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Additional toxicological data

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Endpoint:
additional toxicological information
Type of information:
experimental study
Adequacy of study:
disregarded due to major methodological deficiencies
Study period:
not reported.
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
unsuitable test system
Remarks:
Test performed investigating a specific effect in a rat strain bred specifically to be sensitive to antigen challenge. A non-relevant route of exposure was employed which has no toxicological significance. To base conclusions concerning sensitivity on a breed of rat proven to be oversensitive would be inappropriate.

Data source

Reference
Reference Type:
publication
Title:
Plasmacellular lymphadenopathy produced in rats by tin
Author:
Levine S & Sowinski R
Year:
1982
Bibliographic source:
Experimental & Molecular Pathology, 36: 86-98

Materials and methods

Type of study / information:
Lymphadenopathy induced in rats and mice through the intraperitoneal injection of tin metal.
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Tin powder was suspended in saline at 20% concentration in a plastic syringe and 1 mL (200 mg) was injected intraperitoneally through a 21-gauge needle. The rats were fasted the previous night. Errors in dosing was expected due to the rapid settling of the high-density particles.
Rats were killed 14 days after inoculation, except where specified otherwise. Animals without visible tin deposits in the omentum were discarded. Mediastinal lymph nodes were dissected with care to exclude the thymus and were weighed fresh. Nodes, omentum, and spleen were fixed in Bouin's fluid, embedded in paraffin, sectioned and stained with hematoxylin-eosin and sometimes Periodic acid-Schiff-hematoxylin. When the black tin particles were scanty as in spleen, their detection was facilitated by staining with a red dye (nuclear fast red) instead of hematoxylin, for greater contrast. For ultra structure, lymph nodes were fixed and cut into 1-mm blocks in phosphate-buffered 1 % glutaraldehyde-2 % Formalin (pH 7.2), embedded in Araldite, sectioned at 600 Å. and examined in a Siemens 1A electron microscope.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Tin powder (Amax, type TF1)

Results and discussion

Any other information on results incl. tables

1. Response of various rat strains to ip injection of tin -

14 days after injection of 200 mg tin, the peritoneal cavity of all tester strains was opened. Macroscopic and microscopic examinations revealed wide distribution of tin particles in all strains and a conspicuous lymphadenopathy induced by tin metal, particularly prevalent in the Lewis strain. Most of the strains showed a granulomatous response to absorbed tin particles but the Lewis rats had a peculiar plasma cell response - other investigations have confirmed the genetic nature of the response and postulate a link with the major histocompatibility haplotype for Lewis and Lewis hybrid strains. For the remainder of this assay only Lewis rats were used since they were the sole exhibitors of the lymphadenopathy reaction.

2. Tin distribution and plasmacellular lymphadenopathy after various routes of administration -

The pattern of plasmacellular hyperplasia following ip injection was restricted to the draining medastinal nodes with some occurrence in the associated nodes and splenic red pulp. After subplantar injection reactions were noted in popliteal, inguinal, pelvic and lumbar nodes.

3. Tin preparations and attempts to modify them -

Four differing physical grades of tin powder (particle size 1 -40 µm) were injected- the fine particles effected the plasmacellular response (where 50 % by weight of particle size was less than 22.5, 6.6 or 5.6 µm). When tin with a notably higher particle size was used, absorption fell and the plasmacellular reaction was only slightly apparent.

Various chemical treatments were tried involving oxidising agents, concentration changes, pH alterations and addition of stabilising agents. None of these had any significant effect on the induction of lymphoid adenopathy except for sodium borohydride which virtually eliminated the effect. This reagent caused significant agglomeration and aggregation of tin and consequently absorption was markedly reduced. The chemical changes endeavoured had far less of an effect on the lymphoid response than simple changes in particle size and consequent absorption.

4. Serum proteins -

Pooled serum from four Lewis rats, treated with tin powder, was obtained 15 days after innoculation with tin and similar serum obtained from untreated controls. In the tin treated group 259 mg% of IgG was found but only 139 mg% IgG in the controls. The levels of IgA and IgM were similar in treated and control groups, showing no effect.

5. Tin compounds -

If the stimulation effects of metallic tin are dependent on the ionic form, or the local release of ions, then tin compounds may mimic the metallic tin effects. Strongly ionic forms cannot be used since they induce local irritation and renal tubular necrosis. Stannic and stannous sulphides and oxides are insoluble and not induce lymph node enlargement. Stannous pyrophosphate caused renal damage and death in half of the treated rats but only minimal lymph node enlargement.

6. Other metals -

Previous investigations have addressed the effects on draining lymph nodes following administration (ip injection) of silver, aluminium, bismuth, chromium, iron, manganese, nickel, lead, tungsten, silicon and zinc. Unlike tin, these metals only enlarge lymph nodes moderately, primarily due to granulomas, showing none of the plasma cell proliferation typical of tin. In the current investigation additional metals, germanium, platinum and zirconium, close to tin in the periodic table were investigated but these also failed to induce the proliferative reaction.

Applicant's summary and conclusion

Conclusions:
A review of tin toxicity performed by the authors did not describe plasmacellular lymphadenopathy as a reaction in man or animals to exposure to tin or its compounds. The unique reaction in Lewis strain of rats is dependent upon the injection of a large dose of metallic tin powder, with small particle size, into a highly susceptible animal model. A granulomatous reaction following absorption of metallic tin is common and a plasmacellular hyperplasia is a freqent inflammatory response following subacute or chronic exposure. But the hyperplastic response to acute administration of metallic tin is severe and apparently unique - none of the elements in the IVA gouping of the periodic table replicate the tin effect.
The Lewis rat is markedly susceptible to experimental autoimmune disease but this does not appear to predispose it to the extreme lymphoid response to tin. The particle size appears to be critical - where aggregation occurs or particles exhibit a degree of stickiness, absorption is reduced or impaired and the tin effect reduced. The increase in serum IgG in rats with plasmacellular lymphadenopathy suggested that tin may be functioning as a hapten.
Executive summary:

This assay was conducted to utilise a specific animal model - the induction by tin of plasma cell hyperplasia is observed in the Lewis strain of rat, while other metals produce granulomas in thedraining lymphatics following intraperitoneal injection, metallic tin powder produces a dramatic proliferation of plasma cells and Russell cell bodies.

Metallic tin powder induced granulomatous inflammation at the site of innoculation and also in draining lymph nodes. Draining lymph nodes were enlarged by the proliferation of plasma cells and Russell body cells. The granulomatous response was common to many rat strains but only the Lewis rats developed plasmacellular hyperplasia. The Lewis response lasted for circa 3 weeks - spontaneous abatement was not due to corrosion of the tin particles (tin recovered from tissues two weeks after innoculation were still capable of inducing plasma cells). Heat-treatment of tin, use of organic slvents and several oxidising orreducing agents did not change the potency of metallic tin to induce plasmacellular hyperplasia in Lewis rats. Other metals, and tin coumpounds, did not replicate the effect.

Serum IgG levels were elevated in tin treated rats but the immunological significance of the plasmacellular hyperplasia was not determined.

While the paper suggests tin may be a useful model for the study of plasma cell hyperplasia and tentatively postulates a role for tin as an essential micronutrient, it has to be recognised that plasmacellular lymphadenopathy was only found in a restricted period after innoculation with very large doses of tin metal into a particularly susceptible rodent model (the effect has not been reported for other rat strains).