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Pleomorphic lobular carcinoma of the breast: An aggressive tumour showing apocrine differentiation. The significance of signet-ring cells in infiltrating lobular carcinoma of the breast. Developing a Prognostic index for ductal carcinoma in situ of the breast. Are we there yet? Silverstein MJ, et al. A prognostic index for ductal carcinoma in situ of the breast.

Prognostic classification of breast ductal carcinoma in situ. Intraductal carcinoma ductal carcinoma in situ. Holland R, et al. Microcalcification associated with ductal carcinoma in situ: Semin Diagn Pathol ; Ductal carcinoma in situ: Leal CB, et al. Ductal carcinoma in situ of the breast; histological categorization and its relationship to ploidy, and immunohistochemical expression of hormone receptors, p54, and c-erbB-2 protein.

Sneige N, et al. Ductal carcinoma in situ treated with lumpectomy and irradiation: Douglas-Jones AG, et al. A critical appraisal of six modern classifications od ductal carcinoma in situ of the breast DCIS: Consensus conference on the classification of ductal carcinoma in situ.

Modern Pathology ;11 2: Immunohistochemical detection of steroid receptors inbreast cancer: J Clin Pasthol ; Immunocytochemical estrogen and progestin receptor assays in breast cancer with monoclonal antibodies.

Histopathologic, demographic and biochemical correlations and relationship to endocrine response and survival. Pertschuk LP, et al.

Estrogen receptor immunocytochemistry in paraffin embedded tissues with ER1D5 predicts breast cancer endocrine response more accurately than HSpgamma in frozen sections or cytosol-based ligand assays.

Andersen J, et al. Immunohistochemical estrogen receptor determination in paraffin-embedded tissue. Prediction of response to hormone treatment in advanced breast cancer. Goulding H, et al. A new immunohistochemical antibody for the assessmnet of estrogen receptor status on routine formalin-fixed tissue samples.

Human Pa thol ; If history and physical examination are normal, other staging investigations may not be necessary. If there are any abnormal findings, these should be further investigated as appropriate. If the patient presents with locally advanced breast cancer large tumour, node positive or inflammatory breast cancer, the risk of metastatic disease is higher.

Staging prior to any treatment bone scan, chest CT or x-ray, abdominal CT or US and, laboratory investigations including liver enzymes should be considered. In the absence of symptoms suggesting metastatic disease, staging should be done postoperatively based on final pathology. Staging of breast cancer is based on final pathology. In asymptomatic patients with newly diagnosed cancer, the following staging investigations are recommended based on the pathologic staging: Baseline tumour markers including CEA, CA and CA should only be considered as part of the initial staging for patients with metastatic disease.

If normal, they need not be repeated, unless there is a documented or suspected progression. Other than these investigations, prior to chemotherapy, a hematology and chemistry panel should be done to rule out bone or liver metastases and to ensure adequate marrow, hepatic and renal function. Diagnostic radiologists, medical oncologists, pathologists, radiation oncologists and surgeons typically attend these conferences.

The clinical history, physical examination, pathology slides and diagnostic imaging studies are reviewed and management options are discussed. Family physicians and surgeons are welcome to attend these conferences. Patients with breast cancer should be supported in their decision-making about what treatment pathway is best for them. The information in this section of the Cancer Management Guidelines is our current approach to patients with breast cancer.

It is not intended to be a comprehensive manual on breast cancer and its treatments nor is it intended to imply that the approach given here is the only acceptable approach.

People with a suspected diagnosis of breast cancer should undergo percutaneous core biopsy , to confirm the pathology. Patients with a new diagnosis of non-metastatic breast cancer should be referred initially to a surgeon with experience in breast cancer surgery for assessment regarding operability and discussion of surgical options. The breast should be imaged with a mammogram and ultrasound, and if these investigations are non-diagnostic, an MRI of the breast should be carried out.

Biopsy of any suspicious abnormalities found on imaging should be done. Recommendations for radiation and systemic therapy are based on the pathology of the underlying breast cancer. A margin of underlying breast tissue should be excised with the nipple-areolar complex to evaluate for an associated in-situ or invasive cancer.

Axillary staging is not initially required in the context of breast conserving therapy. Mastectomy represents a surgical option. A referral to plastic surgery for reconstruction of the nipple-areolar complex should be considered. Appropriate management of pure DCIS requires detailed mammographic evaluation of the breast to obtain an assessment of the preoperative extent of the lesion.

Close cooperation and communication between the radiologist, surgeon, pathologist and oncologist is crucial to ensure adequate local therapy in patients treated with breast conservation. Treatment for patients with concomitant microinvasive and invasive disease should be based on the presence of the invasive disease, as discussed in separate sections. Sentinel lymph node biopsy is advised for patients undergoing mastectomy for DCIS due to the possibility of an invasive component in the final surgical specimen.

DCIS is a non-obligate precursor of invasive disease. At present, all patients with pure DCIS are offered treatment. Patients with pure DCIS may be treated with breast conserving therapy or mastectomy. Patients undergoing breast conserving surgery including partial mastectomy, lumpectomy, wide excision, or excisional biopsy with a positive margin defined by ink on DCIS after surgery should undergo wider local excision.

A 2-mm margin is associated with a decreased risk of in-breast tumor recurrence compared to narrower margins. Margin widths greater than 2 mm do not confer a significant benefit in local control compared to a 2 mm margin and thus re-excision for margins wider than 2-mm should not be routinely carried out 2.

Clinical judgment should be utilized for determination of the need for re-excision in patients with a smaller negative margin width 0. Radiotherapy reduces the incidence of in situ and invasive breast recurrences after breast conserving surgery by half. Radiotherapy should optimally start once healing from the partial mastectomy is complete, generally within 10 weeks of partial mastectomy. If post-operative problems occur, including hematoma, large seroma, infection, breast edema with erythema, or wound dehiscence occur, the start of radiotherapy may be delayed to allow resolution.

There is no randomised trial evidence showing detriment to delay the start of radiotherapy however, retrospective data from British Columbia shows that there is no detriment to delay up to 20 weeks after BCS for patients with invasive disease 7 , which likely also applies to DCIS. Radiotherapy planning and prescription is similar to those with invasive disease and are described separately. Women with very diffuse areas of DCIS e. The use of adjuvant hormonal therapy is somewhat controversial.

No randomized trial has shown an improvement in survival with tamoxifen. Contraindications to tamoxifen are discussed more thoroughly below. The role of adjuvant aromatase inhibitors is not clearly established. A randomized study of adjuvant tamoxifen versus anastrozole in women with DCIS treated with lumpectomy showed that anastrozole offers a similar degree of benefit and similar number of side effects as tamoxifen, although the side effect profile differed.

American Society of Clinical Oncology guideline recommendations for sentinel lymph node biopsy in early-stage breast cancer. Epub Sep Effect of radiotherapy after breast-conserving surgery for ductal carcinoma in situ: Breast-conserving treatment with or without radiotherapy in ductal carcinoma in situ: Effect of tamoxifen and radiotherapy in women with locally excised ductal carcinoma in situ: Intervals longer than 20 weeks from breast-conserving surgery to radiation therapy are associated with inferior outcome for women with early-stage breast cancer who are not receiving chemotherapy.

Breast Cancer Res Treat. Epub Aug 9. Nomogram for predicting the risk of local recurrence after breast-conserving surgery for ductal carcinoma in situ. Evaluation of a breast cancer nomogram for predicting risk of ipsilateral breast tumor recurrences in patients with ductal carcinoma in situ after local excision.

A population-based validation study of the DCIS Score predicting recurrence risk in individuals treated by breast-conserving surgery alone. Use of this term is controversial. Most modern authors regard this as indicating a high risk for the development of infiltrating carcinoma in either or both breasts. The risk for subsequent carcinoma is not confined to the segment of the breast involved by the in situ change.

The risk to each breast is approximately equal and approaches fifteen percent within ten to fifteen years. When LCIS is identified on an excision specimen, re-excision is not required, although should be considered in pleomorphic LCIS if the margin is not adequate.

Patients can be given the option of either careful follow-up or occasionally, bilateral mastectomy with or without immediate or delayed reconstruction. Tamoxifen was shown to decrease the risk of invasive cancer in women with LCIS in the NSABP prevention trial using tamoxifen 20 mg daily for 5 years, although there was no improvement in survival.

Tamoxifen can be considered if breast cancer prevention is the primary goal. Classic LCIS behaves as an indicator lesion for higher risk of breast malignancy in any region of the breast. When detected in isolation, PLCIS has a pattern of recurrence more similar to a precursor lesion such as DCIS with a higher risk of malignancy within that region of the breast. There are no randomized trials that describe what margin should be achieved with surgery or the efficacy of adjuvant breast radiotherapy in the setting breast conserving surgery for PLCIS.

