Beryllium oxide

Acute Toxicity: other routes

Administrative data

Endpoint:

acute toxicity: other routes

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well described study with clear endpoints that were addressed properly.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1984

Materials and methods

Principles of method if other than guideline:

Endotracheal injection of BeO to two strains of Guinea pigs.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Automatically generated during migration to IUCLID 6, no data available

IUPAC Name:

Automatically generated during migration to IUCLID 6, no data available

Details on test material:

BeO (from Brush Wellman). No further information

Test animals

Species:

guinea pig

Strain:

other: Strain 2 and strain 13

Sex:

not specified

Details on test animals or test system and environmental conditions:

200-250g. Animals fed pellet diet supplemented by fresh cabbage.

Administration / exposure

Route of administration:

other: Endotracheal

Vehicle:

physiological saline

Doses:

5 mg BeO in 1 ml physiological saline

No. of animals per sex per dose:

Depending on study.
N= 29/35 for investigation of Be-induced lung disease.

Control animals:

yes

Details on study design:

Induction of lung disease:
Two strains of Guinea pigs were administered 5 mg of BeO per endotracheal. Animals were sacrificed after 2, 6, and 10 weeks after dosing. Lung tissue was examined histologically and for Be content. One group of animals was kept for 1.5 years to determine the long term effect of BeO exposure.

Immunization experiment:
Groups of animals received intradermal injection of 10 mg of BeO in saline and Freund's complete adjuvant. Animals were later skin tested by applying 5 ug of BeSO4 or MgSO4 (control) in saline to the skin of animals receiving intradermal injection and endotracheal administration.

The following assays were performed on lymph node cells: Lymphocyte stimulation assay, macrophage migration inhibition assay, fibroblast inhibition assay

Statistics:

Student's T-test, Mann-Whitney test

Results and discussion

Mortality:

Half of strain 13 animals exposed to BeO did not survive until 1.5 years.

Clinical signs:

None reported/not assessed

Body weight:

No changes reported/assessed

Other findings:

Strain 2 but not strain 13 developed granulomatous lung disease by 6 weeks (please see table 1 below). After 1.5 years, the severity of lung disease in strain 2 was significantly reduced. There was a large degree of low grade granulomatous lung disease in the controls from strain 13 animals. Be was persistent in the lungs with significant amounts after 1.5 years (3500-19000 μg/100 g). Approximately half of strain 13 animals exposed to BeO did not survive after 1.5 years.

No evidence of neoplastic changes after 1.5 years.

Lymphocyte proliferation assay:
Spleens and lymph node cells from strain 2 animals exposed to BeO demonstrated significant uptake of tritiated thymidine. This effect was not seen in strain 13 animals exposed to BeO or in animals treated with latex.

Lymphokine assay:
Lymph node cells from strain 2 animals exposed to BeO produced significant migration inhibition factor activity. This effect was not seen in strain 13 animals exposed to BeO or in animals treated with latex.

Strain 2 animals showed an allergic reaction to beryllium but not magnesium salts after being skin-tested with ug BeSo4 (please see table 2 below). This effect was also seen in strain 2 x strain 13 F1 offspring.

Any other information on results incl. tables

Table 1 Granulomatous lung disease in strain 2 and strain 13 guinea pigs

Time after treatment	Strain 2			Strain 13
	Animals affected		Median grade of disease	Animals affected		Median grade of disease
	n	%
Untreated	3/24	12.5	0	2/23	8.7	0
2 weeks	6/8	75.0	1 +*	1/7	14.3	0
6 weeks	16/17	94.1	2 -3 +**	2/14	14.3	0
8 -10 weeks	10/10	100.0	2 -3 +**	3/8	37.5	0

*p<0.025

**p<0.001

Table 2 Skin test in strain 2 and 13

Type of BeO exposure	Number of animals	Mean diameter of skin reaction
		Strain 2	Strain 13	F1 ( 2 x 13)
None	6	1.3 +/-0.99	0	1.3 +/-1.31
Endotracheal	5	7.8 +/-0.38**	0	7.0 +/-1.13*
Intradermal	2	5.0 +/-1.0	0	ND

*p<0.05

**p<0.0001

Applicant's summary and conclusion

Conclusions:

This study confirmed previous observations of formation of granulomas in animals exposed to BeO. There is a large genetic component deciding the response to BeO in guinea pigs since effects of BeO was seen in 1/2 strains tested.

Executive summary:

Strain 2 and strain 13 guinea pigs were administered BeO by endotracheal injection. Another group of animals received BeO by intradermal injection. The animals were observed at week 2, 6, and 10 for presence of lung disease. At the same timepoints spleens and lymph node cells (tracheobronchial) was removed and immunological parameters assessed in a lymphocyte stimulation assay, macrophage migration inhibition assay, and a fibroblast inhibition assay. Another group of animals were kept for 1.5 years and then evaluated for lung disease and neoplasms. Delayed skin hypersensitivity following exposure to BeSO4 and MgSO4 (control) was also determined.

Strain 2 animals demonstrated granulomatous lung disease after 6 weeks. There was also an effect on the immunological assays performed with reduced uptake of thymidine and migration inhibition in lymphocytes observed. Delayed skin hypersensitivity was also observed in this strain. These effects were not seen in strain 13 animals suggesting a genetic component to BeO response.

After 1.5 years there was no neoplasms observed in any of the exposed animals. The BeO concentration in lung tissue was still significant at this timepoint.