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From the Townsend Letter
January 2018

Iatrogenic Metal Burdens
by David Quig, PhD
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An abundance of recent research has drawn attention to the potential, toxic effects of elements associated with metal alloy implants and prosthesis devices. This medically-induced issue warrants serious consideration since it is well established that a variety of toxic elements can have additive or even synergistic toxic effects, and we are all subjected to at least low-level chronic exposure to xenobiotic elements from the environment. Further, too many patients have also been subjected to gadolinium-enhanced MRIs prior to implantation of metal-on-metal prostheses. This review will highlight the potential local and systemic clinical consequences of the persistent release of specific medically introduced metals, and address the current recommendations for assessing the levels of the metals in patients. Rationale for possible clinical interventions to mitigate toxic effects of the persistently released metals will also be discussed.

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Klaire LabsDental Metal Alloy Implants
Dental implants composed primarily of titanium (Ti) have been used for decades to replace missing teeth or to support crowns and bridges. In the vast majority of cases, the implants help maintain the integrity of the underlying bone. Some patients develop immediate or delayed hypersensitivity to the Ti alloy implants. Of potential concern is corrosion, especially when dissimilar metals (mercury, nickel) are in the mouth and galvanic currents are created.1 There is a paucity of research regarding local and systemic effects of Ti dental implants in part because of difficulties in accurately measuring Ti levels (polyatomic interferents).2,3 Potential adverse effects of corrosion-released Ti alloys will be further discussed with respect to metal-on-metal total hip arthroplasty, but it is clear that Ti ion release by electro-corrosion is far less a concern in comparison to metal on metal wear. Titanium levels can be assessed accurately in serum, blood or plasma, by a few commercial laboratories.4 Normal serum Ti levels in the absence of implants are < 1 ng/ml.5 More recently, ceramic and zirconium dental implants have been used to avoid Ti alloy corrosion issues.

