There is significant public concern about the potential health effects of exposure to mercury vapour (Hg(0)) released from dental amalgam restorations. The purpose of this article is to provide information about the toxicokinetics of Hg(0), evaluate the findings from the recent scientific and medical literature, and identify research gaps that when filled may definitively support or refute the hypothesis that dental amalgam causes adverse health effects. Dental amalgam is a widely used restorative dental material that was introduced over 150 years ago. Most standard dental amalgam formulations contain approximately 50% elemental mercury. Experimental evidence consistently demonstrates that Hg(0) is released from dental amalgam restorations and is absorbed by the human body. Numerous studies report positive correlations between the number of dental amalgam restorations or surfaces and urine mercury concentrations in non-occupationally exposed individuals. Although of public concern, it is currently unclear what adverse health effects are caused by the levels of Hg(0) released from this restoration material. Historically, studies of occupationally exposed individuals have provided consistent information about the relationship between exposure to Hg(0) and adverse effects reflecting both nervous system and renal dysfunction. Workers are usually exposed to substantially higher Hg(0) levels than individuals with dental amalgam restorations and are typically exposed 8 hours per day for 20-30 years, whereas persons with dental amalgam restorations are exposed 24 hours per day over some portion of a lifetime. This review has uncovered no convincing evidence pointing to any adverse health effects that are attributable to dental amalgam restorations besides hypersensitivity in some individuals.
Rat locomotor and feeding behavior varies on a diurnal basis; at night the animals actively forage and eat, whereas during the day they are more inactive and somnolent. At night, cardiac output is higher, presumably for enhanced perfusion of the active muscles to support increased metabolism and for enhanced perfusion of the digestive organs to support increased digestion and nutrient absorption. Conversely, it is hypothesized that during the daytime, blood flow to these two tissues is relatively low. The purpose of this study was to test these hypotheses by measuring cardiac output and the distribution of cardiac output in rats at various times in the diurnal cycle (8:00 A.M., 4:00 P.M., and 8:00 P.M.). The radiolabeled microsphere technique was used to measure cardiac output and distribution of blood flow to the tissues. Distribution of the total cardiac output was accounted for by complete dissection, weighing, and counting of organs and carcass. Cardiac output at 8:00 P.M. (136 +/- 9 ml/min) was elevated 13% (P less than 0.05) over that at 4:00 P.M. The proportion of the cardiac output distributed to the skeletal muscles (4:00 P.M.: 25%; 8:00 P.M.: 27%) and to the digestive tract (4:00 P.M.: 14%; 8:00 P.M.: 14%) did not change between the two time periods. Thus total muscle blood flow increased (P less than 0.05) from 31 +/- 2 at 4:00 P.M. to 36 +/- 4 ml/min at 8:00 P.M.; the only digestive organ to show a significant increase in blood flow from 4:00 P.M. to 8:00 P.M. was the stomach (133 +/- 17 to 166 +/- 19 ml/min, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Deltamethrin (DLT) is a type II pyrethroid insecticide widely used in agriculture and public health. DLT is a potent neurotoxin that is primarily cleared from the body by metabolism. To better understand the dosimetry of DLT in the central nervous system, a physiologically based pharmacokinetic (PBPK) model for DLT was constructed for the adult, male Sprague-Dawley rat that employed both flow-limited (brain, gastrointestinal [GI] tract, liver, and rapidly perfused tissues) and diffusion-limited (fat, blood/plasma, and slowly perfused tissues) rate equations. The blood was divided into plasma and erythrocytes. Cytochrome P450-mediated metabolism was accounted for in the liver and carboxylesterase (CaE)-mediated metabolism in plasma and liver. Serial blood, brain, and fat samples were taken for DLT analysis for up to 48 h after adult rats received 2 or 10 mg DLT/kg po. Hepatic biotransformation accounted for approximately 78% of these administered doses. Plasma CaEs accounted for biotransformation of approximately 8% of each dosage. Refined PBPK model forecasts compared favorably to the 2- and 10-mg/kg po blood, plasma, brain, and fat DLT profiles, as well as profiles subsequently obtained from adult rats given 1 mg/kg iv. DLT kinetic profiles extracted from published reports of oral and iv experiments were also used for verification of the model's simulations. There was generally good agreement in most instances between predicted and the limited amount of empirical data. It became clear from our modeling efforts that there is considerably more to be learned about processes that govern GI absorption and exsorption, transport, binding, brain uptake and egress, fat deposition, and systemic elimination of DLT and other pyrethroids. The current model can serve as a foundation for construction of models for other pyrethroids and can be improved as more definitive information on DLT kinetic processes becomes available.
