Building Blocks Towards a Proportionate Chemicals Policy With a Focus on the Netherlands.

In this contribution, we propose that 'sound' government policy should be characterised by a proportionate, integral vision with due consideration to tradeoffs between social costs and benefits. This principle also applies to government policy regarding the protection of workers from exposure to chemicals. It should be taken into account that having a job is a huge health benefit. Less educated people are statistically likely to enjoy ten additional healthy years, if employed. Although there is no debate about the risks of exposure to high doses of chemicals, there is most certainly debate on the magnitude, nature and possible cumulative effects of low-dose exposure to chemicals. These are established by model-based assumptions. The current advisory structure in which the Health Council of the Netherlands restricts its focus to the immediate health benefits for workers on the basis of risk avoidance models, and the Social and Economic Council of the Netherlands which focuses primarily on policy costs for trade and industry, is hardly a sound basis for well-considered decision making. The challenge for the scientific experts is to provide political administrators with an insightful social cost-benefit analysis, including all the concomitant uncertainties.

Nitrogen Critical Loads: Critical Reflections on Past Experiments, Ecological Endpoints, and Uncertainties.

Nitrogen Critical Loads (NCL), as purported ecological dose-response outcomes for nitrogen deposition from anthropogenic sources, play a central role in environmental policies around the world. In the Netherlands, these NCL are used to assess, via calculations using the model AERIUS, to what extent NCL are exceeded for different habitats as a result of different sources such as industry, agriculture, traffic. NCL are, however, not well defined, and are subject to hitherto unrecognized forms of uncertainty. We will address this with reference to a number of key studies that forms the basis for several NCL. We will subsequently propose amendments that could be applicable to future nitrogen studies and their enhanced relevancy in decision making.

Reflections on chemical risk assessment or how (not) to serve society with science.

In this paper, we want to shed light on the demand for chemical and toxicological data growing ever more faster than science can supply and other aspects of assessing chemical risks, including the demand for 'ever greater safety'. The treatise that follows is on the one hand rooted in well-established toxicological theory and on the other hand utilises emerging toxicological insights. Both theoretical conceptions and empirical substantiations are discussed to build up a perspective that produces an outlook on innovation and proliferates insights into our inexorable and invaluable exposure to 'the chemical'. We propose that in toxicology, with the implicit mandatory linear routine of dose-response, there is no tangible scientific drive to understand and unearth the actual empirical dose-response curve for chemicals under scrutiny. This can and should be improved upon as to advance the science of toxicology and to optimise current and future regulatory efforts.

Tradeoffs of chemicals regulation - The science and tacit knowledge of decisions.

In this paper, we want to shed light on the tradeoffs of chemicals regulation. We will discuss two types of tradeoffs: the social-economic impacts of regulation such as cost-induced fatalities and the tradeoffs between 'old' and 'new' chemicals, that is the established chemicals in industry and society deemed in need of replacement with 'new' chemicals. We will show that the progression from the science of chemicals risk assessment to regulation requires the science of regulatory (economic) analyses, with added insight from the philosophy of science. Indeed, risk assessment as such, which is significantly driven but is not limited to the broad toxicological context, does not unescapably dictate regulatory choices. The science of regulatory and economic analyses, we believe, could add considerably to the science of toxicology in a combined effort to improve upon the protection of public health and the environment.

A Short Critique on the Stance of the Netherlands Food and Consumer Product Safety Authority on Melamine Polymer Formaldehyde Exposures.

In February 2021, the Netherlands Food and Consumer Product Safety Authority came out with their risk assessment on formaldehyde exposure from melamine crockery with bamboo fiber to especially young children. In this short commentary, I will critique their assessment of this type of food-contact material (FCM). The main flaws are at least: (i) absence of a proper valuation of the available principal scientific literature yielding a biased risk assessment; (ii) discounting the endogenous formaldehyde formation that outweighs background exposure substantially; (iii) ad hoc positing of an unjustifiable and unfounded low background exposure levels to formaldehyde whereby risks of exposure to melamine formaldehyde is grossly exaggerated. This biased assessment has created societal unrest that is wholly uncalled for. Additionally, it has wide-ranging European consequences for the use of all melamine FCM.

Chloroquine commonly induces hormetic dose responses.

The use of chloroquine in the treatment of COVID-19 has received considerable attention. The recent intense focus on this application of chloroquine stimulated an investigation into the effects of chloroquine at low doses on highly biologically-diverse models and whether it may induce hormetic-biphasic dose response effects. The assessment revealed that hormetic effects have been commonly induced by chloroquine, affecting numerous cell types, including tumor cell lines (e.g. human breast and colon) and non-tumor cell lines, enhancing viral replication, sperm motility, various behavioral endpoints as well as decreasing risks of convulsions, and enhancing a spectrum of neuroprotective responses within a preconditioning experimental framework. These diverse and complex findings indicate that hormetic dose responses commonly occur with chloroquine treatment with a range of biological models and endpoints. These findings have implications concerning study design features including the number and spacing of doses, and suggest a range of possible clinical concerns and opportunities depending on the endpoint considered.

