Reporting of success rates is not standardized. Percentages are indicated in patients, nodal basins or SLNs.Success Rates of Melanoma Sentinel Lymph Node Identification Techniques in Studies with >100 patients*.
\r\n\tAs a result of these research efforts, in the last decade alternative food preservation techniques have emerged being considered promising alternatives (dielectric and ohmic heatings, pulsed electric field, hydrostatic pressure,...) to gradually replace the traditional well-established preservation processes, such as thermal pasteurization, or sterilization, among others.
\r\n\tThis book intends to provide the reader with a comprehensive overview of the current state-of-the-art of the food preservation methods and how they can be combined to achieve the right balance of safety, quality and shelf-life for particular products.
\r\n\tSpecial attention will be given to applications concerning the preservation of fruits and vegetables in view of the increasing consumer demand for this type of products but also their importance in terms of human nutrition and health.
\r\n\t
The initial route of metastases in most patients with melanoma is through lymphatics to the regional nodes (Morton et al., 1992) [Fig.1]. However, routine lymphadenectomy for patients with early stage melanoma is unwarranted because most of these patients (~80%) do not have nodal metastases, are unlikely to benefit from the operation, and may suffer complications including lymphedema, seroma, infection and wound breakdown. However, a significant portion of patients with melanoma, predicted by primary tumor factors, harbor clinically undetectable regionally lymph node metastases at time of presentation. Delay of elective lymph node dissection until the presence of palpable nodes may allow the spread of melanoma to other nodes and distant sites with a decrease in long-term survival (Morton et al., 2006). The key to solving this clinical dilemma is to provide a minimally invasive method to selecting the relevant “sentinel lymph node” (SLN) in a specific basin to determine nodal micrometastasis (Morton et al., 1992). The SLN is accordingly the first lymph node(s) receiving direct afferent drainage from the primary tumor and thus is most likely to contain metastatic disease if any regional lymph nodes are involved. The technique of SLN biopsy is best named selective sentinel lymph node dissection (SLND) and allows surgeons to determine the spread of melanoma through lymphatic channels from the primary tumor; it has substantially impacted the way cutaneous melanoma is staged and managed.
\n\t\t\tThe relatively orderly fashion of melanoma metastasis from the primary site to the SLNs and then to the non-SLNs prior to systemic sites is supportive of the spectrum theory of cancer spread (Hellman, 1994; Leong, 2004) [Fig. 1]. This theory states that for a given malignant lesion, development of nodal and systemic metastasis from localized disease is a genetically driven process of progression within the tumor microenvironment to distant body sites, most often through the “gateway” of the SLN(s). Selective SLND is an ideal procedure because it is minimally invasive, yet powerful enough to select the relevant lymph node of the nodal basin, without a complete node dissection. It is now widely accepted that the SLN status is the most important factor in predicting outcomes and determining further treatment for melanoma and this is the focus of the chapter (Leong, 2004).
\n\t\t\tThe figure depicts progression of melanoma from the primary site to the SLN, then to non-SLN or regional nodes and distant sites. Occasionally, cancer cells may bypass the lymph nodes and spread to distant sites through vascular channels. In the majority of the cases (approximately 80%), the SLN is the gateway for cancer spread (bold arrow pathway in figure).
In 1977, Cabanas described an approach to staging penile carcinoma after using lymphangiograms in patients to determine the lymphatic anatomy of the penis. He hypothesized that if penile carcinoma metastasized, it would do so to a node that was located medially and superiorly to the saphenofemoral junction in each groin (Cabanas, 1977). The term sentinel node, first coined by Gould in 1966 for parotid cancer (Gould et al., 1966), was used to describe the first node in this drainage pathway; if this was found to have metastatic disease, the patient required a lymphadenectomy. Conversely, when the SLN was negative for disease, the likelihood of metastatic disease in the groin was low and lymphadenectomy was unnecessary. The idea that a primary tumor would preferentially drain through the lymphatics to a specific lymph node, and that the status of that node would reflect the tumor status of the regional lymphatic basin, was revolutionary. However, the lymphatic drainage of solid tumors might vary from patient to patient and not necessarily be fixed to an anatomic location (Wong et al., 1991). To accurately identify the SLN, intraoperative techniques were needed to define the lymphatic drainage of a given primary tumor site rather than utilize an operative approach that was dependent upon the defined anatomy.
\n\t\t\t\tThus, in 1992, Morton introduced the concept of identifying and selectively harvesting the SLN from the draining basin of a primary melanoma to identify patients with clinically occult lymph node disease (Morton et al., 1992). This was performed with intradermal injection of vital blue dye around the primary melanoma and then exploration of the regional lymphatic basin to identify blue stained node(s). This technique was based on the observation that when a blue dye such as isosulfan blue is injected around the primary melanoma, it drains into the SLN. With meticulous dissection, the dermal lymphatics could be visualized and utilized to map the lymphatic drainage of the skin to a SLN. In this study, metastases were present in 18% of SLNs, while non-sentinel nodes were the sole site of metastases in only two of 3079 nodes from 194 lymphadenectomy specimens that had an identifiable SLN, resulting in a false-negative (FN) rate of less than 1% (Morton et al., 1992). Therefore, this technique identifies, with a high degree of accuracy, patients with early stage melanoma without nodal metastases who can be spared from a morbid radical lymphadenectomy. Several confirmatory studies, including prospective randomized trials, have provided a wealth of information regarding the SLN, including accuracy, prognostic value and candidate selection (Ross et al., 2011).
\n\t\t\t\tHowever, intraoperative lymphatic mapping with blue dye alone is technically difficult with prolonged learning curves to acquire satisfactory outcomes. Thus, radioguided techniques were sought to provide a simpler method to identify and harvest the SLN while minimizing the extent of the surgical dissection. In 1993, Alex and Krag reported on the use of an intra-operative hand-held gamma probe to identify regional nodes that had taken up technetium labeled sulfur colloid (Alex & Krag, 1993). Additionally, the development of a number of radiopharmaceuticals with appropriate particle size provided the opportunity for the development of cutaneous lymphoscintigraphy, developed by Robinson, Morton and associates in the 1970s (Robinson et al., 1977). Cutaneous lymphoscintigraphy was especially important given the recognition that the dermal lymphatics, particularly in trunk melanomas (Leong et al., 1999), could have substantial variability; this allowed surgeons to define the regional lymphatic basins that were at risk for harboring metastatic disease prior to selective SLND (Fig. 2). Preoperative lymphoscintigraphy to define the SLN from the primary site in combination with the gamma probe could direct the surgical incisions and make the procedure less invasive than the blue dye procedure. Also, selective SLND using lymphoscintigraphy allows the identification of affected lymph nodes that would not be routinely evaluated during an elective nodal dissection such as in-transit lymph nodes and lymph nodes in minor nodal basins (e.g., popliteal and epitrochlear regions) [Sumner et al., 2002]. Lymphoscintigraphy is also essential for selective SLND in head and neck melanomas as these have complex and less predictable lymphatic drainage patterns, resulting in lower SLN identification rates and higher FN rates (Klop et al., 2011; Leong et al., 1999). For these reasons, cutaneous lymphoscintigraphy has become a routine component of the management of most melanoma patients.
\n\t\t\tThe SLN concept has been supported by high accuracy rates and low false-negative (FN) rates in melanoma. The immediate FN rate, defined as the percentage of nodal basins that harbor nodal metastases in nodes other than the SLN as determined by synchronous elective lymph node dissection after a negative SLN biopsy, has been reported to be less than 5% in several studies (Gershenwald et al., 1999; Morton et al., 1992; Nowecki et al., 2003, 2006; Reintgen et al., 1994; Thompson et al., 1995; Uren et al., 1994). In the Multicenter Selective Lymphadenectomy Trial I (MSLT-I) [Morton et al., 2006], 2,001 patients with cutaneous melanoma were randomized to: (1) wide local excision alone with observation only and subsequent lymphadenectomy if nodal relapse occurred, or (2) wide local excision and selective SLND with lymphadenectomy if metastases were found in the SLN.