It is recommended that patients with PLCIS on biopsy have excision to rule out additional pathology and achieve clear margins for PLCIS and should also have a discussion regarding the possible benefits of adjuvant breast radiotherapy or more definitive breast surgery. T3N0 Updated February Management of Invasive Breast Cancer Invasive breast cancer requires multimodality management that is specific to the stage of the disease. Definitive treatment of early invasive breast cancer is surgery.

Typically, the primary tumor is excised and axillary lymph nodes are removed for staging. The decision of when to proceed to surgery and which procedure is best for an individual patient has become more complicated with the options of neoadjuvant chemotherapy and immediate breast reconstruction, and with changing recommendations for radiotherapy and chemotherapy.

Sequencing of breast cancer treatment is more commonly done with multidisciplinary input. A general overview of breast cancer surgery is outlined below and additional information on special circumstances, such as young women, elderly patients, pregnant patients, and male breast cancer are found in following sections.

Breast conserving surgery BCS, lumpectomy, partial mastectomy or segmental mastectomy or breast conserving surgery plus radiotherapy has been shown in multiple randomized control studies to be equivalent to mastectomy in terms of survival and breast cancer outcomes for patients with early-stage disease 1,2. Additional strategies such as oncoplastic lumpectomy resections and tumor shrinkage with Neoadjuvant Chemotherapy NAT can increase the number of patients eligible for BCS. MRI is not recommended in the routine assessment of unilateral breast cancer as there has been no improvement in survival or repeat surgery rates by using MRI and the additional investigations and findings can result in delay or overtreatment to the known cancer.

Patients with a positive margin should be evaluated for further surgery. Patients having BCS should be referred to radiation oncology as radiotherapy significantly lowers the risk of in-breast recurrence in the setting of BCS. However, there is a group of patients felt to be at low risk of recurrence with BCS alone who may be spared radiotherapy.

The addition of a radiation boost to the tumour bed reduces the risk of IBTR. However, re-excision to obtain negative margins may reduce IBTR more than using a radiation boost. The use of systemic therapy also minimally reduces IBTR. Those with positive margins have double the risk of IBTR compared to those with negative margins. There is conflicting data regarding the risk of IBTR with close margins. Most of the randomized trials of breast conservation with radiation vs mastectomy were in the context of no tumour seen at ink at pathologic examination of the resection specimen, although retrospective studies demonstrate an increased IBTR with both positive or close margins.

There is no evidence that re-excision alters survival compared to radiotherapy boost. The degree of survival impact of either, in the setting of close margins in particular, is expected to be small, or negligible, particularly in the absence of other risk factors. For patients with a high systemic failure risk e. It may also be reasonable to accept a higher risk of IBTR in patients for whom further local breast surgery would result in an unacceptable cosmetic result, but for whom there is a strong desire to avoid a mastectomy, or if medical problems preclude further surgery.

In these situations, a radiation boost would likely be used, albeit this can also affect the cosmetic outcome. Guidelines for Re-excision and Radiation Boost following breast-conserving surgery. For patients with invasive disease, invasive or in situ disease at the margin will be treated in the same manner.

The definition of a negative margin is no tumour at the inked margin. A positive margin is defined as tumour touching ink. In British Columbia, a close margin is currently defined as less than 2 mm margin. Re-excision to obtain negative margins is recommended for patients with positive margins. A radiotherapy boost is usually recommended in the setting of a close margin.

Patients with close or positive margins who decline re-excision should be advised that the risk of IBTR is increased. Early consultation with a radiation oncologist is recommended if there is uncertainty about whether re-excision is recommended.

This will facilitate a timely re-excision. Re-excision should be carried out prior to adjuvant radiation but does not need to occur prior to systemic therapy. If, after this, it is still not possible to accurately determine the margins, then the margins should be treated as unknown in which case a re-excision or radiation boost is generally recommended. Total mastectomy TM is defined as the removal of entire breast.

Skin sparing mastectomy SSM is used in conjunction with immediate breast reconstruction and studies have shown no increased recurrence risk with use of this technique When assessing a patient for a NSM, considerations include location of the tumor, nodal status and need for radiotherapy, and tumor biology.

Total Mastectomy TM, SSM, NSM is an option for patients with early stage breast cancer particularly for patients with contraindications to radiotherapy or desire to avoid radiotherapy, patients who would have a poor cosmetic outcome with breast-conserving therapy or those with multicentric disease or associated diffuse, extensive DCIS.

Mastectomy should also be considered in those who continue to have positive margins of invasive disease after multiple breast-conserving surgeries. Axillary surgery provides important prognostic information and can improve regional control for some patients with invasive breast cancer. Traditionally, level I and II axillary node dissection ALND had been the standard of care for all patients with invasive breast cancer.

Axillary lymph node dissection is recommended 12,13,14,15,16,17 Surgical Breast Tumor group consensus in the following situations: Inflammatory breast cancer Occult breast cancer presenting as axillary node metastasis Clinically node positive axilla, confirmed by FNA or core biopsy in a patient for whom neoadjuvant chemotherapy is not planned Axillary nodes that remain positive after neoadjuvant chemotherapy Axillary recurrence following previous breast cancer treatment.

Level 1 and 2 axillary dissection is generally recommended for those with three or more pathologically positive sentinel nodes and those at high risk for gross residual nodal disease after sentinel node procedure e. It is recommended that surgeons report breast cancer procedures using this template to facilitate communication of relevant details to other care providers.

The specimen removed at partial mastectomy must be oriented by the surgeon. At least two boundaries should be marked with sutures of different color or length so that the specimen can be oriented in three dimensions e. With a correctly marked specimen the pathologist will then be able to make an accurate estimate of the size of the tumour-free margin and to identify the location of any margin thought to be inadequately excised.

If the margin is inadequate in a location where it is possible to improve the situation surgically, then a re-excision should be carried out. For a modified radical mastectomy, axillary end should be marked for orientation so that the location as well as the number of nodes removed and involved by malignancy can be ascertained. Patients who require a mastectomy to treat unilateral breast cancer often enquire about contralateral prophylactic mastectomy CPM. A detailed history and family history is required to assess the risk of a contralateral breast cancer CBC.

For the average woman the risk of CBC is less than 0. Systemic treatments also reduce the risk of CBC. CPM in an average risk woman does not improve cancer outcomes. As such, CPM is not recommended for women with unilateral breast cancer. A Canadian expert consensus statement on this issue is a work in progress. The link will be posted here once it is available. All women undergoing mastectomy should be offered a reconstruction and referral to a plastic surgeon if they are clinically candidates.

Reconstruction can be performed at the time of mastectomy immediate reconstruction or as a second procedure delayed reconstruction. Options for reconstruction include autologous tissue vs implant reconstruction.

Current review of breast reconstruction is found in the Surgical Oncology Network Newsletter Spring Fisher B, Anderson S, Br yant J et al Twenty year follow up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J M ed ; Twenty year follow up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med ; Preoperative MRI and surgical management in patients with nonpalpable breast cancer: Epub Dec Schnitt, Armando Giuliano et al.

Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer. Sentinel lymph node resection compared with conventional axillary lymph node dissection in clinically node-negative patients with breast cancer: Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases.

Sentinel lymph node biopsy for patients with early-stage breast cancer: American society of clinical oncology clinical practice guideline update.

Accessed April 21, Judy C. Annals of surgical oncology. October , Volume 23, Issue 10, pp — https: Patients treated with breast conserving surgery BCS; lumpectomy, partial or segmental mastectomy for stage I or II breast cancer should have a consultation with a Radiation Oncologist regarding the role of radiation therapy RT. RT to the breast following BCS reduces the risk of breast recurrence and lowers the risk of systemic recurrence and breast cancer death.

RT should follow BCS unless contraindicated due to patient comorbidites, limited patient life expectancy, patient desire to avoid RT, or in selected low recurrence risk situations see below. If post-operative problems occur, including hematoma, large seroma, infection, breast edema with erythema, or wound dehiscence occur, the start of RT may be delayed to allow resolution.

In such cases or to accommodate patient convenience, there is no randomised trial evidence showing detriment to delay the start of RT until 20 weeks after BCS. If the patient receives adjuvant chemotherapy, then RT should follow the chemotherapy and start approximately weeks after the last intravenous chemotherapy. Trastuzumab as a single agent may be delivered concurrently with radiation therapy.

