Intraarticular carcinogenesis bioassays of CoCrMo and TiAlV alloys in rats

The Journal of Arthroplasty Vol. 10 No. 1 1995

Intraarticular Carcinogenesis Bioassays of CoCrMo and TiA1V Alloys in Rats Courtland

G. L e w i s , M D , * R o b e r t M . B e l n i a k , M D , * M a r i l y n C. P l o w m a n , S i d n e y M . H o p f e r , P h D , t J o s e p h A. K n i g h t , MD,:[: a n d F. W i l l i a m S u n d e r m a n , Jr, M D t

BS,t

Abstract: Wear-debris powders of cobalt-chromium-molybdenum (CoCrMo) and titanium-aluminum-vanadium (TiAIV) alloys, which are widely used for orthopedic implants (eg, hip and knee prostheses), were tested for carcinogenic activity following intraarticular administration (20 mg/rat) to groups of 44 male Fischer-344 rats (Charles River Breeding Laboratories, North Wilmington, MA). Control groups received similar intraarticular injections of either a noncarcinogen (manganese powder, negative control rats) or a potent carcinogen (nickel subsulfide powder, positive control rats). The experimental groups of 8-12 rats were observed for 24 months after injection. No local tumors developed at the injection site in the negative control rats or in rats that received the CoCrMo or TiA1Vpowders; poorly differentiated or pleomorphic sarcomas developed at the injection site in 10 of the 12 positive control rats that were treated with nickel subsulfide. Incidences of primary tumors distant from the injection site did not differ significantly among the experimental groups. This study shows that, under experimental conditions, any carcinogenic activity of CoCrMo or TiA1V weardebris powders is weak in comparison to nickel subsulfide. Based on this study and observations in other laboratories, intraarticular administration of test materials to rats provides a practical, reliable, and biologically relevant method for carcinogenesis testing of biomaterials used for orthopedic implants. Key words: cobalt-chrome-molybdenum alloy, titanium-aluminum-vanadium alloy, orthopedic prostheses, carcinogenesis bioassays, intraarticular injection, wear-debris particles.

Sunderman 1'2 and Visuri and Koskenvuo 3 have summarized the inconclusive evidence for tumorigenicity of metal alloys used in orthopedic prostheses and tabulated 18 patients w h o reportedly developed malignant tumors at sites of metal-containing implants, primarily those fabricated of cobalt or nickel alloys. The International Agency for Research on Cancer has evaluated the carcinogenic risks from cobalt and nickel alloys, concluding that the published

studies on humans are inadequate to allow conclusions about carcinogenicity, but that the studies on experimental animals furnish sufficient evidence for the carcinogenicity of metallic cobalt and nickel and limited evidence for the carcinogenicity of cobalt and nickel alloys. 4,5 Because of such findings, the orthopedic community, including surgeons and prosthesis manufacturers, is becoming concerned about the possibility that patients may, in rare instances, develop tumors after loosening of metal joint prostheses or corrosion of implanted metal alloys. However, alternatives to the use of these alloys are limited, owing to biomechanical and biocompatibility considerations. In previous studies, our research group found increased concentrations of cobalt, nickel, or chromium in the body fluids of several arthroplasty pa-

Prom the Departments of *Orthopaedic Surgery and ~Laboratory Medicine, University of Connecticut Medical School, Farmington, Connecticut, and ~:Department of Pathology, University of Utah Medical School, Salt Lake City, Utah. Supported by research grants from the American Cancer Society (ACS-IN- 152E-68) and Northeast Utilities Company. Reprint requests: Courtland G. Lewis, MD, University of Connecticut Health Center, 10 Talcott Notch Road, Farmington, CT 06034-4037.