\n\t\t\t\tPre-operative lymphoscintigraphy demonstrates varying lymphatic channel patterns in patients with primary melanoma. (A) Drainage of a single channel from the right upper arm leading to one SLN in the right axilla. (B) Drainage of a single channel from a posterior midline neck lesion to multiple contiguous nodes in the right posterior neck. (C) Confluent channels drain from the upper back to a single SLN in the left axilla. (D) Multiple channels from the left upper back draining to a single SLN in the left axilla. (E) Single primary site drainage source from the right arm, diverting into several channels and leading to a single SLN in the right axilla. (F) Changing of drainage patterns from a lesion in the left anterior chest wall to one SLN in the left axilla. (G) Parallel simple channels from the right lower extremity, each draining to a single SLN, each in the same basin in the right groin. (H) Multiple channels from the midline back draining to multiple SLN(s) in different basins, the right and left axilla. This figure has been previously published by our group in Clinical Nuclear Medicine 30(3):150-158, 2005.
Results from 1,269 patients with intermediate-thickness primary melanoma (1.2 mm to 3.5 mm in this study) showed that 16% percent of SLNs had micrometastases, while 3.4% of those with “negative” SLNs developed nodal metastases, which is consistent with the accepted FN rates of the procedure.
\n\t\t\t\tAdditional evidence that regional node metastasis constitutes an orderly, nonrandom event was provided from a study that examined 105 lymphadenectomy specimens in patients with at least one positive SLN (Gershenwald et al., 1998). They found that the SLN was the only node involved in 83 (79%) of the basins, with microscopic nodal metastasis identified in an additional 21% of the lymphadenectomy specimens. In 92% of patients who had at least one positive SLN and were mapped with blue dye and radiocolloid, lymphatic metastases were identified in the SLN that contained the greatest radiotracer uptake.
\n\t\t\tIn our practice, patients chosen for selective SLND have the following: (1) a Breslow thickness of 1 mm or greater; (2) a Breslow thickness less than 1 mm, but with high risk features such as lymphatic invasion, regression, ulceration, increased mitotic figures, or Clarks level IV; or (3) a shave biopsy that resulted in a Breslow thickness of less than 1 mm. Patients who are not recommended to undergo selective SLND have one of the following features: (1) known lymphatic or metastatic disease; (2) melanoma-in-situ; or (3) a Breslow thickness less than 1 mm with no high risk features. These are the most current indications for selective SLND and what most melanoma centers follow. Given this criteria, the positive SLN rate has been documented to be between 14-21% in most studies (Kapteijn et al., 1997; Leong et al., 2005; Morton et al., 1992, 2006; Thompson et al., 2005). Despite these guidelines, population based studies have shown that only 50% of patients with stage IB and II who met the criteria for selective SLND actually undergo selective SLND (Bilimoria et al., 2009; Cormier et al., 2005). The factors for this are likely multi-factorial including insurance, geographic area, socioeconomic factors, and age. This signifies the need for better education, access to health care, and melanoma multidisciplinary centers for patient referral.
\n\t\t\tThe SLN is now reproducibly defined by lymphoscintigraphy and lymphatic mapping performed by the injection of Technetium-99m (Tc 99m) sulfur colloid radiotracer, a vital blue dye, or a combination of both around the melanoma site. Isosulfan blue (Lymphazurin 1%, Hirsch Industries, Inc., Richmond, VA) is the most commonly used blue dye in the United States and is the only dye approved by the Food and Drug Administration for lymphatic mapping. Regarding radiotracer, a more selective agent, Technetium-99m-labeled Tilmanocept, is a mannose receptor–targeted molecule that is being developed for identification of SLNs (\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLeong et al., 2011\n\t\t\t\t\t\t\n\t\t\t\t\t) and will likely be used in the near future.
\n\t\t\t\tA summary of the numerous studies using the blue dye technique, radiotracer mapping by a hand-held gamma probe, or a combination of both techniques is shown in Table 1. The success rate of harvesting the SLN by blue dye alone is less than that of radiotracer alone or the combination of blue dye and radiotracer, both of which now approach 100% (Table 1). Given this data, the use of radiotracer is the most commonly use technique now. With greater surgical experience, the use of blue dye is not essential as radiotracer has a higher sensitivity than blue dye alone and this can avoid reported allergic reactions seen with the injection of blue dye (Leong et al., 2000; Liu et al., 2011).
\n\t\t\t\tFor this technique, filtered Tc99m sulfur colloid is injected intradermally at the primary melanoma site. Dynamic imaging is performed to follow the lymphatic collecting vessels until they reach the draining SLNs. An image should be acquired as the lymphatics reach the nodal basin so that SLN(s) directly receiving the channels can be identified and distinguished from any second tier nodes that may be seen. This phase of the study usually takes 10-20 minutes. Delayed scans are performed 2–2.5 hours later, at which time all regions that possibly drain the primary melanoma site are examined with 5-10 minute static images. The surface location of all SLN(s) is marked on the overlying skin. Close communication between the nuclear medicine physician and surgeon is invaluable, especially in cases where there are unusual draining patterns. Importantly, the SLN is not just the first node seen on dynamic imaging, since there may be multiple separate lymph channels that have different rates of lymph flow. If they drain to different nodes, these are all SLNs, regardless of the time taken for the lymph containing the radiocolloid to reach them (Fig. 2). The SLN is also not necessarily the closest node to the primary site. Lymphatic vessels can bypass many nodes and even whole node fields before reaching a SLN. Therefore, the best way to identify a SLN on lymphoscintigraphy is to see the lymphatic collecting vessel on dynamic imaging as it drains directly to the SLN (Fig. 2).
\n\t\t\t\tAuthor | \n\t\t\t\t\t\t\tYear | \n\t\t\t\t\t\t\tof Patients | \n\t\t\t\t\t\t\tBlue Dye Alone | \n\t\t\t\t\t\t\tRadiotracer | \n\t\t\t\t\t\t\tBoth | \n\t\t\t\t\t\t
Morton et al. | \n\t\t\t\t\t\t\t1992 | \n\t\t\t\t\t\t\t223 | \n\t\t\t\t\t\t\t82% (basins) | \n\t\t\t\t\t\t\t- | \n\t\t\t\t\t\t\t- | \n\t\t\t\t\t\t
Krag et al. | \n\t\t\t\t\t\t\t1995 | \n\t\t\t\t\t\t\t121 | \n\t\t\t\t\t\t\t91% (patients) | \n\t\t\t\t\t\t\t98% (patients) | \n\t\t\t\t\t\t\t- | \n\t\t\t\t\t\t
Glass et al. | \n\t\t\t\t\t\t\t1996 | \n\t\t\t\t\t\t\t148 | \n\t\t\t\t\t\t\t60% (nodes) | \n\t\t\t\t\t\t\t80% (nodes) | \n\t\t\t\t\t\t\t97% (nodes) | \n\t\t\t\t\t\t
Albertini et al. | \n\t\t\t\t\t\t\t1996 | \n\t\t\t\t\t\t\t106 | \n\t\t\t\t\t\t\t70% (nodes) | \n\t\t\t\t\t\t\t84% (nodes) | \n\t\t\t\t\t\t\t96% (basins) | \n\t\t\t\t\t\t
Kapteijn et al. | \n\t\t\t\t\t\t\t1997 | \n\t\t\t\t\t\t\t110 | \n\t\t\t\t\t\t\t84% (nodes) | \n\t\t\t\t\t\t\t99.5% (nodes) | \n\t\t\t\t\t\t\t99.5% (nodes) | \n\t\t\t\t\t\t
Leong et al. | \n\t\t\t\t\t\t\t1997 | \n\t\t\t\t\t\t\t163 | \n\t\t\t\t\t\t\t74% | \n\t\t\t\t\t\t\t98% | \n\t\t\t\t\t\t\t- | \n\t\t\t\t\t\t
Pijpers et al. | \n\t\t\t\t\t\t\t1997 | \n\t\t\t\t\t\t\t135 | \n\t\t\t\t\t\t\t86% (nodes) 85% (basins) | \n\t\t\t\t\t\t\t100% (nodes) 100% (basins) | \n\t\t\t\t\t\t\t- | \n\t\t\t\t\t\t
Gershenwald et al. | \n\t\t\t\t\t\t\t1998 | \n\t\t\t\t\t\t\t626 | \n\t\t\t\t\t\t\t87% | \n\t\t\t\t\t\t\t- | \n\t\t\t\t\t\t\t99% | \n\t\t\t\t\t\t
Gennari et al. | \n\t\t\t\t\t\t\t2000 | \n\t\t\t\t\t\t\t133 | \n\t\t\t\t\t\t\t80.8% (nodes) | \n\t\t\t\t\t\t\t97.1% | \n\t\t\t\t\t\t\t99% | \n\t\t\t\t\t\t
Nowecki et al. | \n\t\t\t\t\t\t\t2003 | \n\t\t\t\t\t\t\t726 | \n\t\t\t\t\t\t\t91.6% | \n\t\t\t\t\t\t\t- | \n\t\t\t\t\t\t\t97.3% | \n\t\t\t\t\t\t
Reporting of success rates is not standardized. Percentages are indicated in patients, nodal basins or SLNs.Success Rates of Melanoma Sentinel Lymph Node Identification Techniques in Studies with >100 patients*.