Adjuvant hormonal therapy may be commenced prior to or after RT. Randomised trials have shown improved local control with a boost of RT to the surgical bed following tangential RT for selected patients. Patients who might be spared radiation therapy after breast conserving surgery. Such women should be informed that RT will further decrease the risk of breast recurrence, but that the absolute benefit of RT on long-term survival is small. Accelerated partial breast radiation therapy following breast conserving surgery.

Randomized trials of partial breast RT compared to whole breast RT have completed accrual but will not report cancer endpoints for several years. Whole breast RT remains the standard local treatment following breast conserving surgery.

Partial breast RT using external 3-D conformal external beam RT has been shown to increase the risk of breast pain and induration at the primary site. Where available, patients undergoing accelerated breast radiation therapy should be treated as part of a defined, clinical trial protocol. Partial breast RT may be considered in particular circumstances, e. Some patients treated with mastectomy with negative nodes may benefit from adjuvant RT. This benefit is significant, even for patients with only a moderate risk e.

Timing of Adjuvant Radiotherapy: Timing is as described above post BCS for node-negative patients. Effect of radiotherapy after breast-conserving surgery on year recurrence and year breast cancer death: Epub Oct Tamoxifen, radiation therap y, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less.

Vinh-Hung V, Verschraegen C. Breast-conserving surgery with or without radiotherapy: Pooled-analysis f or risks of ipsilateral breast tumor recurrence and mortality. J Natl Cancer Inst. Breast conservation is a safe method in patients with small cancer of the breast. N Engl J Med. Impact of a higher radiation dose on local control and survival in breast-conserving therapy of early breast cancer: Whole-breast irradiation with or without a boost for patients treated with breast-conserving surgery for earlybreast cancer: Epub Dec 9.

Role of a gy boost in the conservative treatment of early breast cancer: Results of a randomized clinical trial in lyon, france. Late cosmetic results of short fractionation for breast conservation. Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer. A positive margin is not always an indication for radiotherapy after mastectomy in early breast cancer. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy.

Danish Breast Cancer Cooperative Group 82b trial. Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Locoregional radiation therapy in patients with high-risk breast cancer receiving adjuvant chemotherapy: Effect of radiotherapy after mastectomy and axillary surgery on year recurrence and yearbreast cancer mortality: Epub Mar Erratum in: Does locoregional radiation therapy improve survival in breast cancer? J Clin O ncol.

Adjuvant systemic therapy has been demonstrated to reduce the risk of cancer recurrence and improve survival. Adjuvant systemic therapy with either chemotherapy or hormonal therapy should be offered to women according to the treatment policies as defined in Adjuvant Systemic Therapy.

These policies are reviewed continuously by the provincial breast systemic policy group and updated accordingly. The systemic management of invasive non-metastatic breast cancer is complex. The management of locally advanced and of metastatic breast cancer is discussed separately. The prognosis for a patient following treatment of early breast cancer varies according to their age, co-morbidities, and the stage and the biomarker profile of their cancer.

The majority of patients with early breast cancer will be cured with appropriate multi-disciplinary therapy. Invasive breast cancer can be divided into three broad groups that influence systemic treatment decisions: Within each of these groups, treatment recommendations are also influenced by patient age, co-morbidity, and personal preferences, as well as the stage and other histopathologic features of the cancer.

The majority of advances in the management and improvements in the cure rates of early breast cancer have come from successful completion of scientifically rigorous clinical trials. Patients should be given the opportunity to participate in clinical trials if available for their stage and type of breast cancer. Hormone receptor positive breast cancers express estrogen receptors ER and or progesterone receptors PR, PgR on their nuclei, as evinced by immunohistochemical IHC assay.

There are two main immunohistochemical scoring systems used by the province to describe the degree of ER and PR expression. The Allred score is made up of a measure of the intensity of the IHC stain and the percentage of cells which take up the stain for the receptor. A simpler scoring method is often used in which the hormone receptor staining strength is expressed from 0 no staining to 3 strong, ubiquitous staining.

Cancers with an IHC score of 0 or an Allred score of 2 or 0 do not benefit from hormone receptor targeted therapy. Cancers with an Allred score of 3 have weak staining in a small percentage of cells, and the benefit of therapy targeted at the receptor is debatable in this setting.

The decision to treat cancers with an Allred score of 3 with hormone therapy should be individualized. The current standard of care for most premenopausal women is 5 years of hormone therapy.

Women who remain premenopausal after 5 years of tamoxifen may derive a small additional survival benefit from continuing tamoxifen to a total of 10 years. For postmenopausal women, there are several hormone therapy options. Compared with 5 years of tamoxifen, the use of an aromatase inhibitor for either five years, or for 2. Menopausal women completing five years of tamoxifen should consider an additional years of an aromatase inhibitor or of tamoxifen if unable to tolerate aromatase inhibitors , depending on the recurrence risk of the original cancer.

This is associated with a modest disease free survival improvement over stopping therapy at five years, and for women with node positive breast cancer, a small survival gain. Ongoing studies are examining whether longer than 5 years is beneficial if the first five years of therapy included an aromatase inhibitor. The choice of treatment strategy must take into consideration patient co-morbidities and drug side effects, as well as the absolute recurrence risk associated with their cancer.

Disease characteristics Hormone therapy T1N0 grade 1 Tamoxifen for 5 years, unless not tolerated or contraindicated Any of. Contraindications to starting or continuing Tamoxifen Issue Type of contraindication Notes Personal DVT, PE Absolute Unless patient anticoagulated for duration of tamoxifen use Close family history of DVT, PE Relative Coagulation studies may rule out a familial hypercoagulable state making tamoxifen safer Newly diagnosed Endometrial cancer Absolute Patients should discontinue tamoxifen permanently if they develop endometrial cancer while on tamoxifen.

Patients with remote history of low stage curatively treated endometrial cancer may safely take tamoxifen Severe depression Relative Tamoxifen may exacerbate depression Patients taking buproprion Wellbutrin , fluoxetine Prozac , or paroxetine Paxil Relative These drugs are metabolized by the same enzyme which metabolizes tamoxifen to its active metabolite endoxifen.

Whether this is clinically important is controversial. Each case must be considered individually balancing the potential benefits and risks of switching to a different antidepressant. Patients who can safely and easily switch to a different anti-depressant are encouraged to do so. Chemotherapy may be indicated for some hormone receptor positive breast cancers in addition to hormone therapy and local management.

The decision to recommend chemotherapy is based on a number of patient and tumor factors weighed together. In general, if the cancer exhibits any or several of the characteristics listed below, the benefits of chemotherapy should be considered: None of these features alone or in combination mandates the use of chemotherapy.

The decision making process is complex and involves balancing the potential benefits of adjuvant chemotherapy with the potential harms side effects and must be considered on a case by case basis. Other important factors in this decision making process include patient factors such as age, life-expectancy, and co-morbidities. Patient preference and willingness to accept chemotherapy side effects must also be considered.

Cancers without any of the above features arising in very young women 35 and younger may still warrant chemotherapy, as young age is an independent adverse prognostic factor. Recurrence risk assessment tools such as Adjuvant! Online can facilitate discussion with patients and illustrate the probable benefits of hormone therapy and chemotherapy in individual cases.

There are several tissue based prognostic tools which may be of value in guiding management recommendations for some women with node-negative, ER-positive and HER-2 negative breast cancer. This score provides an estimated risk of breast cancer recurrence over 10 years in the context of appropriate locoregional management and 5 years of hormonal therapy.

Furthermore, retrospective analyses suggest that only cancers with a high RS 31 or higher derive additional protective benefit from chemotherapy. These may not be the same as criteria established by other jurisdictions. At present a provincially funded Oncotype Dx Assay can only be obtained through consultation with a Medical Oncologist and with compassionate access program CAP approval. Patients may choose to pay for the test through their own means; their medical oncologist can facilitate the process.

There are numerous active adjuvant chemotherapy regimens. The choice of regimen drugs, doses, and number of cycles should be evidence based whenever possible.

The standard regimens available to Oncologists practicing in British Columbia can be found on the chemotherapy protocol, breast webpage. Postmenopausal who are relatively young and fit may be considered for the same chemotherapy regimens as for premenopausal women with similar cancer stage and grade. There are a number of adjuvant chemotherapy regimens that do not incorporate anthracyclines.

These are particularly good choices for patients at risk for cardiac injury. Patients with significant cardiac co-morbidities should undergo left ventricular ejection fraction assessment prior to initiating chemotherapy. Patients with an LVEF that is below the institutional lower limit of normal should not receive anthracycline based chemotherapy.