75

76

The Journal of Arthroplasty Vol. 10 No. 1 February 1995

tients with local complications (eg, loosening or corrosion of hip or knee prostheses) or systemic disease (eg, renal insufficiency).6,7 Our studies also demonstrated a gradient of cobalt concentrations in the biopsies of periprosthetic soft tissues from patients with failed hip prostheses that contained cobalt-chromium-molybdenum (CoCrMo) alloy. 8 This study describes a pilot study in which two alloys (CoCrMo and titanium-aluminum-vanadium [TiAlV]), commonly used in orthopedic implants, were tested for carcinogenicity by intraarticular administration to rats.

Materials and Methods Carcinogenesis bioassays were performed on the following materials: (1) wear-debris powder of CoCrMo alloy (American Society for Testing Materials [ASTM] alloy F-75-82: > 59% cobalt, 27-30% chromium, 5-7% molybdenum, 1% manganese, 1% silicon, < 1% nickel, < 0.75% iron, 0.35% carbon; Zimalloy, provided by Dr. H. R. Shetty, Zimmer, Warsaw, IN), (2) wear-debris powder of TiAlV alloy (ASTM alloy F-136-84: > 89% titanium, 5.5-6.5% aluminum, 3.4-4.5% vanadium, 0.25% iron; Tivanium, provided by Dr. n. R. Shetty, Zimmer), (3) manganese powder (negative control group), and (4) crystalline nickel subsulfide powder (otNi3S2 positive control group). The wear-debris samples were prepared by Zimmer as follows. Metal blocks of CoCrMo or TiA1V alloys were passivated in 40% nitric acid for 30 minutes at 25°C prior to grinding by surfaceto-surface friction using a metal-on-metal sliding wear machine with Ringer's saline solution as the lubricant. Energy-dispersive radiographic analyses did not disclose any contamination of the wear-debris samples; measurements by scanning electron microscopy (SEM) yielded particle dimensions from 1.5 to 50 /,m (CoCrMo alloy) and 20 to 650 /,m (TiA1V alloy). The TiAlV sample was ground with an agate mortar to produce particles (diameter, - 50 /_~m) suitable for intraarticular injection. Manganese powder (94% manganese, 6% oxygen; median particle diameter, 1.5/zm by SEM; provided by Dr. L. J. Cralley, National Institute of Occupation Safety and Health, Cincinnati, OH) was used as the negative control material, since it has consistently failed to produce tumors following intramuscular or intrarenal administration to Fischer-344 rats (Charles River Breeding Laboratories, North Wilmington, MA) in previous carcinogenesis bioassays.9-~3 Nickel subsulfide powder (otNi3S2; median particle diameter, 1.5 ~m by SEM; provided by Dr. S. Warner, INCO, Toronto) was used as the positive control material,

since it has consistently induced malignant tumors following administration to Fischer-344 rats by intramuscular, intrarenal, intratesticular, and intraocular injections in previous carcinogenesis bioassays.9-12A4-16 The experimental animals were 44 male albino rats of the Fischer-344 strain. They were kept in polypropylene cages with wood-chip bedding in a laminarflow hood in a temperature-controlled room (25°C _+ I°C) with a 12-hour diurnal light/dark cycle. The rats were fed Ralston Purina rat chow (St. Louis, MO) and tap water ad libitum. The bioassay protocol was approved by the Animal Experimentation Committee of the University of Connecticut Health Center. When the rats were 2 - 4 months old, the test powders were administered by intraarticular injection (20 mg/rat) using an adaptation of the technique described by Uchida ~7 and Howie and Vernon-Roberts. 18'~9 The metal powders were tested without sterilization, to avoid changing their biologic properties by exposure to heat or chemicals. The rats were anesthetized with diethyl ether; the hair around the knee of the right hind leg was removed with an electric shaver and the skin was incised to expose the patellar tendon. With the knee held at - 3 0 ° of flexion, the test material was injected in 0.1 mL of vehicle through the patellar tendon into the suprapatellar synovial pouch by means of a syringe (0.5 mL, Hamilton Company, Reno, NV) and needle (~<21 gauge). The vehicle was either NaC1 solution (150 mmol/L) for the CoCrMo, manganese, and cxNi3S2 powders, or glycerol (50%, v/v) for the TiAIV powder. Distention of the suprapatellar pouch was taken to indicate a successful injection. There were 8-12 rats in each experimental group. During the 2 years after injection, the rats were weighed monthly and examined biweekly for tumors at the injection site. One rat in the negative control group was dropped from the bioassay, as it escaped from the cage at 18 months after injection. Rats that survived until the end of the carcinogenesis bioassay were killed at 24 months after injection. The rats were autopsied, and selected tissues, including the injection site, were fixed in buffered formalin, embedded in paraffin, sectioned at 4 /~m, stained with hematoxylin and eosin, and examined by light microscopy. Statistical comparisons of tumor incidences in the experimental groups were performed by chi-square and Fisher's exact tests, and comparisons of survival periods were performed by the Mann-Whitney U test using the StatView program (version 4.0, Abacus Concepts, Berkeley, CA) on a Macintosh computer.