After lymphoscintigraphy, the patient is transferred to the operating room and no further injection of radiotracer is necessary, but Lymphazurin (1-2 mL) may be injected intradermally prior to the procedure. The surgical sites are prepared and general anesthesia is most often used. Intraoperative mapping of the SLNs is achieved using a hand-held gamma probe (Neoprobe 2000, Neoprobe Corporation, Dublin, OH). A small incision is made over the marked area of greatest activity as detected by pre-operative lymphoscintigraphy and confirmed by the hand-held gamma probe. The incision is carried down through the subcutaneous fat and the fascia is incised as the lymph nodes usually reside beneath the fascia. Using the gamma probe, the SLNs can be located by detecting increased radioactivity in counts per second or blue dye within node. After the removal of the SLN, the gamma probe is used to search the resection bed to make sure that no residual elevated radioactivity remains. Theoretically, the single SLN with the highest radioactive count (“hottest” SLN) or the blue node is most likely to harbor tumor cells and is removed during biopsy. However, literature describes FN rates for SLN biopsy if only the single, “hottest” SLN is removed and the other nodes are left in place (McMasters et al., 2001). Thus, we and others use the 10% rule (Liu et al., 2011; McMasters et al., 2001): the gamma probe is applied and any SLNs that assessed ≥ 10% of the ex vivo radioactive count of “hottest” SLN are removed, including any blue nodes or suspicious nodes by digital palpation.
\n\t\t\tAfter selective SLND, the wound is closed in layers. On a side table we dissect the SLN(s) from the non-SLN(s) or lymphatic tissue within the resected specimen using the gamma probe so that each lymph node is correctly labeled with its respective radioactive counts for pathologic evaluation.
\n\t\t\tThe standard histological technique for evaluating a nodal dissection specimen involves evaluating representative sections from each identified lymph node using hematoxylin and eosin (H&E). In actuality, given the large size of the nodal dissection specimen, <1% of the whole specimen is routinely evaluated (Ross et al., 2011; Sondak et al., 2007). With a smaller sample from a selective SLND, the SLN can be evaluated more intensively with multiple sections using a combination of H&E and immunohistochemistry (IHC) to stain for melanoma associated antigens such as S-100 and HMB-45 (Fig. 3).
\n\t\t\t\tFigure shows staining of melanoma micrometastasis within a SLN.
Therefore, despite the less invasive nature of selective SLND, the staging data is likely more accurate than an elective lymph node dissection.
\n\t\t\tSelective SLND is a safe procedure with a very low complication rate. Additionally, the risk of radiation has been studied in physicians injecting the radiotracer as well as the surgeons removing the nodes. The maximum recorded dose of radiation recorded was 1900 times smaller than the current 1 year dose limit recommended by the International Commission on Radiological Protection, and no limitations are needed in the number of surgical interventions performed yearly (Nejc et al., 2006; Sera et al, 2003).
\n\t\t\tThere have been reports of adverse allergic reactions to blue dye (Leong et al., 2000) which can range from a mild allergic reaction to anaphylaxis associated with hypotension, pulmonary edema, and/or cardiovascular collapse. It is hypothesized that prior exposure to common household products is responsible for patient sensitization to blue dye. Single institution case studies quote allergic reaction rates of 0.7 to 2% for melanoma. A multi-institutional survey by our group of 14,800 melanoma patients treated with blue dye in over 185 institutions revealed a 0.4% rate of adverse blue dye reactions, most of which are mild. Despite this low rate, it is important to be aware of any adverse reactions such as urticaria, respiratory and hemodynamic changes which usually occur in the first 10 to 20 minutes. We recommend that the anesthesiologist and nursing team are made aware of the use of blue dye prior to its injection, an intravenous line always be inserted, and that the proper medications, including epinephrine and corticosteroids, be readily available. If blue dye is to be used, we suggest that the surgeon use as little blue dye as needed; we have found reliable results in head and neck melanoma using less than 1 cc per injection. Additionally, blue dye is not essential as we demonstrated in a recent study that using the 10% radioactivity rule (McMasters et al., 2001) with blue dye does not significantly decrease the Miss Rate when compared to the 10% radioactivity rule with technitium alone (Liu et al., 2011).
\n\t\tFurther support for the SLN concept stems from research that clearly shows that SLN status is the most significant prognostic factor with respect to disease-free and overall survival as shown in Table 2. Selective SLND is an excellent staging technique and can be used to identify patients who would or would not benefit from a complete lymphadenectomy and is also necessary for inclusion in clinical trials.
\n\t\t\tAs shown in Table 2, patients with a positive SLN have a significantly decreased overall 5-year survival compared to patients with a negative SLN. Therefore, for patients with a positive SLN, therapeutic decisions should be made and most often a regional lymphadenectomy is recommended. However, the survival benefit of selective SLND followed by completion lymph node dissection (CLND) is still controversial and many groups have attempted to study this by comparing melanoma patients after CLND after positive sentinel node biopsy and after therapeutic lymph node dissection for clinically detected regional lymph node metastases. In the MSLT-1 trial (Morton et al., 2006), among patients with nodal metastases (primary melanomas ranging from 1.2 to 3.5 mm), the 5-year melanoma specific survival rate of those who underwent selective SLND with immediate lymphadenectomy (72.3%) for a positive SLN was significantly higher than those in the observation group who had lymphadenectomy only when there was clinically evident nodal disease (52.4%; p =.004). However, no overall survival advantage was seen when comparing the entire cohort of patients randomized to selective SLND with those patients who had wide excision only and nodal observation. Other data from meta-analysis of 6 studies showed a significantly higher risk of death for patients who only underwent elective lymph node dissection after clinically evident nodal metastasis versus patients who underwent SLN-guided CLND (Pasquali et al., 2010). However, this is a complex topic and survival benefit is also likely related to other factors including age, primary tumor characteristics, and features of the nodal metastases. Additionally, these studies tend to be underpowered because of a low percentage of patients with positive SLN(s) who could potentially benefit from CLND (Ross et al., 2011).
\n\t\t\tWhen SLNs are negative for micrometastasis, the remainder of the lymph node basin is usually negative (Morton et al., 1992; Reintgen et al., 1994; Albertini et al., 1996; Krag et al., 1995; Ross et al., 1993; Thompson et al., 1994) with FN rates under 5%. This is good evidence to conclude that melanoma metastases are most often spread in an orderly pattern (Fig.1). In general, if the SLNs are negative, there is no need to proceed with a more morbid regional lymph node dissection; selective SLN mapping replaces the more extensive lymph node dissection if SLNs are found to contain no metastasis.
