by Marjory Moreau
As an advocate for PBPK modeling in risk assessment, I want to share with you how PBPK modeling can be used to address vulnerable populations. We all know that individuals won’t respond the same way to chemical exposures. But first, it is important to define “vulnerable population!” I like this definition from Makri et al. 2004:
“Susceptibility is defined as a capacity characterized by biological (intrinsic) factors that can modify the effect of a specific exposure, leading to higher health risk at a given relevant exposure level. The term sensitivity is used to describe the capacity for higher risk due to the combined effect of susceptibility (biological factors) and differences in exposure. Vulnerability incorporates the concepts of susceptibility and sensitivity, as well as additional factors that include social and cultural parameters (e.g., socio-economic status and location of residence) that can contribute to an increased health risk.”
Humans respond differently to chemical exposures based on several factors that can be exogenous and/or intrinsic. Exogenous factors relate to exposure conditions such as chemical concentration/external dose, media, pathway, or dose duration. Physiological, anatomical, and biochemical parameters are intrinsic factors that may also be the basis for differential susceptibility among the population and at different life stages.
Risk assessment is the characterization of the potential adverse effects in humans to exposures of environmental hazards. It is essential to understand and consider how the dose-response to chemicals can change for different populations. Traditional risk assessment methods involve determining a point of departure (POD) from animal toxicity studies and calculating a human reference dose using uncertainty factors to account for data limitations and variability and uncertainty. These uncertainties are associated with extrapolating across species, dose, duration, and routes of exposure, as well as to account for the potential impact of variability of human response. This approach does not explicitly model pharmacokinetic (PK) processes influencing the dose-response, which can vary across dose levels, dose routes, and species. Under the new toxicity testing paradigm that is largely based on in vitro and in silico approaches, alternative strategies are needed to address potentially sensitive populations in chemical risk assessment.
To address the concern for age-related sensitivity to chemicals, we use life-stage physiologically based pharmacokinetic (PBPK) modeling. These models employ in vitro to in vivo extrapolation (IVIVE) to predict age-dependent changes in target tissue exposure to chemicals. PBPK modeling provides the capability to quantitatively describe the potential impact of pharmacokinetic factors on the variability of individual risk. A life-stage PBPK model will include (1) species and age-specific physiology, (e.g., differences in organ size, perfusion, etc.), (2) species and age-specific chemical parameters like protein binding and metabolism, and (3) variation in key enzyme activities within the general population. Intraspecies variation in pharmacokinetics is defined as differences in tissue concentration attained from the same human external exposure that results in different sensitivity among humans. When the exposure is the same, the difference in internal tissue concentrations may be the result of altered absorption, metabolism, distribution and/or elimination. Physical condition, amount of exercise, disease conditions, age, hormonal status, and interactions with other chemicals and medications are also potential modulators of sensitivity that can be quantified using a PBPK model.
In conclusion, PBPK models for a chemical in different ages can be used to predict the target tissue exposure at the age of concern in humans. In 2019, to address the concern for age-related sensitivity to pyrethroids, a life-stage physiologically based pharmacokinetic (PBPK) model was developed to calculate a chemical specific adjustment factor (CSAF) to address age-related pharmacokinetic differences for pyrethroids in humans. The model created by ScitoVation using these methods is the alternative to overcome traditional toxicity testing limitations specifically for age dependent cases. This work successfully addressed important age-related risk assessment challenges associated with USEPA-registered pesticides and the result of the EPA assessment can be found online or in our publications.
If you wish to discuss PBPK modeling and how we can apply it to solve your business problems, email me at firstname.lastname@example.org.