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BACKGROUND: The European Food Safety Authority (EFSA) recommended lowering their estimated tolerable daily intake (TDI) for bisphenol A (BPA) 20,000-fold to 0.2ng/kg body weight (BW)/day. BPA is an extensively studied high production volume endocrine disrupting chemical (EDC) associated with a vast array of diseases. Prior risk assessments of BPA by EFSA as well as the US Food and Drug Administration (FDA) have relied on industry-funded studies conducted under good laboratory practice protocols (GLP) requiring guideline end points and detailed record keeping, while also claiming to examine (but rejecting) thousands of published findings by academic scientists. Guideline protocols initially formalized in the mid-twentieth century are still used by many regulatory agencies. EFSA used a 21st century approach in its reassessment of BPA and conducted a transparent, but time-limited, systematic review that included both guideline and academic research. The German Federal Institute for Risk Assessment (BfR) opposed EFSA's revision of the TDI for BPA. OBJECTIVES: We identify the flaws in the assumptions that the German BfR, as well as the FDA, have used to justify maintaining the TDI for BPA at levels above what a vast amount of academic research shows to cause harm. We argue that regulatory agencies need to incorporate 21st century science into chemical hazard identifications using the CLARITY-BPA (Consortium Linking Academic and Regulatory Insights on BPA Toxicity) nonguideline academic studies in a collaborative government–academic program model. DISCUSSION: We strongly endorse EFSA’s revised TDI for BPA and support the European Commission’s (EC) apparent acceptance of this updated BPA risk assessment. We discuss challenges to current chemical risk assessment assumptions about EDCs that need to be addressed by regulatory agencies to, in our opinion, become truly protective of public health. Addressing these challenges will hopefully result in BPA, and eventually other structurally similar bisphenols (called regrettable substitutions) for which there are known adverse effects, being eliminated from all food-related and many other uses in the EU and elsewhere. [ABSTRACT FROM AUTHOR]

BACKGROUND: People are exposed to numerous chemicals throughout their lifetimes. Many of these chemicals display one or more of the key characteristics of carcinogens or interact with processes described in the hallmarks of cancer. Therefore, evaluating the effects of chemical mixtures on cancer development is an important pursuit. Challenges involved in designing research studies to evaluate the joint action of chemicals on cancer risk include the time taken to perform the experiments because of the long latency and choosing an appropriate experimental design. OBJECTIVES: The objectives of this work are to present the case for developing a research program on mixtures of environmental chemicals and cancer risk and describe recommended approaches. METHODS: A working group comprising the coauthors focused attention on the design of mixtures studies to inform cancer risk assessment as part of a larger effort to refine the key characteristics of carcinogens and explore their application. Working group members reviewed the key characteristics of carcinogens, hallmarks of cancer, and mixtures research for other disease end points. The group discussed options for developing tractable projects to evaluate the joint effects of environmental chemicals on cancer development. RESULTS AND DISCUSSION: Three approaches for developing a research program to evaluate the effects of mixtures on cancer development were proposed: a chemical screening approach, a transgenic model-based approach, and a disease-centered approach. Advantages and disadvantages of each are discussed. [ABSTRACT FROM AUTHOR]

The key characteristics (KC) of human carcinogens provide a uniform approach to evaluating mechanistic evidence in cancer hazard identification. Refinements to the approach were requested by organizations and individuals applying the KCs. We assembled an expert committee with knowledge of carcinogenesis and experience in applying the KCs in cancer hazard identification. We leveraged this expertise and examined the literature to more clearly describe each KC, identify current and emerging assays and in vivo biomarkers that can be used to measure them, and make recommendations for future assay development. We found that the KCs are clearly distinct from the Hallmarks of Cancer, that interrelationships among the KCs can be leveraged to strengthen the KC approach (and an understanding of environmental carcinogenesis), and that the KC approach is applicable to the systematic evaluation of a broad range of potential cancer hazards in vivo and in vitro. We identified gaps in coverage of the KCs by current assays. Future efforts should expand the breadth, specificity, and sensitivity of validated assays and biomarkers that can measure the 10 KCs. Refinement of the KC approach will enhance and accelerate carcinogen identification, a first step in cancer prevention. [ABSTRACT FROM AUTHOR]

