The Cadmium Dietary Exposure Model (CDEM) utilizes national survey data on food cadmium concentrations and food consumption patterns to estimate dietary intakes in the U.S. population. The CDEM has been linked to a modification of the cadmium biokinetic model of Kjellström and Nordlberg (KNM) to derive predictions of kidney and urinary cadmium that reflect U.S. dietary cadmium intake and related variability. Variability in dietary cadmium intake was propagated through the KNM using a Monte Carlo approach. The model predicts a mean peak kidney cadmium burden of approximately 3.5 mg and a 5th-95th percentile range of 2.2-5.1 mg in males. The corresponding peak renal cortex cadmium concentration in males is 15 microg/g wet cortex (10-22, 5th-95th percentile). Predicted kidney cadmium levels in females were higher than males: 5.1 (3.3-7.6) mg total kidney, 29 (19-43) microg/g wet cortex. Predicted urinary cadmium in males and females agreed with empirical estimates based on the NHANES III, with females predicted and observed to excrete approximately twice the amount of cadmium in urine than males. An explanation for the higher urinary cadmium excretion in females is proposed that is consistent with the NHANES III data as well as experimental studies in humans and animals. Females may absorb a larger fraction of ingested dietary cadmium than males, and this difference may be the result of lower iron body stores in females compared to males. This would suggest that females may be at greater risk of developing cadmium toxicity than males. The predicted 5th-95th percentile values for peak kidney cadmium burden are approximately 60% of the peak kidney burden (8-11 mg) predicted for a chronic intake at the U.S. Environmental Protection Agency (EPA) chronic reference dose of 1 microg/kg-d.

Environmental occurrence and biomonitoring data for per- and polyfluoroalkyl substances (PFAS) demonstrate that humans are exposed to mixtures of PFAS. This paper presents a new and systematic analysis of available PFAS toxicity study data using a tiered mixtures risk assessment framework consistent with U.S. and international mixtures guidance. The lines of evidence presented herein include a critique of whole mixture toxicity studies and analysis of dose-response models based on data from subchronic oral toxicity studies in rats. Based on available data to-date, concentration addition and relative potency factor methods are found to be inappropriate due to differences among sensitive effects and target organ potencies and noncongruent dose-response curves for the same effect endpoints from studies using the same species and protocols. Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) lack a single mode of action or molecular initiating event and our evaluation herein shows they also have noncongruent dose-response curves. Dose-response curves for long chain perfluoroalkyl sulfonic acids (PFSAs) also significantly differ in shapes of the curves from short chain PFSAs and perfluoroalkyl carboxylic acids (PFCAs) evaluated, and additional differences are apparent when curves are evaluated based on internal or administered dose. Following well-established guidance, the hazard index (HI) method applied to PFCAs and PFSAs grouped separately is the most appropriate approach for conducting a screening level risk assessment for non-polymeric PFAS mixtures, given the current state-of-the science. A clear presentation of assumptions, uncertainties, and data gaps is needed before dose additivity methods, including HI, are used to support risk management decisions. Adverse outcome pathway(s) and mode(s) of action information for PFOA and PFOS and for other non-polymer PFAS are key data gaps precluding more robust mixtures methods. These findings can guide the prioritization of future studies on single chemical and whole mixture toxicity studies.

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Estimating gastrointestinal absorption remains a significant challenge in the risk assessment of metals. This presentation reviews our current understanding of the gastrointestinal absorption of lead (Pb) to illustrate physiological mechanisms involved in metal absorption, new approaches that are being applied to the problem of estimating metal absorption in humans, and issues related to integrating this information into risk assessment. Absorption of metals can be highly variable in human populations because it is influenced by a variety of factors that include the chemical form of the metal, environmental matrix in which the ingested metal is contained, gastrointestinal tract contents, diet, nutritional status, age, and, in some cases, genotype. Thus, in risk assessment models, gastrointestinal absorption is best described as a variable whose distribution is determined in part by the above multiple influences. Although we cannot expect to evaluate empirically each of the above factors in human populations, we can expect to achieve a sufficiently detailed understanding of absorption mechanisms to develop conceptual and, eventually, quantitative models of absorption that account for some aspects of individual variability. A conceptual model is presented of the physiological processes involved in the transfer of ingested metals from the lumen of the gastrointestinal tract to the blood circulation. Components of the model include delivery to the site(s) of absorption; distribution among intracellular and extracellular ligands and transcellular and paracellular pathways of transfer across the gastrointestinal tract epithelium. The gastrointestinal absorption of Pb is discussed in the context of this model.

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