Carcinogenesis Tests of CoCrMo and TiAIV Alloys

Fig. 1. Cumulative mortality plots for rats in carcinogenesis bioassays of the four metal powders (20 mg/rat) administered by intraarticular injection into the suprapatellar synovial pouch of the right hind leg. The negative control group received manganese (Mn) powder, the positive control group received nickel subsulfide (c~Ni3S2) powder, and the two test groups received either cobait-chromium-molybdenum (CoCrMo) or titanium-aluminum-vanadium (TiAlV) weardebris powders.

•

Lewis et al.

[]

aNi3S2 powder

0

Mn powder

0

CoCrMo powder

&

TiAIV powder

100

77

~ & I

4.~ (--

o£..

80-

4..1

i ,T": i

4~--;

60-

f...

o

E

40-

m

.2

m 20-

E (.3

(i~'"O" -0"0'" 0"" O- -0" ~

00

3

6

9

-o-o--o---" ~ O 12

15

i 18

21

24

Interval after injection (months)

Results C u m u l a t i v e m o r t a l i t y c u r v e s for t h e f o u r e x p e r i m e n t a l g r o u p s are s h o w n in F i g u r e 1. No significant differences w e r e f o u n d b e t w e e n t h e m e d i a n survival p e r i o d of 23 m o n t h s in t h e n e g a t i v e c o n t r o l g r o u p that was treated with manganese powder and the c o r r e s p o n d i n g p e r i o d s of 22 a n d 21 m o n t h s in t h e g r o u p s t h a t w e r e t r e a t e d w i t h C o C r M o o r TiA1V w e a r - d e b r i s p o w d e r s respectively. I n t h e positive c o n t r o l g r o u p t h a t w a s t r e a t e d w i t h ~Ni3Sx p o w d e r , the m e d i a n survival p e r i o d of 10 m o n t h s w a s signific a n t l y s h o r t e r t h a n t h a t in t h e o t h e r g r o u p s (P < .01). T u m o r i n c i d e n c e s in t h e e x p e r i m e n t a l g r o u p s are listed in Table i. T u m o r s d e v e l o p e d at t h e i n j e c t i o n site in l 0 o f t h e 12 rats in t h e p o s i t i v e c o n t r o l g r o u p t h a t w e r e t r e a t e d w i t h (~Ni3S2 (P < .01). I n t h e positive c o n t r o l g r o u p , t h e m e d i a n l a t e n t p e r i o d f r o m

Table 1.

