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A complete mode of action human relevance analysis--as distinct from mode of action (MOA) analysis alone--depends on robust information on the animal MOA, as well as systematic comparison of the animal data with corresponding information from humans. In November 2003, the International Life Sciences Institute's Risk Science Institute (ILSI RSI) published a 2-year study using animal and human MOA information to generate a four-part Human Relevance Framework (HRF) for systematic and transparent analysis of MOA data and information. Based mainly on non-DNA-reactive carcinogens, the HRF features a "concordance" analysis of MOA information from both animal and human sources, with a focus on determining the appropriate role for each MOA data set in human risk assessment. With MOA information increasingly available for risk assessment purposes, this article illustrates the further applicability of the HRF for reproductive, developmental, neurologic, and renal endpoints, as well as cancer. Based on qualitative and quantitative MOA considerations, the MOA/human relevance analysis also contributes to identifying data needs and issues essential for the dose-response and exposure assessment steps in the overall risk assessment.

SYNOPSISMost studies of the sustained release of drugs from subdermally implanted polymer devices have centered on the use of silicone rubber. However, the use of this polymer has serious limitations because of its nonbiodegradability. The depleted capsule has to be surgically removed if one is to eliminate potential problems associated with non-degradable foreign substances remaining in the body for an indefinite length of time. The development of polymer systems which combine the release properties of silicone rubber with biodegradability will represent a significant advance in the technique of controlled release of contraceptives. The polymer system selected for Dur investigations were polyesters comprising homo and copolymers of glycolide, dilactide, s-caprolactone, and s-decalactone. These polymers were found to undergo random hydrolytic degradation under in vitro and in vivo conditions. The polymers were characterized by their rates of biodegradation and their release parameters for contraceptive steroids. Long time release rates of steroids from monolithic and reservoir devices were determined. Especially poly(scaprolactone) was found to come close to meeting the requirements of a biodegradable reservoir device for controlled drug delivery, with a useful lifespan approaching one year. Copolymers of s-caprolactone and racemic dilactide are more permeable than poly(s-caprolactone) and are of value for biodegradable devices with shorter than one year lifespan.

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The effects of gestation day (GD) 10 heat exposure in the rat were studied to determine the temperature-response relationship for the induction of skeletal and other defects. Conscious pregnant rats (Experiment 1) were exposed to various temperatures in a warm air chamber. Body temperature was measured using a rectal probe, and these measurements were confirmed as representing core body temperature in separate animals using telemetric procedures. Those animals whose core body temperature was raised to 41-41.9 degrees C had over 90% malformed pups (examined at postnatal day (PND) 3), and a 25% reduction in the percent of live pups per litter. Animals whose temperature was raised to 39.2-40.9 degrees C had a low incidence of pups with similar types of malformations. The primary types of malformations were of the axial skeleton, consisting of fusions and other abnormalities of the ribs and vertebral elements, and a decrease in the total number of ribs and centra. The acute maternal effects of these temperature increases were signs of heat exhaustion during and 1-2 hr after exposure, but there were no permanent changes in weight gain or other signs. When temperatures were raised to > or = 42 degrees C, all maternal animals died. In a second study (Experiment 2), pregnant rats (from a different supplier) were anesthetized to determine the effect of reducing maternal stress and were exposed to heat as in Experiment 1. Those animals whose core body temperature was raised to 42-42.5 degrees C for 5 min had pups with similar responses to those in Experiment 1 at 41-41.9 degrees C, although the reduction in litter size was not as great. Animals whose temperature was raised to 41 degrees C had a much lower incidence of pups with similar defects, and animals whose temperature was raised to 43 degrees C did not survive. A more detailed analysis of the skeletal defects in Experiment 2 showed rib and vertebral malformations that appear to be related to the stage of somite development at the time of exposure.