BACKGROUND: The current single-chemical-as-carcinogen risk assessment paradigm might underestimate or miss the cumulative effects of exposure to chemical mixtures, as highlighted in recent work from the Halifax Project. This is particularly important for chemical exposures in the low-dose range that may be affecting crucial cancer hallmark mechanisms that serve to enable carcinogenesis. OBJECTIVE: Could ongoing low-dose exposures to a mixture of commonly encountered environmental chemicals produce effects in concert that lead to carcinogenesis? A workshop held at the NIEHS in August 2015 evaluated the scientific support for the low-dose mixture hypothesis of carcinogenesis and developed a research agenda. Here we describe the science that supports this novel theory, identify knowledge gaps, recommend future methodologies, and explore preventative risk assessment and policy decision-making that incorporates cancer biology, environmental health science, translational toxicology, and clinical epidemiology. DISCUSSION AND CONCLUSIONS: The theoretical merits of the low-dose carcinogenesis hypothesis are well founded with clear biological relevance, and therefore, the premise warrants further investigation. Expert recommendations include the need for better insights into the ways in which noncarcinogenic constituents might combine to uniquely affect the process of cellular transformation (in vitro) and environmental carcinogenesis (in vivo), including investigations of the role of key defense mechanisms in maintaining transformed cells in a dormant state. The scientific community will need to acknowledge limitations of animal-based models in predicting human responses; evaluate biological events leading to carcinogenesis both spatially and temporally; examine the overlap between measurable cancer hallmarks and characteristics of carcinogens; incorporate epigenetic biomarkers, in silico modelling, high-performance computing and high-resolution imaging, microbiome, metabolomics, and transcriptomics into future research efforts; and build molecular annotations of network perturbations. The restructuring of many existing regulatory frameworks will require adequate testing of relevant environmental mixtures to build a critical mass of evidence on which to base policy decisions. CITATION: Miller MF, Goodson WH III, Manjili MH, Kleinstreuer N, Bisson WH, Lowe L. 2017. Low-Dose Mixture Hypothesis of Carcinogenesis Workshop: scientific underpinnings and research recommendations. Environ Health Perspect 125:163-169; http://dx.doi.org/10.1289/EHP411 [ABSTRACT FROM AUTHOR]

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/ mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology. [ABSTRACT FROM AUTHOR]

Hypothesis: A standardized description of clinical breast examination (CBE) can predict the risk of delayed diagnosis of breast cancer. Design: Survey of case series. Setting: Breast surgery referral practice. Patients: Consecutive sample of 371 women with 386 breast cancers of any stage for whom overall characteristics of CBE were recorded at the initial consultation. Intervention: None. Main Outcome Measures: Overall breast "durity" (from Latin duritia, meaning "hardness") was recorded as the inverse of whether rib edges could be felt through breast tissue in the most "dur" (firm or hard) part of the breast, usually the upper outer quadrant adjacent to the areola. "Nodularity" was recorded in this same area by means of an ordinal scale ranging from "surface is smooth" to "coarse nodularity." Delayed diagnosis was tabulated if the patient was told that cancer was not present when there was a sign of cancer on CBE, mammogram, and/or pathology slides. Relative risk of delayed diagnosis was determined within categories of nodularity or durity and within nodularity and durity categories combined. Results: Diagnosis was delayed for 35 (9.1%) of cancers. Delay was least common (2 [2.2%] of 92) for less dur and less nodular breasts (relative risk, 1.0), most common (18 [13.5%] of 133) for less dur and more nodular breasts (relative risk, 6.23; 95% confidence interval, 3.58-10.22), and intermediate for other descriptions (χ[sup 2] = 9.08; P = .03). Neither nodularity alone nor durity alone correlated with delay. Conclusions: A standardized system to describe CBE will alert physicians to an increased risk of delayed diagnosis of breast cancer (especially for women with less dur and more nodular breasts), help improve interpretation of CBE, and reduce delayed diagnosis of breast cancer. [ABSTRACT FROM AUTHOR]