Tumors in

Negative

ControlGroup (Mn powder)*

n Rats with sarcomas at the injection site Rats with metastases at distant sites Rats with primary tumors at other sites

i n j e c t i o n of aNi3S2 to d e t e c t i o n of a t u m o r in the k n e e j o i n t w a s 8 m o n t h s ; t h e local t u m o r s in t h e oLNi3S2-treated rats w e r e all p a l p a b l e b y 9 m o n t h s after injection. The t u m o r s g r e w r a p i d l y a n d a t t a i n e d d i a m e t e r s of 4 - 7 c m b e f o r e t h e rats died. No local t u m o r s w e r e f o u n d in rats t h a t r e c e i v e d i n t r a a r t i c u l a r injections of t h e C o C r M o or TiA1V w e a r - d e b r i s p o w ders. I n o r d e r to a t t a i n statistical significance (P < .05), t h r e e or m o r e rats w i t h local t u m o r s w o u l d h a v e b e e n r e q u i r e d in t h e s e test groups. P o w e r a n a l y s e s ( p o w e r = 0.8, P = .05) s h o w e d t h a t 100 r a t s / g r o u p w o u l d b e n e e d e d to s u b s t a n t i a t e a t u m o r i n c i d e n c e of 5% a n d 500 r a t s / g r o u p to s u b s t a n t i a t e a t u m o r i n c i d e n c e o f 1%, a s s u m i n g t h a t n o local t u m o r s w e r e o b s e r v e d in a n e q u a l g r o u p of c o n t r o l rats. Therefore, in v i e w o f t h e s m a l l n u m b e r of rats, t h e n e g a t i v e o u t c o m e of this s t u d y d o e s n o t i n d i c a t e t h a t t h e i m p l a n t m a t e r i a l s are d e v o i d of p o t e n t i a l c a r c i n o g e n i c activity.

the Experimental Groups Positive

ControlGroup

(~Ni3Sz powder)*

CoCrMo Wear-debris Powder*

TiA1V Wear-debris Powder*

11 0

12 i0-{

12 0

8 0

0 3

1 0

0 2

0 4

* Test powders were injected into the suprapatellar synovial pouch of the right hind leg (20 mg/rat). ]- P < .01 versus the negative control group that received an intraarticular injection of Mn powder. Mn, manganese; ~Ni3Sx, crystalline nickel subsulfide; CoCrMo, cobalt-chromium-molybdenum; TiA1V,titanium-aluminum-vanadium.

78

The Journal of Arthroplasty Vol. 10 No. 1 February 1995

The 10 tumors that developed in the positive control rats at the site of the intraarticular injection of ~Ni3S2 were either poorly differentiated or pleomorphic sarcomas and were difficult to classify by the usual clinical criteria. Most of the neoplasms had histologic features of malignant fibrous histiocytomas; some were more suggestive of fibrosarcomas or leiomyosarcomas; no r h a b d o m y o s a r c o m a s or synovial sarcomas were found. Four of the cxNi3S2-induced sarcomas are illustrated in Figure 2. In one o~Ni3S2treated rat with a sarcoma of the injected knee, me-

Fig. 2. Histologic appearance of four sarcomas in the treated joints of rats in the positive control group that received nickel subsulfide (20 rag/rat) by intraarticular injection. Note the poorly differentiated and pleomorphic appearance of the sarcomas, with features suggestive of (a) fibrosarcoma, (b, d) malignant fibrous histiocytoma, and (c) spindle cell sarcoma (hematoxylin and eosin, original magnification ×300). Mitotic figures are identified by arrowheads.

tastases were found in the retroperitoneal l y m p h nodes. No primary tumors at locations other than the injection site were found in the positive control group. A few primary neoplasms were observed in the other experimental groups at locations distant from the injection site. These included four tumors (abdominal papillary adenoma, dermal neurofibroma, abdominal lipoma, and thoracic lipoma) in three rats in the negative control group, two tumors (acinar cell carcinoma of the neck and pigmented a d e n o m a

