Refining risk estimates for lead in drinking water based on the impact of genetics and diet on blood lead levels using the Collaborative Cross mouse population.

Blood lead (Pb) level (BLL) is a commonly used biomarker to evaluate associations with health effects. However, interventions to reduce the adverse effects of Pb require relating BLL to external exposure. Moreover, risk mitigation actions need to ensure protection of more susceptible individuals with a greater tendency to accumulate Pb. Because little data is available to quantify inter-individual variability in biokinetics of Pb, we investigated the influence of genetics and diet on BLL in the genetically diverse Collaborative Cross (CC) mouse population. Adult female mice from 49 CC strains received either a standard mouse chow or a chow mimicking the American diet while being provided water ad libitum with 1000 ppm Pb for 4 weeks. In both arms of the study, inter-strain variability was observed; however, in American diet-fed animals, the BLL was greater and more variable. Importantly, the degree of variation in BLL among strains on the American diet was greater (2.3) than the default variability estimate (1.6) used in setting the regulatory standards. Genetic analysis identified suggestive diet-associated haplotypes that were associated with variation in BLL, largely contributed by the PWK/PhJ strain. This study quantified the variation in BLL that is due to genetic background, diet, and their interactions, and observed that it may be greater than that assumed for current regulatory standards for Pb in drinking water. Moreover, this work highlights the need of characterizing inter-individual variation in BLL to ensure adequate public health interventions aimed at reducing human health risks from Pb.

Peanut butter as an alternative dose delivery method to prevent strain-dependent orogastric gavage-induced stress in mouse teratogenicity studies.

INTRODUCTION: Animal-based studies are essential for assessing toxicity to environmental pollutants, especially when the potential targets are specific developmental time points, teratogenic, or multi-organ systems that cannot be modeled in vitro. Orogastric gavage is a widely used technique for exposure because of its increased accuracy of dose administration over free feeding. However, repeated use of this method has been reported to cause physiological stress on the exposed animals that could interfere with interpretation of results. Previous studies have shown that genetic background also contributes to the level of stress and can affect individual response. METHODS: To evaluate the impact of stress on repeated orogastric gavage, we exposed C67BL/6J and 129S1/SvImJ inbred mouse strains to 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD), a potent xenobiotic that has been extensively studied in vivo. Pregnant females were dosed for ten days after mating using orogastric gavage with olive oil as vehicle or through diet using peanut butter as vehicle. Serum corticosterone levels, body weight, and reproduction endpoints were measured to evaluate levels of stress induced by the dosing technique. RESULTS: The levels of stress caused by orogastric gavage was strongly dependent on strain background and on the phenotypic endpoint. Orogastric gavage-induced stress was more detrimental in 129S1/SvlmJ pregnant female mice than in C57BL/6J. CONCLUSION: These results show that administration of xenobiotics via controlled diet can improve the reproducibility and rigor of exposure studies requiring orogastric delivery.