\n\t\t\t\tPatients with a negative SLN have an overall 5 year survival of 84 to 92%, significantly better than positive node patients. Despite better survival results, a negative SLN is not an absolute predictor of survival. Recurrence and death in SLN negative patients may be related to FN SLN results or a pure hematogenous spread (Leong et al., 2004, \n\t\t\t\t\t\t\n\t\t\t\t\t\t\t2011\n\t\t\t\t\t\t\n\t\t\t\t\t; Ross et al., 2011). In particular, head and neck melanomas have a higher FN rate, over 12% in some studies (Klop et al., 2011); this is likely due to a complex lymphatic drainage pattern with multiple basins in the head and neck (\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLeong, 2011\n\t\t\t\t\t\t\n\t\t\t\t\t). FN results for selective SLND may result from failed preoperative lymphoscintigraphy, including injection techniques and interpretation of the lymphoscintigraphy, failed intraoperative lymphatic mapping, failed pathologic identification of microscopic disease, and “skip” metastasis (Leong, 2004). Predictors of relapse and death in SLN negative patients include increasing tumor thickness and ulceration (Ross et al., 2011).
\n\t\t\t\t\n\t\t\t\t\t\t\t\tAuthor\n\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\tYear\n\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\tof Patients\n\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t5-Year Overall Survival Negative Node Positive Node | \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\tp-value\n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t | \n\t\t\t\t\t\t|
Nowecki ZI | \n\t\t\t\t\t\t\t2003 | \n\t\t\t\t\t\t\t726 | \n\t\t\t\t\t\t\t84% | \n\t\t\t\t\t\t\t40% | \n\t\t\t\t\t\t\t<0.001 | \n\t\t\t\t\t\t
Leong SP | \n\t\t\t\t\t\t\t2005 | \n\t\t\t\t\t\t\t363 | \n\t\t\t\t\t\t\t85.6% | \n\t\t\t\t\t\t\t61.5% | \n\t\t\t\t\t\t\t<0.0001 | \n\t\t\t\t\t\t
Morton DL | \n\t\t\t\t\t\t\t2006 | \n\t\t\t\t\t\t\t1269 | \n\t\t\t\t\t\t\t90% | \n\t\t\t\t\t\t\t72% | \n\t\t\t\t\t\t\t<0.001 | \n\t\t\t\t\t\t
Cascinelli N | \n\t\t\t\t\t\t\t2006 | \n\t\t\t\t\t\t\t1108 | \n\t\t\t\t\t\t\t90.6% | \n\t\t\t\t\t\t\t75.4% | \n\t\t\t\t\t\t\t<0.0001 | \n\t\t\t\t\t\t
Mandalà M | \n\t\t\t\t\t\t\t2009 | \n\t\t\t\t\t\t\t1251 | \n\t\t\t\t\t\t\t88.7% | \n\t\t\t\t\t\t\t42.9% | \n\t\t\t\t\t\t\t<.0001 | \n\t\t\t\t\t\t
Kunter C | \n\t\t\t\t\t\t\t2010 | \n\t\t\t\t\t\t\t1049 | \n\t\t\t\t\t\t\t90% | \n\t\t\t\t\t\t\t58% | \n\t\t\t\t\t\t\t<0.001 | \n\t\t\t\t\t\t
Ellis MC | \n\t\t\t\t\t\t\t2010 | \n\t\t\t\t\t\t\t397 | \n\t\t\t\t\t\t\t92% | \n\t\t\t\t\t\t\t73% | \n\t\t\t\t\t\t\t0.0001 | \n\t\t\t\t\t\t
Overall Survival in Relation To Sentinel Lymph Node Status.
The dimensions and “amount” of micrometastasis in the SLN gives important prognostic data. According to the Rotterdam criteria for SLN tumor burden (van Akkooi et al., 2006, 2008), the maximum diameter of the largest focus of a positive SLN(s) is used as the measurement of record. There were 388 melanoma patients with positive SLNs from three European centers analyzed by this method with a median follow-up of 36 months. Three groups of patients were defined: (1) submicrometastasis with at least 10 cells but less than 0.1 mm (10%); (2) micrometastasis between 0.1 and 1.0 mm (35%); and (3) micrometastasis greater than 1.0 mm (55%). Patients with sub-micrometastasis (<0.1 mm) were identical to the SLN-negative group with an excellent survival rate. Tumor burden in SLNs increased with T-stage. Both T4 and SLN tumor burden were the most important factors for overall survival.
\n\t\t\tSimilarly, 63 melanoma patients with positive SLNs from the UCSF melanoma SLN database with a median follow-up of 8 years were analyzed (Baehner et al., 2011). SLN micrometastasis was recorded for size, number of foci and anatomic location by H&E. Fourteen of 63 patients had positive non-SLNs. Using the log-rank test, maximum metastatic size and primary melanoma thickness were correlated with progression-free survival and overall survival. Neither number of metastatic foci nor microscopic location was statistically significant. Multivariate analysis showed that the maximum metastatic size and primary melanoma thickness were the most important prognostic factors for progression-free survival and overall survival. As a continuous variable, every 5.0 mm increase in maximum metastatic size was predictive of progression-free survival. The estimated 5-year overall survival rate was 90% in patients with maximum metastatic size <0.6 mm, 52% with maximum metastatic size from 0.6 to 5.5 mm, and 55% with maximum metastatic size >5.5 mm. When stratified by thickness, the estimated 5-year progression-free survival rates were 95% for patients with maximum metastatic size <1.6 mm, 70% between 1.6 and 4.5 mm, and 45% >4.5 mm; the overall survival were 82%, 52%, and 5%. Both primary melanoma thickness and maximum metastatic size were independently prognostic of progression-free survival and overall survival in melanoma patients (Baehner et al., 2011). Other studies have also demonstrated that the incidence of SLN metastases correlates directly
\n\t\t\twith increasing tumor thickness (Gershenwald et al., 1998; Ross, 2011) as well as other factors including ulceration, lymphatic invasion, mitotic rate, Clark level, and anatomic site (Ross, 2011).
\n\t\tThe overall challenge in melanoma is to identify patients with truly localized disease versus patients with metastasis to nodal and/or systemic sites, as early detection remains key to successful eradication. With this in mind, selective SLND was introduced 20 years ago and has become essential in the care of patients with cutaneous melanoma, with a multitude of publications validating the importance of the SLN. Selective SLND provides a minimally invasive standard of care (Morton et al, 2008), that allows accurate staging, gives significant prognostic information, facilitates therapeutic lymphadenectomy with regional disease control, avoids unnecessary elective lymph node dissection, and may improve survival in node-positive patients. However, in a minority situations (~20% of the time), cancer cells may spread through the vascular system to distant sites, bypassing the SLNs (\n\t\t\t\t\t\n\t\t\t\t\t\tLeong et al., 2011\n\t\t\t\t\t\n\t\t\t\t). Therefore, it is important that all patients with melanoma be followed closely after their diagnosis.
\n\t\tEmerging and promising nanotechnology represents a field of multidisciplinary knowledge responsible for development and application of materials, which measure less than 100 nm [1, 2]. The Royal Society and Royal Engineering Academy proposed this concept in 2004, which was associated to nanoscience as the branch responsible for studying the phenomenon of materials with atomic, molecular, and macromolecular scales, whose properties differ significantly from those with major scales [3, 4].
\nNanoparticles can be generally described as ultrafine small material with 1–100 nm; however, several types of systems not limited only by small particles of certain material are included in this definition, as nanotubes, nanospheres, and nanocapsules [4, 5]. The properties exhibited by nanomaterials are unique and are being applied in many fields, from industrial to medicine [6, 7]. According to Arora et al. [8], the use of nanomaterials is increasing for commercial purposes as fillers, opacifiers, water filtration agents, cosmetic ingredients, semiconductors, electronic parts, and others. However, these same authors report that nanomaterials are being used in the medical area, mainly as agents for drug delivery, biosensors, and imaging contrast, i.e., human contact can happen both indirectly and directly, also being administered by ingestion or injection [8]. Once nanomaterials are used, environmental releasing turns dependent on the incorporation form of this product in each matrix, intrinsic material properties and also environmental conditions [9]. When there is human exposure or direct intake of nanomaterials, nanoparticles’ physicochemical properties and its possible modifications can influence absorption, distribution, and organism metabolism. Besides the potential to accumulate in some organs, relevant rates of nanomaterials are excreted, being released to the environment [10]. About the nanomaterials presence in the environment, a detailed description regarding its sources and fates can be found in the review of Part [11].
