Safety evaluation of 8 drug degradants present in over-the-counter cough and cold medications.

Although the United States Food & Drug Administration (FDA) has provided guidance on the control of drug degradants for prescription drugs, there is less guidance on how to set degradant specifications for FDA OTC monograph drugs. Given that extensive impurity testing was not part of the safety paradigm in original OTC monographs, a weight of evidence (WOE) approach to qualify OTC degradants is proposed. This approach relies on in silico tools and read-across approaches alongside standard toxicity testing to determine safety.

Mixtures-Inclusive Models of Ocular Toxicity Based on United States and International Hazard Categories.

Computational modeling grounded in reliable experimental data can help design effective non-animal approaches to predict the eye irritation and corrosion potential of chemicals. The National Toxicology Program (NTP) Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) has compiled and curated a database of eye irritation studies from the scientific literature and from stakeholder-provided data. The database contains 810 annotated records of 593 unique substances, including mixtures, categorized according to UN GHS and US EPA hazard classifications.

Human-relevant approaches to assess eye corrosion/irritation potential of agrochemical formulations.

There are multiple and eye irritation and corrosion test methods that are available as internationally harmonized test guidelines for regulatory use. Despite their demonstrated usefulness to a broad range of substances through inter-laboratory validation studies, they have not been widely adopted for testing agrochemical formulations due to a lack of concordance with parallel results from the traditional regulatory test method for this endpoint, the rabbit eye test. The inherent variability of the rabbit test, differences in the anatomy of the rabbit and human eyes, and differences in modelling exposures in rabbit eyes relative to human eyes contribute to this lack of concordance.

Analysis of variability in the rabbit skin irritation assay.

The in vivo rabbit test is the benchmark against which new approach methodologies for skin irritation are usually compared. No alternative method offers a complete replacement of animal use for this endpoint for all regulatory applications. Variability in the animal reference data may be a limiting factor in identifying a replacement.

United States regulatory requirements for skin and eye irritation testing.

Purpose: Eye and skin irritation test data are required or considered by chemical regulation authorities in the United States to develop product hazard labelling and/or to assess risks for exposure to skin- and eye-irritating chemicals. The combination of animal welfare concerns and interest in implementing methods with greater human relevance has led to the development of non-animal skin- and eye-irritation test methods. To identify opportunities for regulatory uses of non-animal replacements for skin and eye irritation tests, the needs and uses for these types of test data at U.

Evaluation and Optimization of Pharmacokinetic Models for to Extrapolation of Estrogenic Activity for Environmental Chemicals.

Background: To effectively incorporate data into regulatory use, confidence must be established in the quantitative extrapolation of activity to relevant end points in animals or humans.

Objective: Our goal was to evaluate and optimize to extrapolation (IVIVE) approaches using in vitro estrogen receptor (ER) activity to predict estrogenic effects measured in rodent uterotrophic studies.

Methods: We evaluated three pharmacokinetic (PK) models with varying complexities to extrapolate to dosimetry for a group of 29 ER agonists, using data from validated [U.

Thyroid toxicants: assessing reproductive health effects.

A thyroid toxicant workshop sponsored by the National Toxicology Program Center for the Evaluation of Risks to Human Reproduction convened on 28-29 April 2003 in Alexandria, Virginia. The purpose of this workshop was to examine and discuss chemical-induced thyroid dysfunction in experimental animals and the relevance of reproductive and developmental effects observed for prediction of adverse effects in humans. Presentations highlighted and compared reproductive and developmental effects of thyroid hormones in humans and rodents.

Role of thyroid hormones in human and laboratory animal reproductive health.

The highly conserved nature of the thyroid gland and the thyroid system among mammalian species suggests it is critical to species survival. Studies show the thyroid system plays a critical role in the development of several organ systems, including the reproductive tract. Despite its highly conserved nature, the thyroid system can have widely different effects on reproduction and reproductive tract development in different species.

A novel phenylaminotetralin radioligand reveals a subpopulation of histamine H(1) receptors.

Previously, (-)-trans-1-phenyl-3-N,N-dimethylamino-1,2,3,4-tetrahydronaphthalene ([-]-trans-H(2)-PAT) was shown to activate stereospecifically histamine H(1) receptors coupled to modulation of tyrosine hydroxylase activity in guinea pig and rat forebrain in vitro and in vivo. Furthermore, the novel radioligand [(3)H](-)-trans-H(2)-PAT was shown to label selectively H(1) receptors in guinea pig and rat brain with high affinity (K(D), ~0.1 and 0.