Anthracyclines may also be best avoided in patients with multiple cardiac risk factors even if they have a normal LVEF. Estrogen receptor ER and progesterone receptor PgR , by ligand-binding assay compared with ER, PgR and pS2, by immunohistochemistry in predicting response to tamoxifen in metastatic breast cancer: A Southwest Oncology Group study. Int J Cancer ; Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and year survival: Endocrine therapy plus zoledronic acid in premenopausal breast cancer.

N Eng J Med ; Is chemotherapy necessary for premenopausal women with lower-risk node-positive, endocrine responsive breast cancer?

Breast Cancer Res Treat ; Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer.

Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol ; Systemic treatment of early breast-cancer by hormonal, cytotoxic, or immune therapy: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: Is chemotherapy alone adequate for young women with oestrogen-receptor-positive breast cancer?

A multi-gene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. Taxane-based combinations as adjuvant chemotherapy of early breast cancer: HER2 and response to paclitaxel in node-positive breast cancer.

All breast cancer cells have some HER2 receptors. This confers a more aggressive natural history to these cancers, which also more frequently have grade 3 than other grade histology. In BC, all breast cancers should be tested for Her2, usually on the core biopsy, although any specimen, including archival tissue, can be used. In randomized clinical trials exploring the benefit of adding trastuzumab Herceptin to chemotherapy for breast cancer, cancers that had a FISH ratio of 2.

Her2 positive cancers can be hormone receptor ER or PR negative or positive. The preferred regimen contains both an anthracycline and taxane. Clinicians wishing to offer chemotherapy and trastuzumab to a patient for a T1aN0 cancer must receive CAP approval first. The primary contraindication to trastuzumab is a left ventricular ejection fraction LVEF below the institutional lower limit of normal, indicating left ventricular dysfunction or borderline function.

Because of synergistic toxicity with concomitant administration, trastuzumab should not be given concurrently with anthracyclines. This is usually transient, self-limited, and responsive to acetaminophen and supportive care measures. With rare exceptions, infusion reactions do not occur after the first infusion, so pre-medication is not required. Care should be taken to determine whether an observed reaction is due to trastuzumab or an accompanying drug, such as a taxane, as reactions to the latter drug can recur with subsequent infusions.

LVEF assessment is required prior to starting trastuzumab, and every three months during trastuzumab therapy. Norepinephrine concentrations were elevated in the midbrain. The present electrocochleographic findings do not support a specific mid- to high-frequency loss of auditory sensitivity. On the contrary, the electrophysiologic data, obtained for audiometric frequencies ranging from 2 to 32 kHz, showed a hearing deficit not only in the mid-frequency region kHz , but also in the mid-low-frequency region kHz.

Actually, the effect of toluene was independent of the frequency in our experimental conditions. Histological analysis was consistent with electrophysiologic data because a broad loss of outer hair cells occurred in both mid- and mid-apical coil of the organ of Corti.

Animals were exposed to toluene for weeks. Nephropathy was seen in almost all rats, and the severity was somewhat increased in exposed rats. A rare renal tubular cell carcinoma in a female rat and an equally uncommon sarcoma of the kidney in another female rat were seen in the 1, ppm exposure group.

Erosion of the olfactory epithelium and degeneration of the respiratory epithelium were increased in exposed rats. Inflammation of the nasal mucosa and metaplasia of the olfactory epithelium were increased in exposed female rats. A rare squamous cell carcinoma of the nasal mucosa was seen in one female rat at 1, ppm.

A squamous cell papilloma of the forestomach was observed in one female rat at 1, ppm, and a squamous cell carcinoma was observed in a second female rat at 1, ppm. No chemically related neoplasms were found in male rats, and the one nasal, two kidney, and two forestomach neoplasms observed in female rats were considered not to be associated with inhalation exposure to toluene. For mice, no biological important increases were observed for any nonneoplastic or neoplastic lesions.

LD50 Rat oral 2. Handbook of Environmental Data on Organic Chemicals. Van Nostrand Reinhold Co. University of Wisconsin-Superior, Histological sections of selected areas of the brainstem were made for the upper medulla oblongata including dorsal and ventral cochlear and vestibular nuclei , lower metencephalon including superior olivary nuclei, trapezoid body and ventral cochlear nuclei , upper metencephalon including the lateral lemniscus, superior olivary nuclei, cochlear and vestibular nuclei, and inferior colliculus and the mesencephalon-diencephalon junction including the medial geniculate.

The investigators reported that the "vast majority" of sections from animals exposed to toluene were indistinguishable from controls.

Shrunken and darkly stained neurons were observed in the corpus trapezoid of one animal exposed to ppm and another exposed to ppm toluene ; these were present in only one section and not in sufficient quantity to be considered a positive response by the investigators. Statistical analysis of the results was not reported. There were significant increases in the hematocrit and hemoglobin levels in females at ppm in the 13th week. There were significant differences in females at week 26 in the following: There were no significant differences between treated and control animals in urinalysis.

The adult female rats were sacrificed on GD 20 and examined. There were no significant differences observed between treated and control animals in the following: Based on preliminary toxicity tests, both nonactivated and S9-activated cultures were treated with 0. None of the nonactivated or activated cultures produced mutant frequencies significantly greater than the solvent DMSO controls.

Based on preliminary bacterial toxicity determinations, toluene , diluted with acetone, was tested for mutagenicity at concentrations up to 5.

Toluene did not cause a positive response in any of the bacterial or yeast tester strains, either with or without metabolic activation. Females were sacrificed 14 days after the midweek of mating. There was no effect of treatment for all dosed male mice as indicated by mortality, body weight and in-life physical observations. None of the cells from any of the treated animals exhibited a significant increase in the frequency of chromosome aberrations.

A glass ring having an area of 13cm 2 was placed against the palm and 2ml of 14C- toluene was applied. After one minute the ring was removed and adherent liquid allowed to evaporate. All urine was collected and analyzed for radioactive content until background levels of activity were approached. Toluene absorption was very low, averaging. Toluene is extensively metabolized via oxidation to benzyl alcohol then to benzaldehyde by alcohol dehydrogenase.

Further oxidation then forms benzoic acid. Conjugation with glycine produces the major metabolite, hippuric acid, which is excreted in the urine. Benzyl glucuronide is formed in smaller amounts by conjugation with glucuronic acid. In humans, the phenylacetic acid metabolite is also conjugated with glutamine to form phenacetylglutamine. Breathing zone samples were monitored for toluene in two Swedish rotogravure printing facilities.

Sc adipose tissues were taken from 37 workers after work on Thursday or Friday and analyzed for toluene. Venous blood samples were taken from 11 workers after work on Friday and at various times over the following weekend and assayed for toluene. Blood and adipose tissue samples were obtained from 11 other workers immediately after work and after 63 and hours nonexposure and analyzed for toluene.

Blood samples were also taken from 21 unexposed workers and analyzed for toluene. Attempts were made to fit the blood toluene data to various pharmacokinetics models. Blood toluene concentrations in the unexposed workers were below the detection limit, 0. Blood samples obtained immediately after work contained 0. Elimination of toluene from the blood could be described by a three compartment model having median halftimes of 9 minutes, 2 hours, and 79 hours. Toluene was eliminated from adipose tissue with a median halftime of 79 hours.

Adipose tissue concentrations were significantly associated with the workers' exposure to airborne toluene during the previous week. Adipose tissue toluene concentrations were significantly correlated with blood toluene concentrations after 70 hours exposure.

It was concluded that the prolonged presence of toluene in the blood means that there is an endogenous exposure from adipose tissue depots that continues long after occupational exposure has ended. Female Donryu, Fischer, Sprague-Dawley, and Wistar rats were exposed to toluene at dose levels of 5, 45, , , and ppm for 8 hours in a dynamic flow type exposure system.

Urine samples were collected for 24 hours from the start of exposure. While the variation in free p-cresol excretion was wide among the rats of the same strain exposed to toluene at the same concentration, it was also noted that the four strains tested could be classified into two groups depending on the free p-cresol levels at toluene concentrations up to ppm.

No significant differences were noted between Sprague-Dawley and Wistar strains nor between Donryu and Fischer strains at the 45 and ppm levels. However, there were significant differences between these two groups.

At higher concentrations of and ppm, the increase in the free p-cresol levels was remarkable only in Donryu rats, reaching the levels of Sprague-Dawley and Wistar rats, while the level in Fischer rats remained unchanged.

The subjects, male Chinese workers employed in shoe manufacturing, printing, audio equipment manufacture, and automobile industries, were divided into four groups based on occupational exposure: The arithmetic mean exposure level of benzene was The mixture contained benzene at The exposure levels were measured using individuals diffusive samplers.