Carcinogenesis Tests of CoCrMo and TiAIV Alloys

of the adrenal cortex) in two rats that received the CoCrMo wear-debris powder, and four tumors (renal adenocarcinoma, cutaneous keratinizing basal cell carcinoma, angiolipoma of the ear, and abdominal lipoma) in four rats that received the TiA1V weardebris powder. The incidences of tumors distant from the injection site did not differ significantly among the experimental groups. Histologic examination of the treated knees in the negative control group, which received intraarticular injections of manganese powder, all showed normal synovia and adjacent tissues. Inflammatory changes or fibrosis were absent and no metallic particles were seen, indicating that the powder had been dissolved or otherwise mobilized from the joint during the 15 months from injection to the first death of a rat in this group. Nonneoplastic lesions in this group included a periprostatic abscess and an infarcted splenic nodule. Two rats in the positive control group, which received intraarticular injections of oLNi3S2, did not develop tumors; w h e n their treated knees were examined at 2 3 - 2 4 months after injection, the joints appeared normal, without evidence of inflammation or metallic particles. Nonneoplastic lesions in this group included a small hepatic nodule, possibly congenital, with bile duct proliferation. The treated knee joints of rats that received intraarticular injections of CoCrMo wear-debris powder showed abundant, spheric, metallic particles in the synovia and surrounding tissue, with no signs of inflammation and little evidence of fibrosis (Fig. 3a).

Fig. 3. Histologic appearance of the synovium and surrounding tissue in the treated joints of rats that received intraarticular injection of (a) cobait-chromium-molybdenum (CoCrMo) wear-debris powder or (b) titanium-aluminumvanadium (TiA1V) wear-debris powder. (a) The synovial villae contain abundant CoCrMo particles, with no fibrotic or inflammatory reaction. (b) The subsynovium contains abundant TiAIVparticles, with mild fibroblastic reaction, but no inflammatory response (hematoxylin and eosin, original magnification x 300).

•

Lewis et al.

79

Nonneoplastic lesions of rats in this group included an organized cardiac atrial thrombus, a fibrotic spleen, and a small hepatic nodule, possibly congenital, similar to that in the positive control group. The treated knee joints of rats that received intraarticular injections of TiA1V wear-debris powder showed abundant metallic particles with irregular edges in the synovia and surrounding tissue, with mild fibroblastic reaction, but no inflammatory cells (Fig. 3b). Most of the metallic particles were dispersed in the fibrous extracellular matrix; none were seen within macrophages. Nonneoplasfic lesions of rats in this group included a renal cyst and a cardiac atrial thrombus.

Discussion This investigation was performed in small groups of 8 to 12 rats as a pilot study to assess the feasibility of conducting carcinogenesis bioassays by intraarticular administration, a route that is especially relevant to h u m a n exposures to metallic wear debris following arthroplasty. 8,18,19-2° Wear-debris powders of CoCrMo and TiA1V alloys, which are widely used for orthopedic implants (eg, hip and knee prostheses), were tested for carcinogenic activity by injection (20 mg/rat) into the knee joints of Fischer-344 rats. In these groups, no local rumors developed during 2 years of observation, and the incidences of tumors at all sites were comparable to a negative control