\nDue to the new scale of some materials, new physicochemical interactions may occur bringing unexpected and also adverse effects because these elements generally become highly reactive [12]. Physicochemical properties observed in engineered nanomaterials are attributed to small size, chemical composition (purity, crystallinity, electronics characteristics, etc.), structural surface (reactivity, organic or inorganic coating, etc.), solubility, form, and agglomeration potential [8].
\nIn view of the properties that the nanomaterials present, studies that evaluate the toxicity, their behavior in different environments, and the interactions with the biological system are of extreme importance. According to Dusinska [6], the safety assessment of nanomaterials is based on principles of risk assessment of “bulk” chemical substances. However, it is known that the behavior of these materials, both in the environment and in the cells, is different from such crude samples, and therefore the monitoring needs to be more specific. Catalán et al. [13] emphasize that the damaging potential of biodurable nanomaterials is not well demonstrated, and thus the classical toxicity evaluation trials must undergo adaptations.
\nAccording to Maynard et al. [14], until the 1990s, many studies that focused on environmental epidemiology indicated a relationship between exposure to aerosols and increased mortality and morbidity of organisms. The relationships between particle size, chemical nature, and toxic effects were demonstrated, with the most pronounced effects observed in the lungs and heart due to exposure to smaller particles. These same authors argue that only in this decade has there been evidence that environmental particles with a diameter of less than 2.5 μm could cause deleterious health effects due to their reduced size [14]. Now it is known that engineered nanoparticles can perform these same activities [12].
\nSince the inception of this science, the studies and applications of nanoparticles have grown exponentially and, to the same extent, heightened concerns about environmental and health implications. In this context, the term nanotoxicology was formalized by a proposal of Donaldson et al. in 2004 [15] in an editorial in the journal Occupational and Environmental Medicine [5] and, since then, has been used to describe specifically the harmful effects of nanomaterials on environmental, animal, and human health. In 2005, nanotoxicology was consolidated as an area of expertise, with the launch of the journal Nanotoxicology, with the first article published by Oberdörster et al. in 2007 [16]. This article discusses the history of nanotoxicology as a science and presents some challenges to be faced by researchers.
\nConsidering that nanoparticles have a greater potential to travel through the body than conventional-sized materials, researchers warn of the possibility of numerous interactions with biological fluids, cells, and tissues. Therefore, in vitro tests are recommended for an initial evaluation of the cytotoxicity and genotoxicity of nanomaterials, as well as for the identification and understanding of cellular mechanisms of toxicity [3]. In vivo methods are also used and, for both, some methods have already been developed by the Organization for Economic Co-operation and Development (OECD) and can be used for regulatory purposes.
\nAccording to Paschoalino et al. [3], the growing investment in nanoscience boosted the world market, as well as increased the use and consumption of products and processes aimed at this area. Despite this, it is true that research aimed at evaluating the toxicity of nanomaterials is still necessary, since the same properties that make nanomaterials so attractive may also be responsible for harmful effects on living organisms.
\nIn this context, there is a recommendation for the analysis of physicochemical properties of nanomaterials in relation to human health and environmental safety (Table 1). In 2006, the OECD established a working party on manufactured nanomaterials to determine the appropriate methods for evaluating nanomaterials. According to the guidance manual developed, 26 physicochemical properties should be considered [6]. However, according to these same authors, only a few methods are available for the characterization of the toxicological properties of the nanomaterials, and the association of the effects with the physicochemical characterization is still a challenge.
\nProperty | \nRelevance | \n
---|---|
Particle size distribution | \nEssential | \n
Degree/state of agglomeration | \nImportant | \n
Particle shape | \nImportant | \n
Chemical composition/purity | \nEssential | \n
Solubility | \nEssential (if applicable) | \n
Physical properties | \n|
Density | \nMatrix dependent | \n
Crystallinity | \nMatrix dependent | \n
Microstructure | \nMatrix dependent | \n
Optical and electronic properties | \nMatrix dependent | \n
Bulk powder properties (important for dosimetry/exposure) | \nMatrix dependent | \n
Concentration (can be measured as mass, surface area, or number concentrations) | \nEssential | \n
Surface properties | \n|
Specific surface area/porosity | \nEssential | \n
Surface chemistry/reactivity | \nEssential | \n
Surface adsorbed species | \nImportant | \n
Surface charge/Zeta potential (especially in aqueous biological environment— may change according the environment) | \nImportant | \n
Surface hydrophobicity | \nEssential | \n
Properties used for nanomaterial characterization regarding toxicity evaluation.
Adapted from Powers et al. [17]
Nanomaterials encompass a broad spectrum of materials with different physical, chemical, and biological properties. Thus, they do not constitute a homogeneous group and are usually defined by the type of core, which may be organic, such as fullerenes (carbon derivatives) and carbon nanotubes (single and/or multilayer), or inorganic, such as those of metal oxides (iron, zinc, titanium, etc.), metals (mainly gold and silver), and quantum dots [4].
\nAccording to Ju-Nam and Lead [4], some nanomaterials can have their surfaces manipulated in order to introduce specific functionalities for new applications. Thus, a vast field of possibilities opens up for materials with different properties and, therefore, also for infinite interactions with organisms and environment. However, the major challenge of nanotoxicology is to understand and prevent the risk of the use and/or exposure to nanomaterials that can cause toxicity by mechanisms not yet known or not yet explained by traditional toxicology [5].
\nConcern about the toxicity of nanomaterials lies primarily in production and commercialization on such a large scale as at present. Thus, the risk of these compounds reaching the different environmental compartments (atmosphere, water, and soil), becoming bioavailable, is very large [3, 17].
\nSince 2005, the European Commission Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR) has published reports on the impacts of nanoparticles on human health. The aforementioned committee focused its efforts on the evaluation of nanoparticles physically capable of entering the human body via inhalation, ingestion, and dermal absorption and reported that the size, shape, surface area, and chemical composition of the nanoparticle are closely associated with its toxicity. In addition, it has been explored how these characteristics affect bioavailability and interactions, as well as influence on exposure and dose. Therefore, the dose, the physicochemical properties, and the biokinetics are also important parameters to be evaluated when considering the toxicology of nanomaterials [14].
\nIn view of the numerous properties and characteristics of nanomaterials, products that are increasingly light, resistant, and often of lower cost are daily produced and marketed by the most different segments, such as electronic, medical, pharmaceutical, cosmetic, food, and agricultural [3]. In this context, when considering the ecotoxicology of particles whose components are nontoxic in the micro- or macrometric scales, studies that elucidate the routes of exposure and effects of nanomaterials on environmental compartments and different organisms are fundamental.
\nAccording to Laux et al. [7], the entry of nanomaterials into the environment occurs by the release of their components during use and by final disposal, so it is important to track and understand the kinetics and transformation of these materials in organisms and the environment. Knowledge of the influence of biopersistence on biokinetics and environmental fate is of utmost importance when determining the toxic potential.
\nWhen a nanomaterial comes in contact with the human body or the environment, it is difficult to track it again. In the environment, some nanomaterials such as metallic (e.g., Ag and Cu) and metal oxides (e.g., ZnO and Fe2O3) can dissolve rapidly, while others are more persistent (e.g., TiO2, SiO2, carbon nanotubes, and graphene) [18]. However, according to these authors, soluble nanomaterials present the best scenario of toxicity evaluation, since their behavior is generally similar to that presented by their ions. However, when cells internalize them, they can solubilize and release toxic metals through a mechanism known as “Trojan Horse” [18].
\nThe aquatic ecosystem is the main route of exposure to a nanomaterial, since this type of environment is usually the final destination of nanocomposites introduced in natural systems [19]. After the aquatic environment, the atmosphere (troposphere), soil, and sediment follow an order of priority as routes of exposure. When present in aquatic environments, nanomaterials can be absorbed by cells, especially during filtration by aquatic organisms, directly interfering with their physiology and/or their ability to feed and breathe [3]. According to these same authors, other pathways of entry of nanomaterials into receptor organisms occur through cellular uptake, inhalation, or ingestion (Figure 1).