The geometric mean levels of the metabolites, phenol, catechol, hydroquinone, hippuric acid, and o-cresol, in unexposed workers were 6. Values corrected for creatinine and specific gravity were different from the values cited above. Multiple correlation coefficients for benzene exposure versus its three metabolites were for phenol, 0. Multiple correlation coefficients for toluene and its two metabolites were 0.

The regression lines for toluene in the mixture and excretion level of hippuric acid and o-cresol showed reduced metabolic conversion compared to when exposure was limited to toluene alone.

It was concluded that simultaneous exposure to benzene and toluene results in mutual suppression of metabolism yielding the urinary metabolites phenol, hydroquinone, hippuric acid, and o-cresol. Whole body autoradiography has been modified and applied to distribution studies of After exposure, all excess hippuric acid was excreted within 4 hr, while o-cresol was eliminated with a half-life of approx 3 hr.

Alveolar air concn of toluene was ppm during constant exposure and ppm during varying exposure, but no difference in mean alveolar toluene concn or in metabolite excretion was seen between the exposure schedules. In study B, 32 men and 39 women aged between 31 and 50 yr were exposed once to either clean air or The background excretion rate of hippuric acid was 0. The corresponding figures for o-cresol were 0. The individual creatinine excretion rate was considerably influenced by sex, body wt, and smoking habits, thus influencing the metabolite concn standardized in relation to creatinine.

Thus, both metabolites are estimates of toluene exposure; o-cresol is more specific than hippuric acid, but the individual variation in excretion of both metabolites is large, and when implementing either of them as biological exposure indexes, the influence of sex, body size, age as well as consumption of tobacco and alcohol has to be considered.

Autoradiographic and liq scintillation methods were used to make possible the distinction between volatile, water sol, and firmly tissue bound radioactivity. Toluene reached high concns immediately after inhalation in lipid rich tissues brain and fat and well perfused organs liver and kidney but were rapidly eliminated resulting in low concns at 1 hr in all maternal tissues, except fat. Metabolites reached peak levels around 30 min to 1 hr after inhalation, but were also relatively rapidly eliminated.

One exception was the very strong accumulation of water sol metabolites at 4 and 24 hr in the nasal mucosa and olfactory bulb after inhalation of toluene. Volatile radioactivity was observed in the placenta and fetuses immediately and up to 1 hr after inhalation of solvent at all stages of gestation.

The fetal levels were, however, much lower than in maternal tissues. In early gestation, an even distribution pattern was observed, while the fetal liver reached a higher concn than other fetal tissues in late gestation.

In similarity with maternal tissues, fetal tissues reached the highest levels of metabolites 30 min to 1 hr after inhalation.

A retention in uterine fluid was seen at 4 hr. Otherwise no retention of metabolites was observed in the fetoplacental unit. No firmly tissue bound metabolites of the studied solvents were observed in the fetal tissues in late gestation, indicating no fetal capacity for formation of reactive metabolites.

Groups of male Sprague-Dawley rats were dosed with toluene either by gavage with 0. Blood samples were taken at 0.

Steady state blood concentrations were reached for both inhaled doses within 30 minutes of the exposure. After 6 hours the steady state toluene blood concentrations for the and ppm dose levels were 2. For the oral doses, the peak blood toluene concentration increased with increasing dosage.

Blood profiles from higher oral doses more closely approximated the steady state inhalation blood profiles. At 24 hours following dosing, blood toluene levels from all doses by either route were below detectable levels, suggesting minimal carry over of toluene concentrations from one day to the next.

An equation was derived which will allow the gavage dose of toluene to be made equivalent to an inhalation dose.

Based on results of other studies, it was suggested that blood toluene levels following sc injection more closely resemble those obtained following inhalation than do blood levels after gavage. However, it is possible to obtain blood concentrations of toluene similar to those generated by a 6 hour inhalation exposure to ppm through gavage dosing.

Tested solvents were acetone, styrene, toluene , xylenes, methylchloroform, and tetrachloroethylene. Lung uptake and urinary concentration Cu were measured in 15 volunteers, 24 to 52 years old, exposed in a chamber for 2 or 4 hours at rest, 2 hours with three alternations of light exercise, 1 hour of light exercise, or 30 minutes or more strenuous exercise. Environmental levels and urinary concentration were measured in occupationally exposed workers before and after 4 hours of work at a light task pulmonary ventilation 12 to 18 liters per minute.

For volunteers, uptake and urinary concentration values were significantly correlated. Environmental levels and urinary concentration showed a close relationship for occupational exposure.

Biological equivalent exposure limits corresponding to threshold limit value TLV time weighted averages were derived from urinary concentration values. For acetone, styrene, and xylenes, uptake for a given time and exposure level was dependent only on ventilation. The toluene retention index was slightly lower for exercise than for rest, and uptake was ventilation dependent during rest and ventilation and retention index dependent during exercise.

Retention indices decreased with increasing ventilation at rest and during exercise for tetrachloroethylene and methylchloroform. Their urinary concentration values were ventilation and retention index dependent. Methylchloroform uptake was higher during light versus heavy exercise. It was concluded that work load profoundly affects the absorbed amount of chemical and should be a factor in implementation of biological exposure indices and TLVs.

Absorption was complete when toluene was given orally to dogs; the blood level in rats increased more slowly after oral administration than after inhalation. Absorption through the skin of mice in vivo was 4. Toluene penetrated rat skin excised three days after clipping and depilation with cream at a rate one-tenth that of benzene and ten times that of ortho-xylene. The label quickly entered the embryo, but uptake was low relative to that in maternal tissues.

All fetal activity was extractable, indicating that no firmly bound metabolite was present. The remainder of the toluene is mainly excreted unchanged with a small percent being excreted as a sulfate or glucuronide of cresol. The calculated skin absorption coefficient was 1. The skin absorption rate for the ppm concentration was 0.

The effects of toluene inhalation on some specific enzymes and glutamate and GABA receptor binding in defined parts of the rat brain were studied following several exposure schemes. The activities of the transmitter synthesizing enzymes glutamic acid decarboxylase GAD , choline acetyltransferase ChAT and aromatic amino-acid decarboxylase AAD were used as markers for permanent loss of neuronal activity. This is most probably due to a reduction in total protein content, to which the activities were related.

The neurotransmitters glutamate and GABA had their specific receptor binding increased in most of the brain areas studied, but decreased in some areas. The glial enzyme, glutamine synthetase, has its activity increased in the cerebellar hemisphere following 4 weeks exposure to ppm. This suggests that glial cells in the area may have proliferated, a frequent phenomenon following CNS damage. Rat liver mitochondria were prepared from male white Wistar rats and assessed for respiration rate, oxygen uptake, glutamate oxidation, succinate oxidation, ATPase activity, and proton permeability in the presence and absence of the alkyl benzene derivatives.

Inclusion of the alkyl benzene derivatives in the incubation medium produced an initial acceleration of oxygen consumption followed by an inhibition of glutamate oxidation, and the stimulatory effect paralleled the aliphatic chain length. Glutamate oxidation was also inhibited by styrene, ethylbenzene, and alpha-methylstyrene but not by butylbenzene or toluene in 2,4-dinitrophenol uncoupled mitochondria.

Styrene and the aliphatic benzene derivative stimulated succinate oxidation in rat liver mitochondria without effect on 2,4-dinitrophenol stimulated succinate oxidation.

Similar stimulatory effects on ATPase activity were observed with maximal stimulation occurring at the same relative concentrations producing maximal succinate oxidation. ATPase stimulation required magnesium, was oligomycin sensitive, and showed an inverse relation to the hydrophobicity of the compounds tested. The inclusion of styrene in the incubation medium markedly increased the rate of passive entry of protons into rat liver mitochondria in a manner comparable to 2,4-dinitrophenol.

It was concluded that styrene and other monosubstituted benzene derivatives act as mitochondrial uncoupling agents. Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: John Wiley Sons, Toluene was found to potentiate the toxic effect of acetylsalicylic acid and to increase both maternal and embryonic toxicity Compared with ethanol alone, toluene given 2 hr after ethanol caused a significantly higher and more prolonged concentration of blood alcohol.

A similar trend of blood alcohol was observed at the later stage with toluene given prior to ethanol. On the other hand, with simultaneous doses of the two substances, the blood toluene concentration was higher for the first min than the ethanol control and the urinary excretion of hippuric acid, a main metabolite of toluene , was markedly decreased for the first 2 hr.

The blood ethanol in this group, on the contrary, was reduced until 1 hr after administration. These results indicate that toluene and ethanol act reciprocally as competitive inhibitors in their metabolism after single administrations. Each subject served as his own control.