80

The Journal of Arthroplasty Vol. 10 No. 1 February 1995

group that received an intraarticular injection of manganese, a noncarcinogenic metal. 9,mA2A3 In contrast, local sarcomas developed in 10 of the 12 rats in the positive control group that was similarly treated with nickel subsulfide, a potent metal carcinogen. x<21'22 This study shows that, under experimental conditions, any carcinogenic activity of TiA1V or CoCrMo powders is weak in comparison to nickel subsulfide. On the other hand, as stressed in the Results section, the negative outcome does not imply that TiAIV or CoCrMo powders are entirely devoid of potential carcinogenic activity. A single carcinogenesis test of TiA1V alloy and five tests of CoCrMo alloy have previously been reported in rats, involving the administration of rods or powders by intraosseous or intramuscular routes. Gaechter et al. 23 performed intramuscular implants of polished rods of TiA1V alloy, wrought CoCrMo alloy, or cast CoCrMo alloy in groups of 30 SpragueDawley rats. Local tumors did not develop in any of the rats, which were observed for 24 months. Memoli et al. x4 found one local tumor (fibrosarcoma with lung metastases) in 18 Sprague-Dawley rats observed for 30 months after intraosseous implantation of CoCrMo alloy powder (42 mg/rat). Pauli et al. 25 administered cylindric sintered aggregates of CoCrMo powder to 100 Sprague-Dawley rats by intraosseous implantation. Two local tumors (osteoma, anaplastic fibrosarcoma) developed in these rats, which were observed for 30 months. Swanson et al. 26 administered finely powdered CoCrMo alloy to hooded rats by intramuscular injection (28 mg/rat; diameter, 0.1-1 /~m; suspended in horse serum). Local tumors (rhabdomyosarcomas, fibrosarcomas) developed in 23 of 80 rats, which were observed for 29 months. Meachim et al. x7 tested CoCrMo alloy in rats by intramuscular implantation (28 rag/rat) of coarse particles (diameter, 1 0 0 - 2 5 0 / ~ m ; 51 Wistar rats) or fine particles (diameter, 0 . 5 - 5 0 /~m; 61 Wistar rats and 53 hooded rats). Local tumors did not develop in any of the rats that were observed for life. The discrepant outcomes of the intramuscular carcinogenesis tests of CoCrMo alloy 2<27 suggest that the greater surface area of the fine particles tested by Swanson et al., 2~ as well as the opsonizing and solubilizing effects of horse serum, may have enhanced carcinogenicity by promoting phagocytosis and dissolution of the metal particles. 2 The synovial response to CoCrMo particles in this study (Fig. 3a) resembled that observed by Howie and Vernon-Roberts.19 They performed intraarticular injections of finely ground (diameter, < 3 /~m) wear-debris particles of CoCrMo alloy into the knees of 80 Lewis rats (0.17 mg/rat) and sacrificed them in groups of 10 at 1, 2, 4, 8, 13, 52, and 104 weeks

after injection. Initial responses in the injected knees included lymphocyte and macrophage infiltration, focal synovial ulceration and necrosis, and slight increase of fibrous tissue. The synovial ulcers, necrosis, and lymphocyte infiltrates were not evident after 4 weeks, but abundant metallic particles, often within macrophages, persisted in the synovium and subsynovium throughout the observation period. No local tumors were found, but tumorigenesis would have been unlikely at the low dosage that was used, even with a potent metallic carcinogen such as ~Ni3Sx. 22 In a similar study, Rae x8 injected finely ground wear-debris particles (diameter, <5 /~m) of TiA1V alloy into the knee joints of 30 Tuck mice and sacrificed them in groups of 5 at 2, 4, 8, 16, 26, and 52 weeks after injection. Metallic particles were evident throughout the joint tissues at each postinjection interval, embedded both in the intimal cell layer of the synovium and in m u c h deeper layers. Even after one year, numerous particles were present in the synovium and subsynovial tissues, sometimes as nodular aggregates with little inflammatory cell response or collagen deposition; multinucleated giant cells were only rarely seen and palpable tumors did not occur in any of the mice. 28 The intraarticnlar route of administration was first used for carcinogenesis bioassays by Ghadially and Roy, 29 w h o reported fibrosarcomas and synovial sarcomas after repeated injections of 9,10-dimethyl1,2-benzanthracene (DMBA) into the knee joints of Wistar rats. Similar intraarticular carcinogenesis tests of DMBA were performed in rats by De Santis et al. 3° and Sakamoto 31 and in rabbits by Homma and Wfinsch. 32 The neoplasms reported by De Santis et al.3° were an assortment of synovial sarcomas, fibrosarcomas, giant cell sarcomas, and malignant fibrous histiocytomas; those reported by Sakamoto 31 and Homma and Wtinsch 32 were predominantly malignant fibrous histiocytomas. Shibata et al. 2~ tested the carcinogenicity of ~Ni3 $2 in four groups of 20 male Fischer-344 rats by intramuscular, subcutaneous, retroperitoneal (fat pad), or intraarticular injections. The cxNi3S2 dosage was 5 mg/rat and the period of observation was 48 weeks. No local tumors developed at the injection sites in four groups of 10 vehicle control rats. The tumors that arose at the sites of oLNi3S2 injections were all sarcomas, the 19 intramuscular tumors were rhabdomyosarcomas, the 18 subcutaneous and 9 fat-pad tumors were predominantly malignant fibrous histiocytomas, and the 16 intraarticular tumors included 8 rhabdomyosarcomas, 3 malignant fibrous histiocytomas, 3 fibrosarcomas, and 2 unclassified sarcomas. 2 1 This study and the previous investigations that