Immunomodulation Through Low-Dose Radiation for Severe COVID-19: Lessons From the Past and New Developments.

Low-dose radiation therapy (LD-RT) has historically been a successful treatment for pneumonia and is clinically established as an immunomodulating therapy for inflammatory diseases. The ongoing COVID-19 pandemic has elicited renewed scientific interest in LD-RT and multiple small clinical trials have recently corroborated the historical LD-RT findings and demonstrated preliminary efficacy and immunomodulation for the treatment of severe COVID-19 pneumonia. The present review explicates archival medical research data of LD-RT and attempts to translate this into modernized evidence, relevant for the COVID-19 crisis. Additionally, we explore the putative mechanisms of LD-RT immunomodulation, revealing specific downregulation of proinflammatory cytokines that are integral to the development of the COVID-19 cytokine storm induced hyperinflammatory state. Radiation exposure in LD-RT is minimal compared to radiotherapy dosing standards in oncology care and direct toxicity and long-term risk for secondary disease are expected to be low. The recent clinical trials investigating LD-RT for COVID-19 confirm initial treatment safety. Based on our findings we conclude that LD-RT could be an important treatment option for COVID-19 patients that are likely to progress to severity. We advocate the further use of LD-RT in carefully monitored experimental environments to validate its effectiveness, risks and mechanisms of LD-RT.

The EPA Cancer Risk Assessment Default Model Proposal: Moving Away From the LNT.

This article strongly supports the Environmental Protection Agency proposal to make significant changes in their cancer risk assessment principles and practices by moving away from the use of the linear nonthreshold (LNT) dose-response as the default model. An alternate approach is proposed based on model uncertainty which integrates the most scientifically supportable features of the threshold, hormesis, and LNT models to identify the doses that optimize population-based responses (ie, maximize health benefits/minimize health harm). This novel approach for cancer risk assessment represents a significant improvement to the current LNT default method from scientific and public health perspectives.

The Integration of LNT and Hormesis for Cancer Risk Assessment Optimizes Public Health Protection.

This paper proposes a new cancer risk assessment strategy and methodology that optimizes population-based responses by yielding the lowest disease/tumor incidence across the entire dose continuum. The authors argue that the optimization can be achieved by integrating two seemingly conflicting models; i.e., the linear no-threshold (LNT) and hormetic dose-response models. The integration would yield the optimized response at a risk of 10 with the LNT model. The integrative functionality of the LNT and hormetic dose response models provides an improved estimation of tumor incidence through model uncertainty analysis and major reductions in cancer incidence via hormetic model estimates. This novel approach to cancer risk assessment offers significant improvements over current risk assessment approaches by revealing a regulatory sweet spot that maximizes public health benefits while incorporating practical approaches for model validation.

Cancer risk assessment: Optimizing human health through linear dose-response models.

This paper proposes that generic cancer risk assessments be based on the integration of the Linear Non-Threshold (LNT) and hormetic dose-responses since optimal hormetic beneficial responses are estimated to occur at the dose associated with a 10(-4) risk level based on the use of a LNT model as applied to animal cancer studies. The adoption of the 10(-4) risk estimate provides a theoretical and practical integration of two competing risk assessment models whose predictions cannot be validated in human population studies or with standard chronic animal bioassay data. This model-integration reveals both substantial protection of the population from cancer effects (i.e. functional utility of the LNT model) while offering the possibility of significant reductions in cancer incidence should the hormetic dose-response model predictions be correct. The dose yielding the 10(-4) cancer risk therefore yields the optimized toxicologically based "regulatory sweet spot".

Antibiotics exposure and health risks: chloramphenicol.

The antibiotic chloramphenicol (CAP) is banned from food production. Besides being a medicinal product, CAP is also a natural product, produced by Streptomyces Venezuelae. The lack of scientific data hampers setting of an Acceptable Daily Intake (ADI). Consequently, a maximum residue limit (MRL) in food could not be established. This was then translated into a zero tolerance using the so-called Minimum Required Performance Limit (MRPL) level, viz. the achievable detection limit in food, to guide the zero tolerance policy. The MRPL is clearly not relevant to food safety and human health but is solely related to analytical technological capabilities. The increase in the latter enables detection at ever-lower levels and ignores toxicological relevance. We here provide arguments to use a Threshold of Toxicological Concern (TTC) for CAP that can accommodate developing toxicological insights.

Nutrition and health ­ transforming research traditions.

