The Conflict between Regulatory Agencies over the 20,000-Fold Lowering of the Tolerable Daily Intake (TDI) for Bisphenol A (BPA) by the European Food Safety Authority (EFSA).

Background: The European Food Safety Authority (EFSA) recommended lowering their estimated tolerable daily intake (TDI) for bisphenol A (BPA) 20,000-fold to . 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.

Modeling Mammary Organogenesis from Biological First Principles: A Systems Biology Approach.

Stromal-epithelial interactions mediate mammary gland development and the formation and progression of breast cancer. To study these interactions in vitro, 3D models are essential. We have successfully developed novel 3D in vitro models that allow the formation of mammary gland structures closely resembling those found in vivo and that respond to the hormonal cues that regulate mammary gland morphogenesis and function.

European Medicines Agency Conflicts With the European Food Safety Authority (EFSA) on Bisphenol A Regulation.

The European Food Safety Authority (EFSA) has revised their estimate of the toxicity of bisphenol A (BPA) and, as a result, have recommended reducing the tolerable daily intake (TDI) by 20 000-fold. This would essentially ban the use of BPA in food packaging such as can liners, plastic food containers, and in consumer products. To come to this conclusion, EFSA used a systematic approach according to a pre-established protocol and included all guideline and nonguideline studies in their analysis.

The cancer puzzle: Welcome to organicism.

During the fifty years since President Nixon declared the "War on Cancer", those inside and outside the cancer community have witnessed the systematic moving of the goalposts attitude to accommodate evidence into an inadequate theory, that is, the Somatic Mutation Theory (SMT). This sorry state promoted a renewable yearly promise that at the end of the next 10-year period the promises uttered in 1971 would become reality. Each failure triggered calls to do more of the same research under the same theory, routinely using more and more sophisticated technology.

Matrix Composition Modulates Vitamin D3's Effects on 3D Collagen Fiber Organization by MCF10A Cells.

Vitamin D3 (vitD3) has been implicated in various cellular functions affecting multiple tissue types. Epidemiological and laboratory studies suggest that vitD3 may be effective as a preventive or therapeutic option for breast cancer. However, randomized clinical trials have yet to confirm these suggestions.

From Wingspread to CLARITY: a personal trajectory.

In the three decades since endocrine disruption was conceptualized at the Wingspread Conference, we have witnessed the growth of this multidisciplinary field and the accumulation of evidence showing the deleterious health effects of endocrine-disrupting chemicals. It is only within the past decade that, albeit slowly, some changes regarding regulatory measures have taken place. In this Perspective, we address some historical points regarding the advent of the endocrine disruption field and the conceptual changes that endocrine disruption brought about.

Information, programme, signal: dead metaphors that negate the agency of organisms.

The metaphorical adoption of the concepts of information, program and signal introduced into biology the logic and implicit causal structure of the mathematical theories of information; this is inimical to biology. In turn, those metaphors have hindered the development of a theory of organisms by transferring the agency of organisms to natural selection and to DNA. Moreover, those metaphors introduced into biology the dualism software-hardware and a Laplacian causal structure.

Over a century of cancer research: Inconvenient truths and promising leads.

Despite over a century of intensive efforts, the great gains promised by the War on Cancer nearly 50 years ago have not materialized. Since 1999, we have analyzed the lack of progress in explaining and "curing" cancer by examining the merits of the premises that determine how cancer is understood and treated. Our ongoing critical analyses have aimed at clarifying the sources of misunderstandings at the root of the cancer puzzle while providing a plausible and comprehensive biomedical perspective as well as a new theory of carcinogenesis that is compatible with evolutionary theory.

Vitamin D3 constrains estrogen's effects and influences mammary epithelial organization in 3D cultures.

Vitamin D3 (vitD3) and its active metabolite, calcitriol (1,25-(OH)D), affect multiple tissue types by interacting with the vitamin D receptor (VDR). Although vitD3 deficiency has been correlated with increased incidence of breast cancer and less favorable outcomes, randomized clinical trials have yet to provide conclusive evidence on the efficacy of vitD3 in preventing or treating breast cancer. Additionally, experimental studies are needed to assess the biological plausibility of these outcomes.

Reductionism, Organicism, and Causality in the Biomedical Sciences: A Critique.

Biology is undergoing a crisis whereby technical innovations designed to overcome the difficulties encountered in explaining complex biological phenomena have not delivered the expected results. To overcome this problem, mainstream biomedical researchers favor adopting new technological wonders without considering that what hinders their research could be due to their philosophical stance, theoretical frame, or looking into the wrong level of biological organization. We address the conceptual problems underlying the scientific crisis by examining the philosophical stances that have illuminated biological thought for the last 200 years and their evolution into the conceptual frames now known as reductionism and organicism.

3D organizational mapping of collagen fibers elucidates matrix remodeling in a hormone-sensitive 3D breast tissue model.

Hormones play an important role in normal and diseased breast tissue development. However, they can also disrupt cell-matrix interactions and their role in extracellular matrix reorganization during epithelial morphogenesis remains poorly understood, partly due to a lack of sensitive approaches for matrix characterization. Here, we assess the hormonal regulation of matrix reorganization in a three-dimensional (3D) breast tissue culture model using a novel metric, i.

