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the information
site on endocrine disruption
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Workshops
Authors
Andersen ME, Conolly RB, Faustman EM, Kavlock RJ, Portier CJ, Sheehan DM, Wier PJ, Ziese L.Title
Quantitative mechanistically based dose-response modelling with endocrine-active compounds.Journal
Environmental Health Perspectives 107 Suppl 4:631-8 1999.Assessment of the risks associated with environmental chemicals has prompted the development of quantitative mathematical models to specifically characterize biochemical parameters such as potency, receptor-ligand interactions and dose response that would contribute to modulation of the endocrine system.
Newly proposed EPA guidelines suggest that risk assessments should emphasize the mode of action of the chemical and tissue dosimetry, thereby enabling the production of dose-response assessments and a reduction of risk assessment uncertainty. A mathematical model would enable the characterization of these and other parameters important for risk assessment. Dose response modelling should not only provide a measure of the potency of an agent, but should also incorporate additional information such as prior exposure, background incidence, heterogeneity, variability and to enable extrapolation to other groups of chemicals. Linking models which associate pharmacokinetic (time-course for tissue distribution) and pharmacodynamic (interactions between chemicals and target tissues) models could be incorporated into an MBDR model for endocrine activating chemicals (EACs). The MBDR model should provide an appropriate dose-response curve that is consistent with the biology of the system and be able to differentiate structurally related compounds. Other parameters such as gender, strains, genetic variability, organ systems, life stages and animal species must also be built into the model so that extrapolations can be made for specific exposure situations in human or animal populations. The authors suggest that key features of an EAC model should include paracrine/autocrine signalling, hormone kinetics, distribution, synthesis, metabolism and binding interactions in addition to multiple receptor isoforms and temporal changes in hormone synthesis, metabolism and release (circadian rhythm, puberty, menstrual cycle, menopause).
The workshop made several key recommendations for the use of MBDR models to investigate EACs. MBDR modelling would be an important first step in the evaluation of an EAC, followed by more traditional scientific investigations to confirm the predictions of the model. The use of MBDR models must gain widespread acceptance in the scientific community before implementation by regulatory agencies. However, MBDR models will need to be developed routinely and to be available for publication and peer review. Contemporary examples of MBDR models should be available to assist in the design of related models. Prototype chemicals that represent a human health concern and are well characterized should be used for MBDR model design. An interdisciplinary approach (i.e., toxicology, endocrinology, pharmacokinetics, statistics) should be used for the development of models. Funding sources should be developed to aid in the development of MBDR models.
The use of MBDR modelling to investigate the risks of EAC to human populations is an exciting proposal. There are many studies characterizing the biochemical parameters of various EACs, however, extrapolating these findings to human populations is difficult. Many studies use animal subjects and employ a much higher EAC dose than would be seen by affected human populations. An MBDR model that could extrapolate dose-response data from animal studies to human populations would be an invaluable tool. MBDR modelling is not a replacement for traditional experimental investigations, but could have important implications for the risk assessment of EAC in humans where controlled chemical exposure experiments are not possible.
