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Comparative Time Course Profiles of Phthalate Stereoisomers in Mice
Wood, C., M. Jokinen, C. Johnson, G. Olson, S. Hester, M. George, B. Chorley, G. Carswell, J. Carter, C. Wood, V. Bhat, C. Corton, AND A. Deangelo. Comparative Time Course Profiles of Phthalate Stereoisomers in Mice. TOXICOLOGICAL SCIENCES. Society of Toxicology, 139(1):21-34, (2014).
ABSTRACT More efficient models are needed to assess potential carcinogenicity hazard of environmental chemicals. Here we evaluated time course profiles for two reference phthalates, di(2-ethylhexyl) phthalate (DEHP) and its stereoisomer di-n-octyl phthalate (DNOP), to identify early key event thresholds related to tumor outcomes in a two-year carcinogenicity bioassay. Male B6C3F1 mice were divided into 7 treatment groups: control; 0.12%, 0.60%, or 1.20% DEHP; and 0.10%, 0.50%, or 1.00% DNOP (n=80-83/group). Phthalates were given in the diet for up to 104 weeks with interim evaluations at weeks 4, 15, 30, 35, 52, and 60-79. Incidence and number of hepatocellular tumors (adenoma or carcinoma) were greater at ≥60 weeks for all DEHP groups with time and dose trends, while DNOP had no significant effects. Key events supported a peroxisome proliferator-activated receptor alpha (PPARα) mode of action for DEHP, with secondary cytotoxicity at the high dose, while DNOP induced modest increases in PPARα activity without proliferative or cytotoxic effects. Threshold estimates for later tumorigenic effects were identified at week 4 for relative liver weight (+24%) and PPARα activity (+79%) relative to the control group. Benchmark doses (BMDs) for these measures at week 4 clearly distinguished DEHP and DNOP and showed strong concordance with values at later time points and tumorigenic BMDs. Other target sites included testis and kidney, which showed degenerative changes at higher doses of DEHP but not DNOP. Our results highlight marked differences in the toxicity profiles of structurally similar phthalates and demonstrate quantitative relationships between early bioindicators and later tumor outcomes.
The AOP framework is being developed at EPA and elsewhere as a foundation for predictive models and risk assessment practices. An important part of the AOP concept is the use of quantitative data to establish relationships between key events leading to a particular health outcome. Models built on these relationships would support chemical screening and prioritization efforts, reduce the number of animals used in long-term testing, and allow for better allocation of resources to chemicals with the greatest potential human health risk. In this study we characterized the time course profiles of key events in the PPARalpha AOP for two reference phthalates and showed quantitative relationships between early bioindicators and later tumor outcomes across the span of a 2-year bioassay. We identified threshold estimates for the earliest key events and showed concordance between benchmark dose estimates at early and late time points for these events. Future work in this area should enable more accurate risk predictions of carcinogenicity based on short-term bioactivity profiles and response thresholds.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB
INTEGRATED SYSTEMS TOXICOLOGY DIVISION