Toluene had no significant effect on the 4 performance tests. A significant but weak depression of heart rate was observed during sleep latency tests By the fourth wk, there was a significant increase p toluene or styrene alone. Toluene has been shown to be a competitive inhibitor of the metabolism of benzene. This competitive interaction alleviates the metabolite-mediated toxicity of benzene A single alcoholic drink has a very strong, acute inhibitory effect on the hepatic elimination of toluene.

Chlorzoxazone is mainly metabolized by the same enzyme Cytochrome P 2E1 as ethanol and many other organic solvents. Ten male volunteers were exposed to solvent vapor 2 hr, 50 watt in an exposure chamber.

Chlorzoxazone mg was taken as two tablets 1 h prior to solvent exposure. Samples of blood, urine and exhaled air were collected before, during and until 20 h post exposure. The time-concentration curves of acetone and toluene in blood were fitted to one- and four-compartment toxicokinetic models, respectively.

Except for a delayed excretion of hippuric acid in urine, no effects on the toluene toxicokinetics were seen after chlorzoxazone treatment. Small increases in chlorzoxazone plasma levels were seen after exposure compared to chlorzoxazone alone. These interactions, although statistically significant, seem to be small compared to the interindividual variability on metabolism and toxicokinetics. Toluene is released into the atmosphere principally from the volatilization of petroleum fuels and toluene -based solvents and thinners and from motor vehicle exhaust.

Toluene 's production and use as an intermediate in the production of benzoic acid, benzaldehyde, benzene, explosives, dyes and many other organic compounds may also result in its release to the environment through various waste streams. Toluene has been detected in emissions from volcanos, forest fires and crude oil.

If released to air, a vapor pressure of Vapor-phase toluene will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 3 days.

Toluene may also be degraded in the atmosphere by reaction with nitrate radicals and ozone molecules, but these reactions are too slow to be environmentally important. If released to soil, toluene is expected to have high to moderate mobility based upon Koc values in the range of Volatilization from moist soil surfaces is expected to be an important fate process based upon a Henry's Law constant of 6.

Toluene may volatilize from dry soil surfaces based upon its vapor pressure. Biodegradation is expected to occur rapidly in soil surfaces, with half-lives in the range of several hours to 71 days. If released into water, toluene is not expected to adsorb to suspended solids and sediment based upon a Koc of measured in lake sediment. Biodegradation is expected to occur rapidly in water, with reported half-lives of 4 and 56 days in aerobic and anaerobic water, respectively.

Volatilization from water surfaces is expected to be an important fate process based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 1 hour and 4 days, respectively. Measured BCF values of 13 and 90 in fish suggest bioconcentration in aquatic organisms is low to moderate. Hydrolysis is not expected to be an important environmental fate process for toluene due to lack of hydrolyzable functional groups.

Exposure to toluene may occur occupationally during its production or subsequent use, particularly as a solvent or in gasoline, via dermal and respiratory routes. The main route of exposure for the general population will be through inhalation from contaminated air and handling of gasoline as well as ingestion of contaminated drinking water and food, and exposure to some consumer products.

Toluene occurs in nature in Toluene 's production and use as an intermediate in the production of benzoic acid, benzaldehyde, explosives, dyes and many other organic compounds 3 may also result in its release to the environment through various waste streams SRC.

Based on a classification scheme 1 , Koc values of measured in soil 2,3 , indicates that toluene is expected to have high to moderate mobility in soil SRC. Volatilization of toluene from moist soil surfaces is expected to be an important fate process SRC given a Henry's Law constant of 6. Toluene may volatilize from dry soil surfaces based on a vapor pressure of Complete biodegradation of toluene was observed in lab microcosm tests during a 40 hour incubation period using soils previously exposed to toluene 6.

The biodegradation half-life in various soils was reported as several hours to 71 days 7. Based on a classification scheme 1 , a Koc value of measured in lake sediment 2 indicates that toluene is not expected to adsorb to suspended solids and sediment SRC. Volatilization from water surfaces is expected 3 based upon a Henry's Law constant of 6. Using this Henry's Law constant and an estimation method 3 , volatilization half-lives for a model river and model lake are 1 hour and 4 days, respectively SRC.

According to a classification scheme 5 , BCF values of 13 6 and 90 7 measured in fish, suggest bioconcentration in aquatic organisms is low to moderate. The half-life of toluene in aerobic and anaerobic water was reported as 4 and 56 days, respectively 8. Amer Chem Soc pp. Vapor-phase toluene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals, nitrate radicals and ozone molecules SRC.

The half-life for the reaction with hydroxyl radicals is estimated to be 3 days SRC , calculated from its rate constant of 5.

The half-life for the nighttime reaction with nitrate radicals is estimated as days SRC calculated from its rate constant of 6. The half-life for the reaction with ozone is estimated as 27, days SRC calculated from its rate constant of 4. Toluene is readily degradable in a variety of standard biodegradability tests using sewage seed or sludge inoculums Degradation has been observed in several die-away tests using seawater or estuarine water The degradation rate is much faster in systems which have been contaminated by oil 9, A 90 day half-life in uncontaminated estuarine water was reduced to 30 days in oil-polluted water The half-life in water collected near Port Valdez, Alaska was 12 days 9.

Microbial attack proceeds via immediate hydroxylation of the benzene ring followed by ring-cleavage or oxidation of the side chain followed by hydroxylation and ring-cleavage 4. First-order degradation rate constants of 0.

These rate constants correspond to half-lives of , days 3. A first-order biodegradation rate constant of 0. Toluene was rapidly biodegraded by indigenous mixed cultures in sandy aquifer material and pure cultures isolated from the aquifer 5.

The half-life of toluene in aerobic and anaerobic water was reported as 4 and 56 days, respectively 6. The rate constant for the vapor-phase reaction of toluene with photochemically-produced hydroxyl radicals has been measured as 5. The rate constant for the vapor-phase reaction of toluene with nitrate radicals has been measured as 6.

This corresponds to an atmospheric half-life of about days at an atmospheric concentration of 2. The rate constant for the vapor-phase reaction of toluene with ozone has been measured as 4. Toluene is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups 4 nor to directly photolyze due to the lack of absorption in the environmental UV spectrum.

According to a classification scheme 3 , this BCF data suggests bioconcentration in aquatic organisms is low to moderate. In association with clay minerals, toluene 's adsorption is inversely proportional to the pH of the soil.

The Koc of toluene in lake sediment was measured as 3. According to a classification scheme 4 , this Koc data suggests that toluene is expected to have high to moderate mobility in soil. The Henry's Law constant for toluene is 6.

This Henry's Law constant indicates that toluene is expected to volatilize rapidly from water surfaces 2. The volatilization half-life from a model lake 1 m deep, flowing 0. Toluene 's Henry's Law constant 1 indicates that volatilization from moist soil surfaces may occur SRC.

Toluene may volatilize from dry soil surfaces based upon a vapor pressure of Toluene was detected in groundwater near contaminated wells from gasoline storage tanks at concns of 0. Groundwater under a gasification site 15 months after gasification contained toluene at ppb 4. In a cluster well study under an old industrial site, mean levels of toluene in bedrock wells were 90 ppb while shallow and deep glacial wells were 10 ppb 5.

Toluene was detected in 1. Toluene was detected in 3 New Orleans area water supplies at ppb 5. The max concn of toluene in tapwater derived from bank-filtered Rhine River water was 1 ppb 7. Toluene was detected in 3 contaminated drinking water wells in New Jersey at 55, , ppb whereas the highest concn in drinking water from surface water sources was 6.

Drinking water supplied from groundwater in England m from a gasoline storage tank contained 0. In a 5-city survey in which the water supplies came from different types of sources with various sources of pollution, 2 contained toluene , one 0. Toluene was detected in 20 of bottled water samples at an avg concn of 6. J Amer Water Works Assoc Toluene was detected in 31 of sites at concns of ppb in 14 heavily industrialized river basins in the US 1. Toluene was identified, not quantified, in various rivers Toluene was detected in the Gulf of Mexico at parts per trillion 6,7 and the Vineland Sound, MA at parts per trillion 8.

Toluene was detected in rain in west Los Angeles at 76 parts per trillion 1. Toluene was detected in Industries in which the mean effluent levels exceed ppb are: Toluene was identified, not quantified, in the exhaust of a moped 3 and 4-stroke lawn mower 4. Toluene was detected in car exhaust under normal operating conditions at concns of 3. Toluene was identified, not quantified in sediment from rivers near industrial facilities in the US 1,2. Toluene was detected in 67 of sediment samples at a median concn of 5.

Toluene was detected at concns of less than 0. In a survey of 3, samples obtained from urban areas in the US, toluene was detected at concns of ppb 11 ppb median 1. Average toluene concns in US cities range from 0. Daily variations in concentrations and ratios of toluene to benzene indicate that auto traffic is the most common source of atmospheric toluene 10,11, An Assessment of Available Data.

