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R Tyl

Publications and source records attributed to R Tyl.

3 recordsLinked to original sources
PubMed2000

Evaluation of biologically based dose-response modeling for developmental toxicity: a workshop report.

Biologically based dose-response (BBDR) modeling represents a novel approach for quantitative assessment of health risk by incorporating pharmacokinetic and pharmacodynamic characteristics of a chemical and by relating the immediate cellular responses to a cascade of aberrant biological actions that leads to detectable adverse outcomes. The quantitative relationship of each of the intervening events can be described in mathematical forms that are amenable for adjustment and extrapolation over a range of doses and across species. A team of investigators at the Reproductive Toxicology Division of the U.S. Environmental Protection Agency has explored the feasibility of BBDR modeling by examining the developmental toxicity of a known teratogen, 5-fluorouracil. A panel of researchers from academic and industrial laboratories, biomathematical modelers, and risk assessment scientists was convened in a workshop to evaluate the approaches undertaken by the EPA team and to discuss the future prospects of BBDR modeling. This report summarizes the lessons learned from one approach to BBDR modeling and comments from the panelists: while it is possible to incorporate mechanistic information into quantitative dose-response models for the assessment of health risks, the process is enormously data-intensive and costly; in addition, the confidence of the model is directly proportional to our current understanding of basic biology and can be enhanced only through the ongoing novel discoveries. More importantly, the extent of "uncertainty" (inherent with the default assumptions associated with the NOAEL or benchmark approach) reducible by BBDR modeling requires further scrutiny and comparison.

Abnormalities, Drug-Induced↗
PubMed1999

Screening methods for thyroid hormone disruptors.

The U.S. Congress has passed legislation requiring the EPA to implement screening tests for identifying endocrine-disrupting chemicals. A series of workshops was sponsored by the EPA, the Chemical Manufacturers Association, and the World Wildlife Fund; one workshop focused on screens for chemicals that alter thyroid hormone function and homeostasis. Participants at this meeting identified and examined methods to detect alterations in thyroid hormone synthesis, transport, and catabolism. In addition, some methods to detect chemicals that bind to the thyroid hormone receptors acting as either agonists or antagonists were also identified. Screening methods used in mammals as well as other vertebrate classes were examined. There was a general consensus that all known chemicals which interfere with thyroid hormone function and homeostasis act by either inhibiting synthesis, altering serum transport proteins, or by increasing catabolism of thyroid hormones. There are no direct data to support the assertion that certain environmental chemicals bind and activate the thyroid hormone receptors; further research is indicated. In light of this, screening methods should reflect known mechanisms of action. Most methods examined, albeit useful for mechanistic studies, were thought to be too specific and therefore would not be applicable for broad-based screening. Determination of serum thyroid hormone concentrations following chemical exposure in rodents was thought to be a reasonable initial screen. Concurrent histologic evaluation of the thyroid would strengthen this screen. Similar methods in teleosts may be useful as screens, but would require indicators of tissue production of thyroid hormones. The use of tadpole metamorphosis as a screen may also be useful; however, this method requires validation and standardization prior to use as a broad-based screen.

Animals↗