Carcinogenesis Tests of CoCrMo and TiAIV Alloys

have been discussed indicate that the administration of test materials to rats by intraarticular injection provides a practical, reliable, and biologically relevant method for carcinogenesis bioassays of materials used for joint prostheses. Clinical experience indicates that any carcinogenic activity of the metal alloys in orthopedic prostheses is extremely low, since published reports of implant-associated tumors are infrequent compared to the hundreds of thousands of arthroplasties that have been performed worldwide annually for more than 20 years. Although the attention of clinicians and researchers has been focused primarily on the possible carcinogenicity of metal alloys in orthopedic implants, local exposures to other potentially carcinogenic materials (eg, methacrylate cement, polyethylene) occurred in m a n y of the reported cases of tumors in proximity to implants. We offer the following recommendations for the experimental design of future bioassays by the intraarticular route to evaluate the carcinogenicity of implant materials: (I) powdered cements and plastic materials used in arthroplasties should be tested, in addition to powdered metallic alloys, (2) the median particle diameters of the powders should be small (<3 /~m), (3) the experimental groups should be large (> 100 males and females), so that t u m o r incidences as low as 5% can be detected, and (4) the rats should be observed t h r o u g h o u t their lives.

8.

9.

10.

11.

12.

13.

14.

15.

16.

Acknowledgments The wear-debris powders of CoCrMo and TiA1V alloys were kindly provided by Zimmer; however, the authors did not receive any financial support or emoluments from Zimmer.

References 1. Sunderman FW Jr: Carcinogenic risks of metal implants and prostheses, p. 11. In Hildebrand HF, Champy M (eds): Biocompatibility of Co- Cr-Ni alloys. Plenum, New York, 1988 2. Sunderman FW Jr: Carcinogenicity of metal alloys in orthopedic prostheses: clinical and experimental studies. Fundam Appl Toxicol 13:205, 1989 3. Visuri T, Koskenvuo M: Cancer risk after McKee-Fartar total hip replacement. Orthopedics 14:139, 1991 4. Nickel and nickel compounds. IARC Monogr Eval Carcinog Risks Hum 49:257, 1990 5. Cobalt and cobalt compounds. IARC Monogr Carcinog Risks Hum 52:361, 1991 6. Linden JV, Hopfer SM, Gossling HR, Sunderman W Jr: Blood nickel concentrations in patients with stainlesssteel hip prostheses. Ann Clin Lab Sci 15:459, 1984 7. Sunderman FW Jr, Hopfer SM, Swift T et al: Cobalt,

17.

18.

19.

20.

21.

22.

23.

24.

•

Lewis et al.