\nMain sources, routes of exposure, and possible interactions between nanoparticles with the environment and organisms (adapted from Paschoalino et al. [3]).
According to Bhaskar et al. [20] and Dusinska et al. [6], nanomaterials can enter the cells actively or passively, overcoming any protective barrier of the organism, including the blood-brain barrier. The capture mechanisms are related to the intrinsic physicochemical characteristics of the nanomaterial, as well as its route of exposure. Considering human health, generally the main route of exposure is inhalation, in which smaller particles reaching the alveoli and depending on their physicochemical properties cross the blood-air barrier of the lungs and reach the liver, heart, spleen, and kidneys [7]. There is a challenge when it comes to nanoparticles developed to cross human body barriers, such as those applied in medicine. There are materials that are developed to pass through barriers, not to enter cells, while there are others that are designed to act within them [10].
\nThe first contact of the cell with any extracellular material occurs through the lipid (e.g., phospholipid) and protein components (e.g., membrane receptors) present in the cell membrane. For Paschoalino et al. [3], the nanomaterials present greater permeability to the skin, mucous membranes, and cell membranes due to their diminutive size.
\nConner and Schmid [21] stated that most nanomaterials are actively incorporated by cells through endocytosis. This is one of the most important mechanisms of cellular communication with the external environment, since it involves the transmembrane and bidirectional flow of vesicles, through the movement of extracellular content internalization [1]. According to Radaic et al. [1], the shape, size, characteristics (such as porosity) of the surface, surface charge, and composition of nanoparticles directly influence endocytosis. According to Drasler et al. [22], cell size, proliferation rate, and surface receptor growth and expression characteristics are the major factors involved in the entry of nanomaterials into cells. Generally, endocytic pathways are essential in this process, where large particles or agglomerates of nanomaterials are obtained by phagocytosis (diameter greater than 250 nm), whereas smaller particles (diameter smaller than 150 nm) are obtained by pinocytosis, specific or not. Valsami-Jones and Lynch [18] have beautifully illustrated the possible mechanisms of nanomaterial uptake by cells.
\nCollins et al. [23] have described that besides penetrating cells, many nanomaterials are able to cross nuclear membranes and gain access to chromatin at any stage of the cell cycle. Thus, in addition to direct damage to DNA, nanoparticles can induce the formation of reactive oxygen species (ROS), such as hydroxyl radicals (˙OH), causing oxidative stress (redox imbalance) and serious damage to the cell. Oxidative stress can be the result of the simple cellular response to the presence of the nanomaterial or a secondary effect of the inflammation generated by them [23]. It is also known that the dissolution of certain nanomaterials may be able to release toxic ions and/or other components, which may induce toxicity [22].
\nROS are highly reactive molecules that disrupt intracellular medium homeostasis, since they interact with cellular macromolecules such as DNA, proteins, and lipids [24]. Singh et al. [24], Louro et al. [25], and Radaic et al. [1] stated that nanomaterials can induce genotoxic damage mediated by oxidative stress and through their interaction with cellular constituents, including mitochondria and NADPH oxidases bound to the cell membrane; by the depletion of antioxidants; or by the release of the metallic ions present in the constitution of many nanomaterials, which can promote the conversion of cellular oxygen metabolites into ROS. When considering the DNA molecule, the major damage induced by ROS is single-strand breaks, double-strand breaks, base modifications (such as the formation of 8-hydroxydeoxyguanosine adducts), and DNA cross-links. According to Singh et al. [24], all of the aforementioned damages have the potential to initiate and promote carcinogenesis. Once the DNA molecule has been damaged, several cellular processes can be triggered, such as cell cycle arrest, apoptosis, or DNA repair [24].
\nApart from the oxidative stress-related lesions, other genotoxic effects may contribute significantly to the promotion of genetic instability, as nanomaterials can cross the pores of the nuclear envelope and interact directly with the genome of the cell and/or with nuclear proteins [25]. Under these conditions, Louro et al. [25] reported that some nanomaterials induce the formation of intranuclear protein aggregates, inhibiting the processes of cell replication, transcription, and proliferation. When the nanomaterials are not able to cross the nuclear envelope, there is still the possibility of interaction with the DNA molecule and nuclear proteins during the mitotic process, which can cause aneuploidies [24, 25].
\nDepending on the organism exposed to the nanomaterials, different interactions can be evidenced. Bielmeyer-Fraser et al. [26] demonstrated that nanoparticles of ZnO, AgO, and CuO were able to induce toxicity to algae bioindicator in a similar way to the respective solubilized metals. However, these researchers noted the metals accumulated in different regions of the cells, and the nanoparticles were retained mainly in the cell wall, while the metals were observed mainly in the organelles, as fragments of the endoplasmic reticulum. However, in both ways, the authors point out that the accumulated metal could be transferred by the trophic chain and carried to other organisms.
\nWhen a nanomaterial enters a living organism, several components can adhere to its surface, drastically modifying its interaction with cellular structures. Proteins are molecules that can adhere to the nanomaterial and form a type of coating, called biomolecular corona [27]. This corona may alter the ability of a nanomaterial to cross physiological barriers, influencing its toxic potential [7].
\nAccording to Drasler et al. [22], in vitro assays performed with cell culture can indicate the biological fate of nanomaterials at the cellular and multicellular level, even in an excluding mode according to the cell type (i.e., to determine which cell type is actually affected by a certain type of nanomaterial).
\nWithin nanotoxicology there is an impasse on how best to assess the possible adverse effects of nanomaterials, both for human health and environmental monitoring. Toxicity tests may be performed employing live (in vivo) organisms, such as microcrustaceans, fishes, rodents, and other animals and/or cell cultures (in vitro). Several standardized toxicological tests are available to measure the biological response of an organism to a chemical. However, there is no standardization for the evaluation of the toxicity of nanomaterials, which hampers the comparison of results and the consensus about their toxicity. Most of the studies performed so far are adaptations of the standard procedures used for other substances [3]. Although some minimal combinations of assays have been proposed, Drasler et al. [22] have described that there is no standard evaluation protocol due to the wide range of physicochemical properties that nanomaterials can present.
\nAnimal tests are more predictive for human effects but have limitations, mainly because of physiological and biochemical differences between the species. In addition, there is a growing public and legal demand that ethically supports the substitution of animal testing for alternatives not based on in vivo testing. New concepts of experimentation have been based on strategies with primary culture of human cells and permanent cultures of well-established cell lines, since they present efficient, cheap, and reliable results [22].
\nUnderstanding the demand for orientation and applicability, this chapter will address some of the main evaluation methods, developed both in vivo and in vitro, to better characterize the toxicity of nanomaterials.
\nIn vitro evaluations have increased considerably, but in vivo validation still is necessary to understand and interpret its results. Furthermore, animal experimentation was also part of the NanoTEST project, whose purpose was to understand the effects on the physiology of organisms tested. Currently, the OECD presents some test guidelines on which biomarkers should be used for each test organism [10].
\nIn general, there are more researches on human toxicity, using rodent models, whereas few in vivo studies addressing the ecotoxicity of nanomaterials are available. Furthermore, most of those found in the literature consider the impact of nanomaterials on aquatic organisms, since the continental and marine waters end up being the main receiving compartment. Some scarce trials address the toxicity of nanomaterials in soil and in atmosphere, commonly as suspended particles. In general, bacteria (e.g., Aliivibrio fischeri), algae (e.g., Raphidocelis subcapitata), nematodes (e.g., Caenorhabditis elegans), microcrustaceans (e.g., Daphnia magna, D. pulex, Ceriodaphnia dubia), mollusks (e.g., Lymnaea stagnalis), fish (e.g., Danio rerio), and rodents (Wistar rat and mice) are the most used test organisms for the evaluation of acute toxicity (Table 2).