Orthopedic Metal Alloy Implants
It is well established that levels of metals in serum are increased indefinitely following all types of metal-on-metal total hip arthroplasty procedures6,7 and there are indeed local and remote adverse tissue responses.8 The long-term physiological responses to elevated levels of the specific metals are largely unknown.7,9 Moreover, there is no acceptable threshold above which serum concentrations of metals such as cobalt, chromium, and titanium are known to be toxic9; individual variability to toxic effects confounds the issue. Additional concern is heightened by the fact that the procedure is being performed on younger and more active patients, which raises questions of potential reproductive effects.6 In that regard, it has been reported that metal concentrations in blood from neonates whose mothers had metal implants were higher than those of controls.10
Total hip arthroplasty (THA) is one of the most successful treatments for patients with severe rheumatism and osteoarthritis, and most THA devices remain functionally intact for upwards of 20-plus years. THA can be a necessary blessing or a major calamity. Development of durable and safe prosthetic materials has proven to be a major challenge, and for decades millions of people have received metal-on-metal paired (M/M) THA prostheses. Until very recently the vast majority of prostheses consisted of pairings of alloys of cobalt (Co), chromium (Cr), and molybdenum (Mo) for the acetabular cup and femoral head (Co:Cr:Mo about 60:30;7).6 The femoral head is attached to a femoral stem/shaft that is composed of Ti alloy; vanadium is a minor component of Ti alloys. The M/M prosthesis bearing surfaces invariably wear and release Co and Cr3. Rates of wear are highly dependent on device design, surgical technique, level of physical activity and other factors that affect the health of involved bone and surrounding soft tissue. There is controversy about the continuous corrosion of the metals, including the more resistant Ti alloys, but it is apparent that physical wear is by far the biggest factor in M/M THA-induced metallosis. 
The primary concern from the orthopedic perspective is excessive wear and failure of the prostheses due to periprosthetic tissue reactions to the metals. The CAM/integrative practitioner is also very concerned about remote tissue deposition and potential systemic toxic effects of the incompatible metal debris. All patients with M/M THA will have elevated levels of Co and Cr in serum as well as in periprosthetic soft tissue and bone, and in remote tissues in the body up to 20 years post-operatively.11,12 Local metallosis can cause pseudotumors (inflammatory soft tissue mass), decreased viability of osteoblastic bone marrow cells, osteoclastic bone resorption (release of lead), necrosis, and infiltration of macrophages, eosinophilic granulocytes, and lymphocytes.13 The net effect can be an aseptic loosening/misalignment of the components that, in turn, further increases wear and release of metal debris. Because it is not possible to assess wear radiographically, the levels of metals in serum (Table 1 pdf) are used as part of the evaluation of the functional condition of prosthetic implants and decisions regarding revision surgery.14 However, there is limited published data on appropriate reference ranges for the metals, which raises questions regarding the clinical utility of the data. It has been emphasized that elevated serum Co and Cr levels in the absence of corroborating symptoms do not independently predict prosthesis failure.15
Researched NutritionalsIn addition to local toxic effects, CAM doctors are also very much concerned about systemic effects of the released metal debris. Transition metals such as Co, Cr, Ti, Mo, nickel, manganese, and iron induce production of highly reactive oxygen species (ROS) by Fenton or Fenton-like reactions in fluids in the body. Excessive ROS compromise redox buffering and can diminish levels of quintessential glutathione. The extremely reactive hydroxyl radical is of particular concern because it causes oxidative damage to proteins, lipids, and nuclear and mitochondrial DNA and RNA.16 Clinical studies have linked M/M THA to white blood cell DNA and chromosomal damage.17 However, underpowered epidemiological studies to date have not found increased risk or incidence of cancer.11 Nonetheless, excessive exposure to such metals can result in excessive oxidative stress, inflammation, low levels of quintessential glutathione, and compromised redox capacity. Further, excessive Co has been shown to compromise hepatic cytochrome P450 activity in laboratory rats (Phase I detoxification).18
It should be noted that it appears that little if any hexavalent Cr (Cr6) is released from the CoCr alloy prostheses.14 Highly genotoxic Cr6 from occupational/environmental exposure is preferentially taken up, reduced, and retained by red blood cells (RBC). Juxtaposed, implant-derived and dietary trivalent Cr is excluded from RBC. RBC Cr is not elevated in association with M/M THA.11,14,19 It is emphasized that Cr in RBCs is attributable specifically to exposure to Cr6 and provides no indication of the nutritional status of physiological Cr.19
The most abundantly released metal from the CoCrMo alloys is Co. Cobalt and Cr particles/ions accumulating in lymph nodes can cause necrosis and fibrosis, and associated inflammation is primarily an immunological response.20 Research regarding systemic toxic effects is rather sparse.21 However there are case reports regarding neurotoxicity and cardiomyopathy associated with the disseminated metal debris, particularly Co.22,23 Possible toxic effects include somatic mutations (animal models), aberrant immune function, impaired renal function, compromised endogenous detoxification (Phases I and II), excessive inflammation, and breakdown of arterial endothelial cell tight junctions.7 Safe levels of serum Co ions have not been established, and Co poisoning is defined by serum Co levels ≥ 5 ng/ml.7  Is one not to be concerned about potential systemic toxic effects when serum Co levels are 4-10 ng/ml just because a prosthetic implant is thereby implied to be in "good condition"?
Signs and symptoms of arthroprosthetic cobaltism include visual and auditory impairment, tinnitus, vertigo, cardiomyopathy, cognitive dysfunction/dementia, mood disorders, hypothyroidism, peripheral neuropathy, and skin rashes.15,22 Adverse reactions to Co ion release can be clinically silent yet severe, so early detection is very important. The American Academy of Orthopaedic Surgeons generally recommended follow up testing/evaluation of M/M THA patients annually (asymptomatic), and every four-six months with mild symptoms. 
Serum Ti levels will be elevated in patients with M/M THA even when only the femoral shaft is composed of Ti alloy.9 Titanium has been long regarded as an inert biocompatible metal due to its corrosion resistance. However, recent studies have shown that Ti and vanadium (minor component of Ti alloys) from non-bearing implant components can be released with potentially consequential effects both locally and systemically. Specifically, Ti may have adverse effects in blood, fibrotic tissues, and osteogenic cells after transport through the circulatory or lymphatic systems.4 That Ti corrosion occurs in bone in the absence of wear was demonstrated in a well-designed long-term study (18 months) in which a Ti wire was implanted into the femurs of rats.4 The corrosion-released Ti increased blood Ti levels, and Ti concentrated primarily in the spleen and lungs. Titanium was also sequestered to a lesser extent in the heart, kidneys, and liver. It has been stated that elevated serum Ti levels associated with prostheses arenot necessarily associated with toxicity.5 However, there is a dearth of clinical data regarding potential adverse health effects. The lack of clinical studies is disconcerting since it has been reported that serum Ti levels can be 18 times greater 10 years post-surgery than at baseline; the M/M hip prostheses in the subjects consisted of Ti alloy acetabular sockets (bearing) and Ti femoral stems.9
Vanadium (V), an element that interferes with a vast array of biochemical reactions, is another metal that is released from THA prostheses. Vanadium is a minor constituent of titanium-aluminum-vanadium alloys used in hip prostheses, both in the femoral stem and less frequently in bearing surfaces (acetabular sockets). Serum V levels are expected to be higher than normal (< 1ng/ml) with Ti-alloy prostheses in good condition (1-2 ng/ml), and even higher with significant prosthesis wear (>5 ng/ml).15 A case report indicated V toxicity associated with a broken Ti alloy femoral stem and a serum V level of 5.8 ng/ml.24 The patient exhibited sensory-motor axonal neuropathy and bilateral sensorineural hearing loss, and did not have Ti alloy bearing surfaces.

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