81

chromium, and nickel concentrations in body fluids of patients with porous-coated knee or hip prostheses. J Orthop Res 7:307, 1989 Lewis CG, Belniak RM, Hopfer SM, Sunderman FW Jr: Cobalt in periprosthetic soft tissue: observations in six revision cases. Acta Orthop Scand 62:447, 1991 Sunderman FW Jr, Kasprzak KS, Lau TJ et al: Effects of manganese on carcinogenicity and metabolism of nickel subsulfide. Cancer Res 36: 1790, 1976 Sunderman FW Jr, Lau TJ, Cralley LJ: Inhibitory effect of manganese upon muscle tumorigenesis by nickel sulfide. Cancer Res 34:92, 1974 Sunderman FW Jr, Maenza RM, Hopfer SM et al: Induction of renal cancers by intrarenal injection of nickel subsulfide. J Environ Pathol Toxicol 2:1511, 1979 Sunderman FW Jr, McCully KS: Effects of manganese compounds on carcinogenicity of nickel subsulfide in rats. Carcinogenesis 4:461, 1983 Sunderman FW Jr, McCully KS, Taubman SB et al: Manganese inhibition of sarcoma induction by benzo(a)pyrene in rats. Carcinogenesis 1:613, 1980 Albert DM, Gonder JR, Papale J e t al: Induction of ocular neoplasms in Fischer rats by intraocular injection of nickel subsulfide. Invest Ophthalmol Vis Sci 22:768, 1982 Damjanov I, Sunderman FW Jr, Mitchell JM, Allpass PR: Induction of testicular sarcomas by intratesticular injection of nickel subsulfide. Cancer Res 38:268, 1978 Sunderman FW Jr, Maenza RM: Comparisons of carcinogenicities of nickel compounds in rats. Res Commun Chem Pathol Pharmacol 14:319, 1976 Uchida S: A histopathologic comparison of the tissue reaction to prosthetic materials in the knee joint of rats. Orthopedics 8:1276, 1985 Howie DW, Vernon-Roberts B: The synovial response to intraarticular cobalt-chrome wear particles. Clin Orthop 232:244, 1988 Howie DW, Vernon-Roberts B: Long-term effects of intraarticular cobalt-chrome alloy wear particles in rats. J Arthroplasty 3:327, 1988 Betts F, Wright T, Salvati EA et al: Cobalt-alloy metal debris in periarticular tissues from total hip revision arthroplasties. Clin Orthop 276:75, 1992 Shibata M, Izumi K, Sano N, Akagi A, Otsuka H: Induction of soft tissue tumors in F344 rats by subcutaneous, intramuscular, intra-articular, and retroperitoneal injection of nickel sulfide (Ni3S2). J Pathol 157: 263, 1989 Sunderman FW Jr: Carcinogenicity and anticarcinogenicity of metal compounds, p. 165. In Emmelot P, Kriek E (eds): Environmental carcinogenesis. Elsevier/ North Holland, Amsterdam, 1979 Gaechter A, Alroy J, Andersson GBJ et al: Metal carcinogenesis: a study of the carcinogenic activity of solid metal alloys in rats. J Bone Joint Surg 59A:622, 1977 Memoli VA, Urban RM, Alroy J, Galante JO: Malig-

82

25.

26.

27.

28.

The Journal of Arthroplasty Vol. 10 No. 1 February 1995 nant neoplasms associated with orthopedic implant materials in rats. J Orthop Res 4:346, 1986 Pauli BM, Urban RM, Galante JO: Carcinogenic evaluation of porous sintered powder composites. Proc Orthop Res Soc 11:102, 1986 Swanson SAV, Freeman MAR, Heath JC: Laboratory tests on total joint replacement prostheses. J Bone Joint Surg 55B:759, 1973 Meachim G, Pedley RB, Williams DF: A study of sarcogenicity associated with Co-Cr-Mo particles implanted in animal muscle. J Biomed Biomater Res 16:407, 1982 Rae T: The biological response to titanium and tita-

29. 30. 31.

32.

nium-aluminium-vanadium alloy particles. Biomaterials 7:37, 1986 Ghadially FN, Roy S: Experimentally produced synovial sarcoma. Cancer 19:1901, 1966 De Santis MA, Oransky M, Sanguinetti C: Experimentally induced synovial sarcoma. Int Orthop 5:37, 1981 Sakamoto K: Malignant fibrous histiocytoma induced by intra-articular injection of 9,10-dimethyl- 1,2-benzanthracene in the rat. Cancer 57:2313, 1986 Hon~na W, Wfinsch PH: Experimental-induced sarcomas after intra-articular injection of 9,10-dimethyl1,2-benzanthracene. Arch Orthop Trauma Surg 102: 111, 1983