Background: Understanding sources of physician delay in diagnosis of breast cancer will assist efforts to expedite diagnosis. Objective: To test whether increased reliance on screening mammography has affected causes of physician delay in diagnosis of breast cancer. Design: Survey of delays in a case series. Setting: Practice specializing in breast diseases in a region with high use of screening mammography. Patients: Four hundred thirty-five consecutive patients treated for 454 breast cancers of any stage. Intervention: Customary patient care. Main Outcome Measures: Whether delay was related to how cancer was identified, patient age, individual cancer characteristics (such as tumor type), mammography reports, or physician expertise. Results: Twenty-one women (5%) were inappropriately reassured that a malignant lump was benign without biopsy, 14 women (3%) had a misread mammogram, 4 women (1%) had a misread pathologic finding, and 5 women (1%) had cancer missed by a poorly performed fine-needle aspiration biopsy. Delay was associated with a benign mammography report (relative risk, 10.8; 95% confidence interval, 5.1-22.8), a woman finding her own mass (relative risk, 3.3; 95% confidence interval, 1.8-6.2), and current hormone replacement therapy (relative risk, 3.1; 95% confidence interval, 1.2-8.5). Conclusions: The leading cause of physician delay in diagnosis of breast cancer continues to be inappropriate reassurance that a mass is benign without biopsy. Reducing delay in diagnosis will require less willingness to rely on clinical examination to decide that a mass is benign, less reliance on benign mammography reports to decide not to biopsy a mass, and a requirement that fine-needle aspiration biopsy be done by persons with demonstrated competence for the procedure. [ABSTRACT FROM AUTHOR]

PURPOSE: Routine breast examination frequently finds differences in palpable density and palpable nodularity, but it is not known if these differences correlate with the presence of high-risk histopathology. PATIENTS AND METHODS: To test for a relationship between clinical breast examination and histopathology, we devised separate, 4-point scales of clinical density and nodularity and validated these scales by repeat examinations 4 or more months apart in 199 separate breasts (the scale was the same or within 1 point on repeat examination 87 % of the time for density and 90% for nodularity). We then used these two clinical scales to compare density and nodularity to histopathology of breast tissue at the margins of segmental resections in 60 women undergoing breast-conserving treatment of primary breast cancer. In cases such as these, a large sample of "normal" tissue is intentionally removed when the wide excision is done to obtain negative margins. Histopathology at the margins was graded according to the consensus panel of the American College of Pathology; as might be expected in women with previous cancer, some higher-risk histopathology was found in 37% of cases. A relationship was sought using Spearman's rank correlation coefficient. RESULTS: Neither clinical breast density (ρ = 0.16) nor clinical breast nodularity (ρ = 0.01) related to the presence of high-risk histopathology in the underlying tissue. Interestingly, breast nodularity increased with age (ρ = 0.28), and clinical density and nodularity were inversely related (ρ = -0.28). CONCLUSION: We conclude that neither clinical breast density nor nodularity correlates with histopathology and that it is unlikely that a larger study would find a clinically useful correlation. Therefore, a clinical examination should not be used to decide that high-risk histopathology is likely to be present in an individual woman's breast. [ABSTRACT FROM AUTHOR]

There are "natural delays" in the healing of older individuals. Open wounds contract more slowly and incised wounds gain strength more slowly. Experimental studies indicate that cellular proliferation, wound metabolism, and collagen remodeling occur later in old animals. Clinical studies show, however, that operations can be performed safely in elderly patients and that the major increased risk to these patients is of non wound medical complications that affect the wound. [ABSTRACT FROM AUTHOR]

Inflammatory cells are not only the defenders of wounds against infection. Nor are they only the removers of unwanted tissue. They are also the directors of the repair mechanism and can be manipulated either to enhance or suppress repair. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor referencing articles and topics on the decline in the practice of screening clinical breast examination, published in previous issues.

Presents a letter to the editor in response to the article "Comparison of screening mammography in the United States and the United Kingdom," by Rebecca Smith-Bindman and colleagues.

Comments on several medical findings in surgery. Tactile imaging and the detection of breast masses; Cause of the delay in the diagnosis of breast cancer; Hypotheses concerning intra-abdominal abscess in patients who undergo laparoscopic appendectomy.