No abstract

Orthopedic medical devices have been extremely successful in restoring mobility, reducing pain, and improving the quality of life for millions of individuals each year. Their success is reflected in the worldwide biomaterials market, in which orthopedic devices dominated sales at approximately $14 billion in 2002. Of this, approximately $12 billion was spent on joint replacements. In spite of their overwhelming benefits and successes, orthopedic medical devices are not without risk of adverse effects. Most adverse joint replacement outcomes are thought to be mediated by degradation products generated by wear and electrochemical corrosion. Infection and flaws in device manufacturing are other noteworthy causes of orthopedic device failure. This article illustrates and discusses the uses, general properties, and limitations (including adverse outcomes) of orthopedic biomaterials, which are fundamental to understanding requirements for improving current orthopedic medical devices.

The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) Project (www.toxpath.org/inhand.asp) is an initiative of the Societies of Toxicological Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying microscopic lesions observed in the skeletal tissues and teeth of laboratory rats and mice, with color photomicrographs illustrating examples of many common lesions. The standardized nomenclature presented in this document is also available on the internet (http://www.goreni.org/). Sources of material were databases from government, academic and industrial laboratories throughout the world.

Bilateral, multicentric renal tubule tumors were found in 4 rats at the termination of 3 separate 90-day toxicity studies during the safety evaluation of 3 unrelated chemicals. The 3 studies were conducted at 2 separate locations, but the rats used were obtained from the same commercial source. The rat strains were (1 male and 1 female case) and Sprague-Dawley (2 female cases). Three of the renal tumor cases were from either the high-dose or mid-dose treatment groups, and 1 case was an untreated control. The tumors were accompanied by multiple foci of atypical tubule hyperplasia but only in the tumor-bearing rats. There were no lesions associated with renal tumor pathogenesis in any of the remaining treated or untreated animals in the 3 studies. In addition, there was no indication of nephrotoxicity in the treated or untreated animals. Tumor morphology was characterized by a generally vacuolated appearance, eosinophilia, cytoplasmic and nuclear pleomorphism, and conspicuously hypertrophied nucleoli. The renal tubule tumors in these 90-day studies were compared to hereditary renal tubule tumors occurring in the Eker rat, a LongEvans derivative with a genetic predisposition to this tumor type. The multiplicity of renal tubule tumors, early age of onset, and tumor morphology described in the cases from the 90-day studies were very similar to those characterizing the hereditary renal tumor model. The following evidence demonstrates that the 4 cases of renal tubule tumor developing in young rats in the course of 90-day studies were of spontaneous origin and not compound-induced: the tumors could not be reproduced by the test compound in a repetition of the 90-day toxicity study in which 2 of the cases occurred; pertinent renal lesions, including atypical hyperplasia, were seen only in tumor-bearing rats; there was an absence of nephrotoxicity in any of the treated rats and an absence of a dose-response relationship for the observed kidney alterations; 1 case was found in an untreated rat. The striking similarity of the tumors in these 4 cases to hereditary renal tumors occurring spontaneously in Eker rats suggests that the 90-day kidney alterations described here may be compatible with a genetic defect. As an alternative explanation, the possibility of a viral etiology was also considered.

Groups of 10 male and 10 female F344/N rats were exposed to 0, 31, 62.5, 125, 250, and 500 ppm of 2-butoxyethanol (BE) by inhalation, 6 hr/day, 5 days/wk, for 13 wk. Four moribund female rats from the 500 ppm group were sacrificed during the first 4 days of exposure, and 1 moribund female from the same group was sacrificed during week 5. Dark irregular mottling and/or loss of the distal tail were noted in sacrificed moribund rats. Similar gross lesions were noted in the terminally sacrificed females exposed to 500 ppm BE. Histologic changes noted in the day 4 sacrificed moribund rats included disseminated thrombosis involving the coccygeal vertebrae, cardiac atrium, lungs, liver, pulp of the incisor teeth, and the submucosa of the anterior section of the nasal cavity. Alterations noted in coccygeal vertebrae from the 500 ppm sacrificed moribund rats included ischemic necrosis and/or degeneration of bone marrow cells, bone-lining cells, osteocytes (within cortical and trabecular bone), and chondrocytes (both articular and growth plate), changes that are consistent with an infarction process. The moribund female rat that was sacrificed during week 5 and those female rats treated with 500 ppm and sacrificed following 13 wk of treatment lacked thrombi, but they had coccygeal vertebral changes consistent with prior infarction and transient or complete bone growth arrest. No bone lesions or thrombi were noted in the male rats treated with the same doses of BE. In conclusion, exposure to 500 ppm BE vapors caused acute disseminated thrombosis and bone infarction in female rats. Possible pathogenic mechanisms are discussed.