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Biomonitoring programs for urinary chromium (Cr) typically attempt to evaluate occupational exposure via the inhalation route. This study investigated whether Cr can be detected in the urine of people following the ingestion of soils that contain relatively high concentrations of chromium in chromite ore processing residue (COPR). To evaluate the reasonableness of using urinary monitoring to assess environmental exposure, six volunteers ingested 400 mg of soil/day (low‐dose group), two others ingested 2.0 g of soil/day (high‐dose group) for 3 consecutive days, and one person ingested a placebo on each of 3 days. The soil and COPR mixture contained concentrations of total chromium (Cr) and hexavalent chromium [Cr(VI)] of 103 ± 20 and 9.3 ± 3.8 mg/kg, respectively. Therefore, the low‐dose group ingested 41 μg Cr/day [including 3.7 μg Cr(VI)] and the high‐dose group ingested 206 μg Cr/day [including 18.6 μg Cr(VI)] on each of 3 consecutive days. All urine samples were collected and analyzed individually for total Cr on the day prior to dosing, during the 3 days of dosing, and up to the first void 48 h after the last dose. No significant increases in urinary Cr excretion were found when background excretion data were compared with data following each of the 3 days of dosing or in daily mean urine concentrations of the high‐ vs the low‐dose groups. It appears that Cr present in a soil and COPR mixture at Cr doses up to 200 μg/day is not sufficiently bioavailable for biomonitoring of urine to be informative. These results are consistent with previously published findings suggesting that incidental exposure to dusts and soils containing comparable levels of Cr will not result in increased concentrations of Cr in urine.

Historically, U.S. regulators have derived cancer slope factors by using applied dose and tumor response data from a single key bioassay or by averaging the cancer slope factors of several key bioassays. Recent changes in U.S. Environmental Protection Agency (EPA) guidelines for cancer risk assessment have acknowledged the value of better use of mechanistic data and better dose–response characterization. However, agency guidelines may benefit from additional considerations presented in this paper. An exploratory study was conducted by using rat brain tumor data for acrylonitrile (AN) to investigate the use of physiologically based pharmacokinetic (PBPK) modeling along with pooling of dose–response data across routes of exposure as a means for improving carcinogen risk assessment methods. In this study, two contrasting assessments were conducted for AN‐induced brain tumors in the rat on the basis of (1) the EPA's approach, the dose–response relationship was characterized by using administered dose/concentration for each of the key studies assessed individually; and (2) an analysis of the pooled data, the dose–response relationship was characterized by using PBPK‐derived internal dose measures for a combined database of ten bioassays. The cancer potencies predicted for AN by the contrasting assessments are remarkably different (i.e., risk‐specific doses differ by as much as two to four orders of magnitude), with the pooled data assessments yielding lower values. This result suggests that current carcinogen risk assessment practices overestimate AN cancer potency. This methodology should be equally applicable to other data‐rich chemicals in identifying (1) a useful dose measure, (2) an appropriate dose–response model, (3) an acceptable point of departure, and (4) an appropriate method of extrapolation from the range of observation to the range of prediction when a chemical's mode of action remains uncertain.

Dioxin (2,3,7,8‐tetrachlorodibenzo‐p‐dioxin; TCDD), a widespread polychlorinated aromatic hydrocarbon, caused tumors in the liver and other sites when administered chronically to rats at doses as low as 0.01 μg/kg/day. It functions in combination with a cellular protein, theAh receptor, to alter gene regulation, and this resulting modulation of gene expression is believed to be obligatory for both dioxin toxicity and carcinogenicity. The U.S. EPA is reevaluating its dioxin risk assessment and, as part of this process, will be developing risk assessment approaches for chemicals, such as dioxin, whose toxicity is receptor‐mediated. This paper describes a receptor‐mediated physiologically based pharmacokinetic (PB‐PK) model for the tissue distribution and enzyme‐inducing properties of dioxin and discusses the potential role of these models in a biologically motivated risk assessment. In this model, ternary interactions among the Ah receptor, dioxin, and DNA binding sites lead to enhanced production of specific hepatic proteins. The model was used to examine the tissue disposition of dioxin and the induction of both a dioxin‐binding protein (presumably, cytochrome P4501A2), and cytochrome P4501A1. Tumor promotion correlated more closely with predicted induction of P4501A1 than with induction of hepatic binding proteins. Although increased induction of these proteins is not expected to be causally related to tumor formation, these physiological dosimetry and gene‐induction response models will be important for biologically motivated dioxin risk assessments in determining both target tissue dose of dioxin and gene products and in examining the relationship between these gene products and the cellular events more directly involved in tumor promotion.

Chloroform is a carcinogen in rodents and its carcinogenicity is secondary to events associated with cytotoxicity and regenerative cell proliferation. In this study, a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model that links the processes of chloroform metabolism, reparable cell damage, cell death, and regenerative cellular proliferation was developed to support a new cancer dose‐response assessment for chloroform. Model parameters were estimated using Markov Chain Monte Carlo (MCMC) analysis in a two‐step approach: (1) metabolism parameters for male and female mice and rats were estimated against available closed chamber gas uptake data; and (2) PD parameters for each of the four rodent groups were estimated from hepatic and renal labeling index data following inhalation exposures. Subsequently, the resulting rodent PD parameters together with literature values for human age‐dependent physiological and metabolism parameters were used to scale up the rodent model to a human model. The human model was used to predict exposure conditions under which chloroform‐mediated cytolethality is expected to occur in liver and kidney of adults and children. Using the human model, inhalation Reference Concentrations (RfCs) and oral Reference Doses (RfDs) were derived using an uncertainty factor of 10. Based on liver and kidney dose metrics, the respective RfCs were 0.9 and 0.09 ppm; and the respective RfDs were 0.4 and 3 mg/kg/day.