Reproductive and developmental toxicity testing: Examination of the extended one-generation reproductive toxicity study guideline

AbstractAn important aspect of safety assessment of chemicals (industrial and agricultural chemicals and pharmaceuticals) is determining their potential reproductive and developmental toxicity. A number of guidelines have outlined a series of separate reproductive and developmental toxicity studies from fertilization through adulthood and in some cases to second generation. The Extended One-Generation Reproductive Toxicity Study (EOGRTS) is the most recent and comprehensive guideline in this series. EOGRTS design makes toxicity testing progressive, comprehensive, and efficient by assessing key endpoints across multiple life-stages at relevant doses using a minimum number of animals, combining studies/evaluations and proposing tiered-testing approaches based on outcomes. EOGRTS determines toxicity during preconception, development of embryo/fetus and newborn, adolescence, and adults, with specific emphasis on the nervous, immunological, and endocrine systems, EOGRTS also assesses maternal and paternal toxicity. However, EOGRTS guideline is complex, criteria for selecting doses is unclear, and monitoring systemic dose during the course of the study for better interpretation and human relevance is not clear. This paper discusses potential simplification of EOGRTS, suggests procedures for relevant dose selection and monitors systemic dose at multiple life-stages for better interpretation of data and human relevance

Rethinking toxicity testing: Influence of aging on the outcome of long-term toxicity testing and possible remediation

Traditionally, toxicity testing is conducted at fixed dose rates (i.e., mg/kg/day) without considering life-changing events, e.g., stress, sickness, aging- and/or pregnancy-related changes in physical, physiological and biochemical parameters. In humans, life-changing events may cause systemic dose non-proportionality requiring modulation of drug dosage; similar changes occur in animals altering systemic dose during chronic/carcinogenic testing leading to late-occurring effects in some studies. For example, propylene monomethyl ether, an industrial chemical, initially induced sedation in rats and mice with recovery upon induction of hepatic CYPs after ~1 week. Sedation reappeared in rats but not in mice after ~12 months of exposure due to decreased CYP activity in rats, elderly mice were able to maintain slightly higher CYP activity avoiding recurrence of sedation. The systemic dose of two pharmaceuticals (doxazosin and brimonidine tartrate) increased up to 6-fold in ≥12-month old rats with no toxicity. In a rat reproductive toxicity study, systemic dose of 2,4-D, an herbicide, rapidly increased due to increased consumption of 2,4-D-fortified diet during pregnancy, lactation and neonatal growth, requiring adjustment to maintain the targeted systemic dose. Ideally, toxicological studies should be based on systemic dose with the option of modulating external dose rates to maintain the targeted systemic dose. Systemic dose can easily be monitored in selected core study animals at desired intervals considering recent developments in sampling and analysis at a fraction of the overall cost of a study

Ontic structural realism as a metaphysics of objects

The paper spells out five different accounts of the relationship between objects and relations three of which are versions of ontic structural realism (OSR). We argue that the distinction between objects and properties, including relations, is merely a conceptual one by contrast to an ontological one: properties, including relations, are modes, that is the concrete, particular ways in which objects exist. We then set out moderate OSR as the view according to which irreducible relations are central ways in which the fundamental physical objects exist. Physical structures thus consist in objects for whom it is essential that they are related in certain ways. There hence are objects, but they do not possess an intrinsic identity. This view can also admit intrinsic properties as ways in which objects exist provided that these do not amount to identity conditions for the objects. Finally, we indicate how this view can take objective modality into account

Moderate structural realism about space-time

This paper sets out a moderate version of metaphysical structural realism that stands in contrast to both the epistemic structural realism of Worrall and the – radical – ontic structural realism of French and Ladyman. According to moderate structural realism, objects and relations (structure) are on the same ontological footing, with the objects being characterized only by the relations in which they stand. We show how this position fares well as regards philosophical arguments, avoiding the objections against the other two versions of structural realism. In particular, we set out how this position can be applied to space-time, providing for a convincing understanding of space-time points in the standard tensor formulation of general relativity as well as in the fibre bundle formulation

The modal nature of structures in ontic structural realism

Ontic structural realism is the view that structures are what is real in the first place in the domain of fundamental physics. The structures are usually conceived as including a primitive modality. However, it has not been spelled out as yet what exactly that modality amounts to. This paper proposes to fill this lacuna by arguing that the fundamental physical structures possess a causal essence, being powers. Applying the debate about causal vs. categorical properties in analytic metaphysics to ontic structural realism, I show that the standard argument against categorical and for causal properties holds for structures as well. Structural realism, as a position in the metaphysics of science that is a form of scientific realism, is committed to causal structures. The metaphysics of causal structures is supported by physics, and it can provide for a complete and coherent view of the world that includes all domains of empirical science