Identifying subsets of complex mixtures most associated with complex diseases: polychlorinated biphenyls and endometriosis as a case study.

BACKGROUND: Exploratory statistical analyses have been conducted on an epidemiologic data set in which the relationship was examined between exposure to polychlorinated biphenyl (PCB) mixtures and risk of endometriosis in women. In that study, the association between endometriosis and the sum of 4 antiestrogenic PCBs (PCBs 105, 114, 126, and 169) was borderline significant (P = 0.079), whereas an association was not found (P = 0.681) with the sum of 12 estrogenic PCBs. This finding was inconsistent with the widely held notion that endometriosis is an estrogen-dependent disease, prompting further statistical analyses to explore these associations in more detail. METHODS: As an alternative method of data reduction, an optimization algorithm was developed to determine weights in a linear combination of scaled PCB levels that has the strongest possible association with the risk of endometriosis. RESULTS: Application of this method to the antiestrogenic PCB subgroup revealed that PCB 114 was responsible for nearly 100% of the association. The fact that PCB 114 is neither the most potent nor abundant antiestrogen in the mixture suggests that PCB 114 might be estrogenic or that the association may be driven by a different mechanism. Use of this statistical weighting method for further analyses of 12 estrogenic PCBs showed that any association with endometriosis was driven mainly by PCBs 99 and 188 and possibly a few others. CONCLUSION: Although the role of PCB mixtures in endometriosis remains unclear, these results demonstrate how the integration of refined statistical methods coupled with toxicologic and biologic interpretation can generate testable hypotheses that might not otherwise have been generated.

Evidence-based toxicology for the 21st century: opportunities and challenges.

The Evidence-based Toxicology Collaboration (EBTC) was established recently to translate evidence-based approaches from medicine and health care to toxicology in an organized and sustained effort. The EBTC held a workshop on "Evidence-based Toxicology for the 21st Century: Opportunities and Challenges" in Research Triangle Park, North Carolina, USA on January 24-25, 2012. The presentations largely reflected two EBTC priorities: to apply evidence-based methods to assessing the performance of emerging pathway-based testing methods consistent with the 2007 National Research Council report on "Toxicity Testing in the 21st Century" as well as to adopt a governance structure and work processes to move that effort forward. The workshop served to clarify evidence-based approaches and to provide food for thought on substantive and administrative activities for the EBTC. Priority activities include conducting pilot studies to demonstrate the value of evidence-based approaches to toxicology, as well as conducting educational outreach on these approaches.

Two generation reproduction study of styrene by inhalation in Crl-CD rats.

This study was conducted to evaluate the potential adverse effects of styrene on reproductive capability from whole-body inhalation exposure of F0 and F1 parental animals. Assessments included gonadal function, estrous cyclicity, mating behavior, conception rate, gestation, parturition, lactation, and weaning in the F0 and F1 generations, and F1 generation offspring growth and development. Four groups of male and female Crl:CD(SD)IGS BR rats (25/sex/group) were exposed to 0, 50, 150, and 500 ppm styrene for 6 hr daily for at least 70 consecutive days prior to mating for the F0 and F1 generations. Inhalation exposure for the F0 and F1 females continued throughout mating and gestation through gestation day 20. Inhalation exposure of the F0 and F1 females was suspended from gestation day 21 through lactation day 4. On lactation days 1 through 4, the F0 and F1 females received styrene in virgin olive oil via oral gavage at dose levels of 66, 117, and 300 mg/kg/day (divided into three equal doses, approximately 2 hr apart). These oral dosages were calculated to provide similar maternal blood peak concentrations as provided by the inhalation exposures. Inhalation exposure of the F0 and F1 females was re-initiated on lactation day 5. Styrene exposure did not affect survival or clinical observations. Rats in the 150- and 500-ppm groups in both parental generations gained weight more slowly than the controls. There were no indications of adverse effects on reproductive performance in either the F0 or F1 generation. Male and female mating and fertility indices, pre-coital intervals, spermatogenic endpoints, reproductive organ weights, lengths of estrous cycle and gestation, live litter size and postnatal survival were similar in all exposure groups. Additionally, ovarian follicle counts and corpora lutea counts for the F1 females in the high-exposure group were similar to the control values. No adverse exposure-related macroscopic pathology was noted at any exposure level in the F0 and F1 generations. A previously characterized pattern of degeneration of the olfactory epithelium that lines the dorsal septum and dorsal and medial aspects of the nasal turbinates occurred in the F0 and F1 generation animals from the 500-ppm group. In the 500-ppm group, F2 birthweights were reduced compared to the control and F2 offspring from both the 150- and 500-ppm exposure groups gained weight more slowly than the controls. Based on the results of this study, an exposure level of 50 ppm was considered to be the NOAEL for F0 and F1 parental systemic toxicity; the NOAEL for F0 and F1 reproductive toxicity was 500 ppm or greater.