In this contribution, we show that current scientific methodologies used in nutrition science and by regulatory agencies, such as the randomized control trial, limit our understanding of nutrition and health as they are to crude to capture the subtle pleiotropic nature of most nutrients. Thereby, regulatory agencies such as the European Food Safety Authority curb the development of scientific knowledge and industrial innovations within the nutritional field. In order to develop insights into the health impact of certain food and food-components, we need to realize that health is adaptation set within a homeostatic range. Increased performance of health, i.e., the maximum stimulation of health, typically seems 30-60% greater than the control group, with a width of no more than about a factor of ten, clarifying the difficulty of documenting responses of food-endogenous components within the homeostatic range of healthy people. A strategy to record subtle responses of food components is the summation of procentual effects of relevant health outcomes. We illustrate this approach with the action of flavanols on vascular health, specifically endothelial function.

"You Can't Always Get What You Want" - Linearity as the Golden Ratio of Toxicology.

Referring to the Golden Ratio (i.e. expressed in the Fibonacci sequence) in nature and art, we conclude that toxicology knows its own Golden Ration, namely linearity. The latter seems imposed on pharmaco-toxicological processes that in fact show far more complexity than simple linearity could hope to elucidate. Understanding physiological and pharmaco-toxicological processes as primarily linear is challenged in this contribution based on very straightforward principles and examples.

Of reductionism and the pendulum swing: connecting toxicology and human health.

In this contribution we will show that research in the field of toxicology, pharmacology and physiology is by and large characterised by a pendulum swing of which the amplitudes represent risks and benefits of exposure. As toxicology usually tests at higher levels than the populace routinely is exposed to, it reverts to mostly linear extrapolative models that express the risks of exposure, irrespective of dosages, only. However, as we will explicate in two examples, depending on dosages, it is less easy to separate risks and benefits than current toxicological research and regulatory efforts suggest. The same chemical compound, in the final analysis, is represented within the boundaries of both amplitudes, that is, show a biphasic, hormetic, dose-response. This is notable, as low-level exposures from the food-matrix are progressively more under scrutiny as a result of increasing analytical capabilities. Presence of low-level concentrations of a chemical in food is a regulatory proxy for human health, but in light of this hormetic dose-response objectionable. Moreover, given that an ecological threshold probably holds for most, if not all, man-made (bio)organic chemicals, these will be found to be naturally present in the food matrix. Both aspects require toxicology to close the gap between reductionist models and its extrapolative deficiencies and real-life scenarios.

Chemicals and health - thought for food.

In our contribution we concisely question and answer some basic notions on food, health, and safety. We show that for some food components such as flavonoids, a whole range of small toxicological effects that have been uncovered the last decade on the whole confer benefits to human health. This development underlines the notion that health is adaptation with respect to the exposures humans experience when consuming food.

Why RDAs and ULs are incompatible standards in the U-shape micronutrient model: a philosophically orientated analysis of micronutrients' standardizations.

Risk assessments of micronutrients are carried out in the customary deficiency-excess model. It is regarded as straightforward and unambiguous. Nevertheless, it is a problematic amalgamation of two different and to a certain extent contrasting perspectives on risk and science that we will criticize in this contribution. Our critique is framed in a conceptual scheme of opposing perspectives highlighted by the rival characteristics of RDAs and SULs and the role of science therein. The one part of our scheme holds the typically modern approach that centers on risks that can be scientifically assessed more or less confidently. Subsequent policies are aimed at preventing major health problems that affect the majority of the population from early on in life. The RDAs are the ideal type-case here. The other part of our scheme holds a much more postmodern approach in which health risks are explicitly recognized as "uncertain." Dealing with those risks has little to do with major health problems from early on in life. Here, we encounter the scientific quandary of disentangling complex factors and impacts that may relate to some extra quality of life later on in life. SULs are exemplarily thereof. We will show that RDAs originally spawned from the scientific aim of securing objective knowledge "to lay down the requirements of an adequate" diet. SULs, conversely, are the upshot of generating acceptable outcomes driven by ever-increasing safety requirements. This shift from securing objective knowledge to generating acceptable outcomes will be addressed in relation to precautionary culture.

Hormesis in precautionary regulatory culture: models preferences and the advancement of science.

The article focuses on flaws in the actual approaches of exposure to a chemical of recipient organisms. It demonstrates the excessive use of arguments based on adverse effects and underlines the necessity to take adaptive effects seriously. Regulators are invited to rethink their inclination to the 'When in doubt, keep it out.' precautionary approach, with results in counter-productive and costly regulations. The authors are clear about the necessity to include hormesis, in the form of a toxicological insignificant exposure (TIE) level, related to the concentration, as a regulatory translation of adaptive effects. This inclusion might well be the 'brake' for the looming 'collision' with reality of the actual linear toxicological models. This analysis includes the advice to EPA, not to follow the 'witch hunt of synthetic chemicals' as embodied in the EU REACH program.