Predicting Chronic Non-Cancer Toxicity Levels from Short-Term Toxicity Data Open Access
This dissertation includes three separate but related studies performed in partial fulfillment of the requirements for the degree of Doctor of Public Health in Environmental and Occupational Health. The main goal this dissertation was to develop and assess quantitative relationships for predicting doses associated with chronic non-cancer toxicity levels in situations where there is an absence of chronic toxicity data, and to consider the applications of these findings to chemical substitution decisions. Data from National Toxicology Program (NTP) Technical Reports (TRs) (and where applicable Toxicity Reports), which detail the results of both short-term and chronic rodent toxicity tests, have been extracted and modeled using the Environmental Protection Agency’s (EPA’s) Benchmark Dose Software (BMDS). Best-fit minimum benchmark doses (BMDs) and benchmark dose lower limits (BMDL) were determined. Endpoints of interest included non-neoplastic lesions, final mean body weights and mean organ weights. All endpoints were identified by NTP Pathologists in the abstract of the TRs as either statistically or biologically significant. A total of 41 chemicals tested between 2000 and 2012 were included with over 1700 endpoints for short-term (13 week) and chronic (2 year) exposures. Non-cancer endpoints were the focus of this research. Chronic rodent bioassays have been used by many methodologies in predicting the carcinogenic potential of chemicals in humans (1). However, there appears to be less emphasis on non-cancer endpoints. Further, it has been shown in the literature that there is little concordance in cancerous endpoints between humans and rodents (2). The first study, Quantitative Relationship of Non-Cancer Benchmark Doses in Short-Term and Chronic Rodent Bioassays (Chapter 2), investigated quantitative relationships between non-cancer chronic and short-term toxicity levels using best-fit modeling results and orthogonal regression techniques. The findings indicate that short-term toxicity studies reasonably provide a quantitative estimate of minimum (and median) chronic non-cancer BMDs and BMDLs. The next study, Assessing Implicit Assumptions in Toxicity Testing Guidelines (Chapter 3) assessed the most sensitive species and species-sex combinations associated with the best-fit minimum BMDL10 for the 41 chemicals. The findings indicate that species and species-sex sensitivity for this group of chemicals is not uniform and that rats are significantly more sensitive than mice for non-cancerous outcomes. There are also indications that male rats may be more than the other species sex groups in certain instances. The third and final study, Comparing Human Health Toxicity of Alternative Chemicals (Chapter 4), considered two pairs of target and alternative chemicals. A target is the chemical of concern and the alternative is the suggested substitution. The alternative chemical lacked chronic toxicity data, whereas the target had well studied non-cancer health effects. Using the quantitative relationships established in Chapter 2, Quantitative Relationship of Non-Cancer Benchmark Doses in Short-Term and Chronic Rodent Bioassays, chronic health effect levels were predicted for the alternative chemicals and compared to known points of departure (PODs) for the targets. The findings indicate some alternatives can lead to chemical exposures potentially more toxic than the target chemical.
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