\nNanomaterial | \nMean diameter of the particles (nm) | \nTest organism | \nMain results | \nReferences | \n
---|---|---|---|---|
Ag | \n13–17 nm | \nLymnaea stagnalis (Mollusca) | \nGrowth alteration and bioaccumulation | \nCroteau et al. [28] | \n
ZnO TiO2 | \n15–30 nm | \nSkeletonema marinoi (Diatom—Skeletomataceae), Thalassiosira pseudonana (Diatom—Thalassiosiraceae), Dunaliella tertiolecta (Algae—Dunaliellaceae), Isochrysis galbana (Algae—Isochrysidaceae) | \nOnly nanoparticles of ZnO have decreased growth rate of diatom and algae population | \nMiller et al. [29] | \n
Graphene family nanoparticles | \n— | \nCaenorhabditis elegans (Nematoda) | \nDecreased reproduction rates | \nChatterjee et al. [30] | \n
ZnO CuO AgO | \nZnO: 20–30 nm CuO: 20–100 nm AgO: 20–70 nm | \nThalassiosira weissflogii (Diatom—Thalassiosiraceae) | \nDecreased diatom population growth in similar way to respective dissolved metals. Bioaccumulation of nanoparticles in cell wall and possible transfer through trophic chain | \nBielmeyer-Fraser et al. [26] | \n
ZnO Al2O3 TiO2 | \n— | \nDanio rerio (Chordata) | \nMetal oxide nanoparticles induced different toxic effects in zebrafish development according to each metal. ZnO delayed larvae and embryo development and also induced serious ulceration in larvae | \nZhu et al. [31] | \n
TiO2 | \n~43 nm | \nPimephales promelas (Chordata) | \nFish immunotoxicity and gene expression alteration | \nJovanović et al. [32] | \n
TiO2 | \n5, 10, and 32 nm | \nXenopus laevis (Chordata) | \nSignificantly affected tadpole growth. The highest concentration caused mortality, suppressed tadpole body length, and delayed animal development | \nZhang et al. [33] | \n
TiO2 | \n— | \nDaphnia similis (Crustacea) | \nThe highest concentration (100 mg L−1) did not induce toxic effects under experimental conditions. A mixture of TiO2 forms induced toxic effects by ROS generation when exposed to UVA light | \nMarcone et al. [34] | \n
TiO2 ZnO CuO | \nTiO2: 25–70 nm ZnO: 50–70 nm CuO: 30 nm | \nVibrio fischeri (Gammaproteobacteria), Daphnia magna (Crustacea), Thamnocephalus platyurus (Crustacea) | \nSuspensions of nano- and bulk TiO2 were not toxic. A nano-ZnO formulation was very toxic to V. fischeri, D. magna, and T. platyurus. Cu compound also showed toxicity; however, for Daphnia magna were less bioavailable than for bacteria | \nHeinlaan et al. [35] | \n
Metallic nanoparticles of Ag, Cu, Al, Co, Ni and TiO2 | \nAg (20–30 nm), Cu (15–45 nm), Al (51 nm), Co (10–20 nm), Ni (5–20 nm), and TiO2 (30 nm) | \nRaphidocelis subcapitata (Algae—Selenastraceae), Ceriodaphnia dubia (Crustacea), Daphnia pulex (Crustacea), Danio rerio (Chordata) | \nNanometals caused acute toxicity in multiple aquatic organisms, but the effect was different according to the metal particle and the species used. Since R. subcapitata, C. dubia, and D. pulex were susceptible to nanometals, trophic chain could be compromised | \nGriffitt et al. [19] | \n
Ag ZnO TiO2 CeO2 Cu | \nAg (15 nm) ZnO (34–42 nm) TiO2 (10–23 nm) CeO2 (10–33 nm) Cu (76 nm) | \nRaphidocelis subcapitata (Algae—Selenastraceae), Daphnia magna (Crustacea), Danio rerio (Chordata) | \nAg and Cu nanoparticles affected all organisms; ZnO was toxic to algae and daphnids; TiO2 and CeO2 were toxic only to algae | \nHund-Rinke et al. [36] | \n
Experimental conditions and obtained results through in vivo tests.
According to Drasler et al. [22], assays can be performed with primary cultures or eternal cell lines. According to these authors, cell lines are preferably chosen because they present great homogeneity and stability, which favors reliability in the results, especially in initial tests. For more specific tests, these same researchers recommend the use of 3D co-cultures, to better understand the mechanisms of action of nanomaterials on tissues.
\nFor the nanomaterial toxicity evaluation, the use of epithelial cell lines (skin, gastrointestinal tract, or lung) is usually indicated as these cells present characteristics of real barriers against harmful agents and are therefore the first to suffer the influence of these compounds [37]. However, it is important to note that some strains may not be responsive to the effects of nanomaterials and, in this case, primary cultures may be more indicated [22].
\nAiming at the reproducibility of in vitro assays with culture of cell lines, it is necessary to record details that are generally missing from the publications. The origin of the cells, the number of the passage, the detailed method of cell culture, the brand of plastics, and reagents used during the cultivation/exposure, besides the description of the morphology, growth, and cell differentiation, before and after the test, are the information that should be included in the results’ publication [22]. Among the in vitro assays, those performed with mammalian cells are considered to be more important than those performed with other cell types [13].
\nFor the in vitro comet assay with mammalian cell culture, Collins et al. [23] make some recommendations: (1) use non-cytotoxic concentrations (less than 20% of cell viability loss; if the nanomaterial is not cytotoxic, concentrations below 100–150 μg/mL are recommended); (2) choose the cell type according to the exposure scenario (based on exposure route and target organ); (3) determine both short (2–3 h) and long (24 h) tests to obtain a better understanding of the mode of action of the nanomaterial; and (4) determine if the genotoxic damage evidenced is a result of the direct effect with the DNA or due to the oxidation of the DNA. According to Drasler et al. [22], the exposure period is one of the main factors related to contradictory toxicity results for identical nanomaterials, as this involves transformations and the aging of their components.
\nIn vitro assays can cover specific endpoints, such as dermal absorption, skin and eye irritation, endocrine disruption, and genotoxicity, among others. Among the tests, most nanomaterial evaluation protocols align the main routes of exposure, being dermal, oral, and inhalation [22].
\nAccording to Catalán et al. [13], the relevance and limitations of genotoxicity/mutagenicity assays should be taken into account when choosing the most appropriate monitoring method. According to these authors, the tests considered in the evaluation should be based on three categories, following the importance order: (1) gene mutation, (2) chromosomal damage, and (3) DNA damage. DNA damage is considered a mild effect because of the possibility of repair, while chromosomal damage and gene mutation are considered to be severe effects because they are irreparable changes.
\nRegarding the mutagenic potential of nanomaterials to humans, the effects observed in vivo should be considered more relevant than those observed in vitro, since the first allow the detection of inflammation and, therefore, secondary genotoxic effects [13]. Although more predictive for human effects, animal tests still have limitations, mainly because of the physiological and biochemical differences between species. Also, there is a trend to substitute animal testing for suitable alternatives that do not promote pain and suffering [22].
\nAmong the tests recognized by the scientific community, those with certified guidelines for nanomaterial assessment have greater “weight” than others that have not been validated in the determination of genotoxicity/mutagenicity [13]. Although they cannot be used to determine mutagenicity, the remaining assays can be used to demonstrate the genotoxic potential of nanomaterials.
\nThere are several recommended tests to assess nanomaterials, especially those described by the OECD. In accordance with the OECD guidelines [38], in order to select a test and evaluate the genotoxicity of a nanoform, exposure, absorption, solubility, metabolites, and other derivatives should be considered, as well as possible side effects (e.g., generation of ROS).
\nComparing the genotoxicity tests for chemical substances, the comet assay and the micronucleus test are also the most indicated and used by the researchers [13]. The comet assay (single cell gel electrophoresis) is a common method of DNA damage evaluation, which can be performed with very diverse cell types. Briefly, a suspension of individualized cells is mixed with agarose and placed on a pregelatinized slide. Then, cell lysis on Triton X-100 removes membranes and soluble cellular components, while NaCl removes the histones from the DNA, promoting a superadhesion of this material to a matrix, forming a structure known as a nucleoid. When there are breaks in DNA strands (single or double), the fragments tend to move toward the anode during electrophoresis. When there is damage and it is observed by fluorescence microscopy, a comet-like image is noted. The percentage of DNA in the tail is proportional to the frequency of breaks, that is, the damage inferred to the genetic material [23].
