.8±3.5

1.7±0.3

T1/2β(days)

30.5±0.9

29.0±1.0

28.3±1.1

29.3±1.2

30.9±0.8

Clb(kBq day-1* 10-3)

27.2±0.5

28.3±1.1

28.6±0.9

30.7±1.0*

27.3±0.5

AUC (kBq * day)

681±13

660±26

652±19

607±20

679±14

Group size

8

8

8

8

8

Aged males

 

 

 

 

 

A (kBq)

33.3±.3.4

32.4±1.8

29.1±5.3

35.4±1.4

28.3±2.1

B(kBq)

27.9±3.4

28.8±1.7

32.1±5.3

25.5±1.5

30.4±1.0

T1/2α(days)

4.6±0.4

4.6±0.5

3.0±1.1

4.1±0.6

4.4±0.3

T1/2β(days)

35.5±3.2

40.9±2.4

33.4±6.0

37.5±1.9

37.5±2.3

Clb(kBq day-1* 10-3)

40.6±4.2

32.4±0.8

40.0±3.6

39.6±1.9

33.9±1.1

AUC (kBq * day)

1603±152

1894±104

1564±129

1564±277

1812±61

Group size

7

6

4

5

6

 

a Clb(total body clearance), T1/2α andT1/2β ( initial and terminal phase elimination half-lives).AUC (area under the curve), A and B (y-intercept associated with the initial and terminal elimination phases)

* Significantly different when compared with air exposed control rats(P<0.05)

 

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study results
This study provides new information about age and gender effects on manganese concentrations in the brain and other tissues following high-dose subchronic manganese inhalation. These studies also contribute to our understanding to the inhalation exposure conditions that lead to increased concentrations of the metal within the central nervous system and other target organs. The data collected during this study should useful in the development of physiologically based pharmacokinetic (PBPK) models for manganese that consider aged individuals and other potentially sensitive subpopulations.