Toluene was detected at mean concns of 4. Toluene was detected in hairdresser salons in Norway at concns of 0. Toluene was detected in the atmosphere of remote samples taken in the US at concns of 0. Toluene was identified, not quantified, in a forest in Germany 2. Toluene was detected at a concn of 0. In a survey of source dominated samples from the US, toluene was detected at concns of 0. Toluene was detected at concns of ppb 4 miles downwind from a General Motors paint plant 3.

The avg concn of toluene around gasoline pumps during fueling was in the range of 0. Toluene was identified, not quantified, in baked potatoes 1 , mountain cheese 2 , fried bacon 3 , fried chicken 4 , peanut oil 5 and raw beef 6. Toluene was identified, not quantified, in the Korean Chamachwi plant 1. Flesh of fish from petroleum contaminated harbor in Japan contained toluene at 5 ppm 1. Toluene was detected in oysters from Lake Pontchartrain, LA at an avg concn of 3.

Toluene was identified, not quantified, in boiled shrimp and crab 3. Toluene is exempted from the requirement of a tolerance when used as a solvent or cosolvent in accordance with good agricultural practice as inert or occasionally active ingredients in pesticide formulations applied to growing crops only. The section 8 d model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies.

Toluene is included on this list. Persons in charge of vessels or facilities are required to notify the National Response Center NRC immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of lb or kg.

The rule for determining when notification is required is stated in 40 CFR U; As stipulated in 40 CFR Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste.

Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations 40 CFR The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements.

Toluene is produced, as an intermediate or a final product, by process units covered under this subpart. The Clean Air Act, as amended in , directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants.

EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Toxic pollutant designated pursuant to section a 1 of the Federal Water Pollution Control Act and is subject to effluent limitations. These regulations apply to discharges of this substance. This designation includes any isomers and hydrates, as well as any solutions and mixtures containing this substance.

Toluene is an indirect food additive for use only as a component of adhesives. Sweet, pungent, benzene-like odor. Miscible with alcohol, chloroform, ether, acetone, glacial acetic acid, carbon disulfide [Budavari, S. Handbook of Chemistry and Physics. Parts I and II. Weinheim, Federal Republic of Germany. Taylor and Francis, It has a fixed input impedance of 47k ohms and can be configured to provide appropriate gain for moving-magnet 39dB or moving-coil 53dB cartridges.

Despite its modest design and price, the LFD was "a sonically refined, musically involving, downright fun piece of gear," with a nice sense of touch, good weight and impact, and beautifully rich timbral colors, said AD. In addition to its chassis-mounted RCA input and output jacks, the B2B-1 provides single input and output XLR jacks for use as a fully differential mono phono preamp.

Jumpers offer five choices of resistive loading and two choices of gain. Though it lacked the Lejonklou Slipski's midrange richness, the B2B-1 produced an extremely quiet, authoritative, ultradynamic sound with deep bass, clean transients, fast attacks, and precise images. The B2B-1 is one of the best-measuring phono preamps in JA's experience. Very nice," he said. Sold factory-direct with a two-week return policy. A pair of dual-triode tubes produces the gain, while a second, direct-coupled pair drives the output.

Resistive and capacitive loading are selectable via rear-panel DIP switches. Though it lacked the slam and intensity of Manley's much more expensive Steelhead, the Chinook had a subtly warm overall sound, with clean transient attacks, generous sustain and decay, reasonably taut bass, and good soundstaging and imaging, said MF.

Three turns-ratio options 1: The SPA-II ran very warm but was exceptionally quiet; it produced sweet highs, a warm midrange, and well-controlled, full-bodied bass, said MF. Fit and finish were rough.

The True Mono SUT worked well with every mono cartridge AD had on hand and exhibited a "tremendous sense of scale and cavernously deep bass response. It had a smooth, well-balanced overall sound with a slightly warm midrange, a moderately deep soundstage, and fair bass extension. Mikey found that the MCP2's overall smoothness made long listening sessions easy, but turning the volume up too far resulted in excessive glare. Gain and loading options are adjustable. This phono pre lacks the drive and impact of the best units I've heard, and is also slightly short on texture, but it's wonderfully quiet and pure-sounding, with a nice sense of flow, sums up AD.

He advises owners of early-production units to call the factory to determine if their Insights are in need of an upgrade: SM was won over by the Statement's dynamic and rather bold, forward sound, especially when compared with his reference, the more reticent NAD PP Above all, SM was impressed by the Statement's high value: It's detailed, sweet, and dynamic, and flexible enough to accommodate almost any MM or MC cartridge.

Powered by a 16V wall wart, the Mani is built around a pair of op-amps, and provides user-adjustable DIP switches for gain and loading, with settings to suit moving-magnet and moving-coil cartridges. In HR's system, the Mani "threw a wide, deep, detailed soundstage that tended to get shadowy as it reached its outer limits.

It produced very quiet backgrounds and reasonably good dynamics, but bass extension and punch were only okay, its imaging was slightly diffuse, and its sound suffered overall from a slight metallic haze. The Tektron's power supply uses an onboard mains transformer with an EZ80 full-wave rectifier tube for the rail voltage and a silicon rectifier bridge for the heater voltages.

Fit and finish were excellent. The sound was "workmanlike," with a slightly bright tonal balance, decent musical flow, and a nice sense of presence, said AD. That's how SM described the sound of this small, dark, Taiwanese phono preamplifier, available for sale through the mail-order megalodon of your choice. So what do you want for 20 bucks plus shipping: Included in the owner's manual are several pages of thorough EQ recommendations for various labels and two pages of helpful tips on record labels and matrix numbers.

Though it added a very slight veiling to the sound, the Re-Equalizer proved effective, useful, and fun. What set the EQ11 apart from other such MM-appropriate preamps are five additional, switch-selectable EQ curves for the most common types of vintage record, including those for early Columbia LPs and Decca and other 78s. The Sentec's raison d'être, per HR: The purpose of the Sentec EQ11 is to make many of those differences go away.

Each alignment option has its own tiny dimple into which the stylus must fit for the alignment to be perfect. Three pop-in adapters 7. A sophisticated sighting and magnification system allow the user to precisely set parallax and zenith angle.

It uses a gooseneck LED lamp powered by three C batteries and a metal disc that doubles as a record weight. Expensive, but works as advertised, said MF. It has an easy-to-read touchscreen display, a nonmagnetic case, and accurately measures a cartridge's vertical tracking force down to 0. Precise and a pleasure to use, said SM. Prices are for oz bottles: The entire cleaning and drying process is relatively quiet and takes about six minutes.

He bought the review sample. The Vinyl Cleaner not only thoroughly cleaned his LPs, it significantly improved their sound, revealing nuances long locked in the grooves. MF also noted that a centering template would be a happy addition to the package. The Outer Limit was "a pain to center. JA's preferred alignment protractor. The DBP can be used to gauge alignment accuracy at any point or points between 44 and mm from the record spindle.

It comes with five pairs of color-coded resistive plugs 10, 20, 50, , and ohms , as well as a pair of empty plugs into which an alternate resistor value can be soldered. VII Omni record-cleaning machine: With its solid idler-driven platter, refined cabinetry, and improved internal wiring, the new machine outclasses the old. After cleaning a record, AD noted clearer instrumental voices and greater low-level detail.

The new machine has at its core an off-the-shelf direct-drive record player, the tonearm of which is modified to accommodate both a fluid-evacuation system and a means of delivering and refreshing the nylon thread used to cushion the vacuum nozzle. Machined with three sets of thin contact rails that ride on the Rega arm's counterweight stub.

The sonic improvement was " amazing ," thought MF; he found the F2 gave better bass response, greater low-frequency extension and control, and an improved sense of overall weight and tonal richness.

JE found just three drops sufficient to remove dirt, dust, and grime from garage-sale records, though he discovered that a subsequent wash with his VPI HW was still required to reduce groove noise to acceptable levels. Some manufacturers caution against it, claiming it migrates up the cantilever and attracts dust, thus clogging the armature.

One reader suggests applying treatment to brush rather than stylus, which would reduce the possibility of over-applying. Don't get any on the cantilever, he warned, and wait 10 seconds before playing a record.

Mikey thinks he noted a slight sound-softening effect, but wouldn't bet the farm on it. Dandy Hydraulic Record Cleaner: Dandy is an inexpensive manual record-cleaning rig that uses a proprietary cleaning solution comprising a degreasing detergent and an alcohol-based carrier, followed by a tap-water rinse.