\nAs described by Collins et al. [23], several nanomaterials (e.g., TiO2, ZnO, Au, Ag, Co3O4, Fe3O4, SiO2, ZrO2, and others) have already been evaluated by variations of the comet assay with specific endonucleases for some lesions, which increase the power of this tool. Among these enzymes, formamidopyrimidine DNA glycosylase (FPG) recognizes lesions of the 8-oxo-7,8-dihydroguanine (8-oxoG) and formamidopyrimidine type (open-ring purines) and is therefore widely used to estimate oxidative damages to DNA caused by nanomaterials [23].
\nHowever, other famous trials are not recommended, such as the Ames test [13]. Catalán et al. [13] discourage the use of this test to evaluate nanomaterials, since some compounds are unable to cross the bacterial wall, while others have bactericidal effect.
\nUndoubtedly, nanoscience and nanotechnology offer the prospect of great advances to the most different sectors of industry and medicine. However, as any area of technology that makes intensive use of new materials/structures, it brings some risks to the health of organisms and the environment. Generally, toxicological studies involving nanomaterials are still scarce, with results often controversial when compared to each other, mainly due to incipient standardization. In this context, the combination of in vitro and in vivo methods in a battery of tests is still the best way to assess the toxicity of nanomaterials [22, 23].
\nOne of the major concerns is the choice of dose/concentration range of nanomaterials to be tested. The inclusion of excessively high doses/concentrations may generate false positives, while excessively low doses may prevent detection or may underestimate the genotoxic potential [23]. Drasler et al. [22] provide all guidelines to be considered in evaluating the toxicity of nanomaterials by cell culture, but in vivo evaluation must not be overlooked. Paschoalino et al. [3] state that the environmental risk analysis of nanomaterials depends mainly on the regulatory structure, which involves the generation of protocols, which must be based on a multidisciplinary interaction, in order to obtain a more risk assessment possible.
\nAs demonstrated by Valsami-Jones and Lynch [18], harmonization of methods and approaches could benefit this young science, as there is still no consensus on basic assessment protocols. Current protocols involve specific techniques and methods to collect and analyze data sufficient to quantitatively describe the release, destination, transport, transformation, exposure, and toxicity of chemicals. Furthermore, in order to be more precise about the toxicity and mechanism of action of nanomaterials on living organisms, the physicochemical characteristics must be sufficiently detailed. So far, a great effort has been made by the OECD to try to standardize test methods that can correctly evidence the risk of nanomaterials. There are a number of internationally accepted test guidelines that are used for toxicity assessment involving trials with organisms for aquatic, soil, and sediment monitoring. Since 2013, experts from all over the world hold strategic meetings to determine what directions the OECD should take regarding the assessment of nanomaterials, as explored in the Petersen et al. [39].
\nAlso, there is a lot of potential in computational models to help elucidate the possible effects of nanomaterials on humans and the environment. Currently, the quantitative structure-activity relationship (QSAR) model seems to be quite adequate because it can relate the structural, physical, and chemical characteristics to the behavior that some nanomaterial can present. To date, the combination of field, laboratory, and computational work still is the most promising technique to ensure reliable responses to the issues involved with nanomaterial toxicity.
\nThe authors declare no conflict of interest.
Edited by Jan Oxholm Gordeladze, ISBN 978-953-51-3020-8, Print ISBN 978-953-51-3019-2, 336 pages,
\nPublisher: IntechOpen
\nChapters published March 22, 2017 under CC BY 3.0 license
\nDOI: 10.5772/61430
\nEdited Volume
This book serves as a comprehensive survey of the impact of vitamin K2 on cellular functions and organ systems, indicating that vitamin K2 plays an important role in the differentiation/preservation of various cell phenotypes and as a stimulator and/or mediator of interorgan cross talk. Vitamin K2 binds to the transcription factor SXR/PXR, thus acting like a hormone (very much in the same manner as vitamin A and vitamin D). Therefore, vitamin K2 affects a multitude of organ systems, and it is reckoned to be one positive factor in bringing about "longevity" to the human body, e.g., supporting the functions/health of different organ systems, as well as correcting the functioning or even "curing" ailments striking several organs in our body.
\\n\\nChapter 1 Introductory Chapter: Vitamin K2 by Jan Oxholm Gordeladze
\\n\\nChapter 2 Vitamin K, SXR, and GGCX by Kotaro Azuma and Satoshi Inoue
\\n\\nChapter 3 Vitamin K2 Rich Food Products by Muhammad Yasin, Masood Sadiq Butt and Aurang Zeb
\\n\\nChapter 4 Menaquinones, Bacteria, and Foods: Vitamin K2 in the Diet by Barbara Walther and Magali Chollet
\\n\\nChapter 5 The Impact of Vitamin K2 on Energy Metabolism by Mona Møller, Serena Tonstad, Tone Bathen and Jan Oxholm Gordeladze
\\n\\nChapter 6 Vitamin K2 and Bone Health by Niels Erik Frandsen and Jan Oxholm Gordeladze
\\n\\nChapter 7 Vitamin K2 and its Impact on Tooth Epigenetics by Jan Oxholm Gordeladze, Maria A. Landin, Gaute Floer Johnsen, Håvard Jostein Haugen and Harald Osmundsen
\\n\\nChapter 8 Anti-Inflammatory Actions of Vitamin K by Stephen J. Hodges, Andrew A. Pitsillides, Lars M. Ytrebø and Robin Soper
\\n\\nChapter 9 Vitamin K2: Implications for Cardiovascular Health in the Context of Plant-Based Diets, with Applications for Prostate Health by Michael S. Donaldson
\\n\\nChapter 11 Vitamin K2 Facilitating Inter-Organ Cross-Talk by Jan O. Gordeladze, Håvard J. Haugen, Gaute Floer Johnsen and Mona Møller
\\n\\nChapter 13 Medicinal Chemistry of Vitamin K Derivatives and Metabolites by Shinya Fujii and Hiroyuki Kagechika
\\n"}]'},components:[{type:"htmlEditorComponent",content:'This book serves as a comprehensive survey of the impact of vitamin K2 on cellular functions and organ systems, indicating that vitamin K2 plays an important role in the differentiation/preservation of various cell phenotypes and as a stimulator and/or mediator of interorgan cross talk. Vitamin K2 binds to the transcription factor SXR/PXR, thus acting like a hormone (very much in the same manner as vitamin A and vitamin D). Therefore, vitamin K2 affects a multitude of organ systems, and it is reckoned to be one positive factor in bringing about "longevity" to the human body, e.g., supporting the functions/health of different organ systems, as well as correcting the functioning or even "curing" ailments striking several organs in our body.
\n\nChapter 1 Introductory Chapter: Vitamin K2 by Jan Oxholm Gordeladze
\n\nChapter 2 Vitamin K, SXR, and GGCX by Kotaro Azuma and Satoshi Inoue
\n\nChapter 3 Vitamin K2 Rich Food Products by Muhammad Yasin, Masood Sadiq Butt and Aurang Zeb
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\n\nChapter 5 The Impact of Vitamin K2 on Energy Metabolism by Mona Møller, Serena Tonstad, Tone Bathen and Jan Oxholm Gordeladze
\n\nChapter 6 Vitamin K2 and Bone Health by Niels Erik Frandsen and Jan Oxholm Gordeladze
\n\nChapter 7 Vitamin K2 and its Impact on Tooth Epigenetics by Jan Oxholm Gordeladze, Maria A. Landin, Gaute Floer Johnsen, Håvard Jostein Haugen and Harald Osmundsen
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\n\nChapter 9 Vitamin K2: Implications for Cardiovascular Health in the Context of Plant-Based Diets, with Applications for Prostate Health by Michael S. Donaldson
\n\nChapter 11 Vitamin K2 Facilitating Inter-Organ Cross-Talk by Jan O. Gordeladze, Håvard J. Haugen, Gaute Floer Johnsen and Mona Møller
\n\nChapter 13 Medicinal Chemistry of Vitamin K Derivatives and Metabolites by Shinya Fujii and Hiroyuki Kagechika
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