The concentration of 10 nM HMGB1 was chosen according to our previous studies [ 3] and to internal dose-response controls performed on different cell lines and in primary cultures obtained from papillary cancer and nonneoplastic lesions (6). Figure 1 shows that treatment with HMGB1 increases expression of miRNAs 221 and 222 significantly in both cell lines (p < 0.01).
Biomonitoring data could eliminate or reduce much of this uncertainty in estimating risk because internal dose and response information would be directly available for a human population.
Although interspecies variation in internal dose and response to BPA is a concern (Doerge et al. 2010), BPA pharmacokinetics appear to be similar in women, female monkeys, and mice (Taylor et al. 2011).
These are direct measurements indicating internal dose and biologic response.
Figure 2 illustrates the distinct effects of different sources of variability on external dose, internal dose, or biological response.
Such criteria, including temporality, dose response, internal and external consistency, strength of observed associations, and biological plausibility, have been used within narrative WOE approaches to come up with supporting causal inferences in the broader context of the impact of environmental EDCs on humans and wildlife (Bergman et al. 2013).
"We were measuring response to internal dose and looking for preneoplastic lesions.
Ideally, these new technologies will generate insight on exposures across the exposure disease continuum, from the point of human contact to the internal dose to the early biological response (see figure above).
This allowed them to derive new dose-response relationships relating the observed health response to the total internal dose of the metabolites at the target tissue (bone marrow in this case), rather than to the external environmental concentrations (doses) of the chemicals in the mixture.
The first category of biological variability is indicated by differences in the parameters governing the relationship of one measureable quantity to the next (e.g., external to internal dose, and internal dose to biological response).