Made mostly of PVC tubing, the Dandy has a vertically mounted clamping mechanism that permits easy rotation of the secured LP. Also included are a faucet-coupling adaptor, a protractor, and a length of clear plastic tubing with a pressurized water nozzle. Dandy can make a mess. However, the Dandy proved "terrific" for cleaning water-damaged and crudded-up records, MF concluded. Slowly squeezing and releasing the trigger produces a neutral static condition, thus removing static cling from record surfaces.

Said to be good for at least 10, squeeze cycles. SM uses the Zerostat religiously: Diehard analog hobbyists will still want the versatility of more complex tools, such as the DB Systems DBP, but "the Geo-Disc is the only alignment protractor most vinyl enthusiasts will ever need," said SM. It uses a log-ratio detector developed by Jim Fosgate for the steering-logic circuits of surround processors. Like other Nitty Gritty machines, the 2.

Instead of a vacuuming "tonearm," as on the professional Keith Monks machine, the NG cleaner uses a vacuum slot, with the record cleaned by fixed, chassis-mounted "lips. Cleaning is efficient and as good as Nitty Gritty's Pro, at a significantly lower price, though it takes twice as long, cleaning each side of an LP in turn.

Don't smear the schmutz from one record to another, MF warned; he suggests manual pre-cleaning of records for best results. He found the effect of both was to produce a less colored, more detailed midband sound from LPs, as well as provide the expected reduction in surface noise. Available directly from www.

Fidgety but worth the hassle, says SM. With the spacer in place and Dynavector's DV 10X5 moving-coil cartridge mounted on his Rega P, SM heard improved clarity, impact, immediacy, and soundstage depth.

For cartridges designed to play at downforces of 3. At less than half the price of the Audio Additives, the Shure is a great little tool, but the AA is easier to use, more precise, and provides an extra measure of comfort, said SM. Three sets of slots allow cleaning of 7", 10", and 12" records. Two velvet-like brushes clean both sides of a record simultaneously as the user rotates the record within the appropriate slot. Though "not nearly as convenient or as efficacious as a vacuum cleaning system," the Spin Clean Record Washing System "got the job done," said Mikey.

Spin Clean claims a single vat of fluid can clean up to 50 records, but MF suggests refreshing the vat more often. Housed in a solid disc of aluminum and Delrin that fits over the platter spindle, the Timeline uses eight laser-projected timing marks with a claimed accuracy within two parts per million. The basic package contains two Groovy Rings LP-sized sheets of black plastic , two heavy metal plates, a few pieces of hardware, a nice storage case, and a table of heating times and cooling cycles.

Using his oven or the Groovy Pouch, SM was able to successfully flatten even severely warped and dished LPs, but cautions: Latest version has a heavier-duty vacuum system. Adjusts automatically to thickness of record; gets hot quickly. It's nicely machined from aluminum and has a sturdy mounting collar. Drill it out yourself or send your armboard to VPI. The Woodsong disc is machined more accurately, from better-quality alloy, and is fitted with a better-fitting hub. And its installation on AD's own , which went smoothly enough, resulted in measurably better speed stability.

What's not to like? Submitted by Staxguy on March 22, - 6: The Audeze LCD-3, though veiled, "digital" too few bits of detail , and non-liquid, at least presents music as beautiful. Not only this, but it 3 is a personal luxury product, with a gorgeous headband, ear-pads, and wood ear-cups. Giving that you are Stereophile, this would be great in the Class C department. It has DSD, etc. Obviously, no imaging like the HD. What an amazing headphone, the HD Shouldn't the class A be the Stax and perhaps some excessive read: This one sounds like shit.

Ok, have only heard the closed. Why the P3 and not the P5 or P7? Isn't the quality of the P3 pathetic? However, the sound is worse than the stock Intel audio chip you'll have in your PC. Does have less hum and noise than an-in PC chip, though. Headphones don't seem as accurately covered here as the big stuff. Maybe the headphones and other portable gear should be covered entirely by Innerfidelity, in Stereophile Recommended Components. They reviewed various products for the magazine, and this is the list they came up with.

The classes are explained in full, in relation to the other products's performance that have made the list. Older products, sometimes equally capable as current products listed, are removed due to age. Lastly, most reviewers have their own benchmarks and their own opinions about component performance, hence their choice of placement in the classes. You can disagree all you want man, just do it with a modicum of respect.

If you want to start your own magazine, go for it dude. Glad to see this mighty monitor included in Class A restricted low frequency. Very well deserved and impeccably engineered at a fair price.

Most importantly it sounds great. An excellent effort by the folks at Technics. It's obvious they care about and love music by making a product like this. I read JA's assessment of the Arcam A19 regarding its ability to handle low impedance, high volume listening.

The owner's manual for my speakers, of about year vintage, states that the speakers can be "unhesitatingly operated with any standard amplifier" with some small qualifications later in the manual.

Stereophile's tests of other Canton speakers show that the speakers tend to operate more towards the 4, rather than the 8 Ohm range of input impedance.

I have used my Canton speakers with my demo model Arcam A18 for several years now. I am not a loud volume listener, but I like room filling sound. For a benchmark of my listening, I will say that audio show rooms, for example, are, for the most part, way too loud. I did a test this morning. On the integrated's volume range of 1 to 99, I did some listening around 38 on the volume scale.

I listened to a Chandos recording of Bryden Thomson's LSO recording of Vaughn Willams's 8th Symphony and assorted string works Chandos , a great audiophile recording still in circulation. This volume is adequate to fill the room amply with sound. Vaughn Williams works will require a bit more gas-pedal than other orchestral works.

Then, for some higher octane listening, but with the volume set at the same 38 position, I did another test. If I had finicky neighbors adjacent to my listening room for this session, they might have complained over the volume in some sections of this work. After listening to these CD tracks, I put my hand over the unobstructed top ventilation grate on the Arcam A After feeling the heat, which was almost imperceptible, I then put my hand to my cheek.

After 5 seconds the heat from my cheek was noticeably warmer. But for my speakers the Arcam never seems over-taxed, and certainly never clips with the music and volume settings that I employ.

If you are a moderate-to-room filling volume listener, have stand-mount speakers of dB, and 8 Ohm nominal impedance, and love peerless sound, I'd say buy the Arcam A19 without hesitation. I'm not a dealer or a professional, but that's my assessment.

A reader wrote in the Stereophile review of the A19 that he found the A19 to be a big improvement from the A My dealer says that if you have an A18, you can probably live with it without going to the A There can be no better amplification in the world. You see right thru the music. Your are drawn into it. All the details of the recording are there. Is there colorization by the tubes? Some may not understand. Raven audios 10 watts,is another tube companies 40 watts and solid states 80 watts.

It is in the power supply and voltage regulation that all the power of god on earth is unleashed. There really isnt anything but maybe my old mac that sounds even close to the raven. I know Art Dudley has used Auditorium cables as a reference for several years, any reason they are not listed in Recommended Components? Listening to the M10's, I am surprised they or other Dynaudio products have never been reviewed on your site. I bought the Dynaudio m20 few weeks ago. I'm not really expert, but I think my amp yamaha r-n is not enough powerful for these speakers.

If you make some emit reviews, could you give us some advices about the good amps to associate with: The dealer claimed he was running Magnepans off of these. For a stereo setup, this receiver would do, however they probably only support 4 ohm impedance for front left and right.

I use the Marantz PM and that is the smallest amp i would recommend for the Dynaudio emit m10's. I am puzzled however at the total lack of mention of any Esoteric Audio product. They are current products well known for their performance and musicality. What criteria being utilized could yield a recommended components lists where at least one of their products or more would not make it into the results?

Oh to live in a country with a reasonable rate of exchange! By the time that customs and excise is added to the cost, and the retailers have added their markup, you would be paying almost as much for the 15 inch model as you would for a new family car!

Log in or register to post comments. There also is the issue of it 3 having phenomenal bass, on the non-Fazor version. It sounds like absolutely nothing. Great that you have it in Class A. Shouldn't it be the HE-6? Where is the HE ? This is Class A guys. Class B Apogee Groove. How about more CEntrance. Is this a poor men's clothing magazine? Shouldn't this be Class E? Where are the audiophile components? Sorry to be a party-pooper. Headphones don Submitted by dalethorn on March 23, - 3: Submitted by Glotz on March 23, - 2: Naw, just haughty, arrogant and disrespectful.

Reid on March 24, - 5: I wanted to add my own, perhaps less scientific assessment of the Arcam A18 predecessor model. Those are my two cents on the Arcam A Other Brands Submitted by makarisma on April 6, - 2: Auditorium cables Submitted by Ladokguy1 on June 21, - 4: Submitted by AndySingh on July 21, - 7:

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