Lifetime cancer or unit risk estimates for TRI have been calculated by the EPA on the basis of metabolized dose-tumor incidence relationships. Previously, it was common practice to directly extrapolate exposure dose-tumor incidence data from laboratory animal studies to predict cancer risks in humans. Such direct species-to-species extrapolations, however, do not take into account potentially important species differences in systemic uptake, tissue distribution, metabolism, deposition at the site(s) of action, and elimination. The consideration and use of pharmacokinetic and metabolic data can significantly reduce, though not eliminate, uncertainties inherent in species-to-species, route-to-route, and high- to low-dose extrapolations. The total amount of TRI metabolized was considered in the most recent EPA Health Assessment Document for Trichloroethylene to be the effective dose (EFD) producing tumors. Exposure dose-metabolism relationships were determined from direct measurement data in inhalation and oral dosing studies in mice and rats. The magnitude of TRI metabolism in these two species closely approximated body surface area. Thus, it was assumed that the amount of TRI metabolized per square meter of surface area was equivalent among species when calculating human equivalent doses from the animal data. Direct measurement data from an inhalation study in humans were used to calculate the amount of TRI metabolized and the unit risk estimate when a person inhales 1 microgram TRI per cubic meter continuously for 24 h. The EPA Cancer Assessment Group (CAG) elected to use this risk estimate for TRI in air, since it was calculated on the basis of a human metabolized dose rather than unit risk estimates based on animal studies. The current survey of literature and ongoing research uncovered no new animal or human studies in which TRI metabolites were directly measured, which would be any more suitable for use in estimating the total metabolized dose of TRI. On the basis of information now available, it is appropriate to continue to use the total amount of TRI metabolized as the EFD producing tumors in the liver. Use of the total amount metabolized represents an important "step in the right direction" in reducing uncertainties in interspecies extrapolations of data on a chemical such as TRI. TRI is believed to be metabolically activated to a reactive intermediate(s), although the identity of the intermediate(s) is unclear. There is evidence that formation of reactive intermediate(s) and TRI hepatotoxicity are directly proportional to the overall extent of TRI metabolism.(ABSTRACT TRUNCATED AT 400 WORDS)
In recent years there has been an increasing focus in environmental risk assessment on children as a potentially susceptible population. There also has been growing recognition of the need for a systematic approach for organizing, evaluating, and incorporating the available data on children's susceptibilities in risk assessments. In this article we present a conceptual framework for assessing risks to children from environmental exposures. The proposed framework builds on the problem formulation → analysis → risk characterization paradigm, identifying at each phase the questions and issues of particular importance for characterizing risks to the developing organism (from conception through organ maturation). The framework is presented and discussed from the complementary perspectives of toxicokinetics and toxicodynamics.
The Fischer 344 (F344) rat and the Sprague-Dawley (SD) rat are used commonly to evaluate potential adverse health effects resulting from environmental exposure to chemicals. They are also the most common rat strain/stock used in physiologically based pharmacokinetic (PBPK) modeling. Accurate characterization of model input parameters will improve the usefulness of PBPK model predictions. Thus, organ (i.e., liver, kidneys, spleen, stomach, small intestine, large intestine, heart, lungs, brain) weights and body fat were measured in male SD rats of different ages (4 to 40 wk) and in young (9 to 10 wk) and old (22 to 23 mo) male F344 rats. Comparison of age-matched (9 to 10 wk) F344 and SD rats revealed that the SD rats weighed significantly more and had significantly higher absolute organ weights. These significant differences usually disappeared when organ weights were expressed as a percentage of body weight (relative organ weight). Percent body fat was significantly lower in the age-matched SD rats (6.48%) than in their F344 counterparts (8.67%). As expected, both body weight and absolute organ weights were significantly higher in old than in young F344 rats. However, these differences were largely reversed when relative organ weights were considered, with most relative organ weights significantly lower in the old F344 rats. Body fat as a percentage of body weight was 14.02% in the old F344 rats. When SD rats of various ages were examined, relative organ weights declined between the ages of 4 and 14 wk. In contrast, significant differences in percent body fat were not detected among the SD rats of different ages and weights examined in this study (4 to 40 wk, approximately 75 to approximately 450 g). In summary, values for physiological input parameters are provided that should prove useful in development and implementation of more accurate PBPK models.
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