Endocrine disruptors - putting the mechanistic cart before the phenomenological horse.

Despite incontrovertible evidence of the harmful effects of endocrine disruptors, a sound public health policy is still absent. Meanwhile, the press has revealed the hindering role of industry lobbyists and conflicts of interest among members of the regulatory bodies. Here, we identify another hindrance; one that stems from current experimental research practices.

Characterization of MCF-12A cell phenotype, response to estrogens, and growth in 3D.

Background: Three-dimensional cultures of mammary epithelial cells allow for biologically-relevant studies of the development of the mammary gland in rodents and humans under normal and pathological conditions, like carcinogenesis. Under these conditions, mammotropic hormones play significant roles in tissue morphogenesis. Therefore, a system that recreates the normal, hormonally responsive epithelium would be a valuable tool to study the normal state and its transition to carcinogenesis.

An Integrative Approach Toward Biology, Organisms, and Cancer.

Over the last two decades, we have challenged the hegemony of the somatic mutation theory of carcinogenesis (SMT) based on the lack of theoretical coherence of the premises adopted by its followers. We offered instead a theoretical alternative, the tissue organization field theory (TOFT), that is based on the premises that cancer is a tissue-based disease and that proliferation and motility is the default state of all cells. We went on to use a theory-neutral experimental protocol that simultaneously tested the TOFT and the SMT.

New insights into fetal mammary gland morphogenesis: differential effects of natural and environmental estrogens.

An increased breast cancer risk during adulthood has been linked to estrogen exposure during fetal life. However, the impossibility of removing estrogens from the feto-maternal unit has hindered the testing of estrogen's direct effect on mammary gland organogenesis. To overcome this limitation, we developed an ex vivo culture method of the mammary gland where the direct action of estrogens can be tested during embryonic days (E)14 to 19.

Evidence of Absence: Estrogenicity Assessment of a New Food-Contact Coating and the Bisphenol Used in Its Synthesis.

Consumer concerns about exposure to substances found in food contact materials with estrogenic activity (EA) have created substantial demand for alternatives. We assessed the potential EA of both a new bisphenol monomer used to synthesize polymeric coatings for metal food-contact applications and the nonintentionally added substances (NIAS) that may migrate into food. We evaluated tetramethyl bisphenol F (TMBPF) using in vitro and in vivo assays.

Modeling mammary organogenesis from biological first principles: Cells and their physical constraints.

In multicellular organisms, relations among parts and between parts and the whole are contextual and interdependent. These organisms and their cells are ontogenetically linked: an organism starts as a cell that divides producing non-identical cells, which organize in tri-dimensional patterns. These association patterns and cells types change as tissues and organs are formed.

Toward a theory of organisms: Three founding principles in search of a useful integration.

Organisms, be they uni- or multi-cellular, are agents capable of creating their own norms; they are continuously harmonizing their ability to create novelty and stability, that is, they combine plasticity with robustness. Here we articulate the three principles for a theory of organisms, namely: the default state of proliferation with variation and motility, the principle of variation and the principle of organization. These principles profoundly change both biological observables and their determination with respect to the theoretical framework of physical theories.

Carcinogenesis explained within the context of a theory of organisms.

For a century, the somatic mutation theory (SMT) has been the prevalent theory to explain carcinogenesis. According to the SMT, cancer is a cellular problem, and thus, the level of organization where it should be studied is the cellular level. Additionally, the SMT proposes that cancer is a problem of the control of cell proliferation and assumes that proliferative quiescence is the default state of cells in metazoa.

Minireview: Endocrine Disruptors: Past Lessons and Future Directions.

Within the past few decades, the concept of endocrine-disrupting chemicals (EDCs) has risen from a position of total obscurity to become a focus of dialogue, debate, and concern among scientists, physicians, regulators, and the public. The emergence and development of this field of study has not always followed a smooth path, and researchers continue to wrestle with questions about the low-dose effects and nonmonotonic dose responses seen with EDCs, their biological mechanisms of action, the true pervasiveness of these chemicals in our environment and in our bodies, and the extent of their effects on human and wildlife health. This review chronicles the development of the unique, multidisciplinary field of endocrine disruption, highlighting what we have learned about the threat of EDCs and lessons that could be relevant to other fields.

The biological default state of cell proliferation with variation and motility, a fundamental principle for a theory of organisms.

The principle of inertia is central to the modern scientific revolution. By postulating this principle Galileo at once identified a pertinent physical observable (momentum) and a conservation law (momentum conservation). He then could scientifically analyze what modifies inertial movement: gravitation and friction.

SAMA: A Method for 3D Morphological Analysis.

Three-dimensional (3D) culture models are critical tools for understanding tissue morphogenesis. A key requirement for their analysis is the ability to reconstruct the tissue into computational models that allow quantitative evaluation of the formed structures. Here, we present Software for Automated Morphological Analysis (SAMA), a method by which epithelial structures grown in 3D cultures can be imaged, reconstructed and